SKINmed - Jul/Aug 2018 by jo-ann kalaka-Adams

Chinese Society of Dermatology

Lebanese Dermatological Society

Dermatology Insights and Inquiries

Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

The Dermatologic & Aesthetic Surgery International League

African Association for Dermatology

July/August 2018 Volume 16 Issue 4

EDITORIAL The 1943 Year Book of Dermatology and Syphilology

THE HEYMANN FILE The Alphabetization of Lymphomatoid Papulosis: Focus on “F”

Parish

Heymann

COMMENTARY Vaccines Hesitancy and the Dermatologist Chinese Society of Dermatology

Hotez and Wolf

Dermatology Insights and Inquiries

Lebanese Dermatological Society

Belarusian Society of Dermatovenereologists and Cosmetologists

ORIGINAL CONTRIBUTIONS Can Sunscreens Harm Coral Reefs? Addressing Environmental Concerns and Offering Practical Recommendations Zirwas and Andrasik

Effect of Fluprostenol Isopropyl Ester and 15-Keto Fluprostenol on Eyelash Growth: A Clinical and Pharmacologic Study Ciro and Luigi

Nonuremic Calciphylaxis: Four Cases Associated with Autoimmune Diseases Costa-Silva, Vide, Cruz, Baudrier, and Azevedo

Efficacy of Folic Acid and Vitamin B12 Replacement Therapies in the Reduction of Adverse Effects of Isotretinoin: A Randomized Controlled Trial Ghiasi, Mortazavi, and Jafari

CORE CURRICULUM A Case-Control Study in Primary Care Settings on the Roles of Dermatoscopy in Infectious Diseases Affecting the Skin, Part 1: Viral and Bacterial Infections Chuh, Zawar, Ooi, and Lee

North American Clinical Dermatologic Society

PHOTO CAPSULE Nigrites Linguae: An Unusual Presentation

The Dermatologic & Aesthetic Surgery International League

African Association for Dermatology

Chatterjee, Chatterjee, Chaudhuri, and Sehgal

HISTORICAL VIGNETTE The Largest Mass Poisoning in History: Arsenic Contamination of Well Water in Bangladesh Mori and Lowenstein

CASE STUDIES Tinea Capitis Masquerading as Basal Cell Carcinoma Chodkiewicz, Ranario, Jahan-Tigh, and MacFarlane

Familial Dyskeratotic Comedones Prabha, Chhabra, Kulkarni, and Hussain

Ripple-Pattern Sebaceous Trichoblastoma Yao, Goldenberg, and Phelps

Recurrent Palisaded Neutrophilic and Granulomatous Dermatitis in the Setting of Systemic Lupus Erythematosus Liebman, Shagalov, and Lowenstein

BOOK REVIEWS Revisiting Flaps Gupta

Urgent Care Dermatology: Symptom-Based Diagnosis Studdiford and Trayes

DEPARTMENTS PERILS OF DERMATOPATHOLOGY Tinea (Pityriasis) Obscurans: Don’t Ignore the Spore! Kim, Singh, John, Jasterzbski, Lambert, Lambert, and Gagna

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TABLE OF CONTENTS July/August • Volume 16 • Issue 4

EDITORIAL

The 1943 Year Book of Dermatology and Syphilology ..................................................................215

Lawrence Charles Parish, MD, MD (Hon)

COMMENTARY

Vaccines Hesitancy and the Dermatologist ...................................................................................219

Peter J. Hotez, MD, PhD; John E. Wolf, Jr., MD, MA

ORIGINAL CONTRIBUTIONS Can Sunscreens Harm Coral Reefs? Addressing Environmental Concerns and

Offering Practical Recommendations ..........................................................................................223

Matthew James Zirwas, MD; Wyatt Andrasik, BS

Effect of Fluprostenol Isopropyl Ester and 15-Keto Fluprostenol on Eyelash Growth: A Clinical and Pharmacologic Study ............................................................................................231

Caruso Ciro, MD; Pacente Luigi, MD

Nonuremic Calciphylaxis: Four Cases Associated with Autoimmune Diseases ................................235

Miguel Costa-Silva, MD; Julia Vide, MD; Maria João Cruz, MD; Teresa Baudrier, MD; Filomena Azevedo, MD

Efficacy of Folic Acid and Vitamin B12 Replacement Therapies in the Reduction of Adverse Effects of Isotretinoin: A Randomized Controlled Trial .................................................239

Maryam Ghiasi, MD; Hossein Mortazavi, MD; Masood Jafari, MD

CORE CURRICULUM A Case-Control Study in Primary Care Settings on the Roles of Dermatoscopy in Infectious Diseases Affecting the Skin, Part 1: Viral and Bacterial Infections ................................................247

Antonio Chuh, MD, FRCP; Vijay Zawar, MD, FRCPE; Catriona Ooi, FAChSHM, MM (HIV/STDs); Albert Lee, MD, FRCP

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

Tinea (Pityriasis) Obscurans: Don’t Ignore the Spore! ...................................................................255

ee J. Kim, BS; Parmvir Singh, BS; Ann M. John, BA; Thomas Jasterzbski; W. Clark Lambert, MD, PhD; H Muriel W. Lambert, PhD; Claude E. Gagna, PhD

209

TABLE OF CONTENTS May/June • Volume 16 •16 Issue 3 4 July/August 2018 • Volume • Issue

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

The Alphabetization of Lymphomatoid Papulosis: Focus on “F” .....................................................259

Warren R. Heymann, MD

Photo Capsule Snejina Vassileva, MD, PhD, Section Editor

Nigrites Linguae: An Unusual Presentation ...................................................................................262

Kingshuk Chatterjee, DNB; Gautam Chatterjee, MS; Anita Chaudhuri; Virendra N. Sehgal, MD

Historical Vignette Charles Steffen, MD, Section Editor

The Largest Mass Poisoning in History: Arsenic Contamination of Well Water in Bangladesh ..........265

Shoko Mori, BS; Eve J. Lowenstein, MD, PhD

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

Tinea Capitis Masquerading as Basal Cell Carcinoma ..................................................................269

Hubert M. Chodkiewicz, MD; Jennifer Song Ranario, MD; Richard Jahan-Tigh, MD; Deborah F. MacFarlane, MD

Familial Dyskeratotic Comedones ................................................................................................273

Neel Prabha, MBBS, MD; Namrata Chhabra, MBBS, MD; Sandeep Kulkarni, MBBS, DNB, MNAMS; Nighat Hussain, MBBS, MD

Ripple-Pattern Sebaceous Trichoblastoma ...................................................................................276

Jonathan L. Yao, MD; Gary Goldenberg, MD; Robert G. Phelps, MD

Recurrent Palisaded Neutrophilic and Granulomatous Dermatitis in the Setting of Systemic Lupus Erythematosus ...................................................................................................281

Tracey N. Liebman, MD; Devorah Shagalov, MD; Eve J. Lowenstein, MD, PhD

BOOK REVIEWS Jennifer L. Parish, MD, Section Editor

Revisiting Flaps ..........................................................................................................................286

Somesh Gupta, MD

Urgent Care Dermatology: Symptom-Based Diagnosis .................................................................288

James S. Studdiford, MD; Kathryn P. Trayes, MD

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July/August 2018

Volume 16 • Issue 4

ABOUT OUR JOURNAL

MANAGING EDITOR Marla Kipp marla@skinmedjournal.com

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

Editorial

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Chinese Society of Dermatology

Lebanese Dermatological Society

Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

211

African Association for Dermatology

The Dermatologic & Aesthetic Surgery International League

Dermatology Insights and Inquiries

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July/August 2018

Volume 16 • Issue 4

EDITOR IN CHIEF

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

DEPUTY EDITORS William Abramovits, MD

Aditya K. Gupta, MD, PhD, FRCPC

W. Clark Lambert, MD, PhD

Vesna Petronic-Rosic, MD, MSc, MBA

Dallas, TX

London, Ontario, Canada

Newark, NJ

Washington, DC

Larry E. Millikan, MD

Marcia Ramos-e-Silva, MD, PhD

Jennifer L. Parish, MD

Cumming, GA

Rio de Janeiro, Brazil

Philadelphia, PA

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

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

Jasna Lipozencic, MD, PhD Zagreb, Croatia

Virendra N. Sehgal, MD Delhi, India

Ada Lo Schiavo, MD Naples, Italy

Charles Steffen, MD Oceanside, CA

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

Alexander J. Stratigos, MD Athens, Greece

George M. Martin, MD Kihei, HI

James S. Studdiford III, MD Philadelphia, PA

Marc S. Micozzi, MD, PhD Rockport, MA

Robert J. Thomsen, MD Los Alamos, NM

Seung-Kyung Hann, MD, PhD Seoul, Korea

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

Julian Trevino, MD Dayton, OH

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

Oumeish Youssef Oumeish, MD, FRCP Amman, Jordan

María Daniela Hermida, MD Buenos Aires, Argentina

Joseph L. Pace, MD, FRCP Naxxar, Malta

Warren R. Heymann, MD Camden, NJ

Art Papier, MD Rochester, NY

Tanya R. Humphreys, MD Bala-Cynwyd, PA

Johannes Ring, MD, DPhil Munich, Germany

Camila K. Janniger, MD Englewood, NJ

Roy S. Rogers III, MD Scottsdale, AZ

Ayse Serap Karadag, MD Istanbul, Turkey

Donald Rudikoff, MD New York, NY

Abdul-Ghani Kibbi, MD Beirut, Lebanon

Robert I. Rudolph, MD Wyomissing, PA

Andrew P. Lazar, MD Washington, DC

Todd E. Schlesinger, MD Charleston SC

Anthony A. Gaspari, MD Philadelphia, PA Michael Geiges, MD Zurich, Switzerland

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

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

SKINmed. 2018;16:213

213

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

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July/August 2018

Volume 16 • Issue 4

EDITORIAL

The 1943 Year Book of Dermatology and Syphilology Lawrence Charles Parish, MD, MD (Hon)

eventy-five years ago, the United States was immersed in World War II, fighting in the Atlantic and Pacific theaters. Patriotic Americans on the home front were saving tin cans and cooking fat for the war effort. Gasoline and meat were rationed (Figure 1), and the country was on War Time (2 hours ahead of standard time). The Mills Brothers had the number one song in 1943 with Paper Doll. Most medical meetings were postponed until 1946, including the annual meeting of the American Academy of Dermatology and Syphilology, although the American Dermatological Association had special dispensation to convene in 1944. PATCH TESTING On the dermatology scene, The 1943 Year Book of Dermatology and Syphilology had just come under the direction of Marion B. Sulzberger (1895–1983) and Rudolf L. Baer (1910–1997), the new editors of the series (Figure 2).1 Their opening essay was devoted to patch testing, not surprising as both of these distinguished New York dermatologists were interested in the allergic aspects of skin disease. Much of the detail of this review would be just as relevant today, but what is worth repeating are several of the admonitions offered: •

“Don’t test uselessly, indiscriminately or in a haphazard manner.”

•

“Don’t test patients with severe or widespread cases during the acute or active period.”

•

“Don’t think that the vehicle or base used is of no consequence.”2

There are extensive lists of potential contactants to use and the suggested concentrations, as there were no pre-made trays, to which we are now accustomed. The detailed contribution was directed toward the general practitioner, for whom the original The Year Book series had been designed in 1900 as the Practical Medicine Series of Year Books. Sulzberger and Baer wrote: “This form of testing is of inestimable value in the management of

allergic dermatoses and often helps the physician to find out why a case has become inveterate and ‘intractable’ and why the patient says, ‘Doctor, everything ever prescribed has only made my skin worse.’” THERAPEUTICS AND PREVENTION The wonder drugs of the era were the recently introduced sulfonamides. Several papers were noted concerning their systemic use for lymphogranuloma venereum. Topical preparations of powder or ointment were formulated for treating “ecthyma, impetigo and other localized superficial pyogenic infections.” Although tried without success for lichen planus, discoid lupus erythematous, and granuloma inguinale, curiously, patients with dermatitis herpetiformis and pemphigus were helped. Of more concern were the adverse events that were beginning to be recognized. In addition to contact dermatitis due to the topical application, systemic administration of sulfonamides was now recognized as causing a maculopapular eruption, bullous dermatitis, photosensitivity, and even fatal agranulocytosis.3 The chapter on “Eczematous dermatitis and urticaria (allergic and nonallergic); allergy” included an excellent assessment of “Evaluation of measures for prevention of ivy dermatitis,” focusing on the paper by J. B. Howell (1914–2003). Highlights included thorough washing with soap and water within 5 to 10 minutes after exposure; however, the patient who is extremely sensitive would not be helped. Rhus dermatitis cannot be prevented by application of ferric chloride ointment, Howell stated. For treatment, poison ivy dermatitis can be lessened by applying potassium permanganate in a 10% solution within 15 minutes of exposure to lessen the dermatitis; for the very sensitive patient, the application should be within 5 to 10 minutes of exposure.4 In the section on “Drug eruptions (allergic and nonallergic),” a variety of unwanted reactions are discussed, ranging from a fixed drug eruption attributed to quinidine to erythema multiforme–like pictures due to nirvanol, its related compound phenytoin, and phenobarbital, a commonly used “sedative”

From the Department of Dermatology and Cutaneous Biology, and Jefferson Center for International Dermatology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA Address for Correspondence: Lawrence Charles Parish, MD, MD (Hon), 1845 Walnut Street, Suite 1650, Philadelphia, PA 19103 • E-mail: larryderm@yahoo.com

SKINmed. 2018;16:215–217

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July/August 2018

EDITORIAL

Figure 1. A US World War II ration card.

of the era. There were discussions of a generalized erythema due to codeine, of bromoderma from an antiepileptic (BromoSeltzer®), a popular headache remedy during this period that contained bromides, and of a lichen planus–like eruption, resulting from arsphenamine injections,5 the mainstay of syphilitic treatment. VENEREAL DISEASE The discovery by John Mahoney (1889–1957) at the US Marine Hospital, Staten Island, NY that penicillin could successfully treat early syphilis was not published until December of 1943, too late for inclusion in the 1943 Year Book. Four men with penile chancres were successfully treated with penicillin, 25,000 units given intramuscularly every 4 hours for 8 days, the total dose being 1,200,000 units.6 Considerable attention was given to serologic testing for syphilis. Mahoney also reported on the Washington Serologic Conference, where there had been much discussion about discrepancies in the various serologic tests for syphilis. The names of some of the tests read like a Who’s Who of syphililogists and their geographic locations: Eagle (Baltimore), Hinton (Boston), Kahn (Ann Arbor), and Kolmer (Philadelphia). For the report, 19 serologists examined 1002 sera and 234 spinal fluid submissions. Concerning the complement fixation tests, “there was a difference between 77.4 per cent of positive findings by the most sensitive and 54.2 per cent recorded by the least sensitive procedure.” Sulzberger and Wise commented: “The terminology which is developing in this field tends toward confusion. Such terms as ‘false positive’ or ‘biologic reaction’ are inexact and carry erroneous implications. A positive result which is repeatable and not due to a technical error should SKINmed. 2018;16:215–217

Figure 2. Title page of The 1943 Year Book of Dermatology and Syphilology.

not be called false; and the positive reaction with a syphilitic serum is a biologic positive, just as positive as a positive result with a serum of a malarial or leprous patient.”7 INVESTIGATIVE STUDIES Tannic acid and its use in treating burns was finally being discredited. A number of studies conducted in mice, guinea pigs, and rabbits confirmed that tannic acid applications could be fatal. The editors noted: “Tannic acid, after having been hailed as ‘a miracle worker’ and one of the great advances of modern medicine, and after a long and almost undisputed rule in the province of the treatment of burns, is now being dethroned. The reasons for this

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July/August 2018

EDITORIAL

are several, but the principal and most valid one is the fact that severe infection can – and under fixed conditions often does – take place under the eschar and that this infection is often either unnoticed at first or becomes difficult to treat when noted.”8 CONCLUDING OBSERVATIONS While diagnosis and treatment of skin disease have made outstanding progress in the last three-quarters of a century, consider the status of dermatology 75 years before 1943. In 1868, the specialty was just developing, teaching of skin disease was limited to a few medical schools, and treatment was rudimentary at best.9 1943 really marked progress in dermatology. REFERENCES 1 Sulzberger MB, Baer RL. The 1943 Year Book of Dermatology and Syphilology. Chicago: Year Book Publishers; 1944:1–584. 2 Sulzberger MB, Baer RL. Skin test and other immunologic procedures in common dermatologic and venereal diseases: A guide for the general practitioner. In: The 1943 Year Book of

Dermatology and Syphilology. Chicago: Year Book Publishers; 1944:7–47. 3 Sulzberger MB, Baer RL. Therapy (exclusive of venereal diseases). In: The 1943 Year Book of Dermatology and Syphilology. Chicago: Year Book Publishers; 1944:48–130. 4 Sulzberger MB, Baer RL. Therapy (exclusive of venereal diseases). In: The 1943 Year Book of Dermatology and Syphilology. Chicago: Year Book Publishers; 1944:131–132. 5 Sulzberger MB, Baer RL. Therapy (exclusive of venereal diseases). In: The 1943 Year Book of Dermatology and Syphilology. Chicago: Year Book Publishers; 1944:169–177. 6 Mahoney JF, Arnold RC, Harris AD. Penicillin treatment of early syphilis: A preliminary report. Am J Pub Health. 1943;33: 1387–1391. 7 Sulzberger MB, Baer RL. Therapy (exclusive of venereal diseases). In: The 1943 Year Book of Dermatology and Syphilology. Chicago: Year Book Publishers; 1944:340–470. 8 Sulzberger MB, Baer RL. Therapy (exclusive of venereal diseases). In: The 1943 Year Book of Dermatology and Syphilology. Chicago: Year Book Publishers; 1944:471–548. 9 Crissey JT, Parish LC. The Dermatology and Syphilology of the Nineteenth Century. New York: Praeger; 1981:1–439.

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July/August 2018

Volume 16 • Issue 4

COMMENTARY

Vaccines Hesitancy and the Dermatologist Peter J. Hotez, MD, PhD;1,2 John E. Wolf, Jr., MD, MA3 ABSTRACT As primary care providers and experts on diseases affecting the skin, such as herpes zoster (shingles) and human papillomavirus–related cancers, dermatologists are often asked to make important recommendations on vaccines and vaccinations; however, a rise in antivaccine attitudes— sometimes referred to as “vaccine hesitancy”—among patient populations, especially in North America and Europe, has created new challenges for the practicing dermatologist. Here we provide a brief overview of some of the major evidence that refutes commonly held misperceptions about vaccines. (SKINmed. 2018;16:219–221)

VACCINES ARE LIFE-SAVING AND PREVENT SERIOUS ILLNESS IN CHILDREN AND ADULTS Vaccines rank among the most effective and cost-effective interventions ever discovered by medical science. Through an initiative created by the Bill & Melinda Gates Foundation known as the Global Burden of Disease Study, we now have abundant data on the true public health impact of vaccines. For example, during the early 1990s measles represented one of the leading causes of global deaths, especially among children, with estimates that almost 1 million people died annually from measles.1 Through an Expanded Program on Immunization led by the World Health Organization, this number was cut to around 600,000 by the year 2000 when Gavi, the Vaccine Alliance, was established. Subsequently, through Gavi programs, the number of global deaths from measles has been brought down for the first time to below 100,000 deaths.1

because organized and outspoken antivaccine movements allege that vaccines may be dangerous or unnecessary.5 In the United States, currently 18 states allow nonmedical vaccine exemptions for schoolchildren due to reasons of philosophical or personal beliefs. We have seen a steep rise in nonmedical vaccine exemptions over the last decade, although there is some evidence that such exemptions may have reached a plateau over the last 3 to 4 years.6 Unfortunately, many states are still seeing a sharp rise in philosophical belief vaccine exemptions. For example the state of Texas where we work has seen a 20-fold rise in these exemptions since 2003, with some private schools having up to 40% of their pupils not receiving vaccines.3 We are concerned about a return of measles to Texas and other US states that allow nonmedical vaccine exemptions. VACCINES DO NOT CAUSE AUTISM OR OTHER CHRONIC ILLNESSES

Our successes in combating vaccine-preventable infections are fragile and can be easily reversed. This is especially true of measles, which is considered one of the most highly contagious human infectious disease pathogens.2,3 In the year 2017, unwarranted fears by the Somali immigrant community in Minnesota resulted in precipitous declines in vaccine coverage that resulted in a terrible measles outbreak, with many children hospitalized. We have also just seen large-scale measles outbreaks in Romania and elsewhere in Europe.

The abrupt rise in nonmedical vaccine exemptions in the United States and similar drops in vaccine coverage in Europe began when antivaccine groups falsely asserted that childhood vaccines can cause autism. The fake autism links emerged out a paper published in The Lancet in 1998 claiming that the live attenuated viruses contained in the measles-mumps-rubella vaccine can replicate in the gut to somehow cause pervasive developmental disorder—a term used to describe autism at that time.7 Although the paper was eventually retracted in 2010, the 12-year intervening period after initial publication empowered and enabled antivaccine groups.

Overall, recent measles outbreaks in the United States and Europe have mostly resulted from a failure to vaccinate children,4 largely

Beyond the measles-mumps-rubella vaccine, it was also alleged that the mercury-containing preservative thimerosal, found

From the Department of Pediatrics;1 and the Department of Molecular Virology and Microbiology;2 Texas Children’s Hospital Center for Vaccine Development, and the Department of Dermatology;3 Baylor College of Medicine, Houston, TX Address for Correspondence: Peter J. Hotez, MD, PhD, National School of Tropical Medicine, Baylor College of Medicine, One Baylor Plaza, Suite 164A, Houston, TX 77030 • E-mail: hotez@bcm.edu

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previously in childhood vaccines (by 2001, it had been removed from all pediatric vaccines in the United States except multidose influenza vaccines), aluminum adjuvants, or spacing vaccines too close together were also somehow tied to autism. The scientific evidence proves otherwise. Recent epidemiologic studies involving more than 1 million children (in addition to experimental evidence in laboratory animals) conclusively show that there is no link between vaccines and autism. One of us recently summarized that evidence,8 which also includes 21 pages of citations that were prepared by the American Academy of Pediatrics listing all the published scientific studies.9 The changes in the brains of children with autism begin months before many parents observe behaviors consistent with autism, or health care professionals actually diagnose children as being on the autism spectrum.10 This observation counters anecdotal reports from parents that their child became “autistic” after being vaccinated in the second year of life.10 There is now strong evidence that autism begins prenatally, well before children ever receive their first vaccine, with overwhelming evidence pointing to the genetic or epigenetic basis of autism spectrum disorder.10 More than 60 autism genes have been identified so far, with that number increasing yearly. In addition to autism, some antivaccine groups have alleged that vaccines cause autoimmune diseases or allergies; however, there is also no evidence to support such claims.11,12

requires abundant evidence through toxicological testing that the vaccines are safe. The assertion that vaccines somehow overwhelm the immune system does not have any scientific basis, especially given that infants and children are likely exposed daily to dozens if not hundreds of new antigens. The Centers for Disease Control and Prevention conspiracies stem from a faux documentary (directed by the lead author of the retracted 1998 Lancet study), known as “Vaxxed: From Cover Up to Catastrophe.” Still another allegation is that more children die from vaccines than the diseases they are intended to prevent. This is a blatantly false statement. CONCLUSIONS It is difficult to cover the entire ecosystem of vaccine hesitancy in a brief commentary, but it is fair to say that today we have massive evidence refuting just about all of the assertions from antivaccine groups. Vaccines do not cause autism or autoimmune disease, and they are not loaded with harmful toxins. Vaccine schedules have been selected through rigorous testing to optimize safety and efficacy. Ultimately, dermatologists are positioned to become important vaccine advocates, especially for some of the newer vaccines to prevent shingles or human papillomavirus–related cancers. In the coming years, leading vaccine advocacy could become an important new activity for the practicing dermatologist.

OTHER ALLEGATIONS AND ASSERTIONS One of the frustrations experienced by many primary care providers, presumably including dermatologists, is that vaccine hesitancy occurs in many different forms. Even after debunking links between vaccines and autism, or autoimmune disease and allergies, vaccine scientists and experts are facing still additional rounds of false assertions, including claims that vaccines contain toxic ingredients,13 or that vaccines somehow overwhelm the immune system.14 Or we hear from parents about a general distrust in the medical community and in particular in the US Centers for Disease Control and Prevention. Some conspiracy theorists even claim that the multinational pharmaceutical companies are deliberately poisoning children.13

REFERENCES

With regards to claims of toxic ingredients, it is important to point out that vaccines go through years, sometimes decades, of clinical testing under the auspices of the Food and Drug Administration in the United States, or comparable European regulatory authorities. These clinical trials typically involve thousands of human volunteers. In addition, the Food and Drug Administration mandates that vaccine manufacturers justify the inclusion of every ingredient contained in a vaccine, and it SKINmed. 2018;16:219–221

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1 Hotez PJ. “Melanie’s measles” is deadly and causes permanent neurologic impairment. Microbes Infect. 2018;20:63–64. 2 Lo NC, Hotez PJ. Public health and economic consequences of vaccine hesitancy for measles in the United States. JAMA Pediatr. 2017;171:887–892. 3 Hotez PJ. Texas and its measles epidemics. PLoS Med. 2016;13:e1002153. 4 Clemmons NS, Wallace GS, Patel M, Gastanaduy PA. Incidence of measles in the United States, 2001-2015. JAMA. 2017;318:1279–1281. 5 Hotez PJ. How the antivaxxers are winning. New York Times, February 25, 2017. https://www.nytimes.com/2017/ 02/08/opinion/how-the-anti-vaxxers-are-winning.html. Accessed November 25, 2017. 6 Omer SB, Porter RM, Allen K, Salmon DA, Bednarcyk RA. Trends in kindergarten rates of vaccine exemption and statelevel policy, 2011–2016. Open Forum Infect Dis 2017;5: ofx244 7 Wakefield AJ, Murch SH, Anthony A, et al. Ileal-lymphoidnodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet 1998;351:637–641. Erratum in: Lancet. 2004;363:750. Retraction in: Lancet. 2010;375:445.

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8 Hotez P. The “Why Vaccines Don’t Cause Autism” Papers. January 20, 2017. http://blogs.plos.org/speakingofmedicine/ 2017/01/20/the-why-vaccines-dont-cause-autism-papers/. Accessed November 25, 2017. 9 American Academy of Pediatrics. Vaccine Safety: Examine the Evidence. 2013. https://www.aap.org/en-us/Documents/ immunization_vaccine_studies.pdf Accessed November 25, 2017. 10 Hotez P. Autism Spectrum Disorder: If Not Vaccines, Then What? Baylor College of Medicine From the Labs Blog. February 24, 2017. https://blogs.bcm.edu/2017/02/24/autism-spectrum- disorder-if-not-vaccines-then-what/ Accessed November 25, 2017.

11 Offit PA, Hackett CJ. Addressing parents’ concerns: Do vaccines cause allergic or autoimmune diseases? Pediatrics. 2003;111:653–659. 12 Offit PA. The HPV Vaccine and Autoimmunity: Reviewing the Research. 2016. https://www.medscape.com/viewarticle/ 868825 Accessed November 25, 2017. 13 Smith TC. Vaccine rejection and hesitancy: A review and call to action. Open Forum Infect Dis. 2017;4:ofx146. 14 Offit PA, Quarles J, Gerber MA, et al. Addressing parents’ concerns: Do multiple vaccines overwhelm or weaken the infant’s immune system? Pediatrics. 2002;109:124–129.

WAX MOULAGE

Sebaceous Adenoma made by Louis Niclet. Pathology Department. School of Medicine. National University of Rosario, Rosario, Argentina.

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Can Sunscreens Harm Coral Reefs? Addressing Environmental Concerns and Offering Practical Recommendations Matthew James Zirwas, MD;1 Wyatt Andrasik, BS2 ABSTRACT The crucial role sunscreen plays in preventing sunburns, photoaging, and skin cancer is unquestionable, and as a result, it is incumbent upon dermatologists to influence patients to appropriately use sunscreens. In addition to explaining the benefits of sunscreen use and how to properly use sunscreen, dermatologists must also address possible barriers or concerns that patients may have regarding sunscreen. One concern that has gained increasing media attention in the recent years has been the environmental impact of sunscreens, especially the impact on coral reefs. There is strong evidence that some sunscreen ingredients, especially oxybenzone, are harmful to corals if the concentration in water is high. In some situations, primarily related to the number of swimmers and the geography of the shoreline, concentrations of oxybenzone far exceed the levels shown to be harmful to corals. As advocates for our patients’ skin health, we need to be prepared to address this issue when asked, so that patients do not forgo sunscreen use in an effort to protect corals. This article will review evidence regarding the effects of sunscreen ingredients on corals and will provide practical guidance for counseling patients on how to select sunscreens that minimize the potential for harm to coral reefs. (SKINmed. 2018;16:223–229)

INTRODUCTION Organic ultraviolet (UV) filters work to protect the skin by absorbing UV radiation, while inorganic UV filters work by absorbing and scattering UV radiation before it penetrates into the living epidermis and the dermis of the skin.1 The American Academy of Dermatology (AAD) recommends sunscreens that are broad spectrum, water-resistant, and have a sun protection factor (SPF) of at least 30.1 Production and consumption of sunscreens and personal care products (PCPs) containing UV filters are increasing worldwide, which is largely attributed to greater public awareness of skin cancer risks in recent decades.2 Despite evidence supporting their photoprotective properties, UV filters are no stranger to controversy as various fringe groups have claimed that UV filters have the potential for carcinogenesis, adverse endocrine effects, and vitamin D deficiency—claims that are all unfounded. Most recently, questions concerning effects on the

environment, specifically on coral reefs, have gained momentum. UV filters enter the aquatic environment directly during marine recreational activities and indirectly as runoff from wastewater treatment plants.3,4 Notably, these chemicals have been found in marine water and wastewater samples in parts per billion (PPB) to parts per million (PPM) concentrations.5,6 Coral reefs are among the most biologically productive and diverse ecosystems on the planet.2 According to the National Ocean Service, coral reefs support more species per unit area than any other marine environment and function to buffer the shoreline against waves, storms, and floods, preventing loss of aquatic and terrestrial life, property damage, and land erosion. In addition to these ecological benefits, corals serve an important role in marine fisheries and tourism.3 Naturally, these valuable ecosystems are monitored closely for viability and risk of extinction. The number of corals at risk of extinction has increased dramatically over the past decade owing to natural impacts, mainly

From the Ohio University College of Osteopathic Medicine, Athens, OH;1 Wright State University Boonshoft School of Medicine, Dayton, OH2 Address for Correspondence: Matthew James Zirwas, MD, Ohio University College of Osteopathic Medicine, Athens, OH, Bexley Dermatology, 2359 E. Main Street, Bexley, OH 43209 • E-mail: Matt.zirwas@gmail.com

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climate change, and anthropogenic impacts such as pollution, costal development, and overfishing.2,7 Corals are particularly susceptible to temperature changes and pollution during early stages of development when coral larvae metamorphose into mature, sessile polyps.8 Larvae metamorphosis is a crucial step in coral viability, necessary to maintain coral communities and allow recovery following mortality events.8 At elevated sea surface temperatures, corals expel their symbiotic photosynthetic algae by a process called “bleaching,” which ultimately results in death if elevated temperatures persist.9 While climate change and subsequent rising water temperatures are generally regarded as the most immediate and widespread threat to coral reef resilience, this threat may be magnified by elevated levels of pollutants.8,9 In recovering from mortality events, coral larvae need uncontaminated waters to survive and rebuild coral communities; however, an estimated 6,000 to 14,0000 tons of sunscreen are released into coral reef areas each year, exposing approximately 10% of reefs worldwide and 40% of reefs along coastal areas.5 Studies have demonstrated that environmentally relevant increases in water temperature and levels of pollutants have additive detrimental effects on coral larvae metamorphosis that become synergistic at high temperatures.8 Efforts to decrease concentrations of pollutants by half has the potential to increase temperature tolerance by more than 3.5°C.8 Unfortunately, sea surface temperatures will continue to rise and are expected to increase by 1.8°C to 4.0°C by the year 2100, making pollution an even greater concern.8 Therefore, limiting local impacts of pollution may reduce the effects of global stressors and improve overall coral resilience.8 TOXICITY DATA To achieve adequate broad-spectrum sun protection, most sunscreens utilize a combination of two or more UV filters.1 Common agents used in sunscreens today include benzophenones, titanium dioxide, zinc oxide, and others. Benzophenones are excellent ultraviolet A (UVA) absorbers used in many sunscreens to complement ultraviolet B (UVB) absorptive agents. Titanium dioxide and zinc oxide are inorganic compounds that scatter as well as absorb UV light within both the UVA and UVB spectrum. Among benzophenones, oxybenzone is the most commonly employed agent and has been labeled an emerging environmental contaminant of concern by the U.S. Environmental Protection Agency.1,5 Over the past several years, evidence that oxybenzone can harm corals and threaten resiliency of coral reefs to climate change has been demonstrated in a number of studies. SKINmed. 2018;16:223–229

Oxybenzone A recent study described the toxicological effects of oxybenzone on the coral larvae, Stylophora pistillata, as well as in vitro cells of six other coral species.5 Because oxybenzone is phototoxic, meaning its toxicity is exacerbated by light, studies were done in both environmentally relevant light and dark conditions. The results demonstrated the effects of oxybenzone on larvae morphology, histopathology, DNA, bleaching, and mortality. In addition, the median effect concentration and median lethal concentration were determined for the coral larvae and in vitro samples. At baseline, coral larvae are elongated and in constant motion, propelled by cilia that surround the organism.5 When exposed to oxybenzone in concentrations ranging from 2.28 PPB to 228 PPM, changes in coral morphology and histology were seen. Within hours of oxybenzone exposure in both light and dark conditions, larvae showed a reduction in ciliary movement and took on a deformed “dewdrop” shape.5 Eventually, all larvae became immobile.5 In addition, ossification of the outer layer of coral larvae was seen at the three highest concentrations of oxybenzone, 2.28 PPM, 22.8 PPM, and 228 PPM; however, evidence of ossification was seen at all concentrations of oxybenzone using an electron microscope, suggesting that the chemical UV filter may disrupt the skeletal-endocrine system. Catastrophic tissue lysis, cellular degradation, autophagy within multiple tissue layers, and complete loss of cilia were also seen with the electron microscope after exposure to 288 PPM for 8 hours in light.5 Oxybenzone is a known genotoxicant, capable of producing DNA apurinic/apyrimidinic (DNA-AP) lesions that have deleterious effects on coral survival and reproduction.5 Larvae samples analyzed for DNA-AP lesions showed that increasing concentrations of oxybenzone caused significantly more lesions in both light and dark conditions when compared to controls.5 Coral bleaching is a stress response in which symbiotic algae, called zooxanthellae, which live within corals and provide nutrients through photosynthesis, are expelled from coral tissues.5 Over the past 20 years, coral bleaching has increased dramatically, contributing to widespread destruction of coral reef ecosystems.2,10 Bleaching can occur in response to excessive temperature, UV light, and pollution.10 When zooxanthellae algae do not repopulate corals following bleaching events, massive mortality occurs.10 In this study, reductions in chlorophyll fluorescence emission was used to measure coral bleaching in response to oxybenzone concentrations ranging from 2.28 PPB to 288 PPM. With increasing concentrations of oxybenzone, chlorophyll fluorescence emission decreased after 8 hours of exposure in both light and dark conditions. The lowest observable effect

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concentration capable of causing bleaching was 2.28 PPB in light and 22.8 PPB in dark conditions.5 Mortality studies found that as the concentration of oxybenzone increased, so did the percent of mortality, resulting in statistically significant differences compared to nonexposed controls at 24 hours with concentrations of 22.8 PPB in light and 228 PPB in dark conditions.5 Median effect concentrations for the coral larvae at 24 hours in light and dark conditions were 49 PPB and 137 PPB, respectively.5 Median lethal concentrations for S. pistillata coral larvae at 24 hours in light and dark conditions were 139 PPB and 799 PPB, respectively.5 In vitro cell cultures of one Indo-Pacific and five Caribbean-Atlantic species representing coral reef communities in Hawaii and U.S. Virgin Islands had median lethal concentrations that ranged from 8 PPB to 340 PPB after 4 hours of light. It is important to mention that this particular study examined the effect of oxybenzone on coral larvae and coral cell cultures, which are more sensitive to the toxic effects of chemicals than adult forms; however, small alterations in these immature coral organisms can lead to major changes in coral diversity and community structure.5 Alarmingly, light levels in tropic latitudes can reach levels up to five times higher than the levels used in this study, suggesting oxybenzone may actually be more toxic in the coralâ&#x20AC;&#x2122;s natural habitat.5 Perhaps even more concerning is the fact that UV filters have been found in concentrations that exceed these median effect and median lethal concentrations in seawater near coral reefs and heavily visited beaches (which will be discussed in Concentration Data section).

Titanium dioxide Metal-oxide agents such as titanium dioxide and zinc oxide are common inorganic UV filters used in sunscreens and PCPs, especially in the United States. Advancements in technology have allowed for the micronization of these previously large particles, increasing their transparency and cosmetic acceptability. In turn, the use of these agents in sunscreens and PCPs has increased because of their broad-spectrum UVB and UVA absorptive and light-scattering properties. One study detailed the effects of titanium dioxide on coral bleaching, gene expression, and bioaccumulation. Montastraea faveolata, a Caribbean reef-building coral, was exposed to two different concentrations of titanium dioxide, a lower environmentally relevant concentration of 0.1 PPM, and a higher concentration of 10 PPM, for 17 days. Bleaching studies found that M. faveolata exposed to titanium dioxide at 10 PPM had a statistically significant decrease in zooxanthellae compared to nonexposed controls; SKINmed. 2018;16:223â&#x20AC;&#x201C;229

however, titanium dioxide at concentrations of 0.1 PPM showed only a 14% decrease in zooxanthellae abundance, which was not statistically significant compared to controls and not particularly concerning in terms of coral mortality.10 The heat shock protein 70 (HSP70) gene is a general biomarker for stress.10 In this study, the HSP70 gene was significantly upregulated when exposed to titanium dioxide in concentrations of 0.1 PPM and 10 PPM on day 2 but showed no significant difference by day 7 when compared to nonexposed controls. This phenomenon suggests that M. faveolata is initially stressed by the introduction of titanium dioxide but eventually adapts to overcome the stress without causing mortality.10 Many UV filters have lipophilic properties and can bioaccumulate in aquatic organisms, which may be relevant to their toxic potential.7 In this study, titanium dioxide concentrations were measured in coral tissue and in posterior coral fragments, which contain a mixture of burrowing sponges, fungi, and bacteria. Bioaccumulation analysis showed that both coral tissue and posterior coral fragments had higher concentrations of titanium dioxide compared to nonexposed controls; however, concentrations in coral tissues were negligible compared to those in the posterior coral fragments.10 The authors hypothesized that this phenomenon demonstrates the coralâ&#x20AC;&#x2122;s ability to entrap pollutants and push them to the posterior aspect of the coral where they mix with burrowing sponges, fungi, and bacteria.10 Because titanium dioxide has mild bactericidal activity, these mechanisms may have toxic effects on the bacterial and fungal communities of coral reefs, although these effects were not studied.10 While this study outlined the possibility that titanium dioxide may adversely affect corals at supra-environmental concentrations, it failed to show statistically significant bleaching at environmentally relevant concentrations. In addition, gene expression data demonstrated that M. faveolata can adapt to the acute stress of titanium dioxide in 7 days at either concentration. While it may be inappropriate to dismiss the modest effects that titanium dioxide has on corals, it appears to be relatively benign.

Zinc oxide Another study looked at the effects of zinc oxide at concentrations ranging from 50 PPB to 200 PPB on lipid membranes of Seriatopora caliendrum, a coral found in the Red Sea and IndoPacific waters. Corals exposed to zinc oxide showed a decrease of 20:4-possesing glycerophosphocholine (GPC), an important compound needed for growth and cellular differentiation.11 In addition, levels of 22:6-possesing and 22:5-possessing GPCs, which sensitize the cellular membrane to oxidative attack, increased following zinc oxide exposure.

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Even small alterations in membrane composition can negatively impact an organism’s ability to function and adapt to environmental stressors.11 In this study, cellular membranes were altered following exposure to zinc oxide to accommodate metaloxide-induced disturbances in the membrane.11 Over time, the authors suggest that these results could affect coral growth and tolerance to oxidative stress, potentially impacting coral fitness. While it appears that zinc oxide can alter cellular membranes in corals, additional studies using environmentally relevant concentrations to study effects at the level of the organism are necessary before implicating zinc oxide as being toxic to corals.

Others In a series of in situ experiments, one study examined the effects of several sunscreens and UV filters on different species of hard corals. Results showed that when corals were exposed to various sunscreen ingredients in concentrations ranging from 10 PPB to 100 PPB, release of zooxanthellae began within 18–48 hours and complete bleaching occurred within 96 hours.2 When specific UV filters such as butylparaben, octyl methoxycinnamate, and enzacamene were tested, complete coral bleaching occurred at concentrations of 33 PPB.2 Conversely, other UV filters such as octocrylene, octyl salicylate, and avobenzone had minimal to no effects at this concentration.2 The data also suggested that bleaching occurred at faster rates when both UV filter concentrations and water temperatures were higher.2 CONCENTRATION DATA Coral reef waters and beaches near corals are tourist hotspots that attract numerous visitors who use sunscreens and PCPs containing UV filters. Furthermore, data collected from seawater samples have shown that oxybenzone can reach concentrations known to harm corals. Oxybenzone concentrations measured in various locations throughout the U.S. Virgin Islands and U.S. Hawaiian Islands varied from unmeasurable levels (<5 PPB) up to 1.4 PPM.5 Specifically, heavily visited areas in the U.S. Virgin Islands showed concentrations of oxybenzone ranging from 75 PPB to 1.4 PPM. In Hawaii, where coral recovery strategies are being developed, concentrations of oxybenzone ranged from unmeasurable levels up to 19.2 PPB.5 A different study measured the concentrations of UV filters in seawater samples from The South China Sea, home to some of the richest coral communities in the world.7 In this study, oxybenzone concentrations were low, reaching only 25.8 parts per trillion (PPT) in seawater samples.7

Dependence on number of swimmers Data collected at U.S. Virgin Islands sites suggest that the number of swimmers may affect UV filter concentrations in SKINmed. 2018;16:223–229

seawater. Samples were collected from three bays—Caneel Bay, Hawksnest Bay, and Trunk Bay located along St. John Island. Caneel Bay is managed by Caneel Bay Resort, which helps limit the number of daily swimmers.5 Only 17 swimmers were noted in the water during the 2-day period when samples were collected and neither had detectable levels of oxybenzone.5 Consequently, corals along this region flourish and have high rates of survival.5 In contrast, Hawksnest Bay is a heavily visited beach that can see more than 1,000 beachgoers daily.5 The two samples collected at this site showed oxybenzone levels of 75 PPB and 95 PPB on a day when over 230 swimmers entered the water. Trunk Bay is perhaps the most densely visited beach of the three measured on St. John Island.5 In 2009, the National Park Service instilled a policy limiting the number of visitors to 2,000 per day.5 Two samples taken from this site showed oxybenzone concentrations of 1.4 PPM and 580 PPB. In contrast to Caneel Bay, survival of immature coral is extremely poor at this location.5 While the purpose of collecting seawater samples was to measure oxybenzone concentrations and not to correlate concentrations to the number of swimmers, it appears that more heavily visited beaches had higher levels of oxybenzone in the surrounding seawater. Additional evidence suggesting that the number of swimmers impacts UV filter concentration was demonstrated at Okinawa Island, Japan, when concentrations were measured at both beach and coral reef sites over several months. At all beach sites, total UV filter concentrations were highest in July or August during the summer holiday season when beaches are crowded with swimmers.3 In these months, up to 900 swimmers can enter the water each day compared to roughly 100 daily swimmers in the months prior.3 Despite the peaks in concentration at beaches, UV filter concentrations at reef sites did not show peaks during the summer months.3 At beach sites, total UV filter concentrations reached 1.4 PPB, with oxybenzone providing the highest concentration of 1.3 PPB. At reef sites, total UV filter concentrations reached only 10 PPT, with octocrylene providing the highest concentration of 8.1 PPT.3 At both beach and reef sites, total UV filter concentrations were lower than the lethal concentration of most UV filter compounds for corals.2,3 Interestingly, UV filters detected in this study were different between beaches and correlated with visitor profiles.3 For example, octyl methoxycinnamate, commonly used in Japanese sunscreens, was the dominant UV filter found at Emerald Beach where Japanese tourists are the primary visitors. In contrast, homosalate, an ingredient that is commonly used in U.S. products, was found at three beaches near U.S. military bases where service members and their families are a significant proportion of the visitors.3

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Dependence on geography Geography may also play a role in UV filter concentrations. Corals located along shorelines, not protected within a bay, may experience lower levels of pollution as pollutants are quickly washed away by prevailing currents.5 For example, seawater samples collected at Kahekili Beach, located along the coast of Maui Island in Hawaii, showed detectable but unmeasurable levels of oxybenzone despite being a heavily visited beach with 71 swimmers in the water at the time of sample collection.5 In contrast, other heavily visited beaches protected in coves had not only measurable but also relatively high concentrations of oxybenzone.5 Corals in shallow water may be at higher risk of UV filter toxicity. Studies have demonstrated that oxybenzone in surface water samples may be present in up to 30 times greater concentrations than bottom water samples, putting corals in the shallowest waters at the greatest risk.7 Other studies have shown that bleaching occurs at a faster rate in corals subjected to higher temperatures.2 These results suggest that coral reefs located in the shallowest, warmest waters may be at the highest risk of morbidity and mortality.2

Dependence on wastewater runoff Wastewater contaminated by regular use of sunscreens and PCPs containing UV filters rinsed off while bathing appears to be a source by which these products enter the environment.12 Unfortunately, standard wastewater treatment processes are not effective in removing organic compounds such as UV filters.12 Therefore, chemicals from sunscreens and PCPs are released directly into the environment after passing through wastewater treatment plants.13 Advanced treatment processes to remove these contaminates are available but are not routinely used due to energy requirements.12 New enzymatic treatment options that are effective at removing oxybenzone at concentrations typical for municipal wastewater with lower energy requirements have been proposed but have yet to be implemented and are associated with higher costs.12 A study on wastewater treatment plants in Hong Kong detected common UV filters including oxybenzone, avobenzone, 2,4-dihydroxybenzophenone, sulisobenzone and octyl methoxycinnamate in more than 80% of influent and effluent water samples. Concentrations ranged from 0.023 PPM to 1.290 PPM for influent samples and from 0.018 PPM to 1.018 PPM for effluent samples, demonstrating almost no removal by the facility.6 RECOMMENDATIONS With over 6,500 sunscreen products on Amazon.com varying in vehicle type, ingredients, SPF, cost and product claims, patients often rely on dermatologists and other health-care professionals to SKINmed. 2018;16:223–229

recommend sunscreens and other PCPs containing UV filters.14 While somewhat cliché, it is still true that the best sunscreen is one that will be used on a regular basis. Therefore, dermatologists should strive to find a sunscreen that is appropriately protective and abides by patient preferences. Understanding consumer preferences can help guide sunscreen recommendations and encourage routine use. A study aimed to understand consumer sunscreen preferences analyzed the highest rated sunscreens on Amazon.com. Among the highest rated sunscreens, those with chemical UV filters were rated above those with inorganic UV filters.14 Sadly, 40% did not adhere to AAD guidelines.14 Using reviews rated as “most helpful,” cosmetic elegance, product performance, and skin type compatibility appeared to be the main determinants of consumer preferences.14 The most cited positive feature of sunscreen products was cosmetic elegance, specifically the products ability to “rub in well.” 14 Other commonly cited positive features were product ingredients and price.14 Interestingly, over 10% of reviews mentioned endorsements from outside organizations as a positive feature. One of the organizations cited was the Environmental Working Group, which is a non-profit group that aims to “protect human health and the environment.” This organization is often controversial and cites dubious sources, yet was mentioned more often than the phrase, “dermatologist recommended.” 14 The most often cited negative features included lack of cosmetic elegance, product ingredients, and cost.14 Cost may be particularly important to those with increased risk of skin cancer because strict, daily use of adequate quantities of sunscreen leads to substantial amounts. Health-care professionals should educate patients about marketing claims and balance adequate photoprotection, cosmesis, and cost when making sunscreen recommendations. Dermatologists must be prepared to offer alternatives to patients concerned about using sunscreens containing specific ingredients and those asking for “environmentally conscious” alternatives. Sunscreens and PCPs containing UV filters shown to be less harmful to corals such as titanium dioxide and zinc oxide can cost more and have potential to leave a residue on the skin.14 As a result, if health-care providers are too rigid in only recommending sunscreens with inorganic UV filters, there is potential for poor compliance, further exacerbating already less than ideal use behaviors. For those not near oceans, it appears that sunscreen ingredients pose little threat to the coral reefs. In this situation, patients should not feel limited in terms of which AAD-approved sunscreen they choose to wear. Even for those that live in close proximity to the ocean, UV filters contaminating seawater from wastewater runoff rarely exceed 1 PPM. Where it may be appropriate to advocate for

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Table I. List of Sunscreens Commonly Recommended to Patients Who Express Concern about Coral Reef Safety Replenix Ultimatte Perfection SPF 50+ Replenix Sheer Physical Sunscreen Cream SPF 50+ Replenix Sheer Physical Sunscreen SPF 50+ Blue Lizard Sensitive SPF 30 CeraVe Sunscreen Body Lotion SPF 30 CeraVe Sunscreen Body Lotion SPF 50 SPF, sun protection factor.

AAD-approved sunscreens and PCPs with inorganic UV filters is when patients plan to visit oceans or beaches in close proximity to coral reefs. This may be especially important for heavily visited beaches and in areas with endangered coral species such as those on the International Union for Conservation of Nature’s (IUCN’s) Red List of Threatened Species.5 The IUCN’s Red List of Threatened Species is widely recognized for using a comprehensive and objective approach to evaluate the extinction risk of a wide range of species.9 Currently, of the 845 species of reef-building corals, 704 have been evaluated and 407 are listed in threatened or near-threatened categories.9 Of these, 40% are shallow water corals, which are already more susceptible to anthropogenic disturbances.9 Other regions where special recommendations may be made are the Caribbean and Coral Triangle. The Caribbean has the largest proportion of corals in high extinction risk categories.9 The Coral Triangle, a 6 million km2 area located in the western Pacific Ocean, is an epicenter of marine biodiversity and has the highest proportion of species in all categories of elevated extinction risk.9 While there are numerous sunscreens on the market that are “coral friendly,” Table I provides a brief list of products that one of the authors (M.J.Z.) recommends to patients who express concerns about the effects of sunscreens on coral reefs.

yourself, protect your reef,” advocating to take a “reef friendly” approach to sun protection. The campaign recommends sunscreens with titanium dioxide or zinc oxide, labeling them natural ingredients that have not been found harmful to corals. Furthermore, the campaign recommends sunscreens sold for children and those with sensitive skin, which often do not provide adequate sun protection. The campaign flyer finishes with, “...if it’s on your skin, it’s on the reef...reduce the amount of sunscreen you leave behind.” While many sunscreens and PCPs containing titanium dioxide and zinc oxide provide adequate sun protection, these campaigns may be easily misinterpreted and lead to a reduction in the already sub-optimal use of sunscreens. Most recently in April 2018, Hawaii passed a bill, SB2571, which bans the sale and distribution of any sunscreen that contains oxybenzone or octinoxate (octyl methoxycinnamate) without a prescription from a licensed physician. The bill was officially signed by Hawaii’s governor in July 2018 and goes into effect on January 1, 2021. Dermatologists are at the front line in protecting patients from the deleterious effects of UV light and, as such, should make every effort to encourage adequate sunscreen use. As advocates for patients’ skin health, educating and addressing potential barriers to photoprotection is essential for optimum use of sunscreen. Dermatologists should be equipped with substantial knowledge regarding sunscreen ingredients that includes their potential effects on the environment and new trends in consumer preferences. At this time, it may be appropriate to recommend sunscreen products composed primarily of inorganic UV filters to patients concerned about the environmental impact of organic UV filters and those who plan to visit waters in the immediate vicinity of coral reefs. As always, these recommendations should be balanced with patient preferences and cosmetic acceptability to ensure maximum compliance. REFERENCES

CONCLUSIONS The effect that sunscreens and PCPs containing UV filters have on the environment has gained momentum among patients and scientific community. Concern that agents used in sunscreens and PCPs may be harmful to environment, along with recent studies demonstrating detectable levels in both seawater and wastewater management systems, has led to local campaigns advocating against the use of sunscreens containing specific ingredients and even banning of sunscreen products.5 In 2012, the National Park Service launched a campaign, “Protect SKINmed. 2018;16:223–229

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1 DeLeo VA. Sunscreens and photoprotection. In: Bolognia JL, Schaffer JV, Cerroni L, editors. Dermatology. 4th ed. Elsevier Limited; 2018:2310–2317. 2 Danavaro R, Bongiorni L, Corinaldesi C, et al. Sunscreens cause coral bleaching by promoting viral infections. Environ Health Perspect. 2008;116:441–447. 3 Tashiro Y, Kameda Y. Concentration of organic sun-blocking agents in seawater of beaches and coral reefs of Okinawa Island, Japan. Mar Pollut Bull. 2013;77:333–340. 4 Tsui MMP, Leung HW, Wai TC, et al. Occurrence, distribution and ecological risk assessment of multiple classes of UV filters in surface waters form different countries. Water Res. 2014;67:55–65. 5 Downs CA, Kramarsky-Winter E, Segal R, et al. Toxicopathological effects of the sunscreen UV filter, oxybenzone (benzophenone-3),

Can Sunscreens Harm Coral Reefs?

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ORIGINAL CONTRIBUTION

on coral planulae and cultured primary cells and its environmental contamination in Hawaii and the U.S. Virgin Islands. Arch Environ Contam Toxicol. 2015;70:265–288.

10 Jovanovic B, Guzman HM. Effects of titanium dioxide (TiO2) nanoparticles on Caribbean reef-building coral (Monstastraea Faveolata). Environ Toxicol Chem. 2014;33:1346–1353.

6 Tsui MMP, Leung HW, Lam PKS, et al. Seasonal occurrence, removal efficiencies and preliminary risk assessment of multiple classes of organic UV filters in wastewater treatment plants. Water Res. 2014;53:58–67.

11 Tang CH, Lin CY, Lee SH, et al. Membrane lipid profiles of coral responded to zinc oxide nanoparticle-induced perturbations on the cellular membrane. Aquat Toxicol. 2017;187:72–81.

7 Tsui MMP, Lam JCW, Yan Ng T, et al. Occurrence, distribution and fate of organic UV filters in coral communities. Environ Sci Technol. 2017;51:4182–4190.

12 Garcia HA, Hoffman CM, Kinney KA, Lawler DF. Laccasecatalyzed oxidation of oxybenzone in municipal wastewater primary effluent. Water Res. 2011;45:1921–1932.

8 Negri AP, Hoogenboom MO. Water contamination reduces the tolerance of coral larvae to thermal stress. PLoS One. 2011;6:19703.

13 Kolpin DW, Furlong ET, Meyer MT, et al. Pharmaceuticals, hormones, and other organic wastewater contaminants in U.S. streams, 1999-2000: A national reconnaissance. Environ Sci Technol. 2002;36:1202–1211.

9 Carpenter KE, Abrar M, Aeby G, et al. One-third of reef-building corals face elevated extinction risk from climate change and local impacts. Science. 2008;321:560–563.

14 Xu S, Kwa M, Agarwal A, et al. Sunscreen product performance and other determinants of consumer preferences. JAMA Dermatol. 2016;152:920–927.

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July/August 2018

Volume 16 • Issue 4

ORIGINAL CONTRIBUTION

Effect of Fluprostenol Isopropyl Ester and 15-Keto Fluprostenol on Eyelash Growth: A Clinical and Pharmacologic Study Caruso Ciro, MD;1 Pacente Luigi, MD2 ABSTRACT 15-Keto fluprostenol isopropyl ester and 15-keto fluprostenol have demonstrated a stimulatory effect on the growth and thickening of the eyelashes without the disadvantages of the prostaglandin derivatives of the PGF2α group, which have a hydroxyl group at position 15 in their structure. The two 15-ketoderivatives have the same efficacy as the 15-hydroxyl derivatives in allowing the regrowth, lengthening, darkening, or thickening of the eyelashes, but without darkening the edge of the eyelid or coloring the iris, even temporarily. (SKINmed. 2018;16:231–233)

air loss is a common problem that can be caused by naturally occurring or chemically promoted factors, as in the use of certain therapeutic drugs (e.g., anticancer drugs).1,2 Although hair loss has plagued mankind for centuries, its cause is not completely understood, and no adequate cure has yet been found. Hair loss may be accompanied by a lack of hair regrowth that causes partial or full baldness.3 Similarly, diseases such as ulcerative blepharitis, trachoma, or caustic injuries can produce partial or even complete loss of the eyelashes.4,5 Whereas the term hypotrichosis may be applied to the periocular region to describe hair loss and lack of hair growth, the term madarosis is now commonly used to designate general loss of the eyelashes and/or eyebrows.6 Madarosis can lead to two different pathologic conditions: the scarring forms of madarosis are responsible for irreversible hair loss resulting from follicle destruction, whereas nonscarring forms allow for hair restoration.7 Permanent madarosis can be treated only cosmetically, using artificial hair, permanent tattooing, or temporary make-up. Another possible approach is represented by eyebrow transplants; this has a high degree of success but must take into account the variability of hair type between different ethnicities.8 Eyelash transplants occur less frequently, given the greater need to maintain hair alignment and avoid poor cosmetic results. Eyelash transplants have been associated with trichiasis, leading to severe adverse effects.9 Another nonpharmacologic approach to eyelash loss is total reconstruction by means of composite eyebrow grafts.10

Pharmacologic treatment of periocular hair deficiency has gained popularity with the introduction of Latisse® (0.03% bimatoprost solution; Allergan, Dublin, Ireland).11 The success of the topical use of bimatoprost in particular, and prostaglandins in general, for the treatment of periocular hypotrichosis has been serendipitous. The role of prostaglandins in the treatment of hair loss has been previously investigated.12,13 Topical minoxidil is capable of stimulating hair growth by stimulating activation of prostaglandin-1 synthase.14 The protective effect of prostaglandins against hair loss in cancer therapies is well known,15 but the effect of prostaglandins on eyelash growth had not been investigated. At that time, bimatoprost was a worldwide-registered ocular drug, recommended for the treatment of glaucoma. Chronic use of bimatoprost was associated with the specific side effect of hypertrichosis at the application site, with increasing length and density of periocular hair. The same formulation (bimatoprost 0.03%) was successfully proposed for the topical treatment of madarosis, and similar results were obtained with other prostaglandins including latanoprost, bimatoprost, and travoprost.16 All these molecules show high efficacy associated with some drawbacks such as periocular skin hyperpigmentation, conjunctivae hyperaemia, and, less frequently, iris darkening.17,18 The mechanism underlying both hair growth regulation and side effects is still unknown. For example, it has been reported how

From the Corneal Transplant Center Eye Bank,1 and the Department of Ophthalmology,2 Pellegrini Hospital, Naples Italy Address for Correspondence: Ciro Caruso, MD, Via S. Nullo, Country Park Marina di Licola Giugliano, 80014 Napoli, Italy • E-mail: cirocarusoeye@gmail.com

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the oxidation of the hydroxyl group in the prostaglandin side chain, producing a keto derivative, is able to reduce affinity for the prostaglandin receptor. Similarly, modification of carboxylic acid to various esters results in greatly reduced affinity and potency.19 Isopropyl ester and keto-analogues of prostaglandin F2a have a strong influence on hair growth in a murine model of alopecia.20 For these reasons, we aimed to evaluate the effect of 15-keto fluprostenol isopropyl ester and 15-keto fluprostenol) on eyelash growth and thickening. The affinity of these compounds for the prostaglandin receptor were initially evaluated using a radioligand binding assay. A clinical study involving 34 patients affected by hypotrichosis, ulcerative blepharitis, and madarosis was conducted. The results obtained from this clinical study highlight the efficacy of the two substances in increasing the length of the eyelashes after 4 weeks of treatment. MATERIALS AND METHODS

Radioligand binding assay Membranes were prepared by differential centrifugation of confluent Swiss fibroblasts, rat vascular smooth muscle cells, HEK-293 cells expressing the cloned human ciliary body prostanoid receptors of F series (FP), human ciliary muscle, and human trabecular meshwork cells (all containing functional FP receptors), and immortalized human nonpigmented ciliary epithelial cells containing FP receptors. The prostanoid receptor binding assay was performed in an incubation volume of 0.2 mL in 10 mM MES/KOH (pH 6.0), containing 10 mM EDTA, 10 mM MnCl2, and 0.95 nM (3H) PGF2a (170 Ci/mmol) radioligand. Radioligands were added in dimethylsulfoxide (Me2SO). Nonspecific binding was determined in the presence of 1 µM of the corresponding non-radioactive prostanoid. Specific binding was calculated by subtracting the nonspecific binding from the total binding. Specific binding represented 85% to 95% of the total binding, and was linear with respect to the concentrations of radioligand and protein used. [3H]-Inositol phosphates produced by agonist-mediated activation of phospholipase C were quantified. In brief, confluent Swiss fibroblasts, rat vascular smooth muscle cells, HEK-293 cells expressing the cloned human ciliary body FP receptor, human ciliary muscle, and human trabecular meshwork cells and immortalized human nonpigmented ciliary epithelial cells containing FP receptors were exposed to 2 to 3 µCi of [3H]-myoinositol in 0.5 mL DMEM for about 24 hours at 37°C. Cells were exposed to the agonist or solvent for 60 minutes at 37°C. The plates were kept cold and then frozen. SKINmed. 2018;16:231–233

Saturation analysis was conducted to determine the equilibrium dissociation constants (Kd) and maximum number of binding sites for prostanoid receptors. Prostanoid receptors expressed in this cell line interact with their preferred ligands with high affinities in the low nanomolar range. Equilibrium competition binding assays were conducted to determine the inhibition constants (Ki) for ligands interacting with prostanoid receptors. The corresponding Ki values were derived from the equation Ki = IC50/11+ (radioligand concentration/Kd) (results reported in Table). Data were analyzed using the sigmoidal fit function of Origin Scientific Graphics software (Microcal Software, Northampton, MA) to determine agonist potency (EC50 value) and efficacy (results reported in Table).

Clinical study Thirty-four patients were enrolled for the clinical study. They were 18 women and 16 men with an age between 18 and 67 years who were affected by hypotrichosis, ulcerative blepharitis, or madarosis. Three different hypotonic solutions, buffered at pH 7.2, were prepared. These were constituted of 0.003 g/mL of hyaluronic acid, 0.00002 g/mL of N-hydroxy methyl glicinate, and 0.001 g/mL of sodium edentate, with the addition of 80 μg/ mL of 15-keto fluprostenol isopropyl ester (solution A), 15-keto fluprostenol (solution B), or travoprost (solution C). Patients were divided into three different group. They were trained to apply the solution, using the specific applicator, after accurate cleansing of the eyes. Solutions were applied twice daily at 12-h intervals for 4 weeks. The length of the eyelashes was evaluated during treatment (at 2 weeks) and at the end of treatment (at 4 weeks, 2 months, and 4 months). Qualitative assessment was made using photographs of the eyelashes taken at different interval times in comparison with time 0. Quantitative assessment was made using a stainless steel digital caliper (Neiko 01407A, New York, USA). RESULTS AND DISCUSSION Results obtained from the radioligand binding assay are reported in the Table. 15-Keto fluprostenol isopropyl ester showed a

232

Table. Ki Values for the Tested Molecules Agonist 15-Keto fluprostenol isopropyl ester 15-Keto fluprostenol

Ki Value (nM) 52+2 5737+889

Effect of Fluprostenol Isopropyl Ester and 15-Keto Fluprostenol

July/August 2018 Before treatment

2 weeks’ treatment

ORIGINAL CONTRIBUTION eyelashes without the disadvantages shown by the prostaglandin derivatives of PGF2α group, which have a hydroxyl group in position 15 in their structure. In conclusion, the 15-keto derivatives of fluprostenol may have a role in stimulating the regrowth of eyelashes and probably also of eyebrows and hair.

4 weeks’ treatment

REFERENCES 1 Kligman AM. Pathologic dynamics of human hair loss. I. Telogen effluvium. Arch Dermatol. 1961;83:175–198. 2 Price VH. Treatment of hair loss. N Engl J Med. 1999;341:964– 973. 3 Cotsarelis G, Millar SE. Towards a molecular understanding of hair loss and its treatment. Trends Mol Med. 2001;7:293–301. 4 Leibowitz HM. The red eye. N Engl J Med. 2000;5:345–351. 5 Modjtahedi BS, Alikhan A, Maibach HI, et al. Diseases of periocular hair. Surv Ophthalmol. 2011;5:416–432. 6 Sachdeva, S, Prasher P. Madarosis: a dermatological marker. Indian J Dermatol Venereol Leprol. 2008;1:74–76.

Figure. Negative images showing the progression of eyelash length and density during treatment.

7 Khong JJ, Casson RJ, Huilgol SC. Madarosis. Surv Ophthalmol. 2006;6:550–560. 8 Laorwong K, Pathomvanich D, Bunagan K. Eyebrow transplantation in Asians. Dermatol Surg. 2009;3:496–503.

lower Ki value than 15-keto fluprostenol, thus showing it to be more potent than the homologous 15-keto fluprostenol. This is in accordance with the results obtained in the clinical study. As shown in the Figure (negative image), an increase in length and density of the eyelashes was observed after 2 weeks of treatment. After 1 month of treatment, 87% of the patients in the three groups showed new eyelash growth (for patients with eyelash loss) or thickening (for patients not suffering a complete loss). Four months after treatment, 100% of patients showed an objective and subjective improvement in eyelash length, growth, and thickening, followed by darkening of the eyelashes in patients with light-colored eyelashes. Eight months after treatment, regression was evidenced. This regression was most evident for the groups receiving solutions B and C (13%), and less for the group receiving solution A (9%). The patients in groups A and B did not suffer either subjective or objective side effects. However, 20% of patients in group C showed conjunctival hyperaemia, increase in tearing, conjunctival reddening, or eyelid edema. About 9% of patients in group C were affected by skin darkening in the periocular zone. All patients belonging to group C evidenced ocular irritation, photophobia, ocular itch, and burns.

9 Murchison AP, Wojno TH. Trichiasis after eyelash augmentation with hair follicle transplantation. Ophthal Plast Reconstr Surg. 2007;4:323–324. 10 Kasai K. Eyelash reconstruction with strip composite eyebrow graft. Ann Plast Surg. 2008;60:649–651. 11 Woodson SA. Latisse: Empirical discovery yields treatment for sparse eyelashes. Nurs Womens Health. 2009;3:243–248. 12 Rogers NE, Avram MR. Medical treatments for male and female pattern hair loss. J Am Acad Dermatol. 2008;4:547–566. 13 Garza LA, Liu Y, Yang Z, et al. Prostaglandin D2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia. Sci Transl Med. 2012;126:126–134. 14 Michelet, JF, Commo S, Billoni N, et al. Activation of cytoprotective prostaglandin synthase-1 by minoxidil as a possible explanation for its hair growth-stimulating effect. J Invest Dermatol. 1997;2:205–209. 15 Malkinson FD, Geng L, Hanson WR. Prostaglandins protect against murine hair injury produced by ionizing radiation or doxorubicin. J Invest Dermatol. 1993;1 suppl:135–137. 16 Tosti A, Pazzaglia M. Drug reactions affecting hair: diagnosis. Dermatol Clin. 2007;2:223–231. 17 Alma A, Grierson I, Shields MI. Side effects associated with prostaglandin analog therapy. Surv Ophthalmol. 2008;1 supp:93–105. 18 Priluck JC, Fu S. Latisse-induced periocular hyperpigmentation. Arch Ophthalmol. 2010;6:792–793.

skin

CONCLUSIONS

19 Ungrin MD, Carrière MC, Denis D, et al. Key structural features of prostaglandin E(2) and prostanoid analogs involved in binding and activation of the human EP(1) prostanoid receptor. Mol Pharmacol. 2001;6:1446–1456.

15-Keto fluprostenol isopropyl ester and 15-keto fluprostenol have shown a stimulatory effect on growth and thickening of the

20 Sasaki S, Hozumi Y, Kondo S. Influence of prostaglandin F2alpha and its analogues on hair regrowth and follicular melanogenesis in a murine model. Exp Dermatol. 2005;5:323–328.

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Effect of Fluprostenol Isopropyl Ester and 15-Keto Fluprostenol

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July/August 2018

Volume 16 • Issue 4

ORIGINAL CONTRIBUTION

Nonuremic Calciphylaxis: Four Cases Associated with Autoimmune Diseases Miguel Costa-Silva, MD; Julia Vide, MD; Maria João Cruz, MD; Teresa Baudrier, MD; Filomena Azevedo, MD ABSTRACT Calciphylaxis is a rare and severe syndrome of vascular calcification with unclear pathogenesis. This disease mainly affects patients with end-stage renal disease; however, it also has been described in nonuremic patients. We report four cases of nonuremic calciphylaxis (NUC) with ulcerated lesions associated with autoimmune disease. These cases support the literature suggesting that bisphosphonates and sodium thiosulfate are effective drugs in the treatment of calciphylaxis regardless of renal function. (SKINmed. 2018;16:235–237)

alciphylaxis is a rare, severe and often fatal disorder, characterized by small vessel calcification and thrombosis leading to cutaneous ischemic necrosis.1 Although traditionally viewed as a complication of end-stage renal disease, calciphylaxis has also been reported in patients without it, and is then referred to as NUC.2 Calciphylaxis is associated with significant morbidity and mortality.2 We report four patients with NUC associated with autoimunne disease who presented to our department between 2009 and 2015. CASE DESCRIPTIONS The four individuals with NUCcomprised three women and one man. All were white, with normal renal function at the time of NUC diagnosis, and they presented with ulcerated lesions mainly on the lower extremities (Figure 1). Histopathologic examination confirmed calciphylaxis (Figure 2). Patient 1 was an obese 62-year-old woman with a history of diabetes mellitus, Sjögren–lupus erythematosus overlap syndrome, and rheumatoid arthritis, chronically medicated with prednisolone, hydroxychloroquine, and methotrexate. Upon diagnosis of the NUC, the patient was treated with intravenous (IV) sodium pamidronate 60 mg per week, with resolution of lesions at week 16; treatment was stopped 1 week later. She died 3 years after diagnosis due to cardiac failure, but no ulcer recurrence was observed during follow-up.

Patient 2, an obese 45-year-old woman with a medical history of deep venous thrombosis and autoimmune hemolytic anemia, was being treated with prednisolone and warfarin. On diagnosis of calciphylaxis, warfarin was switched to low-molecularweight heparin, and IV sodium pamidronate 60 mg per week was started. Ulcer resolution was observed at week 38. Treatment was prolonged for 5 years, because the ulcers recurred each time a reduction in pamidronate dose was attempted. Ulcer recurrence was not seen during the current 18 months of follow-up. Patient 3, a 57-year-old man with history of systemic sclerosis and deep venous thrombosis, being treated with prednisolone and warfarin, had severe chronic ulcers on the extremities. After the diagnosis of NUC, warfarin was switched to low-molecularweight heparin, and the patient was treated with IV pamidronate 60 mg per week. Due, to a lack of responsiveness, the dosage was changed at week 44 to IV sodium thiosulfate (STS) 25 mg twice a week, with the ulcer healing at week 62. During year 3 of treatment, new lesions appeared and IV pamidronate 60 mg per week was added to the patient’s regimen. This regimen was maintained for 2 years, with good control. At year 5, IV treatment was suspended due to the absence of peripheral venous access. Three months later, the patient developed osteonecrosis of the jaw, probably related to prolonged treatment with bisphosphonates. Subsequently, recurrence of the calciphylaxis lesions recurred. Recently, the patient started treatment with oral cinacalcet.

From the Department of Dermatology and Venereology, Centro Hospitalar São João, EPE, Porto, Portugal Address for Correspondence: Miguel Costa-Silva, MD, Alameda Professor Hernâni Monteiro 4200–319 Porto, Portugal • E-mail: miguelcostaesilva. dermato@gmail.com

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Figure 2. Skin biopsy showing medial calcification of the small vessels in patient 1 (A), 2 (B), 3 (C), and 4 (D).

phosphorus levels in all patients, except for patient 2. Patients 3 and 4 had decreased serum albumin and proteins C and S. Patient 2 had decreased levels of protein C with normal protein S and albumin. Patient 1 had normal albumin and protein C and S.

DISCUSSION

Calciphylaxis is most commonly reported in white women during the 5th decade of life.2,3 The biological explanation for these observations is unclear. In our small series, women predominated (3:1), and most patients were middleaged; however, an 81 year patient was diagnosed, demonstrating that calciphylaxis can affect patients of any age. The mortality rate in patients with calciphylaxis may be as high as 30% to 80%.4 Sepsis has been reported as the leading cause of death.5 In our series, two patients (50%) died after six years, from cardiovascular complications, suggesting that calciphylaxis is not just a local vascular disorder but rather a systemic one.

Figure 1. Calciphylaxis skin lesions in patient 1 (A), 2 (B), 3 (C), and 4 (D).

Patient 4, an 81-year-old woman with a history of autoimmune thyroiditis, was treated with IV pamidronate 60 mg per week, and her ulcer was resolved at week 14. Interestingly, 1 year after presentation, the patient was diagnosed with end-stage renal disease and started dialysis treatment. Soon after, the leg ulcers recurred, but pamidronate treatment was not restarted, as the patient then suffered multiple cardiovascular events, and she subsequently died. On diagnosis of NUC, all four patients had normal parathyroid hormone levels. We also noticed normal serum calcium and SKINmed. 2018;16:235–237

A calciphylaxis diagnosis is confirmed by skin biopsy showing medial calcification of the small arteries and arterioles, microthrombosis and intimal proliferation leading to ischemia, subcutaneous fat necrosis, and panniculitis.6 The pathogenesis is largely unclear. Deficiencies in vascular calcification inhibitors and derangements in regulation of extraskeletal mineralization have been postulated to play a key role in NUC.7,8 Other risk factors that have been associated with the development of calciphylaxis include white race, female sex, obesity, decreased albumin level, and drugs such as corticosteroid, warfarin, and methotrexate.2,9 Several cases of NUC associated with connective tissue diseases have been reported. In a systematic review of 36 NUC cases, connective tissue diseases were the fourth most

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prevalent condition.1 Interestingly, all our patients had a history of autoimmune disease, raising the possibility of a potential role for autoimmunity in the pathogenesis of calciphylaxis. Calciphylaxis may represent a final common pathway for a variety of insults.1 At present, there are no guidelines for calciphylaxis treatment. Reports of successful control of NUC with IV STS and bisphosphonates have been published.2,10,11 In our experience, both can be effective, and they can be used in combination in recalcitrant cases. However, STS could be a safer option when prolonged treatment is needed as prolonged bisphosphonate treatment can be associated with osteonecrosis of the jaw.12 In addition, STS can be an effective rescue therapy, when there is no response to bisphosphonate treatment or when it loses effectiveness. Recently, intralesional STS has been reported to be efficacious in the treatment of localized uremic calciphylaxis.13 Other proposed calciphylaxis therapies include cinacalcet, hyperbaric oxygen therapy, negative-pressure therapy, and parathyroidectomy for patients with calciphylaxis and hyperparathyroidism.14–16 CONCLUSIONS Even with increasing reports about NUC, there is still much that we do not know about it. High clinical suspicion for NUC should be maintained while evaluating skin lesions, especially in patients with autoimmune disease, even in the absence of end-stage renal disease. We add these cases to the growing list of reports of NUC, in the hopes of better defining the disease and encouraging a rapid diagnosis and initiation of therapy. REFERENCES

3 Hayashi M. Calciphylaxis: Diagnosis and clinical features. Clin Exp Nephrol. 2013;17:498–503. 4 Fernandes C, Maynard B, Hanna D. Successful treatment of calciphylaxis with intravenous sodium thiosulfate in a nonuremic patient: Case report and review of therapy side effects. J Cutan Med Surg. 2014;18:356–360. 5 Weenig RH, Sewell LD, Davis MD, et al. Calciphylaxis: Natural history, risk factor analysis and outcome. J Am Acad Dermatol. 2007;56:569–579. 6 Musso CM, Enz P, Vidal F, et al. Use of sodium thiosulfate in the treatment of calciphylaxis. J Kidney Dis Transpl. 2009;20:1065–1068. 7 Mendes M, Ferreira AV, Ferreira A, et al. Calciphylaxis: A literature review based in two case reports. Port J Nephrol Hypert. 2014;28:61–68. 8 Weenig RH. Pathogenesis of calciphylaxis: Hans Selye to nuclear factor kappa-B. J Am Acad Dermatol. 2008;58:458–471. 9 Kalajian AH, Malhotra PS, Callen JP, et al. Calciphylaxis with normal renal and parathyroid function not as rare as previously believed. Arch Dermatol. 2009;145:451–458. 10 Ning MS, Dahir KM, Castellanos EH, et al. Sodium thiosulfate in the treatment of non-uremic calciphylaxis. J Dermatol. 2013;40:649–652. 11 Torregrosa JV, Duran CE, Barros X, et al. Successful treatment of calcific uraemic arteriolopathy with bisphosphonates. Nefrologia. 2012;32:329–334. 12 Ruggiero SL, Dodson TB, Fantasia J, et al. American Association of Oral and Maxillofacial Surgeons position paper on medicationrelated osteonecrosis of the jaw-2014 update. J Oral Maxillofac Surg. 2014;72:1938–1956. 13 Baumgartner-Nielsen J, Olesen AB. Treatment of skin calcifications with intra-lesional injection of sodium thiosulphate: A case series. Acta Derm Venereol. 2016;96:257–258. 14 Vedvyas C, Winterfield LS, Vleugels RA. Calciphylaxis: A systematic review of existing and emerging therapies. J Am Acad Dermatol. 2012;67:e253–e260.

1 Nigwekar SU, Wolf M, Sterns RH, et al. Calciphylaxis from nonuremic causes: A systematic review. Clin J Am Soc Nephrol. 2008;3:1139–1143.

15 Kim HJ, Kim H, Shin N, et al. Cinacalcet lowering of serum fibroblast growth factor-23 concentration may be independent from serum Ca, P, PTH and dose of active vitamin D in peritoneal dialysis patients: A randomized controlled study. BMC Nephrol. 2013;14:112.

2 Nigwekar SU, Kroshinsky D, Nazarian RM, et al. Calciphylaxis: Risk factors, diagnosis, and treatment. Am J Kidney Dis. 2015;66:133–146.

16 Raymond CB, Wazny LD. Sodium thiosulfate, bisphosphonates, and cinacalcet for treatment of calciphylaxis. Am J Health Syst Pharm. 2008;65:1419–1429.

WAX MOULAGE

Courtesy of Michael Geiges, MD

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Efficacy of Folic Acid and Vitamin B12 Replacement Therapies in the Reduction of Adverse Effects of Isotretinoin: A Randomized Controlled Trial Maryam Ghiasi, MD; Hossein Mortazavi, MD; Masood Jafari, MD ABSTRACT Previous studies have reported elevated homocysteine levels and folic acid and/or vitamin B12 deficiencies after isotretinoin therapy, which increase the risk of cardiovascular and neuropsychiatric disorders. Homocysteine is metabolized in the liver, a process requiring folate and vitamin B12. We conducted a randomized controlled trial to investigate whether folate and vitamin B12 replacement therapy with isotretinoin would be useful for preventing hyperhomocysteinemia. A total of 66 patients with acne were randomized into two groups: group A took isotretinoin, folic acid, and vitamin B12, whereas group B took isotretinoin alone. Treatment was continued for 2 months. Blood homocysteine, folic acid, and vitamin B12 levels were measured before and after treatment. In group A, a significant decrease in homocysteine level was observed after treatment (P=.0004), although it was still within the normal range. Folic acid and vitamin B12 levels significantly increased (P=.0026 and P=.0002, respectively). In group B, no significant changes were observed in the levels of homocysteine and vitamin B12, but folic acid levels decreased significantly (P=.02). We concluded that folic acid and vitamin B12 supplementation during isotretinoin therapy could be useful for preventing folate deficiency and improving blood homocysteine levels; this might as a result reduce the risks for cardiovascular and neuropsychiatric disorders in patients taking isotretinoin. (SKINmed. 2018;16:239–245)

cne is a common skin disease, affecting many adolescents and with a lifetime prevalence of more than 90%.1 Due to its chronicity, the disease has a considerable impact on patients’ physical and psychological health.2,3 Isotretinoin (13-cis-retinoic acid) has been used to treat severe acne since its approval by the US Food and Drug Administration in 1982. Isotretinoin reduces sebum secretion, regulates follicular keratinization, and reduces surface and ductal colonies of Propionibacterium acnes.4 Although it is indicated for severe or recalcitrant acne, its use is limited neither to this form of the disease nor to acne alone.5 Isotretinoin is generally a well-tolerated medication; however, it has a broad side effect profile. Dyslipidemia and liver dysfunction are two important side effects of this drug,6 with other effects on the mucocutaneous, musculoskeletal, ophthalmic, and central nervous systems.7 Isotretinoin also has some neuropsychiatric side effects such as major depression, psychotic symptoms, and suicidal ideation.8

Some previous studies have reported an increase in plasma homocysteine level and a decrease in folic acid and/or vitamin B12 level after treatment with isotretinoin.9–17 Homocysteine is metabolized to methionine via remethylation, or to cysteine via vitamin B6-dependent transsulfuration in the liver (Figure 1). Most of the homocysteine is remethylated, regenerating methionine, due to the action of methionine synthase, an enzyme that depends on the presence of vitamin B12 and folic acid as cofactors.18 Several drugs and liver dysfunction may adversely affect the enzyme cystathionine-β-synthase, causing an increase in blood homocysteine levels.19 Vitamin B12 and folic acid are also required as cofactors for the enzyme methionine synthase , and deficiency of either of these results in hyperhomocysteinemia.20,21 Folate deficiency and/or hyperhomocysteinemia is known to increase the risk for vascular occlusive diseases,22 neurodegenerative diseases and dementia,23–25 and colorectal cancer.26 As already mentioned, several previous studies have reported hypermomocysteinemia and/or folic acid and vitamin B12

From the Department of Dermatology, Tehran University of Medical Sciences, Razi Hospital, Tehran, Iran Address for Correspondence: Maryam Ghiasi, MD, Razi Hospital, Vahdat Eslami Square, Tehran, Iran • E-mail: mghiasi@tums.ac.ir, ghiasi_ m117@yahoo.com

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Figure 1. Homocysteine metabolism.

deficiency after isotretinoin therapy, some suggesting that folic acid and vitamin B12 supplementation during isotretinoin treatment might be useful for preventing hyperhomocysteinemia. To date, however, no clinical trial has been undertaken to prove this. We conducted a randomized controlled clinical trial with the aim of demonstrating whether starting vitamin B12 and folic acid replacement therapies alongside isotretinoin treatment could prevent hyperhomocysteinemia. MATERIALS AND METHODS

Participants This randomized, controlled, parallel-group study, lasting 2 months, was carried out at the Department of Dermatology, Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran, between July 2015 and December 2015. The study protocol followed the guidelines of the Declaration of Helsinki and was approved by the Ethics Committee of Tehran University of Medical Sciences. Written consent forms were signed by all participants. Before setting up the study, we registered it in the SKINmed. 2018;16:239â&#x20AC;&#x201C;245

Iranian Registry of Clinical Trials, available at http://www.irct. ir/ Â(identifier: IRCT2014081018607N1). A total of 66 patients with moderate to severe acne who had indications for isotretinoin therapy were enrolled in the study. We excluded patients who were taking vitamin or mineral supplements or met any of the following conditions: chronic alcohol intake, vegetarian diet, previous therapy with an oral retinoid, a history of diseases known to affect vitamin B12 and/or folic acid metabolism (pernicious or megaloblastic anemia, malabsorption syndromes, gastric or ileal resection), and use of drugs affecting vitamin B12 and/or folic acid metabolism (phenytoin, cyclosporine, methotrexate, trimethoprim, barbiturates) in the previous 3 months. Women were excluded if they were pregnant or nursing, or were not using effective contraception. All patients were asked to maintain their regular diet.

Methods Participants were assigned to one of two groups (in a 1:1 ratio, giving a total 33 patients in each group) by blocked randomization,

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consisting of blocks of four patients. Group A were treated with isotretinoin (0.25 to 0.5 mg/kg per day depending on the severity of their acne, folic acid (Tab, 1 mg/kg per day), and vitamin B12 (Amp, 1 g, intramuscular injection on the first and 30th days of treatment). Group B were treated only with isotretinoin (0.25 to 0.5 mg/kg per day depending on the severity of their acne). The duration of treatment was 2 months for both groups. In all patients, isotretinoin was continued after the end of the trial if necessary. The primary outcome measure was a comparison of the change in homocysteine level in the study groups after 2 months, relative to baseline. The secondary outcome measures were comparisons of the changes in folic acid and vitamin B12 levels in two groups after 2 months relative to baseline. A fasting sample of venous blood was collected after a 12-hour fast at baseline and after 2 months of treatment. Plasma was separated and stored at −80°C until analysis. Biochemical parameters that were analyzed in all samples included homocysteine, folic acid, vitamin B12, hemoglobin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total cholesterol, triacylglycerols, low-density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol. Serum levels of vitamin B12 and folic acid were measured using the electrochemiluminescence method (ECL, Roche, Basel, Switzerland). Homocysteine levels were measured via enzyme immunoassay (Axis-Shield, Dundee, UK).

Statistical analysis We calculated that a sample size of 28 patients for each parallel group would have a power of 80% at α=0.05, assuming a standard deviation of 10 and a difference of 5.3 in homocysteine levels between the study arms. Because of the possibility of loss of participants, we added an extra five patients to each group. Results were presented as mean±standard deviation. Data were analyzed using SPSS software (version 20.0; SPSS, Chicago, IL). The Kolmogrov -Smirnov test was used to check the distribution of variables. After checking the types of distribution, data with homogenic variability were analyzed using the paired t test, and data with nonhomogenic variability were analyzed using the Wilcoxon signed rank test. A value of P<.05 was considered significant. RESULTS A total of 66 patients were enrolled (33 patients randomly assigned to each group). In group A two participants, and in group B four participants, did not, however, return for laboratory testing after 2 months of isotretinoin therapy. Therefore analyses were carried out on data from 60 patients (31 in group A, and 29 in group B). Of these, 31 (51.7%) were male, and 29 (48.3%) SKINmed. 2018;16:239–245

were female. The mean age was 23.1±9.5, with a range of 16 to 35 years. The groups were comparable in terms of demographics, dosage of isotretinoin, and baseline biochemistry profile (Table I). Table II provides a description of the changes in biochemistry profile after 2 months of treatment in the two groups. Plasma homocysteine levels were significantly decreased in group A, but not in group B, with a significant difference in homocysteine level between the two groups after treatment. In addition, folic acid levels were significantly increased in group A and decreased in group B after treatment. Vitamin B12 levels increased in group A, but showed no change in group B. After treatment, total cholesterol, triacylglycerol, low-density lipoprotein-cholesterol, levels were higher in both groups compared with the baseline values, but no differences were seen in levels of high-density lipoprotein-cholesterol, hemoglobin, and alkaline phosphatase after treatment. DISCUSSION We conducted this randomized controlled trial to assess the benefits of vitamin B12 and folic acid replacement during isotretinoin therapy in terms of the effect on homocysteine levels. The literature includes some studies that have evaluated the effect of isotretinoin on blood levels of homocysteine and/or folic acid and vitamin B12;9–17 the results of these studies are summarized in Table III. Although there are some discrepancies in these results, it can be concluded that homocysteine levels tend to increase, and folic acid and vitamin B12 levels tend to decrease, with isotretinoin therapy. Hyperhomocysteinemia can result from genetic disorders, dietary deficiencies, certain disease states, and drugs.20 One of the drugs that cause hyperhomocysteinemia as an adverse effect is isotretinoin.9,10,12–15 Folic acid and vitamin B12 deficiencies may also cause hyperhomocysteinemia.20,27 Homocysteine is metabolized in the liver and recycled into methionine by a transmethylation reaction requiring folic acid and vitamin B12. Therefore, hepatic dysfunction and/or deficiencies of these vitamins could cause decreased metabolism of homocysteine and hyperhomocysteinemia.28 Some of the studies evaluating changes in plasma homocysteine levels during isotretinoin therapy found that patients had elevated homocysteine levels but no decrease in levels of folic acid and vitamin B12.9,12–14 These studies concluded that the elevation of homocysteine levels despite normal concentrations of vitamins involved in its metabolism might result from an inhibitory action of isotretinoin on cystathionine-β-synthase, or liver dysfunction caused by isotretinoin. Another study showed that isotretinoin can cause elevations in homocysteine with a decrease in folic acid and vitamin B12 levels.10 Chanson et al described a decrease in

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Table I. Demographics and Baseline Biochemistry Profiles

Group A (n=31)

Group B (n=29)

P Value

23.7±8.1

22.6±9.7

0.44

16/15

15/14

0.75

Dose of isotretinoin (mean±SD) (mg/kg per day)

0.30±0.20

0.32±0.21

0.60

Hemoglobin (g/dL)

13.5±0.2

14.1±1.6

0.10

(U/L)

21.0±1.5

17.8±0.8

0.07

(U/L)

16.3±1.1

14.1±0.9

0.14

Alkaline phosphatase (U/L)

222.1±17.7

246.1±19.9

0.28

Cholesterol (mg/dL)

148.4±5.6

148.5±4.7

0.96

Triacylglycerol (mg/dL)

95.6±7.4

86.9±6.8

0.39

Low-density lipoprotein-cholesterol (mg/dL)

90.0±4.9

83.6±4.6

0.44

High-density lipoprotein-cholesterol (mg/dL)

45.8±1.6

47.1±2.0

0.58

Homocysteine (µmol/l)

13.7±1.3

14.2±2.0

0.74

Folic acid (ng/mL)

14.7±0.8

14.6±0.7

0.86

287.0±15.3

277.0±19.0

0.74

Age, years Male/female

Vitamin B12 (pg/mL) Abbreviation: SD, standard deviation.

Table II. Changes in Biochemistry Profile in Two Groups after 2 Months

Baseline

Posttreatment

P Values

Group A (A1)

Group B (B1)

Group A (A2)

Group B (B2)

A1 vs A2

Homocysteine (µmol/l)

13.7±1.3

14.2±2.0

10.0±0.8

16.5±2.1

0.0004*

0.38

0.0029*

Folic acid (ng/mL)

14.7±0.8

14.6±0.7

18.1±1.0

12.7±0.6

0.0026*

0.0219*

0.0008*

Vitamin B12 (pg/mL)

287.0±15.3

277.0±19.0

285.3±18.8

0.0002*

0.52

0.0229*

Hemoglobin (g/dL)

13.5±0.2

14.1±1.6

13.6±0.2

14.3±1.3

0.79

0.88

0.35

(U/L)

21.0±1.5

17.8±0.8

26.7±1.8

21.2±1.1

0.0098*

0.0189*

0.68

(U/L)

16.3±1.1

14.1±0.9

19.9±1.9

17.6±1.3

0.024*

0.0040*

0.44

Alkaline phosphatase (U/L)

222.1±17.7

246.1±19.9

235.1±18.9

247.8±17.3

0.52

0.83

0.31

Cholesterol (mg/dL)

148.4±5.6

148.5±4.7

166.7±6.6

169.5±5.9

0.0222*

0.0064*

0.48

Triacylglycerol (mg/dL)

95.6±7.4

86.9±6.8

119.8±12.0

106.5±7.2

0.0121*

0.0307*

0.52

Low-density lipoproteincholesterol (mg/dL)

90.0±4.9

83.6±4.6

103.3±5.4

102.7±5.2

0.0054*

0.0016*

0.32

High-density lipoproteincholesterol (mg/dL)

45.8±1.6

47.1±2.0

43.9±1.7

46.0±1.9

0.26

0.64

0.18

342±19.6

B1 vs B2

A2 vs B2

Values are expressed as mean±standard deviation (SD). * P value significant. SKINmed. 2018;16:239–245

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Table III. Results of Studies Evaluating the Effects of Isotretinoin Therapy on Homocysteine, Folic Acid, and Vitamin B12 Levels

Authors

Year of Publication

Dose of Isotretinoin (mg/kg/day)

Duration of Isotretinoin Therapy

Homocysteine Levels

Folic Acid Levels

Vitamin B12 Levels

Schulpis et al13

2001

0.5

45 days

Increase

No change

Chanson et al11

2008

0.5

28 days

No change

Decrease

Not evaluated

Polat et al12

2008

0.5

45 days

Increase

No change

Roodsari et al9

2010

0.5

2 months

Increase

No change

Karadag et al10

2011

0.5– 0.7

4 months

Increase

Decrease

Dursun et al15

2011

0.8

6 months

Increase

Not evaluated

Javanbakht et al16

2012

0.5

30 days

Not evaluated

Decreased

Not evaluated

Gokalp et al17

2014

0.6– 1

6 months

Not evaluated

Decreased

Kamal et al14

2015

0.5–1

45 days

Increased

No change

levels of folic acid with no change in the homocysteine levels,11 and our results are similar. Overall, on the basis of previous studies, we believe that isotretinoin can affect both pathways in the metabolism of homocysteine; it can affect the transsulfuration pathway via its inhibitory effect on cystathionine-β-synthase or by causing liver dysfunction, and it can influence the remethylation pathway via a decrease in the levels of folic acid and vitamin B12, which are necessary for the proper action of methionine synthase. The mechanisms leading to vitamin deficiency during isotretinoin therapy have, however, not yet been determined. The different effects of isotretinoin on the levels of homocysteine, folic acid, and vitamin B12 in different studies may be related to multiple factors, such as participants’ genetic polymorphisms and dietary status, and dose and duration of isotretinoin therapy. Hyperhomocysteinemia is a risk factor for coronary artery disease (CAD), and has been found to be associated with endothelial damage and oxidative stress.29–33 It is suggested that elevated blood homocysteine levels are as important as high blood cholesterol levels and can operate independently of these. On the other hand, elevated blood cholesterol and triacylglycerol levels are a well-known adverse effect of isotretinoin treatment, and are risk factors for CAD. Therefore, the combination of elevated lipids and hyperhomocysteinemia might be associated with an increased risk for premature occlusive vascular diseases in patients receiving isotretinoin.12 Low folate concentrations are also associated with risk for CAD, and this appears to be largely mediated through its SKINmed. 2018;16:239–245

effect on homocysteine concentration.34 One study has shown that lower serum folate levels without variations in homocysteine concentrations have notably been found in patients with acute coronary events or atherosclerotic vascular disease compared with healthy control subjects.22,35 Thus, folate deficiency without any increase in homocysteine levels due to isotretinoin therapy, as observed in our study, might be a risk factor for CAD. High homocysteine levels have also been found to be associated with a decrease in cognitive function and increase in dementia.24,25,36 Vitamin B12 and folic acid, with their interrelated metabolism, are important for the maintenance of various metabolic pathways. Deficiency may lead to adverse effects on the cardiovascular, neurologic, psychologic, hematologic, gastrointestinal, musculoskeletal, and immunologic systems.17 Neuropsychatric side effects of isotretinoin are very similar to those seen in vitamin B12 and folate deficiencies. These vitamin deficiencies lead to hyperhomocysteinemia, which is related to neuropsychiatric disorders and is considered an important risk factor for atherosclerotic vascular diseases. Vitamin B12 and folic acid deficiencies might therefore be the missing link between isotretinoin usage, hyperhomocysteinemia, and neuropsychiatric disorders.18 To our knowledge, this is the first study to investigate the effect of folic acid and vitamin B12 replacement therapies during isotretinoin treatment on plasma concentrations of homocysteine. We used both folic acid and vitamin B12 supplements in our study because a study of the effect on homocysteine of either folate or vitamin B12 alone found that the body adjusts its reliance on one

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or the other, and that supplementing with both provides a more certain way to improve homocysteine levels.32 According to our results, homocysteine levels increased, albeit not significantly, after 2 months, folic acid levels decreased significantly, and vitamin B12 levels showed no change in patients taking isotretinoin alone. It should be mentioned that the dosage of isotretinoin in our study was lower than in all previous studies.9–17 In patients taking isotretinoin, folic acid, and vitamin B12 simultaneously, homocysteine levels decreased significantly, although they were still in the normal range, and folic acid and vitamin B12 levels increased significantly, after 2 months of treatment. When posttreatment levels of homocysteine and folic acid were compared between the two groups, the homocysteine levels were lower, and folic acid levels higher, in patients taking isotretinoin with vitamin supplements.

ACKNOWLEDGMENT This study was funded and supported by Tehran University of Medical Sciences (TUMS), Grant no. 94-01-30-27258. REFERENCES

On the basis of these results, we believe that starting vitamin B12 and folic acid replacement alongside isotretinoin (even low-dose isotretinoin) could prevent folic acid deficiency and its related disorders. In addition, even if isotretinoin treatment does not lead to an elevation of homocysteine levels, folic acid and vitamin B12 supplementation could still be beneficial in terms of a reduction on vascular diseases. As it is clear that isotretinoin treatment increases the risk of vascular diseases through elevation of serum lipids, an improvement in homocysteine levels in patients at high risk for CAD could be useful in terms of a reduced risk for vascular diseases. This seems of greater importance when isotretinoin is used for long-term indications such as disorders of keratinization, prophylaxis of nonmelanoma skin cancers in transplant recipients, etc. Because there are some discrepancies in the results of previous studies evaluating the effects of isotretinoin on homocysteine, folic acid, and vitamin B12 levels, we believe that a limitation of our study is that, as it is just one clinical trial, the findings may not be generalizable to all populations; we therefore encourage further studies on patients from different racial groups, to support this new treatment approach. It is also not clear that whether this supplemental treatment will have an effect on the efficacy of isotretinoin; future studies could also address this issue.

1 Stathkis V, Kilkenny M, Marks R. Descriptive epidemiology of acne vulgaris in the community. Australas J Dermatol. 1997;38:115–123. 2 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. 3 Dalgard F, Gieler U, Holm JØ, Bjertness E, Hauser S. Selfesteem and body satisfaction among late adolescents with acne: Results from a population survey. J Am Acad Dermatol. 2008;59:746–751. 4 Strauss JS, Gottlieb AB, Jones T, et al. Concomitant administration of vitamin E does not change the side effects of isotretinoin as used in acne vulgaris: A randomized trial. J Am Acad Dermatol. 2000;43:777–784. 5 Ergun T, Seckin D, Ozaydin N et al. Isotretinoin has no negative effect on attention, executive function and mood. J Eur Acad Dermatol Venereol. 2012;26:431–439. 6 Amichai B, Grunwald MH. Isotretinoin in dermatology. J Dermatolog Treat. 2000;11:219–240. 7 Brelsford M, Beute TC. Preventing and managing the side effects of isotretinoin. Semin Cutan Med Surg. 2008;27:197–206. 8 Kellett SC, Gawkrodger DJ. A prospective study of the responsiveness of depression and suicidal ideation in acne patients to different phases of isotretinoin therapy. Eur J Dermatol. 2005;15:484–488. 9 Roodsari MR, Akbari MR, Sarrafi-rad N, et al. The effect of isotretinoin treatment on plasma homocysteine levels in acne vulgaris. Clin Exp Dermatol. 2010;35:624–626. 10 Karadag AS, Tutal E, Ertugrul DT, Akin KO. Effect of isotretinoin treatment on plasma holotranscobalamin, vitamin B12, folic acid, and homocysteine levels: non-controlled study. Int J Dermatol. 2011;50:1564–1569. 11 Chanson A, Cardinault N, Rock E, et al. Decreased plasma folate concentration in young and elderly healthy subjects after a short-term supplementation with isotretinoin. J Eur Acad Dermatol Venereol, 2008;22:94–100. 12 Polat M, Lenk N, Bingol S et al. Plasma homocysteine level is elevated in patients on isotretinoin therapy for cystic acne: A prospective controlled study. J Dermatolog Treat. 2008;19:229–232.

CONCLUSIONS

13 Schulpis KH, Karikas GA, Georgala S, et al. Elevated plasma homocysteine levels in patients on isotretinoin therapy for cystic acne. Int J Dermatol. 2001;40:33–36.

Our results here indicate that starting folic acid and vitamin B12 replacement therapies alongside isotretinoin treatment could be useful for preventing folate deficiency and improving blood homocysteine levels. This might as a result reduce the risks for cardiovascular and neuropsychiatric disorders, and other possibly related disorders, in patients taking isotretinoin.

15 Dursun R, Alpaslan M, Caliskan M, et al. Isotretinoin does not prolong QT intervals and QT dispersion in patients with severe acne: A surprising finding for a drug with numerous side effects. J Drugs Dermatol. 2011;10:710–714.

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14 Kamal M, Polat M. Effect of different doses of isotretinoin treatment on the levels of serum homocysteine, vitamin B12 and folic acid in patients with acne vulgaris: A prospective controlled study. J Pak Med Assoc. 2015;65:950–953.

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16 Javanbakht AM, Pour HM, Tarrahic MJ. Effects of oral isotretinoin on serum folic acid levels. J Drugs Dermatol. 2012;11:e23–e24. 17 Gokalp H, Bulur I, Gurer M. Decreased vitamin B12 and folic acid concentrations in acne patients after isotretinoin therapy: A controlled study. Indian J Dermatol. 2014;59:630. 18 Gil-Perieto R, Hernandez V, Cano B, Oya M, Gil A. Plasma homocysteine in adolescents depends on the interaction between methylenetetrahydrofolic acid reductase genotypes, lipids and folic acid: A seroepidemiological study. Nutr Metab. 2009;6:39.

27 Ubbink JB, Vermaak WJ, van der Merwe A, Becker PJ. Vitamin B12, vitamin B6, and folic acid nutritional status in men with hyperhomocysteinemia. Am J Clin Nutr. 1993;57:47–53. 28 Malinow MR, Kang SS, Taylor LM et al. Prevalence of hyperhomocysteinemia in patients with peripheral arterial occlusive disease. Circulation. 1989;79:1180–1188. 29 Perry IJ, Refsum H, Morris RW, et al. Prospective study of serum total homocysteine concentration and risk of stroke in middleaged British men. Lancet. 1995;346:1395–1398.

19 Schulpis KH, Georgala S, Papakonstantinou ED, Michas T, Karikas GA. The effect of isotretinoin on biotinidase activity. Skin Pharmacol Appl Skin Physiol. 1999;12:28–33.

30 Kartal Durmazlar SP, Akgul A, Eskioglu F. Homocysteine may involve in the pathogenesis of Behcet’s disease by inducing inflammation. Mediators Inflamm. 2008;2008:407972.

20 Schwartzfarb EM, Romanelli P. Hyperhomocysteinemia and lower extremity wounds. Int J Low Extrem Wounds. 2008;7:126–136.

31 Pancharuniti N, Lewis CA, Sauberlich HE et al. Plasma homocysteine, folate and vitamin B12 concentration and risk of early-onset coronary artery disease. Am J Clin Nutr. 1994;59:940–948.

21 Guttormsen AB, Schneede J, Ueland PM, Refsum H. Kinetics of total plasma homocysteine in subjects with hyperhomocysteinemia due to folate or cobalamin deficiency. Am J Clin Nutr. 1996;63:194–202. 22 Voutilainen S, Lakka TA, Porkkala-Sarataho E, et al. Low serum folate concentrations are associated with an excess incidence of acute coronary events: The Kuopio Ischemic Heart Disease Risk Factor Study. Eur J Clin Nutr. 2000;54:424–428. 23 Ho PI, Ashline D, Dhitavat S, et al. Folate deprivation induces neurodegeneration: Roles of oxidative stress and increased homocysteine. Neurobiol Dis. 2003;14:32–42. 24 Breteler MM, Claus JJ, Grobbee DE, Hofman A. Cardiovascular disease and distribution of cognitive function in elderly people: The Rotterdam study. BMJ 1994;308:1604–1608. 25 Hofman A, Ott A, Breteler MM et al. Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer’s disease in the Rotterdam study. Lancet. 1997;349:151–154. 26 Duthie SJ, Narayanan S, Sharp L, et al. Folate, DNA stability and colo-rectal neoplasia. Proc Nutr Soc. 2004;63:571–578.

32 Quinlivan EP, McPartlin J, McNulty H et al. Importance of both folic acid and vitamin B12 in reduction of risk of vascular disease. Lancet. 2002;359:227–228. 33 Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM. Effect of homocysteine-lowering therapy with folic acid, vitamin B12, and vitamin B6 on clinical outcome after percutaneous coronary intervention: The Swiss Heart study: A randomized controlled trial. J Am Med Assoc. 2002;288:973–979. 34 Phillips DM. Interrelated risk factors for venous thromboembolism. Circulation. 1997;95:1749–1751. 35 Bunout D, Petermann M, Hirsch S et al. Low serum folate but normal homocysteine levels in patients with atherosclerotic vascular disease and matched healthy controls. Nutrition. 2000;16:434–438. 36 Guzelcan Y, van Loon P. Vitamin B12 status in patients of Turkish and Dutch descent with depression: a comparative cross-sectional study. Ann Gen Psychiatry. 2009;8:18.

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A Case-Control Study in Primary Care Settings on the Roles of Dermatoscopy in Infectious Diseases Affecting the Skin, Part 1: Viral and Bacterial Infections Antonio Chuh, MD, FRCP;1,2 Vijay Zawar, MD, FRCPE;3 Catriona Ooi, FAChSHM, MM (HIV/STDs);4,5 Albert Lee, MD, FRCP6 ABSTRACT We aimed to investigate roles of dermatoscopy in skin infections, with Part 1 of our report covering viral and bacterial infections. A casecontrol study was conducted on the medical records of all patients with skin infections who had had dermatoscopy performed over a period of 3 months. Our control participants were all patients with skin infections in two 3-month periods, and sex-pair–matched patients with the same infections, who had not undergone dermatoscopy. Records of 523 study subjects were analyzed. Our first new finding was that dermatoscopy brought forward the diagnosis of herpes zoster by 1.62 days (95% confidence interval [CI] 0.29 to 0.34 days; z-score −2.18). Second, dermatoscopy facilitated the diagnosis of genital (P<.01) and small extragenital risk ratio [RR] 1.28, 95% CI 1.03 to 1.59) viral warts. Third, patients with genital herpes and/or genital warts and/or genital molluscum contagiosum diagnosed by clinical examination and dermatoscopy were significantly more willing to pay US$300 to investigate for other sexually transmitted infections (STIs) (RR 2.52, 95% CI 1.32 to 3.18), and bring partners for investigation (RR 1.32, 95% CI 1.12 to 1.55), compared to patients diagnosed by clinical examination alone. We performed dermatoscope-guided laser ablation on viral warts, and dermatoscopy-guided excisional biopsy to confirm molluscum contagiosum. We conclude that dermatoscopy contributes to the diagnosis of some viral and bacterial infections. In addition, it may modify the help-seeking behaviour of patients with STIs. (SKINmed. 2018;16:247–254)

he usual role of dermatoscopy is to detect of cutaneous malignancies or premalignant skin lesions. As dermatoscopes become increasingly available, further applications in other skin conditions could be explored, to benefit patient managements and maximize cost-effectiveness. The aim of this study was to explore the role of dermatoscopy in infections with cutaneous manifestations. In this Part of the report, we cover viral and bacterial infections. Our findings for mycological infections and ectoparasitic infestations will be covered in Part 2. MATERIALS AND METHODS A case-control study was conducted based in two outpatient surgeries affiliated to a university teaching hospital. The services in

the surgeries were provided by one physician with training and qualifications in dermatology. From January 1, 2017, all patients consulting for skin diseases related to infections underwent dermatoscopy. Informed consent was obtained from all patients, or from the parents of children below the age of 18 years. We did not have an intention for academic endeavours then. A database search was subsequently conducted to identify all patients with infectious diseases affecting the skin who had had dermatoscopy performed over a 3-month period (January 1, 2017 to March 31, 2017, 90 days). Patients with eruptions caused by drugs used to treat infections and eruptions related to vaccinations were excluded. The remaining patients comprised our study subjects.

From the Department of Family Medicine and Primary Care, The University of Hong Kong;1 Hong Kong Society of Primary Care Dermoscopy;2 Department of Dermatology, Dr Vasantrao Pawar Medical college, Nashik, India;3 Western Sydney Sexual Health Centre, Western Sydney Local Health District, Parramatta, New South Wales, Australia;4 Centre for Infectious Diseases and Microbiology, Westmead Clinical School, University of Sydney, New South Wales, Australia;5 and JC School of Public Health and Primary Care, The Chinese University of Hong Kong, Shatin, Hong Kong6 Address for Correspondence: Antonio Chuh, MD, Shops 5 and 6, The Imperial Terrace, 356 Queen’s Road West, G/F, Hong Kong • E-mail: antonio.chuh@yahoo.com.hk

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Two retrospective control groups were established (Table S1; supplemental materials for this contribution can be accessed at: https://www.dropbox.com/s/5z7dlxe6xar33kx/ Supplemental%20Material_SKINmed_SM10320a.pdf?dl=0). Dermatoscopy had not been performed in either of these groups. The first group (C1) comprised all patients diagnosed as having skin diseases in either one of the two periods (January 1, 2015 to March 31, 2015, and January 1, 2016 to March 31, 2016, a total of 181 days). The same months were chosen to eliminate confounding variables such as changes in weather. The C1 group was set up to compare the incidence of diseases in similar periods annually; the two subgroups were termed C1/2015 and C1/2016. For the second control group (C2), we studied the records of the most recent sex-pair–matched patients who had received the same diagnoses before December 31, 2016. The C2 group was used to compare clinical features, dermatoscopic findings, and other parameters to those in the study group.

Table I. Number of Patients Diagnosed as Having Infectious Diseases Affecting the Skin in Whom Dermatoscopy Was Performed over a 3-Month Period

We employed the Poisson means test to analyse the frequencies of events in the two time intervals, and the Wilcoxon signed rank test to investigate paired variables. A paired Student t test was used to measure the most likely magnitudes of the differences. For distribution analyses, we adopted the Fisher exact probability test.

Molluscum contagiosum

Infectious Diseases Affecting the Skin

Number of Patientsa

Viral infections Herpes simplex virus 1 and 2 • Genital

• Extragenital

Varicella-zoster virus • Chickenpox

• Herpes zoster

Human papillomavirus • Genital

• Extragenital

• Genital

• Extragenital

Viral exanthems (all types, excluding chickenpox)

Paraviral exanthems (all types)

RESULTS

Viral hepatitis

The clinical records of 523 study subjects were retrieved (Table I).

HIV

Other viral infections

Viral infections

Bacterial infections

Herpes simplex virus 1 and 2

Impetigo

Clinical diagnoses of herpes simplex virus (HSV)-1 and HSV-2 infections were made in 43 study subjects; 33 had genital HSV infections, and 12 had extragenital HSV infections (two patients having both). This total incidence (43 patients in 90 days) was not significantly different from that for the C1 group (38 patients in 90 days for C1/2015, Poisson means test P=.66; 42 patients in 91 days for C1/2016, P=.96; and 80 patients in 181 days for C1/2015 and C1/2016 combined, P=.74). Subgroup analyses for genital and extragenital herpes also showed there were no significant differences.

Folliculitis, furuncles, carbuncles

Panniculitis, erythema nodosum, cellulitis

The study participants with genital herpes were significantly more likely than those in the C2 control to be willing to pay around US$300 to investigate for other sexually transmitted infections (STIs) (Fisher exact probability test, risk ratio [RR] 1.90, 95% confidence interval [CI] 1.05 to 3.44; P<.05). As a reference, the cost of a single medical consultation with a specialist was around US$100 in Hong Kong. Study subjects were also significantly more likely to attend follow-up (RR 2.86, 95% CI 1.40 to 5.83,

Dermatophytes—not affecting the nails

Fingernail and/or toenail onychomycosis

132

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Pitted keratolysis

Erysipelas

Balanitis and balanoposthitis

Helicobacter pylori (chronic urticaria)

Other bacterial infections

Fungal and yeast infections

Pityriasis versicolor

Candida spp.

Ectoparasitic infestations and protozoa (all types)

This column totals more than 523, as one patient might have multiple infections. a

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P<.01), bring sexual partners to see us (RR 1.29, 95% CI 1.03 to 1.62, P<.05), and follow all three pieces of advice (RR 1.28, 95% CI 1.05 to 1.57, P<.05).

Varicella zoster virus We found no role for dermatoscopy in diagnosing chickenpox or making an earlier diagnosis. For herpes zoster, there was no significant difference between study patients and controls in terms of incidence. Thirteen study patients (mean age 44.9 years, standard deviation 21.3 years; seven male and six female participants) had herpes zoster, which was not significantly different from the figure for group C1 (19 patients for C1/2015, P=.38; 23 patients for C1/ 2016, P=.14). The ages of the study patients also showed no significant difference from those in the C2 group (Wilcoxon signed rank test: z-score −0.73, P=.46). The Wilcoxon signed rank test delivered a z-score of −2.18 and a P value of .03 for the day of diagnosis (Table S2). Dermatoscopy allowed the diagnosis to be made 1.62 days earlier (95% CI 0.29 to 0.34 days, P<.05). In group C2, three participants (23%) were diagnosed within 72 hours, whereas nine (69%) who underwent clinical and dermatoscopic examinations were diagnosed within 72 hours (RR 3.57, 95% CI 1.23 to 10.4; Fisher exact probability test, P<.01). Figure S1a, of patient 4, described in Table S2, depicts around 10 discrete lesions in the middle of the forehead. We were able to visualize vesicles using dermatoscopy (Figures S1B and S1C), and started the patient on antiviral therapy. Bona fide vesicles were visible 2 days later. Figure S2a, of patient 1, features four discrete erosionlike lesions anterior to the right pinna. Clinical examination revealed no vesicles, but dermatoscopy revealed four (Figure S2B), allowing us to prescribe antiviral therapy immediately.

Genital human papillomavirus Genital human papillomavirus (HPV) infection was diagnosed in 32 study subjects in 90 days. This was significantly higher than for the C1/2015 (17 patients in 90 days, P<.05) and C1/2016 (13 patients in 91 days, P<.01) groups, and the two groups combined (30 patients in 181 days, P<.01). Figure S3 shows multiple epidermal cysts on the scrotal skin, and Figure 1 demonstrates the corresponding dermatoscopic views (upper panel, no cross-polarization; lower panel, with cross-polarization). When we inspected the lower panel of Figure 1 meticulously, we were able to identify a tiny viral wart (arrowed). This lesion consisted of compartments, each of which was perfused by a tiny vessel in the center. Excisional biopsy confirmed the SKINmed. 2018;16:247–254

Figure 1. Dermatoscopic image of scrotal skin demonstrating epidermoid cysts. Meticulous examination revealed a viral wart (red arrow). Upper panel, no use of polarized light; lower panel, with polarized light.

diagnosis of a viral wart. This illustrates the power of dermatoscopy in detecting small lesions. The 32 study subjects were also more willing to be investigated for other STIs (RR 2.29, 95% CI 1.09 to 4.79, P=.04), to attend follow-up (RR 3.00, 95% CI 1.24 to 7.27, P=.01), and to bring sexual partners to attend (RR 1.29, 95% CI 1.05 to 1.59, P<.05), than were the patients diagnosed by clinical examination alone (C2 group).

Extragenital HPV Extragenital HPV infection was found in 34 study subjects. This figure was significantly higher than for the C1 groups (18 patients in C1/2015, P<.05; nine patients in C1/2016, P<.001). Clinical examination and dermatoscopy diagnosed significantly more small extragenital warts (<3 mm for the largest diameter) than in patients diagnosed by clinical examination alone (C2 group) (RR 1.28, 95% CI 1.03 to 1.59, P=.04).

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Figure 2 depicts a palmar lesion. Its maximum diameter was 2.2 mm. Dermatoscopy revealed dots representing blood vessels, surrounded by light-coloured halos, which was virtually pathognomonic of extragenital HPV infection. Figure S4 demonstrates a lesion on the cheek with a greatest diameter of 1.4 mm. Under dermatoscopy, we again noted a configuration of a halo circumscribing red dots, and diagnosed a viral wart. One patient was a professional cellist with a viral wart on the ulnar aspect of the distal phalanx of the left index finger, which was affecting his vibrato. We counselled him on the pros and cons of treatment modalities, and warned him regarding the Koebner phenomenon, recurrence, and other complications. As high precision was necessary, we performed dermatoscope-guided ablation with carbon dioxide laser; dermatoscope-guided surgical procedures are another role of dermatoscopy in patients with skin infections.

Molluscum contagiosum Molluscum contagiosum was diagnosed in 17 study subjects. This incidence was not significantly different from that seen in group C1 (15 patients for C1/2015, P=.86; eight patients for C1/2016, P=.10). Qualitatively, we found that dermatoscopy might be helpful for patients with small lesions, like the one shown in Figure S5, which had a diameter of only 2.5 mm. One patient had a single lesion on the shaft of the penis, and requested us to minimize the size of the wound. We performed dermatoscope-guided excisional biopsy, having warned him about the risk of recurrence. If we combine the 71 study subjects who had genital herpes and/ or genital HPV infection and/or genital molluscum contagiosum (some patients having multiple infections), our study group still returned significantly higher results than those in group C2 for the following: willingness to investigate for other STIs (RR 2.52, 95% CI 1.32 to 3.18, P<.01); attendance for follow-up (RR 2.79, 95% CI 1.67 to 4.66, P<.001); bringing sexual partners for investigation (RR 1.32, 95% CI 1.12 to 1.55, P<.001); and all three pieces of advice (RR 1.27, 95% CI 1.08 to 1.50, P<.01) (Table II).

Viral exanthems When producing Table I, we categorized chickenpox under varicella zoster virus rather than viral exanthems. Of the 69 patients with viral exanthems (all types) as defined in this table, most were children with erythema infectiosum (38 infants and children) and roseola (24 infants and children). We detected no significant change in the incidence of these eruptions compared to the C1 group, and no clinical differences compared to C2. Figure S6a depicts the palm of a young child with a febrile illness. It was difficult to identify erythematous macules or papules using the naked eye. On applying crosspolarization, however, six or seven macules became vividly recognizable (Figure S6b). This child subsequently developed hand, foot, and mouth disease. Isolation procedures were put in place. Thus, making an early diagnosis of viral exanthems to enable prompt isolation might be another potential role of dermatoscopy.

Paraviral exanthems

Figure 2. Dermatoscopy of a palmar lesion revealing dots representing arterioles with light-coloured halos in multiple compartments, a configuration virtually pathognomonic of viral warts. Upper panel, no use of polarized light; lower panel, with polarized light. SKINmed. 2018;16:247â&#x20AC;&#x201C;254

As paraviral exanthems are skin eruptions most likely to be caused by viral infections, we included 12 study patients with these. Eight (67%) patients had pityriasis rosea, three (25%) children had Gianotti-Crosti syndrome (also known as papular acrodermatitis of childhood), and one (8%) patient had an asymmetrical periflexural exanthem. We discovered no significant difference in the incidence and no new dermatoscopic features.

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Table II. Relative Compliance of Patients with Genital Herpes and/or Genital Human Papillomavirus Infection and/or Genital Molluscum Contagiosum in Study Subjects and Control Group C2 Means of Diagnosing Genital Herpes, Genital Human Papillomavirus Infection, or Genital Molluscum Contagiosum

Willing to Investigate for Other Sexually Transmissible Infectionsa

Attended Follow-Up

Brought Sexual Partners to Attend

Followed All Three Pieces of Advice

Clinical examination (control group C2)

32 (45%)

5 (7%)

6 (8%)

Clinical examination and dermoscopy (study subjects)

52 (73%)

57 (80%)

21(30%)

20 (28%)

RR 2.52, 95% CI 1.32–3.18, P<.01

RR 2.79, 95% CI 1.67–4.66, P<.001

RR 1.32, 95% CI 1.12–1.55, P<.001

RR 1.27, 95% CI 1.08–1.50, P<.01

Difference and significance

Data showing the proportion of 71 patients with genital herpes and/or genital human papillomavirus infection and/or genital molluscum contagiosum. All P values were two-tailed. Abbreviations: CI, confidence interval; RR, risk ratio. a Patients were responsible for laboratory costs of around US$300.

Bacterial infections Apart from pitted keratolysis, we noted no significant change in the incidence of skin diseases caused by bacterial infections when comparing the study group with the C1 group.

Impetigo, folliculitis, furuncle, and carbuncle Common folliculitis appeared as a solitary lesion under dermatoscopy (Figure S7). In study subjects with eosinophilic folliculitis, rich proliferations of perilesional as well as interlesional capillary networks were seen. Figure 3 depicts the dermatoscopic image of eosinophilic folliculitis in an HIV-positive study subject. Otherwise, we found little role for dermatoscopy in these bacterial infections.

Panniculitis, erythema nodosum, and cellulitis Three study subjects had erythema nodosum, and 18 cellulitis. We believe that dermatoscopy could replace lesional histopathology for some patients with erythema nodosum, and are currently investigating this.

Pitted keratolysis Eight study subjects had pitted keratolysis (most commonly caused by Corynebacterium spp.). Dermatoscopy (Figure 4) showed the highly characteristic appearance of two layers at the same site, with sheets of monomorphic pits and pit walls arranged one layer above another. SKINmed. 2018;16:247–254

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Figure 3. Multiple lesions with perilesional and interlesional vascular proliferations in eosinophilic folliculitis in an HIV-positive patient, as demonstrated by dermatoscopy. Upper panel, no use of polarized light; lower panel, with polarized light. A Case-Control Study in Primary Care Settings

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CORE CURRICULUM The role of dermatoscopy for the early diagnosis of herpes zoster has also previously been reported.2 This is in agreement with our findings. Herpes zoster is significantly less infectious than chickenpox, as acquired immunity has been developed by clonal expansion of T lymphocytes.3 We therefore advocate using dermatoscopy in patients with suspected herpes zoster, provided that anticontamination measures are strictly followed. The incidence of genital HPV infection in the study subjects was significantly higher than in the control group, the difference being 4.72 patients. We reviewed the dermatoscopic images and found that five study subjects had small (<3 mm) genital warts. It is likely that the increase in incidence of patients occurred because dermatoscopy was able to detect small lesions in these patients. We have reported using dermatoscopy for the early detection of genital HPV infection,4 and this has been supported by other reports.5,6 The significant rise (RR 4.72, 95% CI 1.28 to 9.24) in the incidence of genital HPV infection is likely to be related to the detection of small lesions by dermatoscopy. We previously reported the use of dermatoscopy in differentiating genital warts from pearly penile papules,4 and this has been substantiated by other investigators;7 however, we did not perform quantitative analyses here owing to the small number of patients. Dermatoscopy has been reported to assist in diagnosing extragenital HPV infections.8,9 We too found that dermatoscopy has a definite role to play here, particularly for small lesions.

Figure 4. Dermatoscopic view of two distinct layers at the same lesional site in pitted onychomycosis on the sole (upper panel, no use of polarized light; lower panel, with polarized light). These sheets, each with multiple monomorphic holes neatly arranged one layer above another, can only be demonstrated by dermatoscopy.

Dermatoscopy has been reported to enhance the diagnosis of molluscum contagiosum.10 We echo these findings, particularly for patients with small lesions. Of the 17 study subjects with molluscum contagiosum, six (35%) had genital lesions.

Erysipelas Six patients in our series had erysipelas. We failed to detect any dermatoscopic appearance that could lead to earlier diagnosis or increase diagnostic certainty. DISCUSSION

Viral infections In chickenpox, it has been reported that dermatoscopy allows for early diagnosis and treatment.1 Qualitatively, we found an insignificant difference in clinical and dermatoscopic features between the study subjects, group C2/2015, and group C2/2016 in terms of the symptoms, number and size of lesions, and complications. Chickenpox is highly infectious. We recommend against using dermatoscopy in patients with or suspected to be suffering from chickenpox. SKINmed. 2018;16:247–254

We found that dermatoscopic examination modified the helpseeking behaviour of patients with the three viral STIs covered in this study. We noted no change in the appointment system, consultation fees, fees for laboratory investigations, and other potentially confounding factors during the periods when the study subjects and control subjects consulted us. The only significant change in this respect is the visibility of the lesions to the patients concerned. Whereas the control subjects had their lesions examined conventionally, the study subjects were able to see magnified and crosspolarized images on the monitors of our dermatoscopic units if they chose to do so. The impact of this could be greater, leading to a higher motivation to change their help-seeking behaviour. This is analogous to the model known as ‘KAP’—Knowledge, Attitude, Practice. We give this only as a suggestion, however, as we do not yet have any substantiation for this. The result, however, is encouraging. Co-infection with genital herpes has been shown to increase the risk of transmission and

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acquisition of HIV infection. Infection with one STI is furthermore associated with higher risk sexual practice, increasing the need for screening for other STIs.11 Superior patient engagement, demonstrated by improved follow-up attendance rates in study subjects with viral STIs, allows for more holistic patient care and management; this can include review, education, harm minimization, contact tracing where required, and further examination and testing.11 Dermatoscopy might increase such patient engagement. With regard to paraviral exanthems, we have reported the efficacy of dermatoscopy in diagnosing pityriasis rosea.12 Recently, dermatoscopy has also been applied in eruptive pseudoangiomatosis.13 Our findings were negative for any role of dermatoscopy in increasing the diagnoses of HSV-1 and HSV-2, chickenpox, molluscum contagiosum, other viral exanthems, and paraviral exanthems. One possibility is that, with HSV-1 and HSV-2 infections and molluscum contagiosum, the lesions are highly characteristic—vesicles in HSV infections, and hemispherical lesions (some with central umbilication) in molluscum contagiosum—and readily recognizable without image enhancement. For the viral exanthems, the course of the disease in terms of contact history, incubation period, coryzal symptoms, fever, and sequential eruptions of crops of lesions provides crucial diagnostic clues. Dermatoscopy adds virtually nothing to diagnosis from the time course of these eruptions.

CONCLUSIONS The major role of dermatoscopy is in substantiating or excluding infectious disease diagnoses. Dermatoscopy facilitated an earlier diagnosis of herpes zoster by 1.62 days, and facilitated the diagnoses of genital and small extragenital warts. Dermatoscopy might also contribute to excluding important differential diagnoses of skin infections, and might also enhance compliance and facilitate contact-tracing in patients with genital infections. Dermatoscopy did not assist in the diagnoses of HSV-1 and HSV-2 infections, chickenpox, molluscum contagiosum, viral exanthems, paraviral exanthems, and bacterial infections apart from pitted keratolysis. Finally, the advantages and risks of dermatoscope-guided surgical procedures need to be further explored. REFERENCES

The paraviral exanthems are relatively uncommon or rare. For most, the distribution is more important than this lesional morphology, and this might explain our negative findings.

Bacterial infections Dermatoscopy has been reported to be of use in diagnosing various variants of folliculitis.14 We found that the differentiation of staphylococcal folliculitis and eosinophilic folliculitis might be facilitated by dermatoscopy, and have also reported the role of dermatoscopy in patients with pseudofolliculitis barbae.15 Dermatoscopy has not been reported to be useful in patients with erythema nodosum and other types of panniculitis, which is compatible with our findings. Dermatoscopy may assist in diagnosing dissecting cellulitis of the scalp,16 but none of our study subjects had this dermatosis. The dermatoscopic appearance of pitted keratolysis has been reported as heterogenous architecture of pit walls.17 Dermatoscopy revealed such distinct feature in eight study subjects. Dermatoscopy might also exclude some differential diagnoses of bacterial skin infections, such as epidermoid cysts18 (Figure S8) and mucous cysts19 (Figure S9). SKINmed. 2018;16:247–254

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1 Abraham LS, Costa MC, Agozzino M, et al. In vivo reflectance confocal microscopy for varicella prompt diagnosis and treatment in a severely immunosuppressed patient. Skin Res Technol. 2012;18:386–388. 2 Lacarrubba F, Verzì AE, Musumeci ML, et al. Early diagnosis of herpes zoster by handheld reflectance confocal microscopy. J Am Acad Dermatol. 2015;73:e201–e203. 3 Bader MS. Herpes zoster: Diagnostic, therapeutic, and preventive approaches. Postgrad Med. 2013;125:78–91. 4 Chuh AAT, Wong WCW, Lee A. Ten common myths in sexually transmitted diseases. Aust Fam Physician. 2006;35:127–129. 5 Paštar Z, Lipozenčić J. Significance of dermatoscopy in genital dermatoses. Clin Dermatol. 2014;32:315–318. 6 Veasey JV, Framil VM, Nadal SR, et al. Genital warts: Comparing clinical findings to dermatoscopic aspects, in vivo reflectance confocal features and histopathologic exam. A. Bras Dermatol. 2014;89:137–140. 7 Watanabe T, Yoshida Y, Yamamoto O. Differential diagnosis of pearly penile papules and penile condyloma acuminatum by dermoscopy. Eur J Dermatol. 2010;20:414–415. 8 Veasey JV, Framil VM, Nadal SR, et al. Genital warts: Comparing clinical findings to dermatoscopic aspects, in vivo reflectance confocal features and histopathologic exam. An Bras Dermatol. 2014;89:137–140. 9 Blumetti TP, Scope A, de Macedo MP, et al. Dermoscopic and reflectance confocal microscopy findings in extra-genital HPV16-associated pigmented squamous cell carcinoma in situ. Acta Derm Venereol. 2016;96:836–837. 10 Ianhez M, Cestari Sda C, Enokihara MY, et al. Dermoscopic patterns of molluscum contagiosum: A study of 211 lesions confirmed by histopathology. An Bras Dermatol. 2011;86:74–79. 11 Ooi C, Lewis D. Updating the management of sexually transmitted infections. Aust Prescr. 2015;38:204–208. 12 Chuh A, Fölster-Holst, Zawar V. Double overlapping herald patches in a young child with papular pityriasis rosea – A rare variant of this paraviral exanthem. Eur J Pediatr Dermatol. 2017;2:71–74.

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13 Wambier CG, Cappel MA, Danilau Ostroski TK, et al. Familial outbreak of eruptive pseudoangiomatosis with dermoscopic and histopathologic correlation. Dermatology 2017;76:S12–S15. 14 Errichetti E, Stinco G. Dermoscopy: A useful tool for assisting the diagnosis of Pseudomonas folliculitis. An Bras Dermatol. 2016;91:835–836. 15 Chuh A, Zawar V. Epiluminescence dermatoscopy enhanced patient compliance and achieved treatment success in pseudofolliculitis barbae. Australas J Dermatol. 2006;47:60–62. 16 Segurado-Miravalles G, Camacho-Martınez F, Arias-Santiago S, et al. Trichoscopy of dissecting cellulitis of the scalp: Exclamation

mark hairs and white dots as markers of disease chronicity. J Am Acad Dermatol. 2016;75:1267–1268. 17 Lockwood LL, Gehrke S, Navarini AA. Dermoscopy of pitted keratolysis. Case Rep Dermatol. 2010;2:146–148. 18 Mun JH, Park SM, Kim TW, et al. Importance of keen observation for the diagnosis of epidermal cysts: Dermoscopy can be a useful adjuvant tool. J Am Acad Dermatol. 2014;71:e138–3e140. 19 Chae JB, Ohn J, Mun JH. Dermoscopic features of digital mucous cysts: A study of 23 cases. J Dermatol. 2017; 44:1309–1312.

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Volume 16 • Issue 4

PERILS OF DERMATOPATHOLOGY W. Clark Lambert, MD, PhD, Section Editor

Tinea (Pityriasis) Obscurans: Don’t Ignore the Spore! Hee J. Kim, BS;1 Parmvir Singh, BS;1 Ann M. John, BA;1 Thomas Jasterzbski;1 W. Clark Lambert, MD, PhD;2,3 Muriel W. Lambert, PhD;2,3 Claude E. Gagna, PhD4 “It ain’t over ’til it’s over”—Yogi Berra

he term tinea is used for dermatophytoses or dermatophyte infections of keratinized structures such as the stratum corneum, nails, and hair follicles. Most conditions described using the term tinea are fungal infections caused by dermatophytes, except for tinea nigra and tinea versicolor. The global prevalence of dermatophytoses has been reported to be as great as 20%.1 Dermatophytes produce keratinases that digest keratin and create a favorable environment for the fungal organism to survive.2 Major types of epidermal dermatophytoses based on the anatomic sites of infection include tinea pedis, tinea manuum, tinea cruris, tinea corporis, and tinea facialis. Dermatophytosis of the nail is known as tinea unguium. Dermatophytoses of the hair follicle include tinea capitis, tinea barbae, dermatophytic folliculitis, and Majocchi granuloma.2,3 Under microscopy, dermatophytes are recognized as spherical spores or as septated hyphae.3,4 When the tinea infection is resolving, organisms are not as visible on microscopy and are often easily missed, producing a false-negative reading, and causing delay in diagnosis and treatment. EPIDERMAL DERMATOPHYTOSES: TINEA Variations involving the term tinea are based on the anatomic site of dermatophytic infection. Tinea pedis is an epidermal dermatophytosis of the feet, whereas tinea manuum involves the hands. Tinea cruris is a dermatophytic infection of the inguinal and pubic regions, as well as the adjacent areas of the upper aspect of the thigh. Tinea corporis involves the rest of the body: trunk, legs, arms, and neck. Tinea facialis involves the glabrous skin of the face.2 Lesions begin as erythematous, scaling, sharply marginated plaques that develop central clearing and an enlarging peripheral border.4

Tinea incognito describes a dermatophytic infection with atypical manifestations, caused by topical immunosuppressive agents, most commonly a topical glucocorticoid.2,5 Immune suppression caused by topical agents disguises characteristic features of the tinea infection, leading to various clinical presentations. Involved anatomic sites may show epidermal atrophy, folliculitis, or amplified violaceous lesions. When dermatophytoses are mistaken for other differential diagnoses, such as psoriasis and atopic dermatitis, tinea incognito frequently ensues.2 TINEA VERSICOLOR Tinea versicolor is not caused by dermatophytes. It is an infection by the yeast of the Malassezia species. Lipophilic yeasts of the Malassezia genus are found as normal cutaneous flora in 90% to 100% of the population, residing within the stratum corneum and hair follicles, where there is a high concentration of free fatty acids and triglycerides.2,6 Conversion to its mycelial form and superficial overgrowth leading to infection occur under certain endogenous and exogenous conditions.3,4 Lesions are described as chronic, well-demarcated, irregularly shaped macules or patches, covering large areas of the body, with skip regions of normal skin in between. Macules and patches vary in color and may be pale yellow, dark brown, pink, or red. They may appear hypopigmented or hyperpigmented.2–4 Although tinea versicolor has a high response rate to treatment, it also has a high recurrence rate of up to 60% in the first year, and 80% in the second year.4,7 The high recurrence rate may be attributable to persistent exposure to favorable factors and residual organisms deep in the hair follicles.3 Microscopy reveals a mixture of curved hyphae and budding cells in a pattern of “spaghetti and meatballs.”3,4

From the Rutgers – New Jersey Medical School;1 and the Department of Pathology and Laboratory Medicine;2 and Department of Dermatology;3 Rutgers – New Jersey Medical School, Newark, NJ;4 Department of Biological Sciences, New York Institute of Technology, Old Westbury, New York Address for Correspondence: W. Clark Lambert, MD, PhD, Room C520, Medical Science Building, Rutgers – New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103 • E-mail: lamberwc@njms.rutgers.edu

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TINEA (PITYRIASIS) OBSCURANS In a tinea or yeast infection that is resolving, organisms are very difficult to identify on microscopy. Instead of the typical tubular structure of hyphae, just a few tiny oval or spherical spores are seen within the stratum corneum, making diagnosis difficult. Such cases are seen with resolving tinea corporis and tinea versicolor infections (Figures 1 and 2). These residual spores become

progressively smaller and more “obscure,” and hence are easily missed. We have used the term “obscurans” (Latin ablative case) instead of “obscurus” (Latin demonstrative case), because the lesions become progressively more difficult to diagnose microscopically with time. Undiagnosed and untreated tinea infection can recur, especially if the lesion, after misdiagnosis, is treated with a corticosteroid, at which point, or after which, lesions may exacerbate clinically and organisms become more visible on microscopy. We describe here two cases of patients who initially presented with limited clinical manifestations of tinea or yeast infection and negative microscopy readings. When corticosteroid use was stopped, the lesions flared, unmasking the underlying tinea or yeast infection that had been suppressed by corticosteroids, and the organisms became easily identifiable on microscopy.

Figure 1. Tinea (pityriasis) obscurans. This case, occurring on the arm of an 18-year-old man, later showed itself to be tinea (pityriasis) versicolor after topical corticosteroid treatment. Arrows indicate small spores (periodic acid–Schiff stain, original magnification ×620).

Dermatidites not associated with tinea (ie, vitiligo, pityriasis alba, psoriasis, seborrheic dermatitis, papillomatosis) are commonly treated with topical corticosteroids, which suppress the immune reaction and inflammatory response provoked by tinea infection, thereby reducing clinical inflammation while also causing the fungal organism to grow floridly.2–4,8 When the steroid is terminated, the lesions flare clinically and the organisms become more visible; however, it would be preferable to make the correct diagnosis initially, best avoiding this outcome. The term obscurans can be used to describe resolving but persistent tinea or yeast infection that presents with few tiny spores on microscopy. For example, the cases of tinea corporis and tinea versicolor discussed above can be classified as tinea corporis obscurans and tinea versicolor obscurans. OTHER CONSIDERATIONS Studies have shown that some clinicians commonly prescribe combination antifungals and corticosteroids for the treatment of skin conditions that appear to be fungal infection, without confirming the diagnosis with microscopy. The combination of an antifungal with a corticosteroid causes immune suppression, which alters the clinical appearance and may exacerbate tinea infection, resulting in treatment failure.9–11

Figure 2. Tinea obscurans. This case, occurring on the trunk of a 21-year-old woman, later showed itself to be tinea corporis after topical corticosteroid treatment. Arrows indicate small spores (Grocott methenamine silver stain, original magnification ×620). SKINmed. 2018;16:255–257

Detection of a residual fungal organism is important for the diagnosis of persistent dermatophyte infection and prevention of more severe complications. Recently, a case of dermatophyte osteomyelitis infection has been reported.12 Dermatophytes residing in the skin are uncommon causes of osteomyelitis, but infection of the bone marrow is possible with fracture via direct inoculation from the skin. The reported case presented a patient with a previous history of untreated dermatophyte infection

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who developed dermatophyte osteomyelitis after undergoing surgery for ankle fracture. This highlights that failure to diagnose and treat residual tinea infection can lead to more severe consequences.

2 Wolff K, Johnson RA, Saavedra AP. Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology. 7th ed. New York: McGraw-Hill Professional; 2013. 3 Sunenshine PJ, Schwartz RA, Janniger CK. Tinea versicolor. Int J Dermatol. 1998;37:648–655. 4 Schwartz RA. Superficial fungal infections. Lancet. 2004;364: 1173–1182.

CONCLUSIONS When the tinea or yeast infection is resolving, residual organisms can be easily missed on microscopy. Dermatopathologists should recognize tinea or yeast obscurans by microscopic findings of tiny spores in the stratum corneum. Corticosteroids can suppress the immune reaction to tinea or yeast and facilitate organism growth while minimizing clinical manifestations. Termination of corticosteroid use can then cause lesions to flare and organisms to become more visible on microscopy. Dermatologists should routinely confirm the diagnosis of superficial fungal infection with a laboratory specimen. Systemic disease such as dermatophyte osteomyelitis has been shown to be possible after fracture, and may occur as a severe consequence of undiagnosed and untreated dermatophyte infection. REFERENCES 1 Marques SA, Robles AM, Tortorano AM, et al. Mycoses associated with AIDS in the Third World. Medical Mycol. 2000;38:269–279.

5 Kye H, Kim DH, Seo SH, et al. Polycyclic annular lesion masquerading as lupus erythematosus and emerging as tinea faciei incognito. Ann Dermatol. 2015;27:322–325. 6 Schmidt A. Malassezia furfur: A fungus belonging to the physiological skin flora and its relevance in skin disorders. Cutis. 1997;59:21–24. 7 Gupta AK, Lyons DC. Pityriasis versicolor: An update on pharmacological treatment options. Expert Opin Pharmacother. 2014;15:1707–1713. 8 Kallini JR, Riaz F, Khachemoune A. Tinea versicolor in darkskinned individuals. Int J Dermatol. 2014;53:137–141. 9 Alston SJ, Cohen BA, Braun M. Persistent and recurrent tinea corporis in children treated with combination antifungal/ corticosteroid agents. Pediatrics. 2003;111:201–203. 10 Rosen T, Elewski BE. Failure of clotrimazole-betamethasone dipropionate cream in treatment of Microsporum canis infections. J Am Acad Dermatol 1995;32:1050–1051. 11 Greenberg HL, Shwayder TA, Bieszk N, Fivenson DP. Clotrimazole/ betamethasone diproprionate: a review of costs and complications in the treatment of common cutaneous fungal infections. Pediatr Dermatol. 2002;19:78–81. 12 Waryasz GR, Bariteau JT. Trichophyton rubrum osteomyelitis after calcaneus external fixation pin stabilization of a pilon fracture. J Foot Ankle Surg. 2014;53:480–484.

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July/August 2018

Volume 16 • Issue 4

THE HEYMANN FILE Warren R. Heymann, MD, Section Editor

The Alphabetization of Lymphomatoid Papulosis: Focus on “F” Warren R. Heymann, MD

ight years ago, my wife purchased the first iPad on its inaugural release date. The only choices to be made were how much storage was desired and if there should also be 3G connectivity. Today you can choose either an iPad mini, iPad, or iPad Pro (two sizes), combined with different storage and connectivity options. For example, if you want to be specific, you can say that you purchased an iPad Pro, 9.7 inch, 128 GB, cellular and wifi. The fact remains that you still bought an iPad, which basically has all the same implications and functions of every other iPad. THE ORIGINAL REPORT OF LYMPHOMATOID PAPULOSIS This is the 50th anniversary of Warren Macaulay’s (1915–2006) seminal description of lymphomatoid papulosis (LyP). The abstract of this landmark contribution1 follows: A 41-year-old woman has an asymptomatic eruption of three years’ duration. The clinical course is benign and is characterized by a continuing, random, coming and going of papules, some of which undergo necrosis, and all of which involute spontaneously within three to four weeks. Results of repeated physical examinations and laboratory studies are normal. Yet, biopsies of the skin lesions show an alarming infiltrate of anaplastic cells of disputatious origin, suggesting to most reviewers a diagnosis of malignant lymphoma. A number of comparable cases are reviewed, their similarity implying an uncommon entity.

the tumor necrosis factor receptor superfamily, acting as a cell surface cytokine receptor on activated T and B cells. The etiology of LyP is unknown, although it is presumed to be a reactive disorder resulting in the CD30 overexpression. Secondary malignancies in LyP can occur in between 5% and 30% of patients, with the majority being mycosis fungoides, anaplastic large cell lymphoma, or Hodgkin disease. There are currently five accepted histologic subtypes of LyP (A—with large Reed-Sternberg–like cells; B—resembling mycosis fungoides; C—appearing as anaplastic large cell lymphoma; D—CD8+; E—angiocentric/angiodestructive), and a proposed sixth type F (follicular), which will be discussed in greater detail. Although patients with LyP often undergo treatment (with first-line therapies including topical corticosteroids, phototherapy, or methotrexate), to date therapy has not been reported to alter the natural history of LyP or the risk of secondary malignancy.2 FOLLICULAR LYP (TYPE F)

THE CURRENT CONCEPT AND CLASSIFICATION OF LyP LyP is considered within the spectrum of CD30+ lymphoproliferative skin disorders. CD30, previously known as Ki-1 antigen, is a 120-kDa type I transmembrane glycoprotein of

Follicular LyP (FLyP, type F) is a rare variant of LyP. In a study of follicular involvement in 11 patients derived from 113 cases of LyP, six cases were classified as type C and 4 as type A, whereas the remaining case manifested epidermotropism of small lymphocytes in a background of a typical type A lesion (overlapping type A/B). Perifollicular infiltrates of CD30(+) atypical lymphoid cells were seen in all 11 cases, with infiltration of the follicular epithelium in 8 cases. Hyperplasia of the follicular epithelium was observed in 4 cases, ruptured hair follicles in 3 cases, and follicular mucinosis in 2 cases. In addition to hair follicle infiltration, atypical cells were recognized within sebaceous glands in two lesions. New findings were presence of numerous intrafollicular neutrophils in two patients, who clinically had pustules in addition to papules. Other histopathological features encountered included perieccrine infiltration (n=5),

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

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focal subcutaneous involvement (n=4), granulomatous inflammation (n=3), epidermal hyperplasia (n=2), and one each of infiltration of muscle bundles, numerous eosinophils in the infiltrate, and angiocentricity.3

instead of a patient with type A LyP, they could be described as mixed cellular, CD4+ and CD30+, with acral, pustular lesions.

Three cases of typical LyP demonstrating folliculotropism and follicular mucinosis histopathologically were recently reported. The authors suggested that LyP should be considered alongside mycosis fungoides (MF) in the differential diagnosis of follicular mucinosis with accompanying atypical lymphocytic infiltration.4 It has been emphasized that follicular LyP may masquerade as more common folliculocentric diseases including eosinophil-rich folliculitis, bacterial or parasitic infections, follicular MF, eosinophilic dermatosis of hematologic malignancy, and insect bite or hypersensitivity reactions, among others.5 It is quite possible that this mimicry means that follicular LyP is an underreported (or misdiagnosed) entity.

I believe that Kempf et al are correct. It is time for a revitalized reclassification of LyP. By taking their approach (or another similar modification), the likelihood of discerning differences in the subgroups will increase, helping to guide the therapy and management of this enigmatic disease.

CONCLUSIONS

REFERENCES

A BETTER CLASSIFICATION OF LyP? Regarding the alphabetization of LyP, I imagine the alphabet continuing with types G (granulomatous), H (hyperplastic), I (indeterminate), etc. While appealing on one level, does it really matter? There may be histologic overlap in any given patient between different variants. If the therapeutic approach, need to follow patients for secondary malignancies, and ultimate prognosis are uniform for the different subtypes, should we continue to subcategorize LyP patients? Kempf et al believe that the alphabetic approach to categorizing LyP is complex, and not clinically helpful.6 They propose classifying LyP based on histology, immunologic phenotype, genotype (if available), and clinical presentation. For example,

1 Macaulay WL. Lymphomatoid papulosis: A continuing self- healing eruption, clinically benign – histologically malignant. Arch Dermatol. 1968;97:23–30. 2 Sauder MB, O’Malley JT, LeBoeuf NR. CD30+ lymphoproliferative disorders of the skin. Hematol Oncol Clin North Am. 2017;31(2):317–334. 3 Kempf W, Kazakov DV, Baumgartner H-P, Kutzner H. Follicular lymphomatoid papulosis revisited: A study of 11 cases, with new histopathological findings. J Am Acad Dermatol. 2013;68:809–816. 4 Dore E, Swick BL, Link BK, Ghahramani GK, Liu V. Follicular lymphomatoid papulosis with follicular mucinosis: A clinicopathologic study of 3 cases with literature review and conceptual reappraisal. J Cutan Pathol. 2017;44:360–366. 5 Ross NA, Truong H, Keller MS, et al. Follicular lymphomatoid papulosis: An eosinophilic-rich follicular subtype masquerading as folliculitis clinically and histologically. Am J Dermatopathol. 2016;38:e1–e10. 6 Kempf W, Mitteldorf W, Karai LJ, Robson A. Lymphomatoid papulosis – making sense of the alphabet soup: A proposal to simplify terminology. J Dtsch Dermatol Ges. 2017;15(4): 390–394. [Epub ahead of print].

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The 2017 Recipient of the AAD Sulzberger Dermatologic Institute and Education Grants Committee’s Program for Innovative Continuing Medical Education in Dermatology (PICMED) Grant

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July/August 2018

Volume 16 • Issue 4

PHOTO CAPSULE Snejina Vassileva, MD, PhD, Section Editor

Nigrites Linguae: An Unusual Presentation Kingshuk Chatterjee, DNB;1 Gautam Chatterjee, MS;1 Anita Chaudhuri;1,* Virendra N. Sehgal, MD2

n 8-year-old-boy presented with a slowly progressive, black discoloration of the tongue that had been developing for 2 weeks. He had been well until 3 weeks previously, when he had had a fever for which he had taken gray-colored (paracetamol 500 mg) tablets two times a day for 3 days. The fever then subsided, leaving a metallic taste on the tongue and patchy black discoloration that gradually progressed to cover more than half of the dorsal portion of the tongue. Examination of the oral cavity revealed confluent, black, hairy projections on the presulcal portion of the tongue (Figure). The central region of the tongue was predominantly involved, with sparing of a U-shaped area consisting of the lateral parts and tip of the tongue. Cultures were negative for bacterial and/or fungal infections. Histopathologic examination of the affected area revealed no abnormality. The patient was asked to debride the dorsal surface of the tongue with a soft toothbrush.

DISCUSSION Nigrites linguae (lingua villosa nigra, black hairy tongue, keratomycosis linguae, Melanonychia lingua)1,2 is an indolent benign disorder, characterized by a typical carpetlike appearance of the dorsal surface of the tongue, showing elongated filiform lingual papillae. The worldwide prevalence ranges from 0.6% to 11.3% (male:female ratio 3:1).3 Consumption of excessive coffee or black tea, smoking, poor oral hygiene, trigeminal neuralgia, xerostomia, and medications are thought to be predisposing factors. “Hairs on the tongue” was described as long ago as 1557.4 Men aged 60 years and older are the usual candidates, although young

B Figure. (A) Topical podophyllin or isotretinoin and (B) Nigrites linguae: Presenting as black hairy tongue.

From the Skineplex, Center of Dermatology, Burdwan, India;1 and the Dermato-Venereology (Skin/VD) Center, Sehgal Nursing Home, Panchwati Delhi, India2 *Deceased 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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children may also be affected. Abnormal desquamation of the keratinized squamous epithelium and accumulation of keratinized layers in the anterior region of the tongue may lead to hypertrophy and elongation of filiform papillae (length 12 to 18 mm, whereas normal is less than 1 mm), resulting in the development of black tongue. Immunohistochemistry may reveal the hairy projections on the dorsal tongue, elongated cornified spines resulting from delayed desquamation of the central column, and retention of secondary papillary cells.5

an increased intake of raw fruits and vegetables. In addition to maintenance of good oral hygiene involves aggressive oral hydration, rinsing with diluted hydrogen peroxide and topical keratolytics. Salicylic acid, 30% urea solution, trichloroacetic acid, Topical podophyllin or isotretinoin, and oral retinoids are also recommended treatment modalities.8 Resistant lesions, however, may warrant removal of papillae by electrodesiccation or carbon dioxide laser.9 REFERENCES

Friction occurs between food particles and the tongue, resulting in impedance of deglutition, which facilitates the collection of debris, fungi, and bacteria. Tobacco chewing, coffee, tea, and porphyrins produced by chromogenic organisms impart the characteristic black, brown, yellow, green, or even blue color.

1 Waggoner WC, Volpe AR. lingua villosa nigra—a review of black hairy tongue. J Oral Med. 1967;22:18–21. 2 Prinz H. Black tongue. Br Dent J. 1925;46:1265–1274. 3 Avcu N, Kanli A. The prevalence of tongue lesions in 5150 Turkish dental outpatients. Oral Dis. 2003;9:188–195. 4 Waggoner WC, Volpe AR. lingua villosa nigra—a review of black hairy tongue. J Oral Med. 1967;22:18–21.

Local oxidizing mouthwashes, aerosols, lozenges and systemic antibiotics have also been implicated, presumably due to their ability to significantly alter the oral microbial flora.6,7 The current case is highly unusual because it was thought to have been triggered by fever and/or paracetamol. The presence of elongated filiform papillae was conspicuous, thus excluding the possibility of “pseudo-black hairy tongue” characterized by discoloration alone.

5 Gurvits GE, Tan A. Black hairy tongue syndrome. World J Gastroenterol. 2014;20:10845–10850.

Dietary modification in adults, in particular, requires abstinence from smoking and consumption of coffee/black tea, and

9 McGrath EE, Bardsley P, Basran G. Black hairy tongue: What is your call? CMAJ. 2008;178:1137–1138.

6 Thompson DF, Kessler TL. Drug-induced black hairy tongue. Pharmacotherapy. 2010;30:585–593. 7 Pigatto PD, Spadari F, Meroni L, Guzzi G. Black hairy tongue associated with long-term oral erythromycin use. J Eur Acad Dermatol Venereol. 2008;22:1269–1270. 8 Sarti GM, Haddy RI, Schaffer D, Kihm J. Black hairy tongue. Am Fam Physician. 1990;41:1751–1755.

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July/August 2018

Volume 16 • Issue 4

HISTORICAL VIGNETTE Charles Steffen, MD, Section Editor

The Largest Mass Poisoning in History: Arsenic Contamination of Well Water in Bangladesh Shoko Mori, BS; Eve J. Lowenstein, MD, PhD ABSTRACT Arsenic is a naturally occurring compound that is widely distributed in trace quantities in the environment. Levels toxic to humans have been found contaminating certain regions of the world and their groundwater, leading to deleterious effects. In fact, an estimated 150 million people are affected by arsenic contamination worldwide.1 Arsenic poisoning leads to several adverse health effects, including cancer of the lung, bladder, and kidney, neurologic disorders, cardiovascular disease, peripheral vascular disease, hypertension, pulmonary disease, and diabetes mellitus.2 Skin lesions are a common manifestation of arsenic poisoning. Early findings include diffuse or spotted melanosis, leukomelanosis, and depigmentation. Years of chronic arsenic poisoning can lead to acral keratoses and squamous cell carcinoma of the skin.3

rsenic contamination of well water in Bangladesh has been called “the largest mass poisoning in history.”4 Recent reports indicate that some 20 million people living in Bangladesh are presently exposed to water that contains more than 50 μg/L of arsenic, which is above Bangladesh’s acceptable standard for arsenic.5 This public health emergency is notable for the profound failure on the part of the government to remedy the situation, with a disastrously slow response to the issue, attracting major media headline attention. Up until the 1970s, the majority of drinking water in Bangladesh came from surface water sources, such as stagnant ponds. These water sources, contaminated with pathogenic microorganisms, caused significant morbidity and mortality due to gastrointestinal disease.4 In an attempt to solve this problem, the United Nationals Children’s Fund (UNICEF) launched a campaign to implement simple and inexpensive tube wells as a replacement water source.6 Over the next 20 years, an estimated 10 million tube wells were installed, thus providing 95% of the rural population in Bangladesh with drinking water that was free of microorganisms.7 These well-meaning efforts, however, introduced another more alarming problem. The tube wells draw from shallow aquifers (100 m or less), contaminated by high arsenic levels.

Attention was first drawn to this problem with a discovery made by a dermatologist in Bangladesh in 1983. Dr. K. C. Saha at the Calcutta School of Tropical Medicine4,8 was first to observe and publish his findings, eventually involving more than a thousand cases of skin lesions and skin cancer caused by arsenic-poisoned well water. The government turned a blind eye, and Dr. Saha’s academic position was threatened.8 EARLY REPORTS In 1988, the analytical chemist Dipankar Chakraborti learned of the arsenic problem in neighboring West Bengal, India, and began testing well water and interviewing villagers. By 1994, he was sending letters to the government of Bangladesh, UNICEF, and the World Health Organization in the hopes of drawing attention to this public health problem. His letters were largely dismissed; when interviewed, he stated that the “government did not agree. They said I was creating a panic.”9 In 1992, researchers from the School of Environmental Studies at Jadavpur University in Calcutta, while working in West Bengal, noticed a woman from Bangladesh with skin lesions consistent with arsenic poisoning. She stated that her relatives and neighbors in Bangladesh had similar skin lesions. This instigated an inves-

From the Department of Dermatology, SUNY Downstate Medical Center at Brooklyn, Brooklyn, New York, NY Address for Correspondence: Eve J. Lowenstein, MD, PhD, Department of Dermatology, Box 46, SUNY Health Science Center at Brooklyn, Brooklyn, NY 11203 • E-mail: evlow13@yahoo.com

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tigation, culminating in a publication reporting on mass arsenic poisoning in West Bengal and Bangladesh from contaminated tube well water.10 In 1995, the School of Environmental Studies hosted an international conference in Calcutta about the arsenic dilemma, led by Dr. Chakraborti, who presented several patients with arsenic-induced skin lesions.10 The Department of Public Health Engineering of Bangladesh, whose officials were present at the conference, denied, however, the arsenic contamination of groundwater.11 Despite the ignorance of and stone-walling by officials, the conference was successful in increasing awareness of the situation. Local newspapers began reporting on the findings, which led to a massive influx of letters to the School of Environmental Studies from doctors who had seen arsenic skin lesions on their own patients.11 MASS TESTING The public effort to begin mass testing of tube well water finally began in the late 1990s, more than 20 years after arsenic had been first introduced into the drinking water, and more than a decade after this had been discovered. Several surveys conducted by the National Institute of Preventive and Social Medicine, School of Environmental Studies, Dhaka Community Hospital, and the British Geological Survey found an alarming number of wells containing arsenic levels above the Bangladesh threshold of 50 μg/L. The British Geological Survey estimated that, based on the population density at the time in 1998, approximately 21 million people were exposed to arsenic levels above the allowed threshold.4 An extensive movement followed to test all tube wells and gather information on the extent of this public health emergency. The World Bank established the Bangladesh Water Supply Arsenic Mitigation Project, which tested tube wells in 270 upazilas (subdistricts) from 2000 to 2003. By 2005, they had painted approximately 1.4 million wells red, indicating arsenic concentrations greater than 50 μg/L. They also painted 3.5 million wells green to indicate that they were of a safe level for use. A later study noted, however, that many of the wells may have misclassified, and that nearly 500,000 wells that were originally painted green actually contained arsenic levels above 50 μg/L.5,12 In addition, many villagers faced immense social stigma if they lived next to a tube well that was painted red, causing some to repaint them green.13 In 2004, the government adopted a national policy and support unit to oversee the efforts of the multiple organizations taking part in solving the issue. The Bangladesh Water Supply Arsenic Mitigation Project also helped to provide additional training to nearly 2000 physicians and 12,000 health workers in treating the manifestations of arsenic poisoning.5 SKINmed. 2018;16:265–267

PUBLIC COMMENT There were few public statements acknowledging the crisis and resultant response, or lack thereof. Kazi Matin Ahmed, a scientist from Bangladesh who was researching the arsenic problem on behalf of the British Geological Survey, stated, “you could have rightly expected UNICEF to have known a lot sooner about the arsenic, especially after Dr. Chakraborti had issued his warnings. At the very least, someone must be blamed for bad management of such a vast system of water supply.”9 Amin Uddin, who was the Bangladeshi government’s chief engineer, stated, “We were concerned about creating a scare. If you tell people there is arsenic in the water, they won’t even use it for bathing. They’ll be afraid their hair will fall out.”9 Unfortunately, there is no single explanation for why the government ignored these findings for so long. Perhaps it had to do with the fact that the government had no resources and no real solution to this colossal, unforeseen turn of events. Perhaps it was concerned about scaring its citizens. Perhaps it did not want to admit that its solution to one problem had created an even bigger problem. Bangladesh today lacks follow-through on the arsenic mitigation projects that were started. Since the Bangladesh Water Supply Arsenic Mitigation Project survey of the wells, there have been no major movements to test the wells or enforce appropriate water use. Multiple studies have shown that most of the wells that have been tested recently are deep wells. Deep wells, which are more than 200 feet (61 m) deep, are less likely to contain dangerous levels of arsenic, and recent data indicate that deep wells are being tested, in contrast to more shallow wells that likely contain high levels of arsenic, which are less likely to be tested. In addition, George et al found that, among nearly 500 households in 10 villages, only 27% of households were within 50 m of a “safe” well, and 28% of households were within 50 to 100 m of a low-arsenic “safe” well.14 Safer, deeper wells are, furthermore, not being installed in the areas with the highest concentration of arsenic-contaminated wells. This lack of commensurate allocation reflects a corrupt political situation in Bangladesh today. Even though policies dictate that safe wells should be installed on a priority basis in poor communities, the Department of Public Health Engineering also stipulates that “50 percent of the allocation should be finalized after discussion with the relevant Member of Parliament of that area.”5 In some districts, Department of Public Health Engineering officials, speaking on condition of anonymity, have confirmed that 100% of the allocations are in fact being determined by members of parliament. This has led to safe tube wells being supplied to political allies, rather than the poor, who are more likely to live in villages with a high concentration of arsenic-contaminated wells.

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CONCLUSIONS Arsenic poisoning in Bangladesh has had a profound impact on the health of its citizens, and the true extent of the damage remains to be determined. The arsenic poisoning crisis developed in a successful effort to decrease infant mortality, exemplifying a lack of global insight and understanding of the complex regional issues of massive health problem management in impoverished countries. The subsequent public health debacle related to its management furthermore demonstrates how far we have to go as people in governance protecting the interests of all its citizens.

5 Pearshouse R. Nepotism and Neglect: The Failing Response to Arsenic in the Drinking Water of Bangladesh’s Rural Poor. New York: Human Rights Watch; 2016. 6 Flanagan S, Johnson RB, Zheng Y. Arsenic in tube well water in Bangladesh: Health and economic impacts and implications for arsenic mitigation. Bull World Health Organ. 2012;90:839–846. 7 Chowdhury AM. Arsenic crisis in Bangladesh. Sci Am. 2004;291:86–91. 8 Parascandola J. The ubiquitous element: arsenic in the environment. In: King of Poisons: A History of Arsenic. Washington D.C.: Potomac Books; 2012:132–134. 9 Bearak B. Death by arsenic: A special report; New Bangladesh Disaster: wells that pump poison. New York Times. November 10, 1998. 10 Dhar RK, Biswas BK, Samanta G, et al. Groundwater arsenic calamity in Bangladesh. Curr Sci. 1997;73:48–59.

REFERENCES 1 Shankar S, Shanker U, Shikha. Arsenic contamination of groundwater: A review of sources, prevalence, health risks, and strategies for mitigation. ScientificWorld Journal. 2014;2014:304524.

11 Chakraborti D, Rahman MM, Mukherjee A, et al. Groundwater arsenic contamination in Bangladesh–21 years of research. J Trace Elem Med Biol 2015;31:237–248.

2 World Health Organization/International Programme on Chemical Safety. Environmental Health Criteria 224: Arsenic and Arsenic Compounds. Geneva: World Health Organization; 2001.

12 Johnson RB, Sarkar MH. Arsenic mitigation in Bangladesh: National screening data and case studies in three upazilas. J Environ Sci Health A Tox Hazard Subst Environ Eng 2007;42:1889–1896.

3 Ghosh A. Evaluation of chronic arsenic poisoning due to consumption of contaminated ground water in West Bengal, India. Int J Prev Med. 2013;4:976–979.

13 Chowdhury M. Poisoned: the silent screams of arsenic victims. BRAC Blog 2012. http://blog.brac.net/previous/2012/05/ poisoned-the-silent-screams-of-arsenic-victims. Accessed June 7, 2017.

4 Smith A, Lingas E, Rahman M. Contamination of drinking-water by arsenic in Bangladesh: A public health emergency. Bull World Health Organ. 2000;78:1093–1103.

14 George CM, Graziano JH, Mey JL, Geen AV. Impact on arsenic exposure of a growing proportion of untested wells in Bangladesh. Environ Health. 2012;11:7.

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July/August 2018

Volume 16 • Issue 4

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

Tinea Capitis Masquerading as Basal Cell Carcinoma Hubert M. Chodkiewicz, MD;1,2 Jennifer Song Ranario, MD;2 Richard Jahan-Tigh, MD;1 Deborah F. MacFarlane, MD2

A 52-year-old white man with alcoholic cirrhosis presented to the Mohs surgery clinic with a 1-month history of tender “bumps” located diffusely on his scalp. Two biopsies performed at an outside institution were read as “basal cell carcinoma” and “actinic keratosis.” The patient was scheduled for a large excision of the scalp for presumed multiple nodules of basal cell carcinoma and desired a second opinion from our Mohs surgery clinic. (SKINmed. 2018;16:269–271)

hysical examination of the scalp revealed diffuse erythema with fine scale and scattered crusted erythematous nodules, some of which had central pustules (Figure 1). On closer inspection, patches of alopecia with broken hairs were noted. When questioned specifically about hair loss, he reported that his hair had started falling out a few months before presentation. Additional biopsies revealed tinea capitis, and cultures grew methicillin-resistant Staphylococcus aureus and Microsporum audouinii. The patient was started on doxycycline 100 mg orally twice daily for 1 week and itraconazole 200 mg orally daily for one month (in coordination with his hepatologist). Liver function was monitored weekly. Follow-up after 2 weeks of treatment revealed significant improvement in the nodules and scaling, and treatment was continued. The original biopsy slides were reviewed at our institution and read as “nodular and infiltrative basal cell carcinoma with fungal infection.” It was noted that numerous fungal hyphae were seen in almost every hair follicle, with invasion of the hair shaft (Figure 2). As we clinically suspected tinea capitis, we requested that the slides be re-read yet again. Review by a third dermatopathologist and additional recuts revealed that the basaloid islands were present only in one section, and other characteristic features of basal cell carcinoma were not present (Figure 3). The histopathologic diagnosis was amended to tinea capitis.

Figure 1. Diffuse erythema with fine scale.

DISCUSSION Tinea capitis is a common infection, primarily among young patients. It is rare among adults because levels of fungistatic saturated fatty acids in sebum are theorized to increase at puberty.1 In adults, tinea capitis usually occurs in immunosuppressed patients.

From the Department of Dermatology, University of Texas-Houston Medical School,1 and Department of Dermatology, The University of Texas M.D. Anderson Cancer Center,2 Houston, Texas Address for Correspondence: Hubert M. Chodkiewicz, MD, Department of Dermatology, The University of Texas M.D. Anderson Cancer Center, 6655 Travis Street, Suite 980, Houston, TX 77030 • E-mail: Hubert.M.Chodkiewicz@uth.tmc.edu

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Figure 3. Islands of basaloid cells at the same depth as the other folliculosebaceous units lacking stromal retraction, mitotic figures, and apoptotic cells.

B Figure 2. (A) Fungal spores within the hair shaft. (B) Close-up of fungal spores within the hair shaft.

Scalp scaling and the presence of broken hairs are the most frequent clinical features, and were present in our patient. Diagnosis can be made by checking for fungal hyphae under microscopy of scraped scale or plucked hairs. A biopsy for tissue and culture can also confirm the diagnosis. Typically, it is not difficult to clinically distinguish tinea capitis from basal cell carcinoma. Cutaneous malignancy was not in the SKINmed. 2018;16:269â&#x20AC;&#x201C;271

initial differential diagnosis of the biopsying provider, but the Âhistologic diagnosis led to scheduling the patient for excision. Due to the various histologic presentations of basal cell carcinoma, many entities may mimic it histologically (Table). Basaloid hyperplasia seen in histology of dermatofibromas and nevus sebaceus may also appear similar to basal cell carcinoma.2 Additionally, it can be difficult to distinguish tangentially sectioned hair follicles from basal cell carcinoma. Clues to help differentiate the two include clefting, palisading, mitotic figures, and apoptotic cells in basal cell carcinomas. Also, hair follicles are usually surrounded by a fibrous sheath, and further examination of multiple sections may help differentiate between hair follicles and basal cell carcinomas.3 In this case, the tangentially cut hair follicle within and near the inflammation mimicked basal cell carcinoma due to the islands of basaloid cells seen in one section, but these islands were not noted in any other section. These islands of basaloid cells were, furthermore, located at the same depth as the other folliculosebaceous units and lacked stromal retraction, mitotic figures, and

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Table. Histologic Mimics of Basal Cell Carcinoma

1 Rothman S, Smiljanic A, Shapiro AL, Weitkamp AW. The spontaneous cure of tinea capitis at puberty. J Invest Dermatol. 1947;8:81–98.

Ameloblastoma4 Basaloid follicular hamartoma5

2 Stashower ME, Smith K, Corbett D, Skelton HG. Basaloid/follicular hyperplasia overlying connective tissue/mesenchymal hamartomas simulating basal cell carcinomas. J Am Acad Dermatol. 2001;45:886–891.

Basaloid squamous cell carcinoma6 Cloacogenic carcinoma7 Cylindroma3

3 Bouzari N, Olbricht S. Histologic pitfalls in the Mohs technique. Dermatol Clin. 2011;29:261–272.

Desmoplastic trichoepithelioma8

4 Kim YS, Lee SK. Different protein expressions between peripheral ameloblastoma and oral basal cell carcinoma occurred at the same mandibular molar area. Korean J Pathol. 2014;48:151–158.

Hidrocystoma9 Merkel cell carcinoma10

5 Huang SH, Hsiao TF, Lee CC. Basaloid follicular hamartoma: A case report and review of the literature. Kaohsiung J Med Sci. 2012;28:57–60.

Metastatic breast carcinoma3 Microcystic adnexal carcinoma3

6 Webb DV, Mentrikoski MJ, Verduin L, Brill LB 2nd, Wick MR. Basal cell carcinoma vs basaloid squamous cell carcinoma of the skin: An immunohistochemical reappraisal. Ann Diagn Pathol. 2015;19:70–75.

Poroma3 Sebaceous carcinoma11 Spiradenoma3

7 White WB, Schneiderman H, Sayre JT. Basal cell carcinoma of the anus: Clinical and pathological distinction from cloacogenic carcinoma. J Clin Gastroenterol. 1984;6:441–446.

Tinea (current report) Trichoblastoma12

8 Costache M, Bresch M, Böer A. Desmoplastic trichoepithelioma versus morphoeic basal cell carcinoma: A critical reappraisal of histomorphological and immunohistochemical criteria for differentiation. Histopathology. 2008;52:865–876.

Trichoepithelioma3

apoptotic cells. In our patient, a large excision of the scalp was avoided due to clinical suspicion, emphasizing the importance of clinical-pathologic correlation. CONCLUSIONS Clinical-pathologic correlation is crucial, as many entities may appear similar histologically to cutaneous malignancies such as basal cell carcinomas. Knowledge of histologic mimickers of basal cell carcinoma, and clues to distinguish tangentially sectioned hair follicles from basal cell carcinoma, can prevent inaccurate diagnosis and unnecessary surgery.

9 Buckel TB, Helm KF, Ioffreda MD. Cystic basal cell carcinoma or hidrocytoma? The use of an excisional biopsy in a histopathologically challenging case. Am J Dermatopathol. 2004;26:67–69. 10 Succaria F, Radfar A, Bhawan J. Merkel cell carcinoma (primary neuroendocrine carcinoma of skin) mimicking basal cell carcinoma with review of different histopathologic features. Am J Dermatopathol. 2014;36:160–166. 11 Sinard JH. Immunohistochemical distinction of ocular sebaceous carcinoma from basal cell and squamous cell carcinoma. Arch Ophthalmol. 1999;117:776–783. 12 Vega Memije ME, Luna EM, de Almeida OP, Taylor AM, Cuevas González JC. Immunohistochemistry panel for differential diagnosis of basal cell carcinoma and trichoblastoma. Int J Trichology. 2014;6:40–44.

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July/August 2018

Volume 16 • Issue 4

CASE STUDY

Familial Dyskeratotic Comedones Neel Prabha, MBBS, MD;1 Namrata Chhabra, MBBS, MD;1 Sandeep Kulkarni, MBBS, DNB, MNAMS;1 Nighat Hussain, MBBS, MD2

A 21-year-old man presented with extensive asymptomatic comedones and inflammatory papulonodules that had been present for the previous 7 years. The lesions had first appeared on the upper part of the trunk, subsequently spreading to the face, arms, axillae, thighs, groin, and buttocks. Physical examination revealed numerous monomorphic discrete black papules with firm central keratotic plugs. A few painful, inflamed nodules were present over the back (Figure 1). Pocklike scars were located predominantly over the face and back. His general health was otherwise normal, and he had not received any prior treatment for this condition. His father had similar lesions. Skin biopsy from the hyperkeratotic lesions revealed a crater-like invagination filled with lamellar keratinous material with foci of dyskeratosis (Figure 2). (SKINmed. 2018;16:273–274)

he second case was an incidental finding in a 45-year-old man. Physical examination revealed multiple comedolike lesions over the face, arms, trunk, thighs, axillae, and groin (Figure 3), which had appeared 5 years previously. Pocklike scars were also present at these sites. A skin biopsy was not carried out, as the patient did not want any intervention or treatment for this condition. His grandfather had similar lesions. DISCUSSION Familial dyskeratotic comedones represent a rare asymptomatic autosomal dominant condition. This is characterized by comedolike lesions that appear progressively and in a diffuse bilateral distribution, with dyskeratosis on histology.1,2 Only a few cases have been described in the English-language literature, since Carneiro et al first described the condition in 1972.2 So far, only two families have been reported from India with this rare disorder.3 Numerous comedones in disseminated form have been described in several rare skin diseases, including familial dyskeratotic comedones and familial diffuse comedones.4,5 Familial dyskeratotic comedones are characterized by disseminated keratotic papules and comedolike lesions. The lesions show a predilection for the trunk, arms, and legs, and have an onset in childhood or adolescence.1 The histology of the lesions is characterized by a craterlike

Figure 1. Comedones, pock-like scars, and inflamed nodule over the back.

From the Departments of Dermatology, Venereology and Leprology,1 and Pathology,2 All India Institute of Medical Sciences, Raipur, Chhattisgarh, India Address for Correspondence: Neel Prabha, MBBS, MD, Department of Dermatology, AIIMS, Raipur, Chhattisgarh, India • E-mail: ripuneel@gmail.com

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CASE STUDY Our first case had clinical and histopathological features that correlated well with the diagnosis of familial dyskeratotic comedones. As the condition is usually asymptomatic, it is often seen as an incidental finding, as in our second case. The disease usually manifests in childhood; however, the onset of disease in our second patient was in adulthood. Diseases such as acne vulgaris, Kyrle disease, reactive perforating collagenosis, keratosis pilaris, nevus comedonicus, and comedonal Darier disease must be considered in the differential diagnosis.2,4,9 This condition is usually refractory to treatment. The various treatment modalities include topical and oral retinoids, and carbon dioxide laser.10 Significant improvement of the nodular lesions is observed with oral retinoids, but the comedones do not improve greatly.

Figure 2. Crater-like invagination filled with lamellar keratinous material with foci of dyskeratosis (hematoxylin and eosin stain, original magnification ×20).

CONCLUSIONS Only a few cases of familial dyskeratotic comedones have been described in the literature. Because this is an asymptomatic condition usually detected as an incidental finding, we suggest that this condition may be an underreported entity. REFERENCES 1 Van Geel NA, Kockaert M, Neumann HA. Familial dyskeratotic comedones. Br J Dermatol. 1999;140:956–959. 2 Carneiro SJ, Dickson JE, Knox JM. Familial dyskeratotic comedones. Arch Dermatol. 1972;105:249–251. 3 Kumaran MS, Appachu D, Jayaseelan E. Familial dyskeratotic comedones. Indian J Dermatol Venereol Leprol. 2008;74:142– 144. 4 Rodin HH, Blankenship ML, Berstein G. Diffuse familial comedones. Arch Dermatol. 1967;95:145–146. 5 Cantu JM, Gomez-Bustamante MO, Gonzalez-Mendoza A, Sanchez-Corona J. Familial comedones: Evidence for autosomal dominant inheritance. Arch Dermatol. 1978;114:1807–1809. 6 Cheng MJ, Chen WC, Happle R, Song ZQ. Familial disseminated comedones without dyskeratosis: Report of an affected family and review of literature. Dermatology. 2014;228:303–306. 7 Zhang RZ, Zhu WY. Idiopathic disseminated comedones in a child. Pediatr Dermatol. 2006;23:163–166.

Figure 3. Multiple comedones over the neck.

invagination of the epidermis filled with keratin and dyskeratosis.2 The causative gene defect is as yet unidentified. Cases of familial comedones without dyskeratosis are extremely rare.6 Disseminated comedones without a family history have also been reported.7,8

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8 Vano-Galvan S, Hernandez-Martin A, Colmenero I, Torrelo A. Disseminated congenital comedones. Pediatr Dermatol. 2011;28:58–59. 9 Chung J, Kim JY, Gye J, et al. A case of familial comedonal Darier disease. Ann Dermatol. 2011;23:398–401. 10 Hallermann C, Bertsch HP. Two sisters with familial dyskeratotic comedones. Eur J Dermatol. 2004;14:214–215.

Familial Dyskeratotic Comedones

Edward L. Keyes Resident Contest for Outstanding Case Reports 14th World Congress of the International Academy of Cosmetic Dermatology Lima, Peru, March 28 – 30, 2019 Abstract deadline: December 31, 2018 To be awarded for the best Case Report submitted by a physician in training (resident, fellow, or registrar) for presentation at the 14th World Congress of the International Academy of Cosmetic Dermatology in Lima, Peru from March 28 – 30, 2019. We invite you to submit original Case Reports that reflect the presentation of new ideas and original observations to the Academy membership and other attendees of the Congress. The case may be medical, surgical, and cosmetic (or combined) in nature. The author whose abstract receives the highest score during the review process will receive a scholarship by the IACD to present the full paper at the 14th World Congress of the International Academy of Cosmetic Dermatology in Lima, Peru, March 28–30, 2019. The scholarship will provide reasonable travel expenses, lodging for 3 nights, the Congress registration fee, and a basic spending stipend. Please submit your case report abstract via email to VPRosic@ChicagoBooth.edu before noon, CDT, December 31, 2018. The abstract should be no longer than 2,500 characters including spacing. Material that was previously presented, published, or submitted for publication should not be offered. Applications will be graded based upon the educational value of the abstract and the extent to which it presents new and significant work. The Review Committee strongly recommends that abstracts have an organized, coherent, well-thoughtout, and complete presentation. Please note that no paper submitted for consideration will be eligible if it has already been, or is in consideration for publication elsewhere at any time prior to the meeting. The winner(s) agree to publish their outstanding case report(s) in SKINmed: Dermatology for the Clinician, an official publication of the International Academy of Cosmetic Dermatology. By submitting your paper for consideration, you give SKINmed: Dermatology for the Clinician first-rights of refusal for publication through December 31, 2019. The applicant must be in training at the time of the Congress presentation. All applicants will receive e-mail notice of the Resident Case Report Review Committee’s decision by January 31, 2019. Vesna Petronic-Rosic, MD, MSc, MBA Chair, Resident Contest Committee Professor and Chair Georgetown University MedStar Washington Hospital Center Department of Dermatology Tel: +1(302) 455-7546 VPRosic@ChicagoBooth.edu

July/August 2018

Volume 16 • Issue 4

CASE STUDY

Ripple-Pattern Sebaceous Trichoblastoma Jonathan L. Yao, MD; Gary Goldenberg, MD; Robert G. Phelps, MD

A 28-year-old man of Middle-Eastern descent presented with a raised, pearly, slightly pigmented lesion on the right nasal ala. The lesion had been present for approximately 4 months. An excisional biopsy was taken, and the lesion measured 1.0 cm × 0.9 cm in dimension. The cut surface revealed a firm, white to tan nodule located within the dermis. The patient had no other significant medical history. After the initial excision, the lesion did not recur. (SKINmed. 2018;16:276–279)

DISCUSSION Rippled-pattern sebaceous trichoblastoma (RPTB) is a rare and underreported histological variant of trichoblastoma. This entity was first described by Hashimoto et al in 1989 as ripplepatterned trichomatricoma and later redesignated as a trichoblastoma variant by Akasaka et al.1,2 The lesions are characterized by follicular germanitive basaloid cells arranged in alternating parallel rows of cells and eosinophilic stroma, creating structures resembling those of the Verocay bodies seen in schwannomas.3 In total, eight cases have been reported in the English-language literature. Recently, there have been some debates on the exact nomenclature of these lesions. Five case reports of rippled- pattern sebaceoma4 have also been published in the Englishlanguage literature, and these authors believe that RPTB might in fact be sebaceoma. Histopathologic examination of the biopsy taken from our patient revealed a thinned epidermis. The epidermal changes were secondary to a mass effect from the underlying tumor. Adjacent to the lesion were numerous well-spaced anagen hairs with sebaceous hyperplasia. No desmoplastic reaction was noted adjacent to the neoplasm. The lesion was composed of multiple, variably sized, expansive nodules located within the reticular dermis. The tumor was well circumscribed and composed of basaloid cells (Figure 1). The periphery of the nodules was focally lined by palisading cuboidal cells. Within the lobules, there was a conspicuous rippling pattern—alternating parallel linear rows of basaloid cells and eosinophilic stroma (Figure 2). There were scattered mature sebocytes at the periphery of the lesion. Prominent esosinophilic

Figure 1. The tumor was well circumscribed, located within the superficial and deep dermis, and composed of basaloid cells. The surrounding tissue revealed multiple hair follicles with sebaceous hyperplasia (original magnification ×20).

basement membrane material was found within the lesion, along with thick-walled vessels. The lesional cells showed minimal cytologic atypia and scant cytoplasm. In addition, there were no appreciable mitotic figures or apoptotic bodies. Immunohistochemically, the lesion showed strong and diffuse staining for BCL-2 and CK5/6. Low-molecular-weight keratin CAM5.2 (CK8/7) highlighted only rare focal ductular structures within the lesion. The lesion was negative for CEA, EMA, and Ber-EP4. The proliferative index of the tumor using MIB-1 was

From the Department of Dermatopathology, Mount Sinai Medical Center, New York, NY Address for Correspondence: Jonathan L. Yao, MD, Mount Sinai Hospital, One Gustave L. Levy Place, New York, NY10029 • E-mail: Jonathan.Yao@mountsinai.org

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Figure 2. The basaloid cells showed a prominent rippling pattern in which the cells were aligned in parallel rows, much like in Verocay bodies (original magnification ×200).

Figure 3. The proliferative index highlighted with MIB-1 was less than 10% within the lesion (original magnification ×200).

less than 10% (Figure 3). There was no difference in proliferative activity between the rippled areas and areas in the rest of the lesion. The tumor was microsatellite-stable, staining for MHL-1, MSH2, MSH6, and PM2. A review of the literature reveals that, clinically, these lesions have been reported to present as papules, with two cases

showing verruciform changes. The size of these lesions varied from 8 cm to 8 mm in largest dimension (Table I). Five of the reported lesions occurred in men, and three in women. The patients’ ages ranged from 30 to 69 years. All lesions were located on the head and neck region, the scalp being the most common (6/8). One lesion occurred in association with a nevus sebaceous.5

Table I. Summary of Cases of Rippled-Pattern Trichoblastoma Reported in the Literature Reference

Age (Years)/ Race and Sex

Site

Size

Clinical Findings

Sebaceous Differentiation

Akasaka et al2

36/Asian man

Scalp

1.2 cm

Skin-colored nodule

Absent

Hashimoto et al1

30/Asian woman

Cheek

0.9 cm

Ulcerated nodule

Absent

Graham et al6

67/man

Posterior part of the neck

0.8 cm

Pigmented pearly plaque

Present

Graham et al6

58/woman

Vertex of the scalp

1.5 cm × 1.0 cm

Verrucous plaque

Present

Graham et al10

50/man

Occipital area

0.6 cm × 0.8 cm

Verrucous papillomatous papules

Present

Requena et al7

69/No race specified, man

Scalp

8.0 cm

Skin-colored nodule

Present

Swick et al5

36/man

Posterior auricular area

4.0 cm × 0.8 cm

Brownish yellow papules

Absent

Yamamoto et al11

62/Asian woman

Occiput

1.0 cm × 0.8 cm

Pedunculated light red nodule

Absent

Yao et al (present study)

28/Middle-Eastern man

Nose

1.0 cm × 0.9 cm

Pearly pigmented nodule

Present

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Table II. Summary of Cases of Rippled-Pattern Sebaceoma Reported in the Literaturea Reference

Age (Years)/ Sex and Race

Site

Size

Clinical Findings

Sebaceous Differentiation

Kawakami et al12

40/Asian man

Forehead

2.2 cm × 2.2 cm

Pedunculated erythematous nodule

Present

Kiyohara et al9

68/No race specified, man

Back

1.2 cm × 1.3 cm

Dark red nodule

Present

Kurokawa et al13

65/No race specified, man

Frontal scalp

1.5 cm × 1.0 cm

Pale reddish nodule

Present

Misago et al4

71/No race specified, woman

Forehead-scalp region

1.2 cm × 1.0 cm

Dome-shaped, ulcerated, erythematous nodule

Present

Nomura et al14

77/Asian man

Scalp

1.0 cm × 0.8 cm

Domed-shaped, pinkish yellow, papular

Present

The 22 cases reported by Ansai have not been included in the summary.

Trichoblastomas with a ripple pattern on histologic examination are circumscribed expansive masses located within the dermis, with no connection to the epidermis. They are composed of basaloid cells with scant cytoplasm and minimal cytologic atypia. A prominent ripple pattern is seen. Four of the reported TBRPs showed conspicuous sebaceous differentiation.6,7 Ripple-pattern sebaceous trichoblastoma may be a distinct entity. Prominent follicular differentiation, namely follicular germinative and papillary mesenchymal bodies, has not been reported in ripple-pattern trichoblastoma. These tumors stain for cytokeratin. CEA stain is usually negative in these lesions, but four lesions have shown possible ductal structures with EMA staining.5,6 In one report, BCL-2 highlighted peripheral cells in the tumors.5 There is a report of Langerhans cells and melanophages within the tumor. Immunohistochemical characterization of these lesions, however, has not been specific or consistent. Recently, there has been some push to reclassify RPTB with sebaceous differentiation as ripple-pattern sebaceoma, first described in 2001.4 Five individual cases of this rare entity have been published in the English-language literature (Table II). In one study of 80 cases of sebaceoma reviewed, 21 cases showed a ripple pattern.8 This high frequency, however, is not supported by the literature, and it remains rare. According to the literature, these lesions presented as nodules. Four were located on the head and neck region, and one on the back. The size of ripple-pattern sebaceomas ranged from 1.0 to 2.2 cm in largest dimension. The histologic findings were virtually identical to that of the trichoblastoma counterpart. A review of the literature showed that these lesions stained consistently for cytokeratin, but immunohistochemical profiling has proved to be of little help in the diagnosis. SKINmed. 2018;16:276–279

The distinction between RPTB with sebaceous differentiation and ripple-pattern sebaceoma may be difficult. Some authors argue that as previously reported RPTBs have not shown follicular differentiation, a palisading border, or fibrotic stroma, these lesions are better considered as sebaceomas.4,9 The characteristics of RPTB are not always found in trichoblastomas. For example, trichoblastomas can show sebaceous differentiation, many having inconspicuous follicular differentiation, and many lacking fibrous stroma. The histologic distinction between the two entities may be extremely difficult to make. CONCLUSIONS We present here a case of ripple-pattern sebaceous trichoblastoma. Eight cases of RPTB have been published, four of which presented with sebaceous differentiation. Recently, there have been efforts to categorize these lesions as a histologic variant of sebaceoma, but the two entities share almost identical histologic characteristics. Immunohistochemical staining profiles have yet to clearly differentiate one form the other. Molecular and cytogenetic studies have not yet been reported for these rare lesions to offer any help in deciding their origin. REFERENCES

278

1 Hashimoto K, Prince C, Kato I, et al. Rippled-pattern trichomatricoma. Histological, immunohistochemical and ultrastructural studies of an immature hair matrix tumor. J Cutan Pathol. 1989;16:19–30. 2 Akasaka T, Imamura Y, Mori Y, Iwasaki M, Kon S. Trichoblastoma with rippled-pattern. J Dermatol. 1997;24:174–178. 3 Headington JT. Tumors of the hair follicle. A review. Am J Pathol 1976;85:479–514.

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CASE STUDY

4 Misago N, Narisawa Y. Rippled-pattern sebaceoma. Am J Dermatopathol. 2001;23:437–443. 5 Swick BL, Baum CL, Walling HW. Rippled-pattern trichoblastoma with apocrine differentiation arising in a nevus sebaceus: Report of a case and review of the literature. J Cutan Pathol. 2009;36:1200–1205. 6 Graham BS, Barr RJ. Rippled-pattern sebaceous trichoblastoma. J Cutan Pathol. 2000;27:455–459. 7 Requena L, Barat A. Giant trichoblastoma on the scalp. Am J Dermatopathol. 1993;15:497–502. 8 Ansai S, Kimura T. Rippled-pattern sebaceoma: A clinicopathological study. Am J Dermatopathol. 2009;31:364–366. 9 Kiyohara T, Kumakiri M, Kuwahara H, Saitoh A, Ansai S. Rippled-pattern sebaceoma: A report of a lesion on the back with a review of the literature. Am J Dermatopathol. 2006;28:446–448.

10 Melly L, Lawton G, Rajan N. Basal cell carcinoma arising in association with trichoepithelioma in a case of Brooke-Spiegler syndrome with a novel genetic mutation in CYLD. J Cutan Pathol. 2012;39:977–978. 11 Yamamoto O, Hisaoka M, Yasuda H, Nishio D, Asahi M. A rippled-pattern trichoblastoma: An immunohistochemical study. J Cutan Pathol. 2000;27:460–465. 12 Kawakami Y, Ansai S, Nakamura-Wakatsuki T, Yamamoto T. Case of rippled-pattern sebaceoma with clinically yellowish surface and histopathological paucity of lipid-containing neoplastic cells. J Dermatol. 2012;39:644–646. 13 Kurokawa I, Nishimura K, Hakamada A, et al. Rippled-pattern sebaceoma with an immunohistochemical study of cytokeratins. J Eur Acad Dermatol Venereol. 2007;21:133–134. 14 Nomura M, Tanaka M, Nunomura M, Izumi M, Oryu F. Dermoscopy of rippled pattern sebaceoma. Dermatol Res Pract. 2010, 2010. doi: 10.1155/2010/140486.

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MEDIA PARTNER

July/August 2018

Volume 16 • Issue 4

CASE STUDY

Recurrent Palisaded Neutrophilic and Granulomatous Dermatitis in the Setting of Systemic Lupus Erythematosus Tracey N. Liebman, MD;1 Devorah Shagalov, MD;2 Eve J. Lowenstein, MD, PhD2

We present the case of a 66-year-old woman with a history of systemic lupus erythematosus, who presented with tender nodules on the forearms. The patient reported an 8-year history of pink bumps on the extensor surfaces of the forearms bilaterally that would arise episodically for a few weeks and subsequently resolve with no intervention. Her systemic lupus erythematosus was under good control with oral prednisone 10 mg daily, and the development of these lesions was not associated with concomitant flares of the systemic lupus erythematosus. (SKINmed. 2018;16:281–284)

linical examination demonstrated scattered erythematous papulonodules on the extensor surfaces of the forearms (Figure 1). The lesions were slightly tender to palpation. The differential diagnosis included lupus panniculitis, subcutaneous sarcoidosis, palisaded neutrophilic and granulomatous dermatitis (PNGD), erythema elevatum diutinum, and vasculitis. A 4-mm punch biopsy specimen was obtained. Histopathologic examination revealed a diffuse interstitial dermal infiltrate with zones of degenerated basophilic collagen surrounded by palisades of histiocytes, neutrophils, and neutrophilic debris, diagnostic of PNGD (Figure 2). Upon follow-up, the lesions started to resolve within 2 weeks without treatment. For the remaining lesions, the patient was treated with intralesional (Bristol-Myers Squibb Company, New York) Kenalog 10 mg/ml. DISCUSSION PNGD is a neutrophilic dermatosis that can develop in patients with underlying autoimmune conditions.1 While PNGD is a distinct entity, it has been considered by some authors to be on a spectrum and/or overlapping with other entities including interstitial granulomatous dermatitis and interstitial granulomatous drug reaction.1,2

PNGD most commonly develops in the setting of connective tissue diseases such as lupus erythematosus3 and rheumatoid arthritis.4,5 PNGD has also been found in patients with systemic sclerosis,6 ankylosing spondylitis,7 perinuclear antineutrophil cytoplasmic antibody-positive pauci-immune glomerulonephritis and arthritis,8 lymphoproliferative diseases, and other systemic diseases with circulating immune complexes.3 Other reports of PNGD have occurred in the setting of systemic medications given to patients with connective tissue diseases known to be independently associated with PNGD.5,9 PNGD has also been rarely diagnosed in patients without a previously diagnosed underlying systemic disease (Table).10–12 Similar to PNGD, interstitial granulomatous dermatitis has been associated with pharmacotherapy, various autoimmune conditions, and hematologic malignancies. Classic clinical findings of PNGD include tender erythematous to skin-colored papulonodules, symmetrically distributed on the extensor surfaces of the upper extremities,6 particularly around the elbows.3 Lesions of PNGD may have crusting, ulceration, or umbilication,3 and they may be asymptomatic4 or demonstrate tenderness.4 In comparison, the classic clinical presentation of interstitial granulomatous dermatitis consists of the rope sign, with linear strands or palpable cords on the trunk.

From the Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY;1 and the Department of Dermatology, State University of New York Downstate, Brooklyn, NY2 Address for Correspondence: Tracey N. Liebman, MD, The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, 240 East 38th Street, 12th Floor, New York, NY 10016 • E-mail: Tracey.Liebman@nyumc.org

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B Figure 2. (A) Histopathologic specimen demonstrating palisading granulomas with neutrophils and histiocytes (hematoxylin and eosin stain, magnification ×10). (B) Histopathologic specimen demonstrating palisading granulomas with neutrophils and histiocytes (hematoxylin and eosin stain, magnification ×20).

While patients with PNGD may receive systemic therapy, the condition is benign, with 20% of patients experiencing spontaneous resolution.6

Figure 1. (A) Extensor surfaces of the forearms with tender erythematous to brown papules and nodules. (B) Close-up view of extensor surface of the forearm with tender erythematous to brown papules and nodules.

SKINmed. 2018;16:281–284

Histopathologic specimens of PNGD are classically characterized by an intense infiltrate of neutrophils and histiocytes, with vasculitis2; however, findings on pathology can vary along a continuum based on stage of development of the lesion.3 Early lesions may show a dense and diffuse neutrophilic infiltrate with leukocytoclasia and degenerated collagen, whereas late lesions may exhibit palisading granulomas with fibrosis and minimal neutrophilic debris.3 In addition to management of the underlying disease entity, potential treatment options for PNGD include systemic steroids3,

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CASE STUDY

Table. Cases of Palisaded Neutrophilic and Granulomatous Dermatitis (PNGD) in Setting of Systemic Lupus Erythematosus (SLE)

Reference

Year

Number of Cases

Clinical Findings

Site

Other Notable Findings

Management

Chu et al

1994

Six SLE (other cases in series: two RA, one indeterminate connective tissue disease)

Skin-colored to erythematous papules, some with central crust, ulceration, or umbilication

Symmetrical distribution; extremities

—

Several with good response to oral prednisone up to 20 mg daily

Misago et al12

2010

SLE 39 y/o F

Erythematous macules and papules

Symmetrical distribution; all fingers and bilateral palms

In setting of left sole cellulitis and fever without SLE flare

IV cefamezin to treat cellulitis; alleviated PNGD within 1 week

Germanas et al13

2006

SLE 12 y/o black F

Erythematous, annular, mildly tender dermal plaques, with dusky centers

Symmetrical distribution; lateral neck, arms, flank, abdomen, and thighs

In setting of biopsy-proven lupus nephritis

IV Solu-Medrol and cyclophosphamide for nephritis; resulted in improvement of lesions

Gulati et al14,a

2009

SLE 42 y/o F

Repeated episodes of tender red plaques in axilla lasting 2 to 3 weeks

Axilla

Fever, malaise, and arthralgias

Mycophenolate mofetil; prevented recurrence

Later in course: erythematous, warm, tender, indurated subcutaneous linear cords extending from axillary folds across chest wall, suggestive of superficial thrombophlebitis; burning sensation

Axilla and trunk

Abbreviations: F, female; IV, intravenous; RA, rheumatoid arthritis; y/o, years old. a Based on clinical presentation, this case may be more consistent with interstitial granulomatous dermatitis.

intralesional triamcinolone,8 and dapsone.11 Despite treatment, however, the lesions may recur, especially when treatment is tapered.8 The fundamental management strategy for PNGD should involve evaluation and treatment of the underlying systemic disorder. CONCLUSIONS PNGD is a neutrophilic dermatosis associated most commonly with rheumatoid arthritis and systemic lupus erythematosus, although many other autoimmune diseases are also associated with it. PNGD is believed by many to exist on a spectrum with interstitial granulomatous dermatitis and interstitial granulomatous drug reaction. PNGD classically presents with

SKINmed. 2018;16:281–284

symmetrically distributed, tender, erythematous to skin-colored papulonodules on the extensor surfaces of the upper extremities. The course is usually benign, and management typically involves treatment of the underlying disease entity. Targeted treatment with intralesional triamcinolone may be beneficial, while severe cases may require systemic medications such as prednisone and dapsone. REFERENCES

283

1 Rosenbach M, English JC, 3rd. Reactive granulomatous dermatitis: A review of palisaded neutrophilic and granulomatous dermatitis, interstitial granulomatous dermatitis, interstitial granulomatous drug reaction, and a proposed reclassification. Dermatol Clin. 2015;33:373–387.

Recurrent Palisaded Neutrophilic Dermatitis

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CASE STUDY

2 Hawryluk EB, Izikson L, English JC, 3rd. Non-infectious granulomatous diseases of the skin and their associated systemic diseases: An evidence-based update to important clinical questions. Am J Clin Dermatol. 2010;11:171–181. 3 Chu P, Connolly MK, LeBoit PE. The histopathologic spectrum of palisaded neutrophilic and granulomatous dermatitis in patients with collagen vascular disease. Arch Dermatol. 1994; 130:1278–1283. 4 Sangueza OP, Caudell MD, Mengesha YM, et al. Palisaded neutrophilic granulomatous dermatitis in rheumatoid arthritis. J Am Acad Dermatol. 2002;47:251–257. 5 Umezawa Y, Ito K, Nakagawa H. Palisaded neutrophilic and granulomatous dermatitis in a rheumatoid arthritis patient after treatment with adalimumab. Eur J Dermatol. 2013;23:910–911. 6 Hantash BM, Chiang D, Kohler S, Fiorentino D. Palisaded neutrophilic and granulomatous dermatitis associated with limited systemic sclerosis. J Am Acad Dermatol. 2008;58:661–664. 7 de Unamuno Bustos B, Rabasco AG, Sanchez RB, de Miquel VA. Palisaded neutrophilic and granulomatous dermatitis associated with ankylosing spondylitis. Am J Dermatopathol. 2013;35: 847–850. 8 Hunt RD, Hartman RD, Molho-Pessach V, Votava HJ, Schaffer JV. Palisaded neutrophilic and granulomatous dermatitis in an adolescent girl with perinuclear antineutrophil cytoplasmic

antibody-positive pauci-immune glomerulonephritis and arthritis. J Am Acad Dermatol. 2012;67:e164–e166. 9 Stephenson SR, Campbell SM, Drew GS, Magro CM. Palisaded neutrophilic and granulomatous dermatitis presenting in a patient with rheumatoid arthritis on adalimumab. J Cutan Pathol. 2011;38:644–648. 10 Gutte R, Khopkar U. Isolated unilateral palisaded neutrophilic and granulomatous dermatitis. Indian J Dermatol Venereol Leprol. 2011;77:615–617. 11 Fett N, Kovarik C, Bennett D. Palisaded neutrophilic granulomatous dermatitis without a definable underlying disorder treated with dapsone. J Am Acad Dermatol. 2011;65:e92–e93. 12 Misago N, Shinoda Y, Tago M, Narisawa Y. Palisaded neutrophilic granulomatous dermatitis with leukocytoclastic vasculitis in a patient without any underlying systemic disease detected to date. J Cutan Pathol. 2010;37:1092–1097. 13 Germanas JP, Mehrabi D, Carder KR. Palisaded neutrophlic granulomatous dermatitis in a 12-year-old girl with systemic lupus erythematosus. J Am Acad Dermatol. 2006;55: s60–s62. 14 Gulati A, Paige D, Yaqoob M, et al. Palisaded neutrophilic granulomatous dermatitis associated with systemic lupus erythematosus presenting with the burning rope sign. J Am Acad Dermatol. 2009;61:711–714.

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CCV

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

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28/03/12 24/12/11 19/01/12

July/August 2018

Volume 16 • Issue 4

BOOK REVIEW Jennifer L. Parish, MD, Section Editor

Revisiting Flaps Shokrollahi, K., Whitaker, I. S., Nahai, F. Flaps: Practical Reconstructive Surgery. New York, Thieme, 2017: 665 pp, $299.99 “Flaps” as the subject of a book on reconstructive surgery is not new. The earliest-known reference text on this subject is Sushruta Samhita, written by Sushruta in India between 1000 and 800 BCE, in which he described reconstruction of the nose using a pedicle cheek flap.1 “Flaps” have continued to remain a major subject of interest in the field of reconstructive surgery, with a never-ending demand for an updated textbook on this subject. Flaps: Practical Reconstructive Surgery is a welcome addition. The single-volume book is divided into three major sections. The first section, on planning and decision making in reconstructive surgery, covers the basic principles. It is heartening that an advanced book on flaps does not ignore some very basic aspects of reconstructive surgery, such as wound healing, the structure and function of skin, Langer lines, facial esthetic subunits, the use of skin tension lines to plan reconstruction, suturing methods, split skin graft harvesting and placement, tissue expansion, bolster dressing, Z-plasty, W-plasty, muscle flaps, and nonsurgical adjunctive wound healing techniques. A chapter dedicated to microsurgery discusses instrumentation, microsurgical techniques, microvascular anastomosis, and key physiologic concepts.

though I would have loved to see more examples for the head and neck region. Section III is focused on a masterclass in reconstructive flaps. The emphasis here is on the esthetic challenges of reconstruction, and it includes a good number of illustrative case reports. The chapters in this section cover topics from nasal reconstruction to face transplantation.

The chapters are lucidly written and heavily supplemented with images. A chapter on head and neck reconstruction would interest dermatologic surgeons most. Full of images, it provides a ready guide for almost every reconstructive challenge in the head and neck region. A chapter dedicated to postoperative monitoring of microvascular free flaps deserves special mention; this discusses the history and chronology of microsurgery and free flap monitoring.

The videos are mostly a demonstration of the anatomy of flaps on cadaveric skin, rather than of actual flap surgery on patients, which is the only disappointment.

Section II provides step-by-step pictorial examples of all kinds of flaps, and this is a visual feast for a reconstructive surgeon, al-

1 Champaneria MC, Workman AD, Gupta SC. Sushruta: Father of plastic surgery. Ann Plast Surg. 2014;73:2–7.

The book will be a good addition to the bookshelf of reconstructive surgeons, as well as for libraries of all medical institutions and hospitals involved in reconstructive surgery. REFERENCE

Reviewed by Somesh Gupta, MD, Professor of Dermatology and Venereology, All India Institute of Medical Sciences, New Delhi, India • E-mail: someshgupta@hotmail.com

SKINmed. 2018;16:286

286

Botulinum Toxins:

CosmetiC and CliniCal appliCations edited by Joel l. Cohen and david m. ozog Video editor: dennis porto

Use code VBN58 to save 25% at www.wiley.com Botulinum Toxins: Cosmetic and Clinical Applications provides a comprehensive and in-depth review of the use of botulinum toxin for esthetic procedures and medical applications as a stand-alone treatment and as combination therapy with other non-surgical procedures. Benefits from a wealth of color images, procedural videos, and expert tips and tricks Takes a region oriented approach, providing guidance on treatment of the glabella, forehead, periocular and perioral areas, plus contouring of the lower face, lower leg and calf, and neck rejuvenation Contains a thorough review of non-cosmetic treatments such as correction of facial asymmetry and treatment of axillary hyperhidrosis, plus palm, sole, and craniofacial hyperhidrosis Covers exciting new topics, such as future

9781444338256 | 392 pages | Fall 2017 $199.95, ÂŁ139.99, â&#x201A;Ź182.00

injectables, topical botulinum toxin, and facial contouring including treatment for benign

Includes considerations for darker skin types

For further information please go to

www.wiley.com

Also available as an eBook 17 - 320209

masseter hypertrophy

July/August 2018

Volume 16 • Issue 4

BOOK REVIEW

Urgent Care Dermatology: Symptom-Based Diagnosis Fitzpatrick J.E., High W.A., Kyle W.L. Urgent Care Dermatology: Symptom-Based Diagnosis. Philadelphia, PA, Elsevier, 2018: 632 pp, $59.99. By writing Urgent Care Dermatology, authors James E. Fitzpatrick, Whitney A. High and Consulting Editor W. Lamar Kyle have thoughtfully crafted a timely addition to the dermatologic and primary care literature. During the last decade, we have witnessed the shift in the locus of care away from busy primary care offices and crammed emergency rooms to urgent care centers. Taking a cue from a physician working in such settings, W. Lamar Kyle, MD, the authors have compiled a work focusing on entities that a health care provider is likely to encounter. To enhance timely diagnosis, all such entities are grouped by physical findings rather than pathogenesis.

the life-threatening entities, including meningococcemia, Rocky Mountain spotted fever, and purpura fulminans. The publication of this book in the age of hurry-up medicine prompted by the forces of managed care is most timely. This reference enables more rapid and comprehensive dermatologic diagnosis, and deserves a prominent place on the same shelf as other classic texts pertinent to outpatient medicine.

As primary care physicians, we very much appreciated the authors’ sage advice to approach skin complaints like a dermatologist: namely, to identify the primary lesion, the secondary morphology, the dominant configuration, and the anatomic distribution. Pattern recognition follows, enabling the diagnostician to parse out the likely causes: inflammatory, neoplastic, etc. The utility of this book predicated on “symptom-based diagnosis” enables the reader to research the various entities relevant to the findings. Unlike other texts, the reader is briefed at the beginning of each chapter on the upcoming entities by a series of questions and answers regarding the key history and physical findings. The discussion of each entity is captured on the left-hand page, and the pertinent photographs are laid out on the right-hand side, allowing for rapid text-visual correlation. The early inclusion of the fundamentals of dermatologic techniques underscores the simplicity and importance of punch and shave biopsies, and the basic potassium hydroxide preparation and Tzanck smear. Topics then flow smoothly, covering such common diseases such as urticarial eruptions, scaly disorders, and abscesses, up to the uncommon and more serious conditions such as panniculitis, polyarteritis nodosa, systemic lupus, and vasculitis. Finally, special emphasis is given to

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

SKINmed. 2018;16:288

288

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

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

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

•

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

•

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

•

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

•

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

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

Patents: 5,954,703,

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

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

LAB-1442AW Rev D

REDISCOVER

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

MKT-1790AW Rev C