Volume 37 March 2017 JAOCD Journal Of The American Osteopathic College Of Dermatology

Why is Skin Cancer Still on the Rise? A standardized survey exploring screening behaviors, tanning attitudes, and sun-protective measures in a general U.S. sample population

Also in this issue: Locally Advanced BCC with Subtle Skin Findings Chronic Inflammation and Vascular Density in Sun-Exposed Skin SCC in a Pediatric Patient with NF-1

Journal of the American Osteopathic College of Dermatology

2016-2017 AOCD OFFICERS

PRESIDENT Alpesh Desai, DO, FAOCD

PRESIDENT-ELECT Karthik Krishnamurthy, DO, FAOCD

FIRST VICE-PRESIDENT Daniel Ladd, DO, FAOCD

SECOND VICE-PRESIDENT John P. Minni, DO, FAOCD

Co-Editor-in-Chief THIRD VICE-PRESIDENT Reagan Anderson, DO, FAOCD Karthik Krishnamurthy, DO SECRETARY-TREASURER Steven Grekin, DO, FAOCD Co-Editor-in-Chief TRUSTEES Derrick Adams, DO Danica Alexander, DO, FAOCD (2015-2018) Michael Whitworth, DO, FAOCD (2015-2016) Tracy Favreau, DO, FAOCD (2013-2016) Assistant Editor David Cleaver, DO, FAOCD (2014-2017) Julia Layton, MFA Amy Spizuoco, DO, FAOCD (2014-2017) Peter Saitta, DO, FAOCD (2015-2018)

IMMEDIATE PAST-PRESIDENT Rick Lin, DO, FAOCD

EEC REPRESENTATIVES James Bernard, DO, FAOCD Michael Scott, DO, FAOCD

FINANCE COMMITTEE REPRESENTATIVE Donald Tillman, DO, FAOCD

AOBD REPRESENTATIVE Michael J. Scott, DO, FAOCD

EXECUTIVE DIRECTOR Marsha A. Wise, BS

AOCD • 2902 N. Baltimore St. • Kirksville, MO 63501 800-449-2623 • FAX: 660-627-2623 • www.aocd.org COPYRIGHT AND PERMISSION: Written permission must be obtained from the Journal of the American Osteopathic College of Dermatology for copying or reprinting text of more than half a page, tables or figures. Permissions are normally granted contingent upon similar permission fromthe author(s), inclusion of acknowledgement of the original source, and a payment of $15 per page, table or figure of reproduced material. Permission fees are waived for authors wishing to reproduce their own articles. Request for permission should be directed to JAOCD c/o AOCD, PO Box 7525, Kirksville, MO 63501. Copyright © 2003 by the Journal of the American Osteopathic College of Dermatology Layout by: John Grogan Copy editing by: Julia Layton, Freelance Writing and Editing

Page 3 JOURNAL OF THE AMERICAN OSTEOPATHIC COLLEGE OF DERMATOLOGY Journal of the American Osteopathic College of Dermatology Volume 37 Table of Contents March 2017 Review Board...... 5 Letter from the Editor...... 6 Letter from the Executive Director ...... 7 Letter from the President ...... 8

FEATURE ARTICLE Understanding Skin Cancer Screening Behaviors, Tanning Attitudes, and Sun Protective Measures of a General U.S. Sample Population Using Standardized Skin Cancer Survey Questions...... 11 Miguel Villacorta, DO, MPH, Simona Bartos, DO, MPH, Cyril Blavo, DO, MS, MPHTM, Patrick Hardigan, PhD, Tracy Favreau, DO

Atypical Fibroxanthoma: A Case Report and Literature Review...... 17 Jacqueline C. Fisher, DO, Megan Jones, BA, Daniel S. Hurd, DO Childhood Exanthems: A Differential Challenge...... 20 Samuel Ecker, DO, Jacquiline Habashy, DO, Stanley Skopit, DO, MSE, FAOCD, FAAD Chronic Inflammation and Vascular Density in Sun-Exposed Skin...... 25 Karan Lal, DO, Maria Plummer, MD, Mariya Milko, DO, Mariya Belyayeva, DO, Min-Kyung Jung, PhD, Dirk Elston, MD Clear Cell Acanthoma: A Clinical, Dermoscopic and Histological Review...... 29 John Howard, DO, Andrei Gherghina, DO, MS, Jacquiline Habashy, DO, MS, Angela Poulos Combs, DO, FAOCD, FAAD, Stanley Skopit, DO, MSE, FAOCD, FAAD Guaifenesin-induced Acute Generalized Exanthematous Pustulosis (AGEP): A Case Presentation and Discussion...... 31 Christine Sickles, DO, Danielle R. Lazzara, BS, Garrett Bohrnstedt, DO Leser-Trélat Sign Presentation with Mediastinal Squamous Cell Carcinoma...... 33 Paloma Reiter, BA, Leeor Porges, DO, Jacqueline Thomas, DO Locally Advanced Basal Cell Carcinoma with Subtle Skin Findings...... 35 Shana Rissmiller Schroeder, DO, Mina Le, MD, Robert Taylor, MD Oculocutaneous Albinism, A Family Matter...... 38 Summer Moon, DO, Katherine Braunlich, DO, Howard Lipkin, DO, Annette LaCasse, DO Porphyria Cutanea Tarda: A Case Presentation and Discussion...... 40 Jordan Harris, DO, Craig Parson, Michael Eyre, DO, FAOCD A Rare Case of SCC in a Pediatric Patient with NF-1...... 44 Christopher Mancuso, DO, Mojgan Hosseinipour, BA, Craig Austin, MD, Charles Gropper, MD, Cindy Hoffman, DO Sclerotic-Type Chronic Graft-Versus-Host Disease: A Case Presentation and Discussion...... 46 Madeline Tarrillion, DO, Jenifer Lloyd, DO Secondary Syphilis: The Great Masquerader: A Case Presentation and Discussion...... 48 Gina Caputo, DO, Roxanne Rajaii, MS, DO, Gary Gross, MD, Daniel S. Hurd, DO Segmental Speckled Lentiginous Nevus Exacerbated by Pregnancy in an Otherwise Healthy Female: A Case Report...... 51 Logan Kolb, DO, Jessica Schweitzer, DO, Mary Veremis-Ley, DO

JOURNAL OF THE AMERICAN OSTEOPATHIC COLLEGE OF DERMATOLOGY Page 4 Co-Editor-In Chief Co-Editor-In Chief Founding Editor Assistant Editor Karthik Krishnamurthy, DO Derrick Adams, DO Jay Gottlieb, DO Julia Layton, MFA Editorial Review Board Sami Abbasi, DO Matthew Elias, DO Angela Leo, DO Andrew Racette, DO Brownstown, MI Lighthouse Point, FL New York, NY Phoenix, AZ

Ali Banki, DO Merrick Elias, DO Scott Lim, DO Richard Rudnicki, DO Glastonbury, CT Pembroke Pines/Davie, FL Erie, PA Mesquite, TX

Brett Bender, DO Michelle Foley, DO Chava Lustig, DO Amara Sayed, DO Farmington Hills, MI Ormond Beach, FL Weston, FL San Marcos, TX

Aaron Bruce, DO Marcus Goodman, DO Jere Mammino, DO Joseph Brant Schneider, DO Bozeman, MT Roswell, GA Winter Springs, FL Shawnee Mission, KS

Ryan Carlson, DO Melinda Greenfield, DO John Minni, DO Michael Scott, DO Hilliard, OH Albany, GA Port St. Lucie, FL Seattle, WA

Igor Chaplik, DO Andrew Hanly, MD Tony Nakhla, DO Sean Stephenson, DO Aventura, FL Miami, FL Orange County, CA Troy, MI

Michael P. Conroy, MD Joel Harris, DO Navid Nami, DO Jacqueline Thomas, DO Columbus, OH Madison Heights, MI Newport Beach, CA Fort Lauderdale, FL

John Coppola, DO David Horowitz, DO Jon Keeling, DO Jim Towry, DO Ormond Beach, FL Torrence, CA Lexington, KY Ocala, FL

Jonathan Crane, DO Mark Lebwohl, MD Dimitria Papadopoulos, DO Wilmington, NC New York, NY Bellmore, NY

Page 5 EDITORIAL REVIEW BOARD Letter from the Editor

Derrick Adams, DO, FAOCD Co-Editor-in-Chief, JAOCD

Dear Readers,

Yet another year has passed, and the JAOCD is celebrating its 14th year in publication. It was founded by Dr. Jay Gottlieb in 2003 and has attracted many talented and dedicated editors and reviewers over the decades. As our current Editor-in-Chief, Dr. Karthik Krishnamurthy, assumes the responsibilities of the AOCD presidency, I will be piloting the ship.

As early as this spring, you should be able to claim category 1B credit for reading the journal and taking a brief quiz. Rather than reinventing the wheel, we have been working with other specialty DO organizations to ensure our CME credits are valid and recognized by the AOA. My hope is that this helps our members attain the few category 1 hours sometimes unavailable at our meetings. Of course, I also hope it incentivizes more of us to include the JAOCD in our regular reading regimen.

We also have published our last printed issue. Going forward, all issues will be online and always available for you to peruse. In an era of shrinking sponsorship, it no longer makes sense to continue printing and mailing our journal. This decision also allows us to practice good environmental stewardship and will help us to more accurately assess our true readership, allowing us to approach more sponsors and tweak our journal to better fit your needs.

Many of us, myself included, first published in the JOACD, and I wish to keep this option open for future authors. We need your help, though, to make this happen. The residency requirement of a yearly publishable paper has not produced the volume of quality submissions we need to become a suitably prestigious reflection of our College and our profession. We rely on Program Directors to thoroughly review their residents’ papers, a responsibility that may be getting lost in the shuffle. I kindly ask that Program Directors take this task seriously, as subpar submissions clog our review process and continue to hinder our bid for MedLine indexing. We ask that authors honestly assess their work to determine whether it represents the thoughtfulness and professionalism required of great physicians -- and if not, change it. We want to see the best you have to offer.

Finally, I would like to invite submissions that broaden our scope. We receive plenty of case reports. Consider producing original research and in-depth reviews, and focusing on topics specifically related to osteopathy. We also welcome opinion pieces, letters to the editor, comments on current or historical events, clinical pearls and tidbits of wisdom, and comments and opinions on AOA/ AOCD policies and procedures.

I hope you find increased value in our new electronic format, and I look forward to seeing what our authors produce for upcoming issues.

Stay well,

Derrick

Derrick Adams, DO Co-Editor-in-Chief, JAOCD

LETTER FROM THE EDITOR Page 6 Letter from the Executive Director

Marsha Wise Executive Director, AOCD

Hello, Everyone,

Welcome to the first online issue of the JAOCD!

The new year will hopefully open up new opportunities for our members to obtain CME credits. We applied to award category 1B credit for reading the JAOCD, and we have now received approval from the AOA. We will begin to offer 1B credit for reading the journal on March 1, 2017. We also plan to begin offering online category 1A credit.

The AOCD staff has been working to obtain ACCME accreditation in order to provide AMA credit for our CME meetings. The application has been submitted, and we learned recently that we are scheduled for our initial interview in March 2017. By August 1, we will have an official determination from the ACCME on whether the AOCD qualifies to provide AMA credit. Wish us luck!

We hope you will make plans to attend our Spring 2017 meeting in Atlanta, GA, from March 29 through April 1. The meeting will take place at the Ritz-Carlton Atlanta. More information on the meeting can be found on our web site at www.aocd.org and in our weekly Thursday Bulletin email blasts.

Save The Dates!

• 2017 Fall Meeting: October 24-28 at the Intercontinental New Orleans • 2018 Spring Meeting: March 19-25 at the Hilton West Palm Beach • 2018 Fall Meeting: October 9-13 at the Westin San Diego, Gaslamp Quarter

We would like to remind everyone that the Foundation for Osteopathic Dermatology is accepting applications for research grants. For more information, visit the Foundation page at https://aocd.site-ym.com/?page=Foundation.

As always, please call (1-800-449-2623) or email ([email protected]) the AOCD office if you need assistance.

Here’s to a happy and healthy 2017!

Sincerely,

Marsha Wise Executive Director, AOCD

Page 7 LETTER FROM THE EXECUTIVE DIRECTOR Letter from the President

Alpesh Desai, DO, FAOCD President, AOCD

Happy New Year! January 1, 2017 ushered in new opportunities and challenges. Last year is but a vapor. With the new year comes a change in leadership in the White House. We witnessed an election season like no other in history. As with any change in leadership, we and our practices will all experience some form of change and growth as a result of that election. Let us remain true to our practice of medicine, regardless of political view.

As President of the AOCD, I welcome you to the winter edition of the Journal of the American Osteopathic College of Dermatology. It seems but yesterday we gathered in Santa Monica for our Fall meeting. In March, we will gather in Atlanta to learn, develop fellowship, and share new knowledge and ideas. I encourage all of our membership to make a special effort to join us in Atlanta. The cast of presenters is both broad and deep in knowledge and experience.

You have all honored me with your support throughout this year, and Dr. Lin, our Immediate Past President, continues to guide me through some unchartered waters as we move into the future. Please continue your invaluable support of all our AOCD leadership.

During this holiday season, I pondered my own professional and personal accomplishments and goals. I realized I had not updated my plan over the last several years, mostly because it remains grounded in my core values. Although a few of the desired outcomes of those values have changed, I determined I must become more proactive in shaping those outcomes.

I decided I will be a verb in 2017!

As humans, we declare resolutions with conviction. We begin with such steadfastness, but soon, our persistence wanes, with the ever-present pressures of life. I believe that is why so many New Year’s resolutions come and go before the end of winter (or even before January 31!). Our goals are descriptive of what we want, and perhaps not what we need to be to accomplish what we want. Our goals are but nouns and adjectives to describe success, health, happiness, or anything else upon which we set our sights.

Conversely, “being” requires conscious choice. Being a verb communicates a commitment to action. Assuming the role of a verb means honoring whom we want to be. Try “being a verb” in this wonderful new year!

Let’s keep the AOCD strong as a provider of service and support to dermatologists who chose the path of osteopathy. As you read this edition of the JAOCD, think about how we can keep the vision and legacy of DO dermatology alive and well. Keep the main thing the main thing. Let me know the verb you choose.

See you in Atlanta!

Alpesh Desai, DO President, American Osteopathic College of Dermatology

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*Dermatology Resident, 1st year, Broward Health Medical Center, Ft. Lauderdale, FL **Traditional Rotating Intern, Broward Health Medical Center, Ft. Lauderdale, FL ***Director and Professor of Public Health, College of Public Health, Nova Southeastern University, Ft. Lauderdale, FL ****Executive Director of HPD Research, College of Osteopathic Medicine, Nova Southeastern University, Ft. Lauderdale, FL *****Dermatologist, Ft. Lauderdale, FL

Disclosures: None Correspondence: Simona Bartos, MPH, MS; [email protected]

Abstract Skin cancer is the most commonly diagnosed cancer in the United States, and its incidence is increasing over time. Despite this, screening guidelines are not agreed upon, and there are few standardized tools to analyze sun-exposure attitudes and behaviors. This study examines the frequency of self-reported burns, tanning attitudes, sun- protection behaviors, self-skin exams (SSE), and clinical skin exams (CSE) and aims to contribute to skin cancer screening research through the use of this standardized skin-surveillance survey measure. Through these measures, this study aims to add to the growing body of research in skin surveillance as well as improve the validity of comparisons between studies.

Cancer Society, recommend routine skin cancer deployment of our survey, the Nova Southeastern Introduction 11-13 Skin cancer, the most common form of cancer screenings. However, the U.S. Preventive Task University Institutional Review Board (IRB) 1 Force has concluded that there is insufficient granted exempt IRB status for the study on in the United States, is divided into three main 14 categories: melanoma, basal cell carcinoma and evidence for these screenings. This lack of December 15, 2014. The survey was open for squamous cell carcinoma. Over the last few decades, agreement demonstrates the need for additional data collection during a three-day period between the number of cases of skin cancer has increased.2,3 research in this area. March 9, 2015 and March 11, 2015. Melanoma is among the most aggressive and hard- To our knowledge, the only skin-screening program Before completing the questionnaire, the to-treat cancers. In 2014, an estimated 76,100 new that has led to a significant reduction in mortality participants were informed that their participation cases and 9,710 deaths were expected in the United occurred in 2004, when Germany implemented was voluntary and anonymous. Participation in States, with melanoma accounting for 75% of all 4 the first effective population-based skin cancer the survey implied informed consent. Participants skin cancer deaths. screening program. It decreased mortality by were recruited using the SurveyMonkey.com 11 One in five Americans may develop skin cancer in about 50% after five years. Germany went on Audience service. This service consists of a diverse their lifetime.5 More than $8.1 billion is spent on to implement a nationwide skin cancer screening group of over 45 million members utilizing treating skin cancer annually.6 initiative in 2008. multiple channels to attract diverse participants and incorporates multiple data sources to reduce 15 Despite the increasing incidence of skin cancer, it is Further complicating this area of research are bias. In addition, SurveyMonkey utilizes one of the most preventable types of cancer.7 While the variations in study design and methods profiling and screening as well as TrueSample fair skin complexion is a risk factor, the major used in different skin cancer screening studies. Validation to validate each respondent. Gallup, a modifiable risk factor is exposure to ultraviolet These variations make it difficult to draw clear proven and reputable full research business service, radiation (UV).8 Public health efforts have focused conclusions. Recent studies have begun to take conducts phone interviews with 1,500 people each steps to streamline this area of research by creating day. 15 SurveyMonkey, like Gallup’s metrics, fall on reducing UV exposure, increasing adoption 7 15 of sun-protective habits, promoting regular skin standardized skin screening survey items. Most consistently within a 5% margin of error. cancer screenings, and educating patients on the studies involving skin cancer screening have sampled data from patients that have recently SurveyMonkey Audience members participate dangers of UV exposure. Despite these efforts, skin 8 cancer rates continue to increase in the United had a clinical skin exam. The use of convenience in surveys via the Internet and can participate States.4 samples may be a source of bias in the literature. only in a limited number of surveys each week. The variability in the data from non-standardized Participants do not receive direct compensation Understanding skin-screening habits, ultraviolet- question sets and the lack of generalized sample for answering surveys, but receive non-monetary population studies have contributed to the incentives including contributions to charities of exposure risk, tanning attitudes, and perceptions 16,17 are essential for implementation and evaluation of underdevelopment of formal skin cancer screening their choice. interventional efforts. However, there are no clear guidelines. Standardized questionnaires and studies guidelines to guide the practitioners. involving skin-screening behaviors in the general Criteria for survey participation included (a) population are needed.8 adults between 18 years of age and 100 years Early detection of melanoma offers the best of age; (b) English proficiency; (c) residence in chance for a cure.9 Melanoma invades vertically Purpose the United States; (d) a participating member and becomes metastatic over time, with the The aim of this study is to report the frequency of of SurveyMonkey.com Audience service; (e) best prognostic indicator being tumor thickness self-reported self-skin exams (SSE), clinical skin unmet survey participation quota according to (Breslow depth).10 A retrospective study found exams (CSE), tanning attitudes, and sun protection SurveyMonkey’s policies; and (f ) acceptance of that full skin examination increases the detection behaviors in a U.S. general population sample of informed consent. of melanoma, decreases overall Breslow thickness adults utilizing standardized skin-surveillance at diagnosis, and decreases patient morbidity and survey measures. Various definitions of skin examinations exist in mortality.9 the literature, and for this study we used the Sharon Research Design and Methods Manne and Nadine Kasparian definition.8,18 It In light of the variability present in the published Our study utilized a survey that was designed and states that the skin examination is “the careful and literature, the benefit of skin examinations continues administered using the web-based SurveyMonkey. deliberate checking for changes in spots or moles com platform. For security measures, the web- on all areas of your skin, including those areas rarely to be debated. Many organizations, including the 8,18,19 American Association of Dermatology (AAD), based questionnaire was conducted using standard exposed to the sun.” Self-skin examination was the Skin Cancer Foundation and the American web-based https security protocols. Prior to the defined as “a skin examination performed by yourself

Page 11 UNDERSTANDING SKIN CANCER SCREENING BEHAVIORS, TANNING ATTITUDES, AND SUN PROTECTIVE MEASURES OF A GENERAL U.S. SAMPLE POPULATION USING STANDARDIZED SKIN CANCER SURVEY QUESTIONS with the help of a partner or a mirror.” A clinical included gender, age, ethnicity, and self- Results skin examination was defined as “a skin examination assessed Fitzpatrick skin type obtained by A total of 1,044 respondents initiated the survey, performed by a health care professional.” utilizing a photographic reference and text. The and 1,026 completed it, for a completion rate of skin phenotype is commonly classified using 98.2%. There were 987 total surveys included in In 2005, a collaborative research group led by Karen the Fitzpatrick classification system, which our analysis after 39 were excluded of the basis of Glanz worked toward developing standardized combines constitutional skin color and tanning age. Of these respondents, 54% (529) were female core measures to evaluate sun exposure and sun- ability.20 Skin history was assessed by questions 7 and 46% (458) were male. Most respondents were protection habits. This group established a set of regarding prior personal or family history of skin White/Caucasian (82%, 810), from the Pacific consensus-based, standardized skin survey items for cancer. Family history was defined as a first- or region (29%, 282), and of Fitzpatrick Skin Type III adults, adolescents, and children. The current study second-degree relative such as a parent, sibling, (37%, 368). Of note, Fitzpatrick Skin Types V and used the research group’s standardized skin cancer or grandparent. VI accounted for only 3% (30) and 1% (8) of the screening questions in addition to survey questions responses, respectively (Table 1). developed based on the work of Kasparian. Efforts The survey also included questions about annual were made to maintain the question type, answer sunburns, clinical skin examinations, self-skin A total of 64% (628) of respondents reported no choices, and formatting of the standardized examinations, sun-protection behavior and use of familial or personal history of skin cancer. The questions wherever possible. indoor tanning. Tanning attitudes as well as social second largest group reported a family history of perceptions of the perceived frequency of skin skin cancer (28%, 278). The remaining respondents The survey questionnaire was divided into exams by friends and family were assessed. reported a personal history (6%) or both family and various sections. Demographic information personal history (3%). Most respondents reported that they have never visited a dermatologist (74%, Table 1. Survey responses: demographics, Fitzpatrick skin type, online platform. 734) and have never used an indoor sun bed (94%, Frequency Percent Cumulative 929) (Table 2). Female 529 53.6% 53.6% Gender Male 458 46.4% 100.0% Regarding skin cancer screenings, 59% (586) reported they have never received a clinical skin American Indian or Alaskan Native 12 1.2% 1.2% screening examination, and 34% (331) reported Asian/Pacific Islander 42 4.3% 5.5% yearly clinical skin examinations. Also, 58% (570) Black or African American 37 3.7% 9.2% reported they have never performed self-skin Race examinations with or without partner assistance, Hispanic or Latino 51 5.2% 14.4% while 11% (109) reported biannual self-skin Prefer to not say 35 3.5% 17.9% examinations, and 16% (158) reported yearly self- White/Caucasian 810 82.1% 100.0% skin examinations (Table 2). Fitzpatrick I 138 14.0% 14.0% In this study, 63% (618) of the respondents had Fitzpatrick II 300 30.4% 44.4% not experienced a sunburn during the previous Fitzpatrick III 368 37.3% 81.7% Skin Type 12 months, 23% (225) experienced one sunburn, Fitzpatrick IV 143 14.5% 96.1% 10% (100) experienced two sunburns, and 4% (44) Fitzpatrick V 30 3.0% 99.2% experienced three or more sunburns. Fitzpatrick VI 8 0.8% 100.0% There were some differences in the prevalence 18-29 207 21.0% 21.0% of sun-protective behaviors. The most common 30-44 230 23.3% 44.3% behavior, wearing sunglasses, was reported by Age 45-60 283 28.7% 72.9% 42% (413) of respondents. In addition, 29% (285) 61+ 267 27.1% 100.0% of respondents reported “sometimes” wearing sunscreen, and 40% (398) of respondents reported $0 to $9,999 55 5.6% 5.6% never spending time in the sun to get a tan. $10,000 to $24,999 91 9.2% 9.2% $25,000 to $49,999 91 9.2% 9.2% Most respondents (56.1%) agreed that tanning $50,000 to $74,999 42 4.3% 4.3% makes them look better. However, most respondents (83.1%) disagreed that their skin was healthier $75,000 to $99,999 33 3.3% 3.3% when tanned. Most (59.9%) disagreed that tanning Income $100,000 to $124,999 19 1.9% 1.9% makes them feel better about themselves, and most $125,000 to $149,999 56 5.7% 5.7% (55.3%) reported avoiding tanning due to the $150,000 to $174,999 133 13.5% 13.5% associated risks of skin cancer and premature aging $175,000 to $199,999 148 15.0% 15.0% (Table 3). $200,000+ 157 15.9% 15.9% Prefer not to answer 159 16.1% 16.1% Discussion The Healthy People 2020 goal for number of U.S. East North Central 140 14.2% 14.2% adults experiencing a sunburn over a 12-month East South Central 28 2.8% 2.8% period is 33.8%.21 Data from this study suggest that Middle Atlantic 176 17.8% 17.8% 37.4% of U.S. adults have had at least one sunburn Mountain 60 6.1% 6.1% in the last 12 months. This data is comparable to U.S. New England 45 4.6% 4.6% the 37.5% of U.S. adults experiencing at least Region one sunburn over the last 12 months as reported Pacific 282 28.6% 28.6% 22 South Atlantic 110 11.1% 11.1% by the 2010 NHIS report. The 2000 National Health Interview Survey (NHIS) also found that West North Central 54 5.5% 5.5% 36.2% of U.S. adults experienced a sunburn in the West South Central 79 8.0% 8.0% last 12 months.23 This increase of 1.2% represents Android Phone/ Tablet 98 9.9% 9.9% a negative trend that may suggest current public- health efforts remain largely ineffective. Mac Desktop / Laptop 148 15.0% 15.0% Other 11 1.1% 1.1% Device Sunburns and episodic UV exposure increase Other Phone/ Tablet 2 0.2% 0.2% the risk of melanoma and basal cell carcinoma, Windows Desktop/ Laptop 538 54.5% 54.5% while squamous cell carcinoma is associated with iOS Phone/ Tablet 189 19.1% 19.1% cumulative UV exposure.24-26 The number of

VILLACORTA, BARTOS, BLAVO, HARDIGAN, FAVREAU Page 12 Table 2. Survey responses: skin cancer history, UV light exposure, frequency of skin exams. adults who experience fewer sunburns per year is Frequency Percent Cumulative increasing. In this study, the proportion of adults Family and personal 26 2.6% 2.6% who experienced one sunburn over the last 12 History of skin Neither family nor personal 628 63.6% 66.3% months was 22.8%, compared to 18.5% of adults cancer Family only 278 28.2% 94.4% who experienced one sunburn over 12 months as Personal only 55 5.6% 100.0% reported by the 2000 NHIS. The current study reports that 4.5% had three or more sunburns 0 618 62.6% 62.6% per year, compared to 8.0% reported by the 2000 1 225 22.8% 85.4% NHIS. This suggests that, while more adults are Sunburn in past 2 100 10.1% 95.5% experiencing sunburns, the number of adults 12 months 3 25 2.5% 98.1% experiencing multiple sunburns is decreasing. This 4 11 1.1% 99.2% decrease in the number of multiple annual sunburns 5+ 8 0.8% 100.0% may suggest that U.S. adults are decreasing their episodic sun exposure. Daily 4 0.4% 0.4% Monthly 7 0.7% 1.1% Our data show that 43.5% of adults always or often Clinical skin Never 586 59.4% 60.5% wear sunscreen during the summer on a warm, exam Twice a year 56 5.7% 66.2% sunny day. Other studies report anywhere from 7% Weekly 3 0.3% 66.5% to 72% of adults using sunscreen regularly.8 The Yearly 331 33.5% 100.0% present findings demonstrate 27.7% of adults rarely or never wear sunscreen. Other published studies Daily 16 1.6% 1.6% report this figure to be between 9% and 61%.8 This Monthly 94 9.5% 11.1% wide range may be due to the lack of standardized Never 570 57.8% 68.9% Self-skin exam measures, which reduces the ability to make valid Twice a year 109 11.0% 79.9% comparisons of sun exposure and sun-protection Weekly 40 4.1% 84.0% behaviors between studies.7 Yearly 158 16.0% 100.0% Most adults (71.6%) reported always or often No 734 74.4% 74.4% Dermatological wearing a shirt with sleeves that cover their Cosmetic 54 5.5% 79.8% patient shoulders during the summer, while only 11.0% of Medical 199 20.2% 100.0% adults reported spending time in the sun in order Daily 3 0.3% 0.3% to get a tan. Most respondents in this study, 60.2%, Monthly 12 1.2% 1.5% avoid tanning due to the risk of skin cancer, and Use of tanner/ Never 929 94.1% 95.6% 55.3% avoid tanning due to the risks of skin aging. sunbed Twice a year 13 1.3% 97.0% This may suggest that many adults are exposed to Weekly 9 0.9% 97.9% UV incidentally while outdoors. It may be beneficial Yearly 21 2.1% 100.0% for future public-health educational interventions to focus on daily skin protective behaviors, such

Table 3. Survey Responses: Sun safety measures, Tanning attitudes, and Social perceptions of friends and family. For the following questions, think about what you do when you are Always Often Sometimes Rarely Never outside during the summer on a warm sunny day. How often do you wear SUNSCREEN? 159 (16.1%) 270 (27.4%) 285 (28.9%) 175 (17.7%) 98 (9.9%) How often do you wear a SHIRT WITH SLEEVES that cover your 338 (34.2%) 369 (37.4%) 177 (17.9%) 73 (7.4%) 30 (3.0%) shoulders? How often do you wear a HAT? 121 (12.3%) 217 (22.0%) 239 (24.2%) 236 (23.9%) 174 (17.6%) How often do you stay in the SHADE or UNDER AN 66 (6.7%) 313 (31.7%) 356 (36.1%) 174 (17.6%) 78 (7.9%) UMBRELLA? How often do you wear SUNGLASSES? 413 (41.8%) 262 (26.5%) 160 (16.2%) 83 (8.4%) 69 (7.0%) How often do you spend time in the sun in order to get a tan? 18 (1.8%) 91 (9.2%) 214 (21.7%) 266 (27.0%) 398 (40.3%)

Please state whether you agree or disagree with each statement. Agree Disagree Tanning makes me look better. 554 (56.1%) 433 (43.9%) Tanning makes me look more attractive. 490 (49.6%) 497 (50.4%) Tanning improves the appearance of my skin. 449 (45.5%) 538 (54.5%) My skin is healthier when tanned. 167 (16.9%) 820 (83.1%) Tanning makes me feel better about myself. 396 (40.1%) 591 (59.9%) I avoid tanning due to the risk of skin cancer. 594 (60.2%) 393 (39.8%) I avoid tanning due to the risk of aging. 546 (55.3%) 441 (44.7%)

The following questions are related to your belief of the frequency All Most Few None of skin exams by friends and family. What proportion of your family do you think currently performs self- 40 (4.1%) 149 (15.1%) 500 (50.7%) 298 (30.2%) skin exams? What proportion of your friends do you think currently performs self 3 (0.3%) 97 (9.8%) 608 (61.6%) 279 (28.3%) skin exams? What proportion of your family do you think currently performs 26 (2.6%) 143 (14.5%) 455 (46.1%) 363 (36.8%) clinical skin exams? What proportion of your friends do you think currently performs 8 (0.8%) 83 (8.4%) 550 (55.7%) 346 (35.1%) clinical skin exams?

Page 13 UNDERSTANDING SKIN CANCER SCREENING BEHAVIORS, TANNING ATTITUDES, AND SUN PROTECTIVE MEASURES OF A GENERAL U.S. SAMPLE POPULATION USING STANDARDIZED SKIN CANCER SURVEY QUESTIONS as the daily use of sunscreen. These interventions should take into account the factors associated with adherence to sun-protective practices and screening, which include female gender, sun-sensitive skin type, greater perceived risk, greater perceived benefits, and a recent physician recommendation.8

Published studies report that the percentage of adults engaging in annual clinical skin examinations is between 8% and 21%.27-31 In this study, 59.4% of respondents reported never receiving a clinical skin examination, while 33.5% reported annual clinical skin examination by a health care professional. In contrast, the percentage of adults engaged in annual self-skin examinations, as reported in the published literature, is between 23% and 61%.32-37 In this study, 57.8% of adults reported they never perform self-skin examinations, 11.0% perform biannual self-skin examinations, and 16.0% perform yearly self-skin examinations.

The variations in the data from skin cancer studies may also be influenced by different definitions of clinical and self-skin examinations and by variations in the frequency and thoroughness of examinations, making comparisons between studies difficult.8 One of the clearest findings from a literature review by Kasparian et al. was the variation among reported behaviors across 91 studies.8 A strength of the current study was the use of standardized skin screening tools. This tool can be used in future studies to better describe the prevalence of sun protection, exposure, and skin cancer screening behavior.

Most studies assess the frequency of clinical skin examinations by sampling attendees of skin cancer screening clinics. Many studies utilize a convenience sample of dermatological patients, which introduces a selection bias.8 In contrast, most of the respondents in this study were non- dermatological patients. Only 25.6% of the respondents in this study had seen a dermatologist.

Unlike other studies that utilize convenience samples, this study surveyed a large sample of the general population. Other strengths of this study include the use of standardized definitions of clinical and self-skin examinations. These definitions included criteria for frequency as well as thoroughness of the examination.

A limitation to this study is the use of self-reported samples limited to those with an internet connection and access to SurveyMonkey’s services. Most surveys on sun-exposure and sun-protection behaviors utilize verbal reports and self-reported surveys.38 These are practical and feasible tools for population surveillance. Social desirability bias may have played a role in this study. Other limitations of the study are the low sample of minorities and individuals with a darker skin complexion as well as those without internet access. Future studies can focus on gathering additional data with a higher representation of these groups. Conclusion This study implemented standardized core measures and aims to add to the growing body of research on skin screening behaviors. It is our opinion that the continued use of standardized survey measures will improve the validity of comparisons between studies.

A future study is planned to analyze correlations and perform subset analysis on the collected data. A copy of our standardized questionnaire is available by request.

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VILLACORTA, BARTOS, BLAVO, HARDIGAN, FAVREAU Page 16 Atypical Fibroxanthoma: A Case Report and Literature Review Jacqueline C. Fisher, DO,* Megan Jones, BA,** Daniel S. Hurd, DO***

*Dermatology Resident, PGY-3, LewisGale Hospital Montgomery/Edward Via College of Osteopathic Medicine, Blacksburg, VA **Osteopathic Medical Student, 4th year, Ohio University Heritage College of Osteopathic Medicine, Athens, OH ***Dermatology Residency Program Director, LewisGale Hospital Montgomery/Edward Via College of Osteopathic Medicine, Blacksburg, VA

Disclosures: None Correspondence: Jacqueline C. Fisher, DO; [email protected]

Abstract Atypical fibroxanthoma (AFX) is a rare, rapidly growing mesenchymal neoplasm that often presents on sun-exposed head and neck regions of older individuals. The diagnosis relies on knowledge of its clinical and histological features combined with immunohistochemistry markers used primarily to exclude other cutaneous neoplasms that may share a similar clinical presentation. Current treatment guidelines recommend wide local excision or Mohs micrographic surgery to prevent local recurrence and, on rare instances, metastasis of AFX, combined with long-term clinical monitoring. We report the case of an 88-year-old male presenting with a rapidly growing atypical fibroxanthoma and discuss diagnosis and treatment of this rare cutaneous neoplasm.

Introduction less than 2 cm, but can range in size from 0.3 cm to On clinical examination, his left posterior neck Atypical fibroxanthoma (AFX) is a rare, rapidly 10 cm. Due to its nonspecific clinical appearance, had a solitary, fixed and firm, nontender, red to growing, mesenchymal neoplasm that comprises diagnosis of AFX is challenging. Other pathologies slightly blue, indurated nodule measuring 1.0 cm 0.2% of skin tumors.1,2 AFX was first described in to consider based on physical examination include x 0.8 cm (Figure 1). Significant solar elastosis of 1963 by Helwig et al. as a low-grade dermal tumor squamous cell carcinoma, basal cell carcinoma, surrounding skin was observed. A saucerization consisting of atypical spindle cells with an uncertain pyogenic granuloma, malignant melanoma, adnexal biopsy was performed to remove the bulk of the 3 tumor, cutaneous soft tissue sarcoma, and Merkel tumor, which was sent to a dermatopathology etiology. Since then, research has supported that 2,5 AFX likely arises from a fibroblast or myofibroblast- cell carcinoma. Therefore, biopsy is imperative to laboratory for tissue processing. The differential like cell. The most widely agreed upon predisposing achieve the correct diagnosis. diagnosis included basal cell carcinoma, squamous factor for development of AFX is ultraviolet (UV) cell carcinoma, metastatic prostate carcinoma, 1,2,4,5 AFX was once considered benign secondary to its radiation exposure. Additional risk factors atypical fibroxanthoma, cutaneous soft tissue excellent prognosis. However, reports of metastatic include a history of radiation exposure, previous AFX resulting in death have challenged this Figure 2a burn or trauma to the area, immune suppression, and 1,2 2,4–6 claim. Herein, we report the case of an 88-year- a history of xeroderma pigmentosa. In a recent old male who presented with a rapidly growing review, Koch et al. determined that the majority of atypical fibroxanthoma and provide a discussion cases occur on sun-exposed head and neck regions th th regarding diagnosis and treatment of this rare in males in their 5 to 7 decade of life, with a mean 1 cutaneous neoplasm. age of 75.8. Fewer cases occurred on non-sun- exposed regions, such as the trunk and limbs, of a Case Report slightly younger population. Other reports have An 88-year-old Caucasian male presented to our indicated that AFX occurs in patients ranging from 1,7 dermatology clinic for evaluation of a rapidly 3 to 115 years old. enlarging solid cutaneous tumor present for approximately six months on his posterior neck. Clinically, an atypical fibroxanthoma (AFX) He denied associated symptoms of pain, pruritus, manifests as an asymptomatic, solitary, rapidly 4,5 tenderness, or bleeding. His past medical history growing, exophytic papule or nodule. The was significant for ­­­­basal cell carcinoma, squamous overlying skin may be smooth and intact with a cell carcinoma, and prostate cancer. Family history yellow hue, or it may ulcerate and bleed. AFX is rarely 2 was noncontributory. pigmented. Typically, the diameter of the nodule is

Figure 2b Figure 1 Figures 2a (1x), 2b (5x). H&E stain demonstrating atypical spindled epithelial cells Figure 1. AFX on left posterior neck with background of solar elastosis. with mitosis and multinucleated giant cells.

Page 17 ATYPICAL FIBROXANTHOMA: A CASE REPORT AND LITERATURE REVIEW sarcoma, leiomyosarcoma, amelanotic malignant melanoma, and dermatofibrosarcoma protuberans. The dermatopathology report described sheet-like and fascicular proliferation of atypical spindled cells with admixed multinucleate giant cells using hematoxylin and eosin (H&E) staining (Figures 2a, 2b). Atypical mitotic figures were readily observed along with focal intralesional hemorrhage with siderophage accumulation. Immunohistochemistry demonstrated strong positivity of spindle cells for CD10 and some associated smooth muscle actin (SMA) positivity (Figures 3, 4). Immunohistochemistry was Figure 3 Figure 4 negative for S-100 protein, SOX10, cytokeratin 5/6, high molecular weight keratin and desmin. Figure 3 (1x). Positive CD10 showing significant Figure 4 (5x). Positive SMA showing light The surgical margins were positive. brown staining of AFX on left posterior neck. brown staining of AFX on left posterior neck. Our patient was referred for Mohs micrographic surgery, which required two stages for tumor it helps differentiate a spindle cell SCC from predicting the clinical course of AFX. Patients clearance. The resulting defect measured 4.5 cm x AFX. Furthermore, if S100 and SOX-10 stains with a history of radiation therapy or those who are positive, this frequently distinguishes desmoplastic immunocompromised have a higher risk for AFX 4.0 cm and was reconstructed with a complex linear 10 closure. The patient is currently followed in our melanoma from AFX. Finally, a staining pattern recurrence or metastasis. Previously reported dermatology clinic monitoring for AFX recurrence positive for desmin, smooth muscle actin, and locations for AFX metastases include parotid and metastasis. h-Caldesmon discerns a leiomyosarcoma from gland (most common), subcutaneous fat, lymph AFX (Table 1).1,4,5 nodes, lungs, and abdomen.6,10 Because AFX Discussion has the potential to recur and metastasize, initial Atypical fibroxanthoma (AFX) is typically a Although the goal of immunohistochemical treatment should focus on complete excision with diagnosis of exclusion that requires histopathologic analysis is to distinguish AFX from other tumors clear margins. and immunohistochemical analysis to distinguish it in its histopathologic differential diagnosis, clinical from tumors with similar clinical and microscopic correlation is required because of the potential Treatment appearances. Histopathologically, AFX appears for stain cross-reactivity and/or aberrant staining Due to the rarity of AFX, there are no standardized extremely abnormal, with a dermal proliferation of among neoplasms. Moreover, undifferentiated treatment recommendations. Previously reported haphazardly arranged spindle cells, multinucleated pleomorphic sarcoma (UPS) is argued to be treatments include wide local excision, Mohs giant cells, or epithelioid cells that demonstrate histopathologically and immunohistochemically micrographic surgery, modified Mohs micrographic indistinguishable from AFX.1,4 In fact, some argue surgery (slow Mohs), radiation therapy, cryotherapy, pleomorphism with frequent mitotic figures, 2,6 hyperchromatic nuclei, and intracytoplasmic that AFX is a superficial type of UPS. However, a and electrocautery. Since the majority of cases 2,4 study by Lazova et al. suggested LN-2 stain may be of AFX occur on the head and neck, tissue lipidization. There are several AFX variants 9 based on microscopic morphology. These include specific to UPS (Table 1). It is also proposed that conservation is a priority. spindle cell, desmoplastic, granular, angiomatoid, identification of H-ras, K-ras, and N-ras mutations by gene analyses is diagnostic of UPS since these Mohs micrographic surgery is recommended hemosiderin pigmented, osteoid, clear cell, 4,8 chondroid, keloidal, and myxoid.4,5,8 mutations are absent in AFX. Additionally, because it is an efficient treatment modality to analyzing the deep component of a biopsy may spare tissue and obtain tumor-free margins. Most Due to a lack of distinguishing morphological be helpful in differentiating AFX from UPS, as treatment studies focusing on wide local excision features, immunohistochemical analysis is required evidence of subcutaneous fat invasion, perineural or Mohs have shown recurrence rates ranging from or vascular invasion, or necrosis favors the more 0% to 16%. Furthermore, most of the recurrences to differentiate AFX from spindle cell and squamous 2 11–15 cell carcinoma, malignant melanoma (specifically aggressive UPS neoplasm. Distinguishing occurred within one to two years post-surgery. the desmoplastic variant), leiomyosarcoma, and between AFX and UPS is critical because the For example, Davis et al. (n=44) showed a 16% latter has significantly higher rates of recurrence recurrence and 0% recurrence in AFX cases treated undifferentiated pleomorphic sarcoma (formerly 4 known as myxofibrosarcoma or malignant fibrous and metastasis. Still, there have been limited cases by wide local excision or Mohs surgery, respectively. 5 of metastatic AFX with aggressive characteristics The patients treated by wide local excision were histiocytoma). There is no immunohistochemical 2 stain specific for AFX; however, this tumor should indicative of a poorer prognosis. followed for an average of 73.6 months, and the Mohs patients were followed for an average of stain positive for vimentin, CD10, CD68, and 11 smooth muscle actin. Additionally, AFX should Other primary tumor characteristics of an AFX 29.6 months. Huether et al. (n=33) showed stain negative for CAM5.2, CD34, Melan-A, S100, that may indicate a more aggressive course include patients with AFX treated by Mohs surgery had increased tumor size, depth, ulceration, and a 6.9% recurrence rate over an average follow-up HMB-45, cytokeratin AE1/AE3, and cytokeratin 10 16 5/6. If a tumor stains positive for cytokeratins, necrosis. Patient status is also important when of 3.3 years. Finally, Seavolt and McCall treated 13 AFX patients with Mohs surgery and reported

Table 1. Immunohistochemical staining patterns for AFX vs. tumors in histopathologic differential diagnosis Atypical Fibroxanthoma Spindle/Squamous Cell Carcinoma Melanoma Leiomyosarcoma Undifferentiated Pleomorphic Sarcoma Positive Negative Positive Positive Positive Positive Vimentin Cytokeratins Cytokeratins S100 Desmin CD74 CD68 P63 P63 Melan-A/Mart1 Actin CD10 CD10 S100 HMB-45 H-Caldesmon CD99 Procollagen 1 Desmin MIB-1 CD1A HMB-45 LN-2 (CD74) Fascin Melan-A/Mart1 A1At EMA CD99 CD34 CD31 NGFR CD15 CD74

FISHER, JONES, HURD Page 18 no recurrences; however, the follow-up period was 17 References noted to be short. 1. Koch M, Freundl AJ, Agaimy A, et al. Atypical fibroxanthoma-Histological diagnosis, Radiation or chemotherapy is recommended once 2,8 immunohistochemical markers and concepts of an AFX has recurred or metastasized. There are therapy. Int J Cancer Research and Treatment rare cases where AFX recurrences or metastases 2015; 35:5717–35. resulted in death. A recent review by Koch et al. showed a 0.7% mortality rate in 1,488 patients 1 2. Iorizzo LJ, Brown MD. Atypical fibroxanthoma: with metastatic AFX. Since the literature supports A review of the literature. Dermatol Surg. a risk of recurrence or metastasis, and subsequent 2011;37:146–57. death from an AFX, regular follow-up is highly 6 encouraged for five years after initial treatment. 3. Helwig EB. Atypical fibroxanthoma. Proceedings Although Mohs micrographic surgery is favored of the 18th Annual Tumor Seminar of San Antonio for primary AFX, physicians must use their clinical Society of Pathologists, 1961. Texas State J Med. judgment to determine treatment based on patient 1963;59:664-7. status, comorbidities, and life expectancy. 4. Mahalingam S, Shah A, Stewart A. Atypical Conclusion Fibroxanthoma: A case series and review of Atypical fibroxanthoma is currently considered to literature. Auris Nasus Larynx. 2015;42:469–71. have an intermediate malignant potential requiring timely diagnosis and treatment. It is a rare 5. Gru AA, Santa Cruz DJ. Atypical fibroxanthoma: neoplasm that commands a multi-step diagnostic A selective review. Semin Diagn Pathol. 2013;30:4-12. process including a biopsy with histopathologic analysis, immunohistochemical staining, and 6. Wollina U, Schönlebe J, Koch A, Haroske G. potentially genetic analysis. Once identified, Atypical fibroxanthoma: A series of 25 cases. J Eur Mohs micrographic surgery is supported as the Acad Dermatol Venereol. 2010;24:943–6. best treatment modality for obtaining tumor-free margins and conserving healthy tissue. If treated 7. Goktas FB, Akdeniz H, Ozer K, et al. Atypical appropriately, AFX has an excellent prognosis. Fibroxanthoma in a 115-Year-Old Patient. Arch However, there is a low risk of recurrence, metastasis, Plast Surg. 2015; 42:803–5. and death from a primary AFX. Therefore, regular long-term monitoring for AFX recurrence and 8. Withers AH, Brougham ND, Barber RM, et metastasis is required. al. Atypical fibroxanthoma/ malignant fibrous histiocytoma. J Plast Reconstr Aesthet Surg. 2011;64:e273–8.

9. Lazova R, Moynes R, May D, et al. LN-2 (CD74): A marker to distinguish atypical fibroxanthoma from malignant fibrous histiocytoma. Cancer. 1997;79:2115–24.

10. Giuffrida TJ, Kligora CJ, Goldstein GD. Localized cutaneous metastases from an atypical fibroxanthoma. Dermatol Surg. 2004;30:1561–4.

11. Davis JL, Randle HR, Zalla MJ, et al. A Comparison of Mohs Micrographic Surgery and Wide Excision for the Treatment of Atypical Fibroxanthoma. Dermatol Surg. 1997 Feb;23(2):105-10.

12. Starink TM, Hausman R, Delden LV, et al. Atypical fibroxanthoma of the skin with metastasis. Br J Dermatol 1977; 97:167–77.

13. Fretzin DF, Helwig EB. Atypical Fibroxanthoma of the Skin. Cancer. 1973;31:1541–52.

14. Ang GC, Roenigk RK, Otley CC, et al. More than 2 decades of treating atypical fibroxanthoma at mayo clinic: What have we learned from 91 patients? Dermatol Surg. 2009; 35:765–72.

15. Zalla MJ, Randle HW, Brodland DG, et al. Mohs surgery vs wide excision for atypical fibroxanthoma: follow-up. Dermatol Surg. 1997;23:1223-4.

16. Huether MJ, Zitelli JA, Brodland DG. Mohs micrographic surgery for the treatment of spindle cell tumors of the skin. J Am Acad Dermatol. 2001;44:656–9.

17. Seavolt M, McCall M. Atypical fibroxanthoma: Review of the literature and summary of 13 patients treated with mohs micrographic surgery: Commentary. Dermatol Surg. 2006;32:439–41.

Page 19 ATYPICAL FIBROXANTHOMA: A CASE REPORT AND LITERATURE REVIEW Childhood Exanthems: A Differential Challenge Samuel Ecker, DO,* Jacquiline Habashy, DO,** Stanley Skopit, DO, MSE, FAOCD, FAAD***

* 2nd year resident, Larkin Community Hospital-Dermatology Residency, Miami, FL **Medical Student, 4th year, Western University of Health Sciences, Pomona, CA ***Program Director, Larkin Community Hospital-Dermatology Residency, Miami,FL ; Advanced Dermatology & Cosmetic Surgery, Margate, FL

Disclosures: None Correspondence: Jacquiline Habashy, DO; [email protected]

Abstract Childhood exanthems are frequently related to recent viral or bacterial infection. Other causes involve medications and inflammatory conditions such as immune-mediated vasculitis. We present a challenging case of an asymptomatic 7-year-old girl with an atypical exanthem and discuss differential diagnoses, focusing on common viral and bacterial causes.

Introduction cryoglobulins, and serum protein electrophoresis, disease, erythema infectiosum and roseola infantum. Viral and bacterial infections are common causes were all within normal limits except for the anti- Physicians no longer recognize Duke’s disease as a streptolysin O titer. The ASO titer was markedly distinct entity, but rather an atypical presentation of generalized rashes in children, and patients 2,3 may present with systemic signs and symptoms elevated (1248), and throat culture was positive for of another classical exanthem. Overlapping and such as pharyngitis, fever or malaise. Common Group A beta-hemolytic streptococci. Parvovirus atypical exanthematous clinical presentations are infectious agents include adenovirus, echovirus, B19 IgG and IgM anti-bodies were not detected. often encountered. In order to establish a prompt coxsackievirus, EBV, HHV6, HHV7, parvovirus diagnosis, it is important to have a detailed 1,3 Biopsy and lab findings were consistent with B19 and streptococcus pyogenes. Determining the streptococcal toxin-mediated exanthem. Due underlying pathogen relies heavily on characteristic Figure 3 to a history of penicillin intolerance, the patient skin findings and detailed history gathering of was treated with cefadroxil 30 mg/kg for 10 days, timing, progression and immunization status. hydrocortisone 2.5% cream twice daily as needed The morphology and distribution of cutaneous for two weeks, and camphor/menthol lotion as and mucosal lesions are also essential diagnostic needed. On follow-up, 14 days after initiating clues that help distinguish between childhood treatment, the eruption had completely resolved exanthems. We present a challenging exanthem (Figure 4). diagnosis in a 7-year-old female, providing insights into diagnostic tools that can help guide diagnosis and treatment in patients who present with atypical Discussion physical exam findings. We review characteristic Exanthematous eruptions occur most commonly in features of several childhood exanthems and school-aged children. In the early 1900s, six classical discuss appropriate workup and treatment for each infectious childhood exanthems were described. condition. These include measles, scarlet fever, rubella, Duke’s Figure 1 Figure 4 Case Report A 7-year-old female presented to our dermatology clinic with a two-day history of a generalized erythematous pruritic eruption. She stated the lesions first appeared on her face, and spread to her trunk and extremities after one day. The patient denied cough, fever, chills, sore throat, abdominal pain, arthritis, dysuria, hematuria, diarrhea, bloody stools, sick contacts or recent travel. On physical exam, there were generalized, bright red, erythematous, blanchable macules and confluent patches affecting the malar cheeks, torso, arms, palms and legs, with sparing of the eyelids, chin, axilla and antecubital fossae (Figure 1). Oral exam revealed a white strawberry tongue (Figure 2). There were no lesions on the buccal or palatal mucosa. Pharyngeal erythema, tonsillar Figure 2 enlargement and exudates were also absent. There was no cervical or axillary lymphadenopathy.

Two punch biopsies were performed on the lower back. Histopathology showed polymorphous dermatitis with neutrophils, nuclear dust and red cell extravasation. Fibrinoid necrosis was not observed (Figure 3).

Vasculitis protocol, which included a complete blood count, complete metabolic panel, urine analysis, stool guaiac, anti-streptolysin O titer (ASO), antinuclear antibody, erythrocyte sedimentation rate, antineutrophil cytoplasmic antibodies, rheumatoid factor, hepatitis panel, complement levels, antiphospholipid antibodies,

ECKER, HABASHY, SKOPIT Page 20 understanding of the clinical characteristics that Although our patient had a positive throat culture, Papular-purpuric gloves and socks syndrome help distinguish between various viral, bacterial and we could not rule out the possibility that she was (PPGSS) is another clinical variant of parvovirus inflammatory cutaneous eruptions. a chronic GABHS carrier. In the U.S. population, B19 infection. Many patients experience non- 5% to 15% of children are asymptomatic colonized specific prodromal symptoms including fever, In the following sections, we discuss identifying carriers; therefore, ASO titer may be useful for myalgia, arthralgia and fatigue. As the disease features such as cutaneous distribution and confirmatory purposes.10 The presence of elevated progresses, the hands and feet develop bright progression, associated signs and symptoms, and ASO titer confirmed that our patient had a recent red erythema and edema, as well as papular and appropriate laboratory workup of common viral streptococcal infection. purpuric lesions on the palms and soles.22 and bacterial exanthems. First-line treatment for scarlatina is penicillin Both erythema infectiosum and PPGSS are self- Streptococcal infection (amoxicillin). In the case of an anaphylactic reaction limiting and resolve without treatment. In the Scarlet fever (scarlatina) is caused by infection to penicillin, clindamycin or erythromycin may be United States, the seropositive rate of parvovirus with group A beta-hemolytic streptococcus used. If pruritus is present, oral antihistamines and reaches 50% in adolescents.23 Diagnosis primarily (GABHS), mainly Streptococcus pyogenes, which emollients may be added to the treatment plan. relies on clinical findings. IgM and IgG antibodies produces pyrogenic exotoxins A, B and C. These Children may return to school or daycare 24 hours are elevated in acute infection, with IgM elevation exotoxins produce local inflammatory mediators after initiation of antibiotics.11,12 lasting two to three months. The vast majority of and alterations of the cytokine milieu, leading to cases resolve without serious long-term sequela. dilation of blood vessels and delayed-type skin The prognosis of scarlatina is excellent when Complications may arise when infection occurs 4 reactivity. Streptococcal infections are most caught in a timely manner. Prior to the existence of during pregnancy, possibly resulting in hydrops commonly seen in children between 1 year old antibiotics, GABHS infections had a 20% mortality fetalis, miscarriage or intrauterine death. These and 10 years old. The infection is spread person- and morbidity rate. Since the introduction of risks are greatest when infection occurs during to-person via respiratory droplets and is typically antibiotics, the mortality rate has fallen to less than the first or second trimester. Complications may 5 easy to contract in close-contact settings, such as 1%. The primary goal of treatment is to prevent also occur when patients with hemolytic anemia 5 schools, daycares, and households. the long-term nonsuppurative complications or sickle-cell disease become infected, imparting of GABHS infections: rheumatic fever and the risk of transient aplastic crisis. Lastly, patients Unlike in our case, once infected, patients typically glomerulonephritis. The sequela of rheumatic who are immunocompromised face the risk of life- develop an abrupt onset of fever with sore throat, fever is specific to GABHS pharyngitis, whereas threatening chronic anemia.20 tonsillar enlargement, headache, nausea, vomiting, glomerulonephritis may be caused by both abdominal pain, myalgias, and malaise. The rash pharyngeal and cutaneous GABHS infections, Gianotti-Crosti syndrome typically appears 12 hours to 48 hours after the such as perianal streptococcal infection. 13-15 Gianotti-Crosti syndrome (CGS), or papular onset of fever and is classically characterized by acrodermatitis of childhood, is a type IV 6,7 a sandpaper-like texture. Our patient did not Acute rheumatic fever typically occurs two to four hypersensitivity reaction to viral antigens. The most develop sandpaper-like skin findings, nor did weeks post GABHS infection. The Jones criteria common viral triggers include hepatitis B and she experience associated pharyngitis or tonsillar for diagnosis include both major and minor clinical EBV, but other causes include hepatitis A and C, enlargement. Her lesions also lacked the lacey findings. The major criteria include arthritis, rotavirus, EBV rubella, CMV, coxsackievirus (A16, reticular pattern classically observed in parvovirus pancarditis, Sydenham chorea, subcutaneous nodules B4 and B5), adenovirus enterovirus, respiratory eruptions. Laboratory testing confirmed diagnosis and erythema marginatum. The minor signs include syncytial virus, parainfluenza virus (types 1 and 2), with a positive throat culture and elevated anti- arthralgia, fever, elevated acute phase reactants, and paravirus B19, HHV 6, echovirus, poxvirus, and 16 streptolysin O antibody titer, strongly supporting a prolonged PR intervals. By the Jones criteria, in HIV. 24 streptococcal etiology. In addition, parvovirus B19- order to diagnose rheumatic fever, a patient must specific IgM and IgG antibodies were absent. present with either two major signs or one major plus CGS is typically an abrupt eruption of two minor signs.17 Prompt diagnosis and treatment erythematous, flat-topped papules affecting the Scarlatina classically begins in the skin folds is essential in order to prevent the severe long-term face, extensor extremities and buttocks. These and then rapidly expands to cover the trunk and complication of rheumatic heart disease. papules may coalesce into hemorrhagic plaques and extremities; the palms and soles are usually spared. are either asymptomatic or pruritic.25 Diagnosis The skin-fold lesions often exhibit a linear petechial Acute glomerulonephritis is the leading cause of relies exclusively on clinical presentation. Recent character, known as Pastia’s lines, which was not acute nephritic syndrome. It occurs approximately studies have proposed diagnostic criteria for GCS, 5 observed in our case. Desquamation occurs after 10 days after GABHS pharyngitis and two weeks which include the clinical findings described above approximately four to five days in a cephalocaudal after GABHS skin infection. Most patients present along with symmetrical distribution, duration of progression. with oliguria, hematuria, flank pain, headache, 10 days, and a lack of truncal lesions and scaled 18 malaise, nausea, vomiting and anorexia. Diagnosis lesions.26 GCS is self- limiting, and treatment is 19 Strawberry tongue is another distinct finding of is based on clinical and serological findings. Acute supportive. scarletina. On day one or two, the tongue has a post-streptococcal nephritis in children generally heavy white coating that overlies edematous red resolves with a return to normal renal function and Epstein-Barr virus papillae, known as the “white strawberry tongue.” carries an excellent prognosis, while adults may Epstein-Barr virus (EBV), also known as human By day four or five, the white coating sloughs experience long-term effects such as hypertension herpesvirus 4, is best known as the causative off, leaving red, edematous papilla that produce a and proteinuria. agent of infectious mononucleosis. Transmission 5 strawberry tongue appearance. occurs via saliva. In the United States, 50% of the Parvovirus B19 population is infected by the age of 5.27 Diagnosis and treatment of strep throat is based Erythema infectiosum, or fifth disease, is a common on clinical manifestations delineated by the Centor childhood illness caused by parvovirus B19, a Cutaneous involvement is usually seen in children 8 criteria. The main criteria, each of which is worth single-stranded DNA virus that causes suppression and may be the only symptom present. The eruption one point, include: absence of cough; swollen and of erythrogenesis and pancytopenia. Although most is described as an erythematous macular rash in tender anterior cervical lymph nodes; temperature patients are asymptomatic, approximately 15% of a scattered, haphazard distribution. Cutaneous greater than 100.4° F (38° C); tonsillar exudates patients report a prodromal period characterized by findings are seen in 3% to 15% of those infected or swelling; and an age between 3 and 14 years fever, headache and flu-like symptoms. Cutaneous with EBV. Additional symptoms include fever, old. A score of 0-1 indicates a 1% to 10% chance features appear in roughly 25% of patients.20 hepatomegaly, splenomegaly, posterior cervical of GABHS infection, and no further testing or lymphadenopathy and pharyngitis.27 These treatment is required at this point. A score of 2-3 The exanthem typically begins on the malar cheeks symptoms are rare in children but may be seen in has an 11% to 35% probability of infection and as bright red, macular erythema, known commonly adolescents and adults. supports further testing with a rapid antigen test or as a “slapped cheek appearance.” Later, a lacy, throat culture. If either test is positive, antibiotics reticulated macular eruption spreads to the trunk Patients with EBV mistakenly diagnosed as should be administered. A score of 4 or greater has and extremities.21 In addition, approximately 10% streptococcal infection and treated with amoxicillin a 51% to 53% chance of infection and supports of patients develop transient mild arthralgia that or ampicillin will also present with a cutaneous prompt empiric treatment with antibiotics.9 lasts a few weeks.22 eruption. This rash is typically described as a

Page 21 CHILDHOOD EXANTHEMS: A DIFFERENTIAL CHALLENGE bright red, morbilliform eruption that occurs There are also two variants of the measles: modified The gold standard of treatment includes the full approximately one week after receiving improper and atypical. Modified measles is a milder dose of intravenous immunoglobulin (IVIG) and treatment. The eruption resolves spontaneously presentation with a longer incubation period, and high-dose aspirin. It is also imperative to screen for after treatment is discontinued.28 Infectious it occurs in patients who have preexisting measles coronary artery aneurysms with EKG at the time mononucleosis is self-limited and only requires immunity.36 Atypical measles, on the other hand, of diagnosis, at two weeks, again at six to eight supportive care. occurs in patients who received the previous weeks, and finally at one year after the onset of killed-virus vaccine rather than the live-attenuated symptoms.45 Coxsackie A16 virus vaccine. Because the killed-virus vaccine was Coxsackievirus is a single-stranded RNA distributed between 1963 and 1967, the atypical Henoch-Schönlein purpura enterovirus that most commonly affects children variant occurs in the current adult population.37 Henoch-Schönlein purpura (HSP), a vasculitis and infants. The virus is spread through multiple mediated by immunoglobulin A (IgA), affects routes, including fecal-oral and respiratory Measles can be diagnosed by clinical presentation small vessels mainly of the skin, kidneys, joints and droplets.29 Coxsackieviruses are associated with a alone, but confirmation by laboratory testing is gastrointestinal tract. Although there is a confirmed variety of clinical manifestations including upper required due to the necessity of reporting any role for IgA in HSP, infectious, genetic, antigenic respiratory tract infection, pericarditis, meningitis measles case to public health officials. Tests should and environmental factors are all thought to play and non-specific cutaneous eruptions. Coxsackie include a complete blood count, liver enzymes, a role in the disease. HSP is the most common A16 is responsible for the exanthem hand, foot serological markers (IgG and IgM antibodies), viral vasculitis in children, with 90% of cases presenting and mouth disease (HFMD) and the enanthem cultures, and reverse transcriptase polymerase chain between the ages of 3 years and 10 years, but it can herpangina. reaction testing.31 The measles virus is self-limited, also occur in adults.46 but patients should be given supportive care and HFMD begins as vesicular lesions typically on the vitamin A supplementation. Vitamin A has been The cutaneous eruption is usually the complaint palms, soles, and oral mucosa but can also present on shown to reduce mortality in up to 50% of cases, upon presentation. It typically occurs symmetrically 30 the extremities, trunk and neck. Herpangina, on as well as prevent ocular damage and blindness.38 and in crops, with new crops occurring for up to the other hand, presents as vesicles in the posterior three weeks.47 The rash usually begins as a macular oropharynx. In HFMD and herpangina, patients Kawasaki disease or urticarial eruption on the lower extremities and often report sore throat, fever and headache. Kawasaki disease is a febrile vasculitis affecting buttocks. The initial lesions coalesce and form small- and medium-sized vessels. It is the leading petechiae and palpable purpura, marking the Diagnosis of HFMD and herpangina relies cause of acquired cardiac disease in children.39 hallmark finding of HSP. primarily on clinical exam findings; however, viral Although the cause of Kawasaki is unknown, it is culture of vesicular fluid may be performed for theorized to be an infectious process worsened by The American College of Rheumatology has confirmatory purposes. Both conditions are self- genetic components.40 developed clinical diagnostic criteria for HSP, which limited, and treatment consists of supportive care. include: palpable purpura, presentation before age Patients with Kawasaki disease go through three 20, abdominal pain, and a cutaneous biopsy showing Measles clinical phases: acute, subacute and convalescent. granulocytes in the walls of arterioles or venules.48 Measles, also known as rubeola, is a highly In the acute phase, patients initially present with If suspicion is present, the vasculitis workup should contagious, single-stranded RNA virus most an abrupt onset of fever that does not subside with also be completed as a confirmatory measure. In our commonly seen in children, though it can occur antibiotic or antipyretic treatment. This phase may patient, the maculopapular rash distribution and at any age. Individuals who are susceptible to the last for up to four weeks. The cutaneous findings of absence of abdominal pain made the diagnosis of virus have a 90% chance of becoming infected upon perianal, palm and sole erythema and desquamation HSP unlikely. Furthermore, our biopsy did not show exposure. Transmission occurs through respiratory present in the acute phase, as well. The rash begins granulocytes on the walls of the vasculature. droplets, either airborne or on a surface. People to evolve into a macular, morbilliform eruption on immunized with the live-attenuated vaccine are the trunk and extremities. Bilateral nonexudative Because HSP is self-limiting, treatment is typically protected from contracting the virus upon conjunctivitis, anterior uveitis, strawberry tongue, supportive. If gastrointestinal and renal complaints 31 exposure. lip fissures, secondary organ dysfunction and are present, hospitalization is required to monitor lymphadenopathy may also present in the acute patients to prevent further complications. Those In 2000, the virus was considered to be eliminated phase. When the fever begins to subside, the who do not require hospitalization need close in the United States, but due to a decrease in patient has entered the subacute phase. The follow-up with urine studies to confirm the childhood vaccinations, measles has been on an hallmarks of this phase are desquamation on the disease has run its course without further systemic uptrend. Between 2000 and 2014, 288 cases were complications.48 32 digits and a risk of coronary aneurysm that may confirmed by the CDC. Of those infected, lead to sudden death. Once the clinical signs and patients were either unimmunized or had an symptoms have cleared, with the exception of Erythema multiforme unclear vaccination history. Beau’s lines,41 the patient is considered to be in Erythema multiforme (EM) is considered a type the convalescent phase. IV hypersensitivity reaction to infection, drugs, The clinical manifestation of measles occurs in radiation, autoimmune diseases, malignancies and four stages: incubation, prodromal, exanthematous various other factors. Of reported cases, 90% were 33 The diagnosis of Kawasaki disease is clinical; and recovery. In the incubation period, which laboratory tests and imaging are confirmatory. caused by an infectious process, and of those, HSV lasts for up to three weeks post exposure, patients The diagnostic criteria, created by Tomisaku was the most common. Mycoplasma pneumoniae is are typically asymptomatic or may begin to show also a common cause, mainly in children.49 34 Kawasaki, include a fever that lasts for at signs of fever, respiratory symptoms and rash. least five days and at least four out of the five The prodromal period usually lasts for two to following signs: bilateral conjunctival injection, As the name implies, erythema multiforme has a four days and marks the stage of characteristic mucosal changes (erythematous or fissured lips, wide range of cutaneous presentations; however, symptoms including cough, coryza and the hallmark of EM is a target lesion. This may 35 erythematous pharynx, or strawberry tongue), conjunctivitis. Fever, malaise, and anorexia are extremity changes (erythematous or edematous be the initial presentation, or it may start as an also seen in this stage. The cutaneous outbreak palms or soles, or desquamation), polymorphous erythematous macule, papule or urticarial plaque occurs two to four days after the fever begins, cutaneous eruption, and cervical lymphadenopathy that later morphs into a target lesion. A target whether in the incubation or prodromal phase. (measuring greater than 1.5 cm). Patients who do lesion has a central clearing and/or blistering, along The rash is described as blanchable, erythematous, with an edematous and pale periphery surrounded not meet the criteria but prompt high suspicion for 50 maculopapular lesions that begin on the face and the diagnosis are considered to have incomplete by an erythematous halo. spread downward to the trunk and extremities. Kawasaki disease.42,43 The soles and palms are typically spared. The The diagnosis is based on clinical findings; however, rash usually lasts for two days and then begins to Appropriate laboratory testing includes complete a skin biopsy is warranted in the case of uncertainty improve, indicating the recovery phase. Although blood count, liver enzymes, C-reactive proteins, due to atypical presentation or suspicion of the description, distribution and time frame of erythrocyte sedimentation rate and urine analysis. underlying autoimmune disease. Due to the high the rash fits our case, the prodromal characteristic In studies, urine proteins filamin C and meprin A incidence of HSV and mycoplasma pneumoniae, findings were absent. have shown promise as confirmatory biomarkers.44 serological testing for both is also warranted.

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Group A Streptococcal Carriage: tests can help narrow differential diagnoses 2004;21(5):542–7. and guide appropriate treatment to prevent Can the Troll Be Tamed? Paediatr Child Health. complications and long-term sequela. 1998;3(4):229-30. 27. Bennett NJ. Pediatric Mononucleosis and Epstein- Barr Virus Infection: Background, Pathophysiology, 11. Bass JW. Antibiotic management of group A Epidemiology [Internet]. Medscape. 2016 Nov 1 streptococcal pharyngotonsillitis. Pediatr Infect [cited 2016 Mar]. Available from: http://emedicine. Dis J. 1991 Oct 10;10:S43-9. medscape.com/article/963894-overview. 12. Derrick CW. Erythromycin Therapy for 28. Patel BM. Skin rash with infectious Streptococcal Pharyngitis. Arch Pediatr Adolesc mononucleosis and ampicillin. Pediatrics. Med. 1976 Jan;130(2):175. 1967;40:910–1. 13. Steer A, Gibofsky A. Acute rheumatic fever: 29. Muller M. Coxsackieviruses: Background, Epidemiology and pathogenesis. 2017 Jan [cited Pathophysiology, Epidemiology [Internet]. Medscape. 2016 Mar]. In: UpToDate [Internet]. Available 2016 Aug 15 [cited 2016Mar]. Available from: http:// from: http://www.uptodate.com/contents/acute- emedicine.medscape.com/article/215241-overview. rheumatic-fever-epidemiology-and-pathogenesis 30. Feder HM, Bennett N, Modlin JF. Atypical 14. Kaplan EL, Bisno AL. Antecedent Streptococcal hand, foot, and mouth disease: a vesiculobullous Infection in Acute Rheumatic Fever. Clin Infect eruption caused by Coxsackie virus A6. Lancet Dis. 2006;43(6):690–2. Infect Dis. 2014;14(1):83–6.

Page 23 CHILDHOOD EXANTHEMS: A DIFFERENTIAL CHALLENGE 31. Chen S. Measles: Practice Essentials, Background, 44. Kentsis A, Shulman A, Ahmed S, Brennan Pathophysiology [Internet]. Medscape. 2015 Nov 10 E, Monuteaux MC, Lee Y-H, et al. Urine [cited 2016 Mar]. Available from: http://emedicine. proteomics for discovery of improved diagnostic medscape.com/article/966220-overview. markers of Kawasaki disease. EMBO Mol Med. 2012;5(2):210–20. 32. Papania MJ, Wallace GS, Rota PA, Icenogle JP, Fiebelkorn AP, Armstrong GL, et al. Elimination 45. Wood L, Tulloh R. Kawasaki disease: diagnosis, of Endemic Measles, Rubella, and Congenital management and cardiac sequelae. Expert Rev Rubella Syndrome from the Western Hemisphere. Cardiovasc Ther. 2007;5(3):553–61. JAMA Pediatr. 2014 Jan;168(2):148. 46. Trapani S, Micheli A, Grisolia F, Resti M, 33. Perry RT, Halsey NA. The Clinical Significance Chiappini E, Falcini F, et al. Henoch Schonlein of Measles: A Review. J Infect Dis. 2004 Purpura in Childhood: Epidemiological and May;189(Suppl 1):S4-16. Clinical Analysis of 150 Cases Over a 5-year Period and Review of Literature. Semin Arthritis 34. Richardson M, Elliman D, Maguire H, Rheum. 2005;35(3):143–53. Simpson J, Nicoll A. Evidence base of incubation periods, periods of infectiousness and exclusion 47. Schenfield N. Henoch-Schonlein Purpura: policies for the control of communicable diseases Practice Essentials, Background, Pathophysiology in schools and preschools. Pediatr Infect Dis J. [Internet]. Medscape. 2016 Nov 10 [cited 2016 2001;20(4):380–91. Mar]. Available from: http://emedicine.medscape. com/article/984105-overview. 35. Babbott FL, Gordon JE. Modern Measles. Am J Med Sci. 1954;228(3):334–61. 48. Mills JA, Michel BA, Bloch DA, Calabrese LH, Hunder GG, Arend WP, et al. The American 36. Rosen JB, Rota JS, Hickman CJ, Sowers College of Rheumatology 1990 criteria for the SB, Mercader S, Rota PA, et al. Outbreak of classification of Henoch-Schönlein purpura. Measles Among Persons with Prior Evidence of Arthritis Rheum. 2010;33(8):1114–21. Immunity, New York City, 2011. Clin Infect Dis. 2014;58(9):1205-10. 49. Huff JC, Weston WL, Tonnesen MG. Erythema multiforme: A critical review of characteristics, 37. Atkinson W, Wolfe C, Hambrossky J. diagnostic criteria, and causes. JAMA Dermatol. Epidemiology and Prevention of Vaccine- 1983;8(6):763–75. Preventable Diseases [Internet]. Centers for Disease Control and Prevention. 2015 [cited 50. Huff JC. Erythema multiforme. Dermatol Clin. 2016 Mar]. Available from: http://www.cdc.gov/ 1985;3:141. vaccines/pubs/pinkbook/index.html. 51. Plaza JA. Erythema Multiforme: Background, 38. Pickering LK. Measles. Report of the Pathophysiology, Etiology [Internet]. Medscape; Committee of Infectious Disease [Internet]. 2016 May 24 [cited 2016 Mar]. Available from: American Academy of Pediatrics. 2006 [cited 2016 http://emedicine.medscape.com/article/1122915- Mar]. Available from: http://redbook.solutions. overview. aap.org/chapter.aspx?sectionid=88187186&book id=1484 52. Helmick CG, Bernard KW, D’angelo LJ. Rocky Mountain Spotted Fever: Clinical, Laboratory, and 39. Newburger JW. Summary and Abstracts of Epidemiological Features of 262 Cases. J Infect the Seventh International Kawasaki Disease Dis. 1984 Jan;150(4):480–8. Symposium: December 4-7, 2001, Hakone, Japan. Pediatr Res. 2003 Jan;53(1):153–7. 53. Kaplan JE, Schonberger LB. The sensitivity of various serologic tests in the diagnosis of Rocky 40. Burns JC, Shimizu C, Gonzalez E, Kulkarni Mountain spotted fever. Am J Trop Med Hyg. H, Patel S, Shike H, et al. Genetic Variations in 1986;35:840. the Receptor‐Ligand Pair CCR5 and CCL3L1 Are Important Determinants of Susceptibility to 54. Procop GW, Burchette JL Jr, Howell DN, Sexton Kawasaki Disease. J Infect Dis. 2005;192(2):344–9. DJ. Immunoperoxidase and immunofluorescent staining of Rickettsia rickettsii in skin biopsies. 41. Scheinfield N. Kawasaki Disease: Practice A comparative study. Arch Pathol Lab Med. Essentials, Background, Pathophysiology 1997;121:894. [Internet]. Medscape. 2016 Oct [cited 2016Mar]. Available from: http://emedicine.medscape.com/ 55. Chapman AS, Bakken JS, Folk SM. Diagnosis article/965367-overview. and management of tickborne rickettsial diseases: Rocky Mountain spotted fever, ehrlichioses, and 42. Centers for Disease Control and Prevention anaplasmosis--United States: a practical guide for [Internet]. Kawasaki Disease. 1983 Feb [cited 2016 physicians and other health-care and public health Mar];32(7);98-100. Available from: http://www. professionals. MMWR Recomm Rep. 2006 Mar cdc.gov/mmwr/preview/mmwrhtml/00001256. 31;55:1-27. htm.

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ECKER, HABASHY, SKOPIT Page 24 Chronic Inflammation and Vascular Density in Sun-Exposed Skin Karan Lal, DO,* Maria Plummer, MD,** Mariya Milko, DO,*** Mariya Belyayeva, DO,**** Min-Kyung Jung, PhD,***** Dirk Elston, MD******

*Intern, Department of Internal Medicine, University of Connecticut Health Center, Farmington, CT **Assistant Professor, New York Institute of Technology College of Osteopathic Medicine, Old Westbury, NY ***Resident, Department of Internal Medicine, Largo Medical Center, Largo, FL ****Resident, Department of Emergency Medicine, Coney Island Hospital, Brooklyn, NY *****Biostatistician, New York Institute of Technology College of Osteopathic Medicine, Old Westbury, NY ******Chairman, Department of Dermatology and Dermatologic Surgery, The Medical University of South Carolina, Charleston, SC

Disclosures: None Correspondence: Karan Lal, DO; [email protected]

Abstract Introduction: Prior studies have identified increased chronic inflammation in sun-exposed sites compared to sun-protected sites. Ultraviolet radiation has also been found to promote angiogenesis. We propose a possible relationship between inflammation, angiogenesis and photocarcinogenesis.Materials and Methods: Two elliptical biopsies from sun-exposed skin and sun-protected skin were taken from 13 Caucasian cadavers. Dermal vessels and inflammatory cells were counted in H&E stained slides per 10 consecutive high-power fields (400 X).Results: Sun-exposed biopsies showed a significant increase in mean numbers of both chronic inflammatory cells and vessels compared to sun-protected biopsies (p < 0.001). No statistically significant correlation was found between mean number of vessels and mean number of chronic inflammatory cells in either exposed and protected specimens (r= -0.37; p=0.21 and r =0.24; p=0.43, respectively).Conclusion: Sun-exposed skin demonstrates an increase in chronic inflammatory cells and vessels compared to sun-protected skin.

Abstract originally presented at the American Osteopathic Association 2014 Research Conference and published in the Journal of the American Osteopathic Association, 2014 Dec; 114:e124-e125.

Introduction line; and one from a sun-protected site, designated within each field at the same magnification. In sun- Cutaneous photoaging and carcinogenesis induce as the upper and inner thigh regions. The tissue exposed skin, we observed solar elastosis as evidence microscopic and macroscopic changes resulting underwent routine processing and staining with of UV exposure. We were able to perform multiple from short-term and long-term exposure to H&E. Only data from 13 cadavers were statistically field counts due to the amount of tissue available. ultraviolet light type B (UVB). Clinically, chronic analyzed due to poor tissue preservation from two Statistical evaluation was performed with IBM exposure may result in fine lines, wrinkles, fragility, cadavers. SPSS Grad Pack 22. A paired t-test was used and malignant neoplasms. Acute exposure to Chronic inflammatory cells (lymphocytes, to compare mean numbers of inflammatory UVB radiation has been found to cause epidermal macrophages, and plasma cells) were manually cells between sun-exposed and sun-protected hyperplasia, dilation and enhancement of the 1,2 counted from 10 consecutive high-power fields specimens. A paired t-test was also used to compare dermal vasculature. In addition, biochemical at 400x magnification, with field placement the mean numbers of dermal vessels from sun- alterations with decreased levels of IFN-beta, an immediately below the basal layer of the epidermis. exposed and sun-protected specimens. A Pearson’s anti-angiogenic mediator, and increased levels In addition, superficial dermal vessels including correlation was performed to assess the relationship of vessel-endothelial-growth factor, TNF-alpha, arterioles, veins, and lymphatic vessels were counted between mean vessel quantities and mean number IL-8, and fibroblast growth factor have been 3-5 reported following UV radiation. The most commonly documented histological changes in Figure 1. Mean inflammatory cells and mean vessels in sun-exposed vs. sun-protected skin. chronic sun-exposure include accumulation of glycosaminoglycan, loss of collagen fibers, and production and laying down of abnormal elastin fibers, resulting in solar elastosis.6,7 These changes may be due to UVB induction of fibroblasts, mast cells, keratinocytes, endothelial cells, and infiltrating inflammatory cells.7,8

The goal of our study was to observe inflammatory and vascular changes in sun-exposed versus sun-protected skin areas, and determine if these findings of chronic inflammation and vascular changes associated with chronic sun-exposure are consistent in a simple model. The use of cadaver skin allowed for larger specimen sampling. Based on this information and data from other studies, the implications of chronic inflammation and angiogenesis in chronic sun exposure and associated lesions will be discussed. We used a quantitative approach with hematoxylin and eosin (H&E) stained specimens from cadavers. Materials and Methods Institutional review board approval for exempt status based on work with cadavers was obtained.

From each of 15 randomly selected Caucasian cadavers, two 2-inch elliptical skin biopsies were obtained: one from a sun-exposed site, defined as the area from the face anterior to the ear, inferior to the hairline and superior to the chin and jaw

Page 25 CHRONIC INFLAMMATION AND VASCULAR DENSITY IN SUN-EXPOSED SKIN of inflammatory infiltrates of the two cohorts. interstitial collagenase (MMP-1). MMP-1 is photocarcinogenesis in chronic inflammation. For both statistical analyses, p < 0.05 was used to primarily responsible for the collagen damage designate statistical significance. found in photodamaged skin.10,11 One study NSAIDs target a group of pro-inflammatory employed the use of sunscreen, compared to enzymes known as cyclooxygenases, COX-1 17 Results sunscreen and anti-oxidants, and noted a 43% and COX-2. COX-2, although not present in Determination of age and gender as covariates was and 60% decrease in MMP-1 expression, normal skin, can be produced in the presence of 18 not statistically significant, allowing for justified respectively.12 Of greater clinical significance UVB radiation. UVB is a known environmental comparison. Paired samples t-test between the is the role of inflammatory cells, MMPs, and carcinogen that allows for the formation of mean inflammatory cell counts in the upper thigh photocarcinogenesis. MMP gene expression is (6-4) pyrimidine-pyrimidine cyclobutane (5.86, [2.50]) and the inner thigh (6.98, [5.43]) evident in many cell types, including macrophages, pyrimidine dimers, which initiate and promote 19,20 revealed no statistical significance (p = 0.40). T-cells, monocytes, fibroblasts, keratinocytes, and photocarcinogenesis. UV-induced COX-2 has Based on this, the mean value of both inner thigh endothelial cells.13 Ultraviolet radiation stimulates been shown to induce prostaglandin-E2 synthesis and upper thigh were used to represent the sun- growth factor and cytokine receptors located on (PGE-2), resulting in elevated PGE-2, which is protected value. Comparison of the mean number keratinocytes and fibroblasts, further upregulating able to bind various EP receptors on the surface of of inflammatory infiltrates between face (sun- transcription of AP-1, a nuclear transcription cells. EP-1, EP-2, and EP-4 have been identified exposed) (19.17, [8.08]) and the average of upper factor, which then stimulates the production of as playing a role in photocarcinogenesis in murine 21 thigh and inner thigh (sun-protected) (6.42, [3.56]) collagenase (MMP-1), stromelysin 1 (MMP-3), models. Through its diverse action on various biopsy specimens was statistically significant (p and 92-kda gelatinase (MMP-9).10 Metallomatrix receptors, PGE-2 has been determined to cause an < 0.001). More chronic inflammatory cells were proteinases act to degrade the extracellular matrix inflammatory response, aide in tumoral invasion, 22 present in sun-exposed skin versus sun-protected basement membrane, altering cellular architecture and inhibit apoptosis. COX-2 has been identified skin (Figures 1-3). and facilitating tumor invasion and metastasis.14 in epithelial cells of UVB-induced SKH-1 tumors in mice, in addition to dermal fibroblasts and Comparison of the mean vessel quantity between A Chinese study compared MMP-12 expression in macrophages within the tumor stroma.23 One study face (5.69 [1.71]) and inner thigh (4.15 [1.52]) 298 melanoma specimens to MMP-12 expression found COX-2 expression significantly increased in biopsy specimens was statistically significant (p = in 60 normal skin specimens, and found elevated actinic keratoses, Bowen’s disease, and squamous 0.011), with a greater number of vessels in sun- levels of MMP-12 expression in melanoma cell carcinoma lesions, compared to normal skin, exposed versus sun-protected skin (Figures 1-3). specimens with a significant association with tumor with normal skin having no expression based on invasion and metastatic potential.15 It has been study-specific staining standards.24 A direct relationship between inflammatory- reported that increased expression of MMP-1 and cell quantity and dermal-vessel quantity was not MMP-3 in melanoma metastases correspond with Another study found COX-2 expression in established. Correlation of mean inflammatory significantly shorter disease-free survival periods.16 90%, 100%, and 88.9% of basal cell carcinomas, cell count and mean dermal vessel count in sun- Although the relationship between inflammatory- squamous cell carcinomas, and actinic keratosis, exposed specimens was not statistically significant cell counts/types, MMP expression, and cutaneous respectively, with expression not only in the (r = -0.37, p = 0.21), nor was correlation of mean progression have not been completely ascertained, epithelial components of the tumors but also in 25 dermal vessel count and mean inflammatory cell together these individual findings may point vessel walls and inflammatory cells. The presence count in sun-protected specimens (r = 0.24, p = to a clearer mechanism for photoaging and of COX-2 within inflammatory cells may be 0.43). Discussion A limited number of studies have examined the relationship between chronic sun exposure and inflammation. A French study examined specimens of pre-auricular (sun-exposed) and post-auricular (sun-protected) skin for comparative differences in inflammation.9 They identified a greater number of mononuclear cells in the dermis of pre-auricular specimens, specifically around areas of elastolysis and perifollicular areas, whereas inflammatory infiltrates of post-auricular skin showed greater evidence of intrinsic aging and were perivascular, perifollicular, and interfollicular in nature.9 Immunohistochemical studies with anti-CD68 Figure 2a Figure 2b antibodies to detect macrophages, and tryptase to detect mast cells, have identified a greater number Figures 2a, 2b. H&E of sun-exposed specimens, demonstrating: a) increased inflammatory-cell and of dermal macrophages and mast cells in sun- dermal-vessel counts (200x); b) increased perivascular inflammation, dilated vessels with increased exposed skin compared to sun-protected skin.9 number of smaller surrounding vessels (400x). Specific T-cell antibodies identified a greater number of CD4+ T cells and fewer CD8+ T cells in sun-exposed skin sites compared to sun- protected skin sites. These results, combined with our results, support an association between chronic UV exposure and inflammation. In our study, we designated sun-protected skin as the upper and inner thigh rather than post-auricular skin. It’s possible post-auricular skin may have some degree of sun exposure, whereas the inner and upper thigh were less likely to be sun-exposed in a general elderly population.

Inflammatory cells play many roles in the skin, covering both destruction and repair. One study found a greater number of mast cells in sun- Figure 3a Figure 3b exposed skin specimens.9 These cells, along with other inflammatory cells, secrete cytokines and Figures 3a, 3b. H&E of sun-protected specimens, demonstrating: a) decreased dermal-vessel count and metallomatrix proteinases (MMP), specifically comparatively less inflammation (200x); b) few focal inflammatory cells and vessels (400x).

LAL, PLUMMER, MILKO, BELYAYEVA, JUNG, ELSTON Page 26 related to tumorigenesis. The cellular presence and older.31 A reduction in vessel size was noted an inflammatory perspective, but from a vascular role of COX-2 remains questionable, as studies in patients 40 years of age and older.31 Linear component as well. have shown that mice with COX-2 deletions in regression revealed a negative correlation between epithelial cells are not devoid of UVB-induced skin age and vessel density, vessel size, and vessel area.31 Studies have recently identified a significant tumors.23 They theorized that repeated, acute exposure to association between COX-2 immunoreactivity UV radiation causes inflammation, angiogenesis, and proliferating endothelial cell fractions in Diclofenac sodium 3% gel, an NSAID with and extracellular matrix degradation, cumulatively actinic keratoses, Bowen’s disease, and squamous preferential activity on COX-2, has been FDA- causing an unfavorable physical environment for cell carcinoma lesions compared to normal skin. 24 approved in the United States for actinic dermal vessels.31 However, it should be noted However, this is not true for microvessel density. 26 keratoses. A review of 18 articles studying that sun exposure may be avoided in many Asian This may indicate COX-2 plays an indirect role diclofenac 3% gel in the treatment of actinic countries as an effort to prevent tanning.32 in angiogenesis in skin cancers without increasing keratoses has suggested it is effective.27 The vessel numbers. However, COX-2 expression evidence for NSAIDs in the management of basal In contrast, a murine study subjected skh-1 hairless has been significantly associated with microvessel cell carcinoma is weaker; however, a recent meta- mice to UVB radiation, gradually increasing minimal density in colorectal and breast cancers.35,36 analyses identified a 10% risk reduction in basal cell erythema doses over a 10-week period to reach 4.5, cancer in patients deemed high-risk (history of skin in an effort to examine the angiogenic changes that Our subjects were from any elderly Caucasian cancer and/or high prevalence of AKs) who were occur with chronic UVB exposure in actinically population, representative of an at-risk skin taking any oral NSAID.28 Another meta-analysis sun-damaged skin.33 Irradiated mice had evidence cancer population in the general U.S. population. determined, despite significant study heterogeneity, of UV exposure, with wrinkling of skin compared Limitations of our study include a small sample a significantly reduced risk of SCC among people to non-irradiated mice. CD31 immunostaining size and lack of data on actual cumulative sun- taking any NSAIDs.29 Our results bolster these of irradiated skin specimens revealed not only an exposure, personal and family history of pre-cancer findings, as inflammation resulting from chronic increased number of vessels, along with significantly and cancerous skin, and presence of risk factors sun exposure may play a role in inflammatory and increased size and density, but also an inflammatory for increased incidence of skin cancer. Skin cancer angiogenic changes of photocarcinogenesis. The infiltrate in the upper dermis.33 This may indicate a was not a cause of death in any of the subjects. use of NSAIDs has helped elucidate the possible direct relationship between inflammatory cells and Prospective studies examining pre-cancer-prone roles of chronic inflammation in chronic sun- dermal vasculature changes that occur in response skin and inflammation might help determine an exposed skin lesions, further lending support to to chronic UVB exposure. The authors subjected effective time to intervene with topical NSAID their pathogenetic role. transgenic mice with skin-specific overexpression therapy to treat and prevent photocarcinogenesis. of thrombospondin-1 (TSP-1), an angiogenic Vascular changes occur, as well, both in photoaging inhibitor, to the same UVB radiation regimen. Conclusion and carcinogenesis. Traditionally, a noted They reported an absence of clinical wrinkling Vessel density and chronic inflammation were reduction in vasculature has been described in in transgenic mice subjected to the same UVB increased in sun-exposed skin compared with sun- 30 elderly skin. Most elderly individuals have some regimen as wild type mice, in addition to reduced protected skin. These changes could play a role in evidence of cumulative sun damage in commonly numbers of dermal inflammatory cells and vessels photoaging and photocarcinogenesis. sun-exposed regions, such as the head and neck, and a reduction of more than 55% in average vessel compared to relatively sun-protected areas like the size of dermal vessels compared to wild-type mice.33 inner thigh. One case series from South Korea Of note, ki-67 and CD31 immunostaining of examined biopsies form 21 patients from the face specimens of irradiated transgenic mice revealed a and buttocks, performing immunohistochemical reduced number of proliferating dermal endothelial and computer-assisted morphometric analyses cells compared to exposed wild type mice.33 It has 31 of dermal vessels. The authors identified a been reported that thrombospondins may inhibit significant reduction in the number of dermal zymogens of MMP-2 and MMP-9.34 This may vessels in photodamaged skin compared to sun- help further explain the multiple actions of these protected skin in patients 70 years of age and MMPs in cutaneous carcinogenesis from not only Figure 4. Scatter-plot and linear correlation between mean inflammatory cells and mean vessels.

r= -0.37 p= 0.21 r= 0.24 p= 0.43

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14. Kerkela E, Saarialho-Kere U. Matrix 28.Muranushi C, Olsen CM, Green AC, Pandeya metalloproteinases in tumour progression: focus on N. Can oral nonsteroidal antiinflammatory drugs basal and squamous cell skin cancer. Exp Dermatol. play a role in the prevention of basal cell carcinoma? 2003;12:109-25. A systematic review and metaanalysis. J Am Acad Dermatol. 2016 Jan;74(1):108-119.e1. 15. Zhang Z, Zhu S, Yang Y, Ma X, Guo S. Matrix metalloproteinase-12 expression is increased in cutaneous melanoma and associated with tumor aggressiveness. Tumour Biol. 2015;36(11):8593-600.

LAL, PLUMMER, MILKO, BELYAYEVA, JUNG, ELSTON Page 28 Clear Cell Acanthoma: A Clinical, Dermoscopic and Histological Review John Howard, DO,* Andrei Gherghina, DO, MS,** Jacquiline Habashy, DO, MS,*** Angela Poulos Combs, DO, FAOCD, FAAD,**** Stanley Skopit, DO, MSE, FAOCD, FAAD*****

*Dermatology Research Fellow, Larkin Community Hospital, Miami FL **Dermoscopy Fellow, Skin and Cancer Associates, Plantation, FL ***Traditional Rotating Intern, PGY1, Larkin Community Hospital, Miami, FL ****Dermatopathologist, Global Pathology/Aurora Diagnostics, Miami Lakes, FL *****Program Director, Larkin Community Hospital/NSU-COM Dermatology Residency, South Miami, FL

Disclosures: None Correspondence: Jacquiline Habashy, DO; [email protected]

Abstract Clear cell acanthoma (CCA) is an uncommon, benign epidermal tumor that may be easily misdiagnosed on a clinical basis alone. Although biopsy is commonly performed for diagnosis, perceptive clinicians may suspect a CCA with the use of clinical and dermoscopic findings. We present a case of a suspected clear cell acanthoma confirmed by biopsy along with a clinical, dermoscopic and histological review of the condition.

Introduction arranged in a linear “string of pearls” distribution, of lesions can range from approximately 3 mm to CCA was first described in 1962 and was also revealing the characteristic dermoscopic vascular 20 mm, and they can slowly grow for up to 10 years. pattern seen in clear cell acanthoma (CCA) When closely examining the surface of the lesion, known as “Degos acanthoma” and “acanthome 3,4 cellules claires of Degos and Civatte.”1 There are (Figure 2). vascular puncta are present, which easily bleed currently no known risk factors, and the etiology is following minor trauma. These lesions are usually unknown. It is theorized that the cause may be an Discussion found on the lower extremities in middle-aged to CCA is a rare, benign lesion that is oftentimes elderly adults, with both sexes affected equally.5,6 inflammatory reaction secondary to an unknown difficult to diagnose with clinical observation alone. trigger.2 Yet further investigation is necessary CCA shares clinical features that overlap with Although this is the most common presentation, to conclude the actual cause. CCA typically a variety of other lesions, making the differential there are a variety of clear cell acanthoma types, presents as an erythematous, solitary papule with diagnosis extremely broad. Dermoscopically, creating a large list of differential diagnoses. These a peripheral scale, usually on the lower extremities. however, this lesion has unique and specific features, Because this description clinically coincides with a which greatly improves diagnostic accuracy. The multitude of other lesions, our aim is to describe dermoscopic features show a stereotypical vascular Figure 3 how dermoscopy can distinguish CCA from its pattern composed of dotted vessels distributed differentials, making diagnosis biopsy-free. linearly in a “string of pearls” configuration.

Case Report Clinical Findings A 68-year-old white female presented to our CCAs are generally solitary, asymptomatic, red or outpatient clinic for a full-body skin exam. Her brown, dome-shaped papules or nodules. They may past medical history was significant only for be covered by scaled edges or appear moist. The size chronic obstructive pulmonary disease. She denied personal or family history of skin cancer. Physical exam revealed a sharply demarcated, 0.3 cm x 0.3 Figure 2 cm, shiny, pink, moist, blanchable papule with a collarette scale located on the left anterior distal shin in conjunction with varicose veins (Figure 1). Figure 3. H&E (10x): CCA demonstrating Dermatoscopic evaluation showed dotted vessels circumscribed area of psoriasiform epidermal hyperplasia with cytoplasmic pallor, overlying parakeratosis containing neutrophils and papillary dermal telangiectasia.

Figure 4

Figure 1 Figure 2. Dermoscopic presentation of CCA Figure 4. H&E (20x): Shave biopsy showing under contact polarized light with isopropyl abrupt border between pale and normal cells in Figure 1. Clinical presentation of CCA. alcohol immersion medium. epidermis.

Page 29 CLEAR CELL ACANTHOMA:A CLINICAL, DERMOSCOPIC AND HISTOLOGICAL REVIEW types include giant, polypoid, pigmented, eruptive, cause, one case report showed regression of CCA 6 2 References atypical and cystic. after a two-month trial of calcipotriol. In the 1. William J, Berger T, Elston D, Odom R, case of our patient, shave excision combined with Andrews G. Andrews’ Diseases of the Skin: In addition, there have been three recent literature electrofulguration was used for diagnosis and Clinical Dermatology. Philadelphia: Saunders reports detailing “atypical CCA,” which some treatment. Elsevier, 2006. authors argue is a malignant counterpart of CCA. These cases were clinically described as Conclusion 2. Gaetano S, Giovanni P. Topical Calcipotriol CCAs have a large differential including many erythematous, moist nodules, all of which were as a New Therapeutic Option for the Treatment lesions that are less benign and occur with much located on the face. Dermoscopically, these lesions of Clear Cell Acanthoma. An Bras Dermatol. higher frequencies in the population. Under these portrayed a dot-like pattern of globular capillary 2014;89(5):803-5. vasculature, similar to benign CCA. The literature conditions, the diagnosis of CCA is usually made is still pointing toward calling them benign lesions, histologically, after a biopsy has been performed. 3. Zalaudek I, Kreusch J, Giacomel J, Ferrara G, secondary to the lack of recurrence. Further Since the features of this lesion are dermoscopically Catricalà C, Argenziano G. How to diagnose 7 research is required for atypical CCA. distinct, this may afford the clinician more diagnostic nonpigmented skin tumors: a review of vascular confidence. The use of routine dermoscopy may structures seen with dermoscopy: part II. Differential Diagnosis therefore reduce the number of biopsies performed Nonmelanocytic skin tumors. J Am Acad Dermatol. CCA has a vast differential diagnosis that includes on this benign dermatologic entity. 2010 Sep;63(3):377-86; quiz 387-8. actinic keratosis, lichenoid keratosis, pyogenic granuloma, dermatofibroma, basal cell carcinoma, 4. Miyake T, Minagawa A, Koga H, Fukuzawa squamous cell carcinoma, inflamed seborrheic M, Okuyama R. Histopathological correlation keratosis, eccrine poroma, clear cell hidradenoma, to the dermoscopic feature of “string of pearls” in 7 amelanotic melanoma, and psoriasis. When clear cell acanthoma. Eur J Dermatol. 2014 Jul- considering non-pigmented skin lesions such as Aug;24(4):498-9. these, dermoscopic vascular structures are often helpful in making a correct diagnosis.1 Among this 5. Tempark T, Shwayder T. Clear Cell Acanthoma. wide differential base, clear cell acanthomas are Clin Exp Dermatol. 2012;37(8):831-7. unique in their dermoscopic distribution of dotted or globular vessels, arranged in a curvilinear pattern. 6. Fine RM, Chernosky ME. Clinical Recognition of Clear Cell Acanthoma. Arch Dermatol. Diagnosis 1969;100:559-63. CCA may be suspected on physical exam, especially when combined with the clues and patterns 7. Lin C, Lee L, Kuo T. Malignant Clear Cell visualized with a dermatoscope. Confirmatory Acanthoma: Report of a Rare Case of Clear Cell diagnosis of clear cell acanthoma requires a skin Acanthoma-Like Tumor With Malignant Features. biopsy. Dermoscopically, these lesions are set apart Am J Dermatopathol. 2016 Jul;38(7):553-6. from their differentials by the pattern of their vasculature, rendering a skin biopsy practically 8. Ardigo M, Buffon R, Scope A, Cota C, unnecessary. Under a dermatoscope, clear cell Buccini P, Berardesca E, et al. Comparing in vivo acanthomas portray pinpoint vessels in a linear reflectance confocal microscopy, dermoscopy, and pattern, described as pearls on a string.8 histology of clear-cell acanthoma. Dermatol Surg. 2009;35:952-9. Histopathology Typically, CCAs are characterized by well- 9. Husein E, Cachaza J, Fernandez J. Dermoscopy demarcated epidermal hyperplasia made up of large of Clear Cell Acanthoma. J Am Acad Dermatol. keratinocytes and basal cells full of a glycogen-rich 2011;64(2):AB77. cytoplasm positive to periodic-acid-Schiff staining. An abundance of densely packed, dilated capillaries is seen in a well-demarcated distribution that correlates with the dermoscopic vascular features or red dots and globules outlined above. Parakeratosis, neutrophilic exocytosis and mild spongiosis are also present (Figures 3 and 4).1,6

In the atypical variant of CCA, histological findings consist of cytological atypia of tumor cells with enlarged nuclei, some of which show mitotic figures. In one study, these tumor cells were positive for p63.7

Management and Therapy Management of a solitary CCA lesion is by excisional removal. This can be done through a variety of methods including, but not limited to, standard surgical excision, Mohs micrographic surgery, cryotherapy, electrofulguration, curettage and carbon dioxide laser. For cases of multiple or larger lesions, cryotherapy and carbon dioxide laser have been successfully used.6 In addition, in line with a theorized inflammatory reactive

HOWARD, GHERGHINA, HABASHY, COMBS, SKOPIT Page 30 Guaifenesin-induced Acute Generalized Exanthematous Pustulosis (AGEP): A Case Presentation and Discussion Christine Sickles, DO,* Danielle R. Lazzara, BS,** Garrett Bohrnstedt, DO***

*Dermatology Resident, 1st year, LewisGale Hospital Montgomery/VCOM, Blacksburg, VA **Medical Student, 4th year, Rowan University School of Osteopathic Medicine, Stratford, NJ ***Dermatologist, New River Dermatology, Blacksburg, VA

Disclosures: None Correspondence: Christine Sickles, DO; [email protected]

Abstract Guaifenesin is an expectorant medication available as a single-ingredient formula or combined with pseudoephedrine or dextromethorphan to serve as an over-the-counter cold and cough medication. Cutaneous adverse reactions, albeit rare, have been attributed to pseudoephedrine and dextromethorphan.1-4 We present a case of cutaneous pustular eruption secondary to ingestion of guaifenesin 1200 mg extended-release bi-layer tablets consistent with acute generalized exanthematous pustulosis (AGEP). To our knowledge, this is the first reported case of AGEP associated with single-ingredient guaifenesin. Introduction have been described, including bacterial or viral Case Report Acute generalized exanthematous pustulosis infection (cytomegalovirus, chlamydia pneumonia, A 67-year-old, febrile, Caucasian female was parvovirus B19), exposure to mercury or contrast (AGEP), also known as pustular drug eruption, is 1,5-7 admitted to the hospital for a painful, erythematous, a rare cutaneous adverse reaction characterized by agents, and spider bites (Table 1). Laboratory pustular eruption that evolved over a four-day abnormalities often include leukocytosis with the rapid development of numerous non-follicular, 9 period after ingesting guaifenesin 1200 mg for sterile, pinpoint pustules on an erythematous elevated neutrophil count (> 7.5x10 /L) and fever congestion. The patient noted the rash appeared (≥ 38o C).1-10 AGEP can recur with a second base, commonly associated with high fever and 5-7 within a few hours of ingesting the medication leukocytosis.1,3,4-10 Incidence is estimated as one to exposure to the offending medication. and began as erythema involving the intertriginous five cases per million per year.6 The eruption can be areas of the groin. The rash worsened and rapidly 5-7 The time interval between drug exposure and pruritic or painful. It generally begins on the face spread to the trunk, eventually evolving into presentation of symptoms varies by offending and extends to the trunk, with a predilection for the pustules. The patient stated she had experienced agent, but it often occurs within 48 hours of major intertriginous regions. Mucosal membranes, 5-7 flu-like symptoms two weeks prior. She did not ingestion. AGEP should be suspected in patients most commonly the oral mucosa, may be affected. take any medications regularly and had no personal with characteristic cutaneous features presenting When this occurs, it is often confined to a single site. 5 or family history of psoriasis or other skin disease. within hours or days after starting a new drug. Severe AGEP, with mucous membrane and systemic Discontinuation of the causative agent results in organ involvement (hepatic, renal, or pulmonary Physical examination displayed intertriginous rapid resolution of eruption within four to 10 days, insufficiency), accounts for approximately 20% of erythema with numerous, coalescent pustules 5 and subsequent post-inflammatory desquamation reported cases. More than 90% of AGEP cases 1-10 most prominent under the breasts and axilla, as of the affected areas is common. are due to medications; however, other causes well as mucous membrane involvement (Figure 1). Petechial lesions were appreciated on the upper Table 1. Medications reportedly associated with AGEP extremities and at the periphery of the erythematous patches. No scaling or desquamation of the post Class Medication(s) auricular skin or scalp was noted. An erosion on the Pristinamycin* right labia was noted, likely secondary to trauma of Aminopenicillins* the pustular eruption. Antibiotics Quinolones* Admission laboratory analysis revealed a marked Sulfonamides* increase in white blood cell count (37.6 K/ Macrolides mm3) with neutrophilia (36% band neutrophils), Terbinafine Fluconazole Antifungals Ketoconazole Nystatin Amphotericin B Pseudoephedrine Decongestants Dextromethorphan Diuretics Hydroxychloroquine Chemotherapy agents Imatinib5 Alpha-1-blockers Terazosin Calcium channel blockers Diltiazem Corticosteroids Dexamethasone Proton pump inhibitors Omeprazole Clopidogrel Antiplatelet agents Ticagrelor NSAIDS (Oxicam) Analgesics Acetaminophen Stimulant laxatives Senna glycoside (sennoside) Figure 1 *Most commonly reported offending antibiotics in AGEP cases

Page 31 GUAIFENESIN-INDUCED ACUTE GENERALIZED EXANTHEMATOUS PUSTULOSIS (AGEP): A CASE PRESENTATION AND DISCUSSION hypokalemia (3.3 mmol/L), hypocalcemia (7.3 While severe cutaneous adverse reactions to References mg/dl), and hypoalbuminemia (2.0 g/dl). Rapid guaifenesin have not been previously documented 1. Ben SC, Slim R, Denguezli M, Sriha B, Hmouda influenza and beta hemolytic strep tests were in the literature, there are three well-documented H, Bouraoui K. Pseudoephedrine-induced acute negative. Throat culture and blood cultures were cases of AGEP associated with exposure to generalized exanthematous pustulosis. Int J also negative at 48 hours. pseudoephedrine, a sympathomimetic agent found Dermatol. 2008 Apr;47(4):418-9. in nasal decongestants such as guaifenesin 600 mg/ 1,3,4 Based on gross clinical appearance and laboratory pseudoephedrine 60 mg. Despite extensive use 2. Otero Rivas MM, Sanchez Sambucety P, Garcia- findings, AGEP secondary to guaifenesin was of pseudoephedrine, reported adverse reactions are 1 Ruiz de Morales JM, Perez Paredes G, Rodriguez diagnosed. After discontinuation of the offending rare. Prieto MA. Acute generalized exanthematous medication, the eruption rapidly improved. Routine pustulosis due to dextromethorphan. Dermatol wound care and supportive therapy was recommended. Conclusion Online J [Internet]. 2013 Oct [cited 2016 April To our knowledge, this is the first reported case of 14];19(10). Available from: http://escholarship. Discussion AGEP secondary to guaifenesin 1200 mg extended- org/uc/item/8j79f8sb?query=acute generalized The pathophysiology of AGEP is not well release bi-layer tablets. This case demonstrates exanthematous pustulosis due to dextromethorphan. understood. Cultured peripheral blood studies the importance of recognizing guaifenesin as a suggest a T-cell-mediated disease; it is postulated possible offending agent in patients presenting 3. Mayo-Pampin E, Florez A, Feal C, et al. Acute that following exposure to the offending agent, with acute cutaneous eruptions characteristic of generalized exanthematous pustulosis due to drug-specific CD4 and CD8 T cells are activated, AGEP. It is critical for internists and emergency pseudoephedrine with positive patch test. Acta proliferate and migrate into the epidermis and physicians to be aware of these potential offending 5-8 Derm Venereol. 2006;86(6):542-3. dermis. The CD8 cells induce keratinocytes agents in order to promptly recognize significant to undergo apoptosis via perforin and granzyme dermatologic reactions, elucidate the diagnosis 4. Padial MA, Alvarez-Ferreira J, Tapia B, B mechanisms, leading to tissue destruction and of severe drug eruptions and initiate appropriate 5,7 Blanco R, Manas C, Blanca M, Bellon T. Acute epidermal vesicle formation. Keratinocytes treatment measures. generalized exanthematous pustulosis associated release neutrophil-attracting interleukin-8 (IL-8) with pseudoephedrine. Br J Dermatol. 2004 or CXCL8, causing neutrophils to enter vesicles, Jan;150(1):139-42. with resultant formation of sterile pustules.5-7 Analysis of AGEP patients’ CD4 T cells reveals 5. Szatkowski J, Schwartz RA. Acute generalized a Th1-dominant cytokine profile with increased γ exanthematous pustulosis (AGEP): A review and interferon- and granulocyte-macrophage colony update. J Am Acad Dermatol. 2015 Nov;73:843-8. stimulating factor (GM-CSF) production, which promotes neutrophil survival and enhances pustule 6. James WD, Berger TG, Elston DM. Andrews’ 5,6 formation. A Th2 pattern with high IL-4 and Diseases of the Skin: Clinical Dermatology. 11th ed. IL-5 production causes eosinophil proliferation China: Elsevier Saunders; 2011. p. 119-20. and resultant eosinophilia in 30% of reported AGEP cases.5 It is also suspected that Th17 cells 7. Bolognia JL, Jorizzo JL, Schaffer JV. Dermatology. may lead to the release of IL-17 and IL-22, further 3rd ed. Saunders; 2012. p. 335-43. promoting keratinocyte production of CXCL8. 8. Heinemann C, Wiesend CL, Hipler C, Norgauer Histological findings can help differentiate J, Ziemer M. Acute generalized exanthematous AGEP from other clinically similar, severe, pustulosis (AGEP) after oral use of amphotericin acute cutaneous eruptions such as acute pustular B. J Am Acad Dermatol. 2007 Aug;57(2):s61-2. psoriasis, drug reaction with eosinophilia and systemic systems, Steven’s Johnson syndrome, and 9. Lee S, Artemi P, Holt D. Acute generalized toxic epidermal necrolysis. AGEP is characterized exanthematous pustulosis. Australas J Dermatol. by intracorneal, subcorneal, and intraepidermal 1995;36:25-7. spongiform pustules.5-7 Papillary dermal edema with a perivascular neutrophil and eosinophil 10. Maybrook RJ, Fischer R, Deibert B, Gillihan R, mixed infiltrate is suggestive of AGEP.5,7 Laarman R, Fraga G, Aires D, Gollub S. Ticagrelor- Leukocytoclastic vasculitis (LCV) and necrosis induced acute generalized exanthematous of keratinocytes may also be seen on histology. In pustulosis. Intern J Cardiol. 2015 Jul;191:11-2. comparison, characteristic histologic findings of acute pustular psoriasis include papilloacanthosis, increased mitotic figures, and dilated blood vessels typically absent in AGEP.

It can be challenging to differentiate AGEP from acute pustular psoriasis.5-8 Apart from histologic evidence, cutaneous presentation time of onset can aid in differentiation of the eruptions, as pustular psoriasis has a more gradual course of onset compared to AGEP.5 The presence of additional cutaneous findings such as petechiae, purpura, atypical target lesions, and vesicles favors a diagnosis of AGEP.7 A lack of personal or family history of psoriasis also makes the diagnosis of pustular psoriasis less likely.5,7

The primary treatments for AGEP are discontinuation of the offending drug and supportive therapy. Moist dressings and antiseptic solutions may be applied during the pustular phase to prevent infection.5 Topical corticosteroids can be prescribed to alleviate pruritus and inflammation.5-7 Antibiotics should be avoided except in the case of superinfection.5

SICKLES, LAZZARA, BOHRNSTEDT Page 32 Leser-Trélat Sign Presentation with Mediastinal Squamous Cell Carcinoma Paloma Reiter, BA,* Leeor Porges, DO,** Jacqueline Thomas, DO***

*Medical Student, 3rd year, Nova Southeastern University College of Osteopathic Medicine, Ft. Lauderdale, FL **Dermatology Resident, 4th year, Nova Southeastern University College of Osteopathic Medicine/Broward General Medical Center, Ft. Lauderdale, FL ***Board-certified Dermatologist, Physicians Regional Medical Group, Naples, FL

Disclosures: None Correspondence: Paloma Reiter, [email protected]

Abstract The sign of Leser-Trélat is a rare dermatological manifestation of a paraneoplastic syndrome. It is characterized by an abrupt onset of numerous seborrheic keratoses in association with adenocarcinomas and lymphoproliferative disorders. Herein, we review a case of a 59-year-old female with the classic cutaneous presentation of the sign Leser-Trélat. Our patient’s cutaneous expression coincided with a mediastinal squamous cell carcinoma.

7 Introduction corneum. The similarity in hyperactivity of these region suspicious for irritated benign growths were European surgeons Edmund Leser and Ulysse Trélat growth factors during cutaneous malignancies treated with cryotherapy. first independently associated internal malignancies and cutaneous paraneoplastic syndromes could The patient initially sought medical assistance in with these skin lesions in 1890. In addition, Eugen provide the link between the expression of Leser- September 2012 for aphasia. A CT of the neck Holländer first associated “verrucae seborrheicae” Trélat sign and squamous cell carcinoma. In many 1 and chest noted a hypodense 0.8 cm nodule in with internal malignancy in 1900. Leser-Trélat reported cases, the removal of the malignancy the lower left lobe of the thyroid and a 3.8 cm left sign is a rare dermatological manifestation of greatly reduced the appearance of the Leser-Trélat 3,4,7,8 anterosuperior mediastinal mass and adenopathy. a paraneoplastic syndrome characterized by an sign. 2 Biopsies of both lesions determined that the thyroid abrupt onset of numerous seborrheic keratoses. nodule was benign; however, the mediastinal mass Associated symptoms often include pruritus and Case Presentation A 59-year-old Caucasian woman, Fitzpatrick was consistent with squamous cell carcinoma velvety, lichenified skin characteristic of acanthosis type III, with history of mediastinal squamous (TxN2M0, stage IIIA). Mass effect caused aphasia nigricans. Typically, the sign of Leser-Trélat presents cell carcinoma, Ehlers-Danlos syndrome, molar secondary to left vocal cord paralysis resulting from in the elderly, and it has been associated with pregnancy, COPD, osteoarthritis, chronic fatigue recurrent laryngeal nerve involvement. adenocarcinoma as well as lymphoproliferative 3,4 and smoking, presented with several lesions of disorders. The adenocarcinoma most frequently 4 concern on her back and submammary region. The mass was treated with stereotactic body radiation originates from the colon, breast, or stomach. The lesions were numerous, stuck-on plaques that therapy (SBRT), and the patient underwent Although potentially paraneoplastic, the eruptive were waxy brown to dark brown in coloration CyberKnife radiosurgery in five fractions. The seborrheic keratoses in Leser-Trélat occur in (Figures 1, 2). Dermoscopically, they presented patient was not offered chemoradiation therapy nor malignancies of other organs and in non-malignant 5 with comedone-like openings, milia-like cysts, neoadjuvant chemotherapy. In May 2013, a PET ailments. The validity of this dermatological and bulbous projections. The lesions were first scan showed the mediastinal mass had reduced to phenomena has been challenged due to the fact noted nine years prior and appeared rapidly, 2.5 cm in size. that seborrheic keratoses and neoplasms are both 4 but the patient became concerned with a more common in the elderly population. recent development of plaques. The patient could The follow-up PET scan on November 2013 noted not correlate the exact onset of her seborrheic a hypermetabolic lesion in the region of the aortic The exact pathogenesis of Leser-Trélat sign is arch on the mediastinal mass, with no change from unknown; however, it is theorized that it may be keratoses with her malignancy, although she denied significant keratotic lesions prior to her diagnosis. prior imaging. In addition, the patient had an related to an overproduction of growth hormone, elevated CEA of 11.52 ng/ml. CT of the chest in epidermal growth factor (EGF) and transforming The patient denied change in size and color but 6 February 2014 demonstrated a gradual increase of growth factor alpha (α-TGF). The latter is not admitted to intermittent pruritus. In addition, she displayed generalized hair thinning and non- the mediastinal mass in the left mid lung zone that found in normal adult cells, but in fetal cells and measured 3.5 cm x 2.5 cm. A stable subcentimetric transformed cell lines. Both EGF and α-TGF scarring alopecia of the scalp. On remaining physical exam, the patient appeared generally thin, nodular density along the lateral aspect of the left bind to the EGF receptor found in keratinocytes, major fissure was noted, as well. No abnormal hilar especially in actively proliferating cells of the with aphasia, but no palpable lymphadenopathy 7 was appreciated. or mediastinal adenopathy were noted, but it was basal layer of normal epidermis. Normally EGF subsequently determined that the malignancy was receptors are present mainly on basal keratinocytes Two lesions suspicious for atypical processes were unresectable. and decrease as keratinocytes differentiate in biopsied, by shave removal, from the mid back the upper epidermal layers. However, acanthosis and left submammary regions. The biopsy revealed A CT-guided biopsy and Theros CancerType ID nigricans, seborrheic keratoses, and acrochordons findings characteristic of seborrheic keratoses. noted a persistent primary keratinizing squamous contain a dense population of receptors in all Several other lesions on the back and submammary cell carcinoma of the lung, with necrosis and layers of the epidermis except for the stratum calcifications. Further evaluation included whole- body radiological imaging, and results showed Figure 1 no additional areas of focus or abnormality. The patient denied palliative chemotherapy and elected to be closely monitored. Discussion We report a case with a characteristic presentation of Leser-Trélat sign associated with mediastinal squamous cell carcinoma. Although our patient’s case has an unusual origin, there are several cases of Leser-Trélat sign in the literature with similar features. Heaphy et al. presented a case of a 58-year-old woman who was not only similar in Figure 2 age to our patient but also experienced fatigue and had a smoking history. However, in their case, the Figure 1. Posterior presentation of seborrheic Figure 2. Anterior presentation of seborrheic Leser-Trélat sign was caused by adenocarcinoma keratoses keratoses of the lung, which is commonly associated with

Page 33 LESER-TRÉLAT SIGN PRESENTATION WITH MEDIASTINAL SQUAMOUS CELL CARCINOMA 4 this cutaneous manifestation. The similarities References in presentation support our conclusion that our 1. Moore R, Devere T. Epidermal Manifestations patient’s dermatologic manifestation is the sign of Internal Malignancy. Dermatol Clin. 2008 Jan of Leser-Trélat. In both cases, the patients are 1;26(1):17-29. not elderly, and therefore the onset of seborrheic keratosis and malignancy cannot be attributed to 2. Holdiness MR. The Sign of Leser-Trelat. Int J age alone. In addition, Mukherjee et al. described a Dermatol. 1986 Nov;25(9):564-72. case of squamous cell carcinoma of the lung with a paraneoplastic presentation. However, in that case, 9 3. Venegas FA, Vaccaro PM, Abudinen GA, Reydet the paraneoplastic type was acanthosis nigricans. CV, Brunie FV, Arcuch JD. [Leser-Trelat Sign associated with gastric adenocarcinoma: clinical The variation in ailments that present with eruptive case]. Rev Med Chil. 2012 Dec;140(12):1585-8. seborrheic keratosis makes the criteria for Leser- Spanish. Trélat sign a controversial topic in the medical community. Several studies have been conducted 4. Heaphy Jr MR, Millns JL, Schroeter AL. The that analyze the ailments of patients who present sign of Leser-Trelat in a case of adenocarcinoma with eruptive seborrheic keratosis and compare of the lung. J Am Acad Dermatol. 2000 Aug;43(2 them with a control group. These case-control Pt 2):386-90. studies reveal no significant association of specific internal malignancies with eruptive seborrheic 5. DeWitt CA, Buescher LS, Stone SP. Fitzpatrick’s 10,11 keratosis versus other ailments. Dermatology in General Medicine. 8th ed. USA: McGraw Hill; c2012. Chapter 153, Cutaneous Conclusion Manifestations of Internal Malignant Disease: Although widely debated and disputed in multiple Cutaneous Paraneoplastic Syndromes; p. 1880- studies, there continues to be a large database of 1900. literature validating the sign of Leser-Trélat as a paraneoplastic syndrome. In order to gain a better 6. Siedek V, Schuh T, Wollenberg A. Leser-Trelat understanding of this condition, it is essential to sign in metastasized malignant melanoma. Eur continue documenting all possible presentations. Arch Otorhinolaryngol. 2009 Feb;266(2): 297-99. Regardless of cause, it is critical to be aware of the presentation of the sign of Leser-Trélat and its 7. Ellis DL, Kafka SP, Chow JC, Nanney LB, Inman implication of malignancies, internal or cutaneous. WH, McCadden ME, King Jr LE. Melanoma, Growth Factors, Acanthosis Nigricans, The Sign of Leser-Trélat, and Multiple Acrochordons: A Possible Role for Alpha-Transforming Growth Factor in Cutaneous Paraneoplastic Syndromes. N Engl J Med. 1987 Dec 17;317(25):1582-7.

8. Ceylan C, Alper S, Kilinc I. Leser-Trelat sign. Int J Dermatol. 2002 Oct;41(10):687-8.

9. Mukherjee S, Pandit S, Deb J, Dattachaudhuri A, Bhuniya S, Pulakesh B. A case of squamous cell carcinoma of lung presenting with paraneoplastic type of acanthosis nigricans. Lung India. 2001 Jan- Mar;28(1):62-4.

10. Fink A, Filz D, Krajnik G, Jurecka W, Ludwig H, Steiner A. Seborrhoeic keratoses in patients with internal malignancies: a case–control study with prospective accrual of patients. J Eur Acad Dermatol Venereol. 2009 Nov;23(11):1316-9.

11. Lindelof B, Sigurgeirsson B, Melander S. Seborrheic kerstoses and cancer. J Am Acad Dermatol. 1992 Jun;26(6):947-50.

REITER, PORGES, THOMAS Page 34 Locally Advanced Basal Cell Carcinoma with Subtle Skin Findings Shana Rissmiller Schroeder, DO,* Mina Le, MD,** Robert Taylor, MD***

*Dermatology Resident, 3rd year, West Palm Hospital, Palm Beach Consortium for Graduate Medical Education, West Palm Beach, FL **Otolaryngologist, U.S. Department of Veterans Affairs, West Palm VA Medical Center, West Palm Beach, FL ***Dermatologist, U.S. Department of Veterans Affairs, West Palm VA Medical Center, West Palm Beach, FL

Disclosures: None Correspondence: Shana Rissmiller Schroeder, DO; [email protected]

Abstract Osseous destruction of the cranium by basal cell carcinoma (BCC) is extremely rare. A case of a 73-year-old man with multiple recurrences of morpheaform BCC involving the right nasal ala is presented. Years after his last re-excision, he presented with a small erosion along the supra-alar crease. He additionally reported intermittent epistaxis and nasal congestion. He was subsequently found to have infiltration of the right orbital floor, hard palate, and anterior maxillary sinus by basal cell carcinoma. Due to the size and extent of infiltration of the tumor into the orbital floor and hard palate, the patient was considered a poor surgical candidate. He was placed on daily vismodegib, and follow-up CT scan has demonstrated a partial tumor response.

Introduction reconstructed with a paramedian forehead flap and and the right nasolacrimal duct. Significant osseous While basal cell carcinoma (BCC) is the most right auricular cartilage graft. destruction was identified, including the orbital common malignancy found in humans, with more floor, hard palate, and anterior maxillary sinus. The In addition to the non-healing area involving the than 2 million cases diagnosed each year in the first four maxillary teeth were encompassed by soft right supra-alar crease, the patient also admitted United States, the disease remains localized in tissue. Overall, the mass measured approximately 7 1 to intermittent bleeding from the right naris. He the great majority of cases. Locally advanced and cm craniocaudally x 4.4 cm transversely x 3.8 cm denied facial numbness, paresthesia, weakness, metastatic disease is quite rare, with an incidence anterior-posterior (Figures 2-4). 2 change in vision, or epiphora. ranging from 0.18% to 3%. Complications of local A multi-disciplinary conference was held, including disease include local tissue destruction, functional 3 Physical exam demonstrated a well-healed specialists from dermatology, otolaryngology, impairment, and cosmetic disfigurement. forehead flap donor scar along the left paramedian oncology, pathology, radiology, and dentistry. forehead. Due to the extensive past excisions, most There are many risk factors contributing to the Due to the size and infiltration of the tumor of the right nasal ala was gone. The right soft tissue development of recurrent, locally advanced, or into the orbital floor and hard palate, the patient triangle and most of the right nasal sidewall were metastatic basal cell carcinoma. Anatomical was considered a poor surgical candidate. After replaced by a flap Figure( 1). A superficial, 3 mm locations with higher risk of recurrence include a discussion with the patient, he was placed on x 4 mm erosion was noted in the supra-alar crease. the eyelid, periocular region, nose, lip, temple, ear, vismodegib 150 mg daily. His treatment course was 3 There was no obvious recurrent cancer externally hands, feet, and genitalia. Increased recurrence complicated by non-compliance. Over the course either on the nose or on the paranasal cheek. A rates are further observed when poorly defined of six months, he took 103 doses. He reported 3 mm punch biopsy was performed. Pathology borders are present, in tumors larger than 2 cm muscle spasms, a 30-pound weight loss, dysgeusia, demonstrated morpheaform BCC extending to the in diameter, in tumors with aggressive histologic fatigue, hair loss, and diarrhea. A repeat CT scan margins. patterns (morpheaform, micronodular, metatypical, was performed and demonstrated a modest tumor response to treatment. This study showed that the basosquamous), in tumors with perineural The patient was evaluated by Otolaryngology for involvement, and in patients with prior history of tumor was approximately 6.2 cm craniocaudally 3 further delineation of the epistaxis. On anterior recurrent BCC. x 2.5 cm transversely x 1.4 cm anterior-posterior rhinoscopy, the right nasal cavity was significantly (Figures 5, 6). For the time being, the patient is narrowed and obstructed by amorphous masses of Very few cases of osseous destruction of the continuing vismodegib in hopes that the tumor yellowish, irregular granulation tissue. The patient cranium by advanced basal cell carcinoma have will continue to shrink. In the future, surgery may was subsequently sent for a CT scan, which been reported. The incidence is estimated to be become a treatment option. 4 demonstrated an irregular, infiltrating, enhancing approximately 0.03%. The majority of reported mass along the right side of the face, centered cases involve longstanding lesions on the scalp or Discussion along the right nasal soft tissues and nasal ala. The face. Presenting symptoms vary depending on the Treatment of locally advanced and metastatic basal mass extended from just below the frontal sinus, location and extent of infiltration. In one case, the cell carcinoma is managed on a case-by-case basis. at the level of the upper orbits, and crossed the patient presented with cerebrospinal fluid otorrhea, Standard therapy does not exist due to the rarity of midline, involving the anterior olfactory recesses facial nerve palsy, and trigeminal nerve impairment cases and the variations in presentation. Treatment secondary to destruction of the petrous bone by recurrent auricular BCC.5 The primary tumor had been excised three years prior, and there were no signs of recurrent disease on the skin surface at the time of presentation. Here we present an additional case of basal cell carcinoma with extensive bony infiltration but very subtle skin findings. Case Report A 73-year-old Caucasian male presented for evaluation of a 4 mm, non-healing erosion at the site of a prior excision. He had an extensive history of recurrent basal cell carcinoma involving the superior aspect of the right nasolabial fold. This was initially resected with frozen sections in 1998. The surgical defect was closed with an advancement flap. In July 2003, he presented with a large recurrence, which was resected. Two subsequent re-excisions (August 2003 and October 2003) were Figure 1 necessary due to positive margins and were again performed with frozen sections. His nose was then Figure 1. Overview of patient’s face showing extensive post-surgical changes.

Page 35 LOCALLY ADVANCED BASAL CELL CARCINOMA WITH SUBTLE SKIN FINDINGS is mostly individualized, depending on the patient’s signaling pathway, including vismodegib, offer an in patients with locally advanced or metastatic co-morbidities, anatomical location of the lesion, alternative treatment in metastatic or unresectable BCC.7 While this study is not yet complete, extent of infiltration, previous treatment history, BCC. interim analysis of 499 patients was performed. Of and patient preference.1 For advanced localized the patients with locally advanced disease, 66.7% disease, surgical excision followed by radiation In the majority of basal cell carcinomas, both responded to the drug: Of 453 patients, 153 had therapy is commonly performed if the lesion is sporadic and those arising in Gorlin’s syndrome, complete responses, and 149 had partial responses.7 amenable and there are no contraindications. A alterations in the hedgehog signaling pathway have Partial response was defined as at least a 30% patient may not be a surgical candidate for a number been identified. Most commonly, a loss of function decrease in the sum diameters of target lesions. In of reasons including co-morbidities, inoperable mutation in patched homologue 1 (PTCH1) leads those who did respond, the median time to best disease, substantial anticipated disfigurement, or to unopposed activity of smoothened homologue response was 2.6 months. a low likelihood of surgical cure due to history of (SMO). Smoothened signal transduction leads multiple recurrences.6 Inhibitors of the hedgehog to activation and nuclear translocation of GLI The optimal duration of treatment with vismodegib transcription factors and induction of genes has not been defined. Studies have typically Figure 2 involved in cell proliferation, survival, and continued patients on vismodegib until they differentiation.3,6,7 In approximately 10% of basal experienced intolerable side effects, progression of cell carcinomas, there is an activating mutation in disease, complete cure, or the end of the study.6-8 In SMO that results in constitutional activation.7 the interim analysis from the STEVIE trial, 80% of patients had discontinued treatment at clinical Vismodegib is a small-molecule inhibitor of cutoff.7 The median duration of treatment was 36.4 smoothened. In 2012, it was approved by the Food weeks.7 The reasons for cessation included: adverse and Drug Administration (FDA) for the treatment events (36%), progressive disease (14%), patient of metastatic or locally advanced BCC. Phase 1 request to stop treatment (10%), investigator studies from 2009 showed an objective response request, and death.7 to treatment in 18 out of 33 patients; two had a complete response, and 16 had a partial response.8 Drug intolerance can potentially present an This study combined data from 15 patients with obstacle in treatment of advanced basal cell locally advanced disease and 18 patients with carcinoma. Ninety-eight percent of patients from metastatic BCC. In the phase 2 study (ERIVANCE the STEVIE interim analysis experienced an BCC), 27 of 63 patients with locally advanced adverse event.7 The most commonly reported side disease responded to vismodegib, with 13 patients effects included muscle spasms, alopecia, dysgeusia, having a complete response.6 The Safety Events weight loss, asthenia, decreased appetite, ageusia, in Vismodegib (STEVIE) trial, a large, ongoing, alopecia, nausea, and fatigue. Most of the adverse Figure 3 multicenter, open-label study, is monitoring the events were grade 1 or 2. Pretreatment counseling safety and efficacy of 150 mg vismodegib daily regarding possible medication side effects is essential.

For patients who are refractory to vismodegib or develop resistance, few treatment options exist. Sonidegib, another smoothened inhibitor, was approved by the FDA in 2015 for locally advanced BCC recurring after surgery or radiation therapy, and for patients who are poor candidates for surgery or radiation therapy. The BOLT study, a phase 2 trial of 230 patients with locally advanced BCC, found an objective response rate in approximately 35% of participants.9 The side effect profile is similar to that of vismodegib. A recent study was undertaken using sonidegib 800 mg daily in nine patients with advanced BCC previously resistant to treatment with vismodegib.10 The study did not find better outcomes with sonidegib. Of the nine patients, five experienced progressive disease, three remained Figure 5 stable, and one was not able to be evaluated.10 In the future, therapies with targets in the hedgehog pathway downstream of SMO may prove more Figure 6 beneficial for refractory or resistant cases.10 Conclusion Advanced basal cell carcinoma with intracranial invasion is rare. Once the tumor has infiltrated and destroyed the facial bones, treatment becomes extremely challenging. This case highlights the importance of closely monitoring patients who have a history of multiple recurrences, especially in high risk anatomic locations or with more aggressive histologic subtype. A detailed review of systems should be elicited at each follow-up visit. Based on the history and physical exam, imaging Figure 4 studies may be warranted to rule out progressive disease. Hedgehog pathway inhibitors should be Figures 2-4. CT scan: Coronal and axial images considered in patients with unresectable disease. demonstrating a large enhancing mass on the right side of the face infiltrating the orbital Figures 5, 6. Repeat CT scan: Coronal and axial floor, hard palate, and anterior maxillary sinus. views showing interim decrease in tumor size.

SCHROEDER, LE, TAYLOR Page 36 References 1. Lear J, Corner C, Dziewulski P, Fife K, Ross G, Varma S, Harwood C. Challenges and new horizons in the management of advanced basal cell carcinoma: a UK perspective. Br J Cancer. 2014 Oct 14;111(8):1476–81.

2. Bechert C, Stern J. Basal cell carcinoma with perineural invasion: reexcision perineural invasion? J Cutan Pathol. 2010 Mar;37(3):376-9.

3. Kauvar A, Cronin T, Roenigk R, Hruza G, Bennett R. Consensus for Nonmelanoma Skin Cancer Treatment: Basal Cell Carcinoma, Including a Cost Analysis of Treatment Methods. Dermatol Surg. 2015 May;41(5):550-71.

4. Lo JS, Snow SN, Reizner GT, Mohs Fe, Larson PO, Hruza GJ. Metastatic basal cell carcinoma: report of twelve cases with review of the literature. J Am Acad Dermatol. 1991;24:715-9.

5. Mahvash M. Intracranial Basal Cell Carcinoma with Extensive Invasion of the Skull Base. Turk Neurosurg. 2014;24(4):571-3.

6. Sekulic A, Migden M, Oro A, Dirix L, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012 June;366:2171-9.

7. Basset-Seguin N, Hauschild A, Grob J, Kunstfeld R, Dréno B, Mortier L, Ascierto P, Licitra L, Dutriaux C, Thomas L, Jouary T, Meyer N, Guillot B, Dummer R, Fife K, Ernst D, Williams S, Fittipaldo A, Xynos I, Hansson J. Vismodegib in patients with advanced basal cell carcinoma (STEVIE): a pre-planned interim analysis of an international, open-label trial. Lancet Oncol. 2015 June;16(6):729–36.

8. Von Hoff D, LoRusso P, Rudin C, et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med. 2009 September;361:1164-72.

9. Migden, M, et al. Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial. Lancet Oncol. 2015 June;16(6):716-28.

10. Danial C, Sarin K, Oro A, Chang A. An Investigator-Initiated Open-Label Trial of Sonidegib in Advanced Basal Cell Carcinoma Patients Resistant to Vismodegib. Clin Cancer Res. 2016 March;22(6):1325-9.

Page 37 LOCALLY ADVANCED BASAL CELL CARCINOMA WITH SUBTLE SKIN FINDINGS Oculocutaneous Albinism, A Family Matter Summer Moon, DO,* Katherine Braunlich, DO,** Howard Lipkin, DO,*** Annette LaCasse, DO***

*Dermatology Resident, 3rd year, Botsford Hospital Dermatology Residency Program, Farmington Hills, MI **Traditional Rotating Intern, Largo Medical Center, Largo, FL ***Program Director, Botsford Hospital Dermatology Residency Program, Farmington Hills, MI

Disclosures: None Correspondence: Katherine Braunlich, DO; [email protected]

Abstract Oculocutaneous albinism (OCA) is a group of autosomal-recessive conditions characterized by mutations in melanin biosynthesis with resultant absence or reduction of melanin in the melanocytes. Herein, we present a rare case of two Caucasian sisters diagnosed with oculocutaneous albinism type 1 (OCA1). On physical exam, the sisters had nominal cutaneous evidence of OCA. This case highlights the difficulty of diagnosing oculocutaneous albinism in Caucasians. Additionally, we emphasize the uncommon underlying genetic mutations observed in individuals with oculocutaneous albinism.

2,5 Introduction people has one of the four types of albinism. of exon 4. Additionally, patient A was found to Oculocutaneous albinism (OCA) is a group of We present a rare case of sisters diagnosed with possess the c.21delC frameshift mutation in the autosomal-recessive conditions characterized by oculocutaneous albinism type 1, emphasizing the C10orf11 gene. Patient B was found to possess the mutations in melanin biosynthesis with resultant uncommon genetic mutations we observed in these same heterozygous mutation and deletion in the two individuals. absence or reduction of melanin in the melanocytes. Figure 1 Melanin-poor, pigment-poor melanocytes phenotypically present as hypopigmentation of the Case Report 1,2 Two Caucasian sisters were referred to our hair, skin, and eyes. dermatology clinic after receiving a diagnosis of There are four genes responsible for the four principal oculocutaneous albinism type 1. Patient A was a types of OCA. OCA type 1A (OCA1A) and OCA 2-year-old Caucasian female, and Patient B was type 1B (OCA1B) are caused by a mutation in the a 5-year-old Caucasian female. On physical exam, tyrosinase gene (TYR) on chromosome 11q14.3.2,3 the sisters had nominal cutaneous evidence of OCA type 2 is caused by a mutation in the OCA2 OCA (Figures 1, 2). gene.2,3 OCA type 3 is caused by a mutation in the Patients A and B were diagnosed with OCA after tyrosinase-related protein 1 gene (TYRP1), and a retinal specialist recommended genetic testing to OCA type 4 is caused by a mutation in SCL45A2 2,3 identify the cause of the sisters’ underlying optical (a.k.a. MATP). OCA1A is considered the most impediments. The mother initially identified severe type of OCA due to a complete absence of optical difficulties in her younger daughter, patient melanin production. OCA1B, OCA2, OCA3 and A, around 8 weeks of age. She noticed the infant OCA4 are considered less severe, as they often displaying nystagmus and an inability to track. At show small amounts of pigment accumulation over 4 seven months, patient A began crawling, and it time. Overall, there is significant clinical overlap quickly became evident the infant could not see between the variants of OCA. Thus, molecular more than a few feet in front of her. The mother diagnosis is often necessary to establish the specific became increasingly concerned when, at one year of OCA subtype. The clinical characteristics found age, her daughter had difficulty seeing beyond 20 in individuals afflicted with OCA type 1 include feet (6 m). At that time, the child was evaluated by hypopigmentation of the skin and hair and the an ophthalmologist, who told the mother nothing distinctive ocular changes characteristic of all forms Figure 1. Patient A, 2-year-old female. 4 was structurally wrong. The mother insisted on of albinism. Decreased melanin production does further workup. The mother’s primary clue to the not alter the development of skin, but it does alter underlying abnormality was her older daughter, Figure 2 the color. The absence of melanin in the eye, on the patient B, who did not display these apparent optical other hand, leads to anomalous development and 2 difficulties. Patient A was referred to a neuro- function. The ocular changes associated with OCA ophthalmologist at the University of Michigan. include severe nystagmus, prominent photophobia, An electroretinogram (ERG) and magnetic reduced pigmentation of the retinal epithelium and 4 resonance imaging (MRI) were conducted for the reduced visual acuity. A pathognomonic finding initial ruling out of Leber congenital amaurosis of albinism is misrouting of the optic nerve at the (LCA). The MRI displayed no abnormalities. The optic chiasm, resulting in strabismus and reduced 2,4 ERG identified normal cones but decreased rods. stereoscopic vision. Mutations in the TYR gene Patient A was referred to a retinal specialist, who may entirely abolish tyrosinase activity, resulting in recommended genetic testing. OCA1A, or decrease the activity of the tyrosinase enzyme, resulting in the development of OCA1B. Both children underwent molecular analysis for Clinically, the difference between OCA1A and underlying genetic anomalies. The genetic testing OCA1B is seen over time, as OCA1B individuals was performed using PCR amplification and DNA often accumulate minor quantities of melanin and 2 sequencing in two directions. Quantitative PCR begin to display small amounts of pigmentation. analysis was performed using the ABI TaqMan copy number assay and CopyCaller software. Ultimately, OCA is considered a clinical diagnosis. qPCR primers for the OCA1 gene were used for The diagnosis is made if the individual has amplification and detection, namely Hs03778472_ hypopigmentation of the skin or hair in conjunction cn (intron 4), whereas RNAse P was used as the with the aforementioned characteristic ocular reference. signs. Molecular genetic testing is often used in combination with the clinical diagnosis to establish Patient A was found to possess a herterozygous the specific genetic mutation and thus the OCA 2 mutation and a heterozygous deletion in the subtype. Approximately one out of every 17,000 OCA1 gene, namely c.1217C>T, and deletion Figure 2. Patient B, 5-year-old female.

MOON, BRAUNLICH, LIPKIN, LACASSE Page 38 OCA1 gene, but she did not possess the c.21delC individuals at greater risk for the harmful effects References frameshift mutation in the C10orf11 gene. Both to UV radiation. Patients with OCA type 1, due 1. Oetting W, Brilliant M, King R. The clinical girls were found to have clinical and molecular to a pigment reduction in hair and skin, often spectrum of albinism in humans. Mol Med findings consistent with OCA1. Both mother develop solar keratosis, basal cell carcinoma and Today.1996 Aug 2;2(8):330–5. and father underwent molecular genetic testing. squamous cell carcinoma.4 Additionally, and The mother was found to possess the c.1217C>T arguably most commonly, these patients may 2. Grønskov K, Ek J, Brondum-Nielsen K. mutation and the father the deletion of exon 4. develop numerous actinic keratoses, predisposing 12-14 Oculocutaneous Albinism. Orphanet J Rare Dis. them to squamous cell carcinoma. Morbidity 2007 Nov 2;2:43. To date, both patients are doing well and being is influenced by phenotype, education and resource monitored with close follow-up. availability. Dermatologic consultation is essential, 3. Kamaraj B, Rituraj P. Mutational Analysis of as patients (and in juvenile cases, their parents) Oculocutaneous Albinism: A Compact Review. Discussion must be made aware of the importance of sun- Biomed Res Int. 2014 (2014), Article ID 905472, To date, 12 genetic mutations have been identified 6 protection in patients with OCA1. Extensive solar 10 p. in the development of albinism. OCA type 1 is exposure without protection results in a cumulative caused by a mutation in the tyrosinase gene (TYR) 2,3,7,8 increase in the risk of cutaneous neoplasms. Five 4. Lewis R. Oculocutaneous Albinism Type 1. on chromosome 11q14.3. The TYR gene to 10 minutes of sun exposure in individuals with GeneReviews [Internet]. 2000 Jan 19 [updated consists of 529 amino acids and five exons that 4 8 OCA1A is considered substantial. 2013 May 16; cited 2016 Aug 15]. Available from: span 65 kb of genomic DNA. The gene encodes http://www.ncbi.nlm.nih.gov/books/NBK1166/. tyrosinase, an enzyme that catalyzes the first It is also important to emphasize that while 8,9 two steps in the melanin biosynthesis pathway. melanoma is rare in individuals with OCA, it does 5. Witkop C. Albinism: hematologic-storage Tyrosinase converts tyrosine to L-dihydroxy- occur. In one case, a patient with OCA was found disease, susceptibility to skin cancer, and phenylalanine (DOPA) and then to dopaquinone. to have malignant amelanotic melanoma that optic neuronal defects shared in all types of The TYR gene mutation causes a complete or developed from an intradermal nevus.15 8,10 oculocutaneous and ocular albinism. Ala J Med Sci. partial loss of the catalytic activity of tyrosinase. 1979 Oct;16(4):327-30. Patients with OCA need to be screened regularly The current case emphasizes a rare molecular for changes to their skin. Ongoing surveillance 6. Oetting W, Fryer J, Shriram S, et al. presentation of OCA type 1, increasing awareness is imperative, particularly in those whose visual Oculocutaneous Albinism Type 1: The Last 100 of the condition’s varied clinical manifestations. impairments make it difficult to appropriately Years. Pigment Cell Res. 2003 Jun;16(3):307-11. Current literature on albinism suggests 90% of assess and monitor their own skin. Finally, patients OCA1A patients have two mutations. Among and families should be assured that persons with 7. Tomita Y, Takeda A, Okinaga S, et al. Human OCA1B patients, 37% have two mutations, and OCA have normal intelligence, fertility and, with oculocutaneous albinism caused by single base 63% have only one. In both forms, less than 1% proper skin protection, natural lifespans.2 insertion in the tyrosinase gene. Biochem Biophys of patients have an exonic or whole-gene deletion Res Commun. 1989;164:990-6. identified after molecular review.4 Both of our Conclusion patients possessed a deletion of exon 4. Additionally, As with any genetic condition, a patient’s 8. Kamaraj B, Purohit R. Mutational Analysis of patient A had a distinctive mutation in the morbidity and mortality can be vastly improved Oculocutaneous Albinism: A Compact Review. C1Oorf11 gene. A mutation in the gene C10orf11 with identification, education and support. In this Biomed Res Int. 2014 Jun 29;1-10. on chromosome 10q22.2-q22.3 is associated case report, we showcase a rare genetic mutation with a new form of OCA, known as OCA7.8 observed in individuals with oculocutaneous 9. Kwon B, Haq A, Pomerantz S, et al. Isolation and However, the specific structural and functional albinism, aiming to provide additional information sequence of a cDNA clone for human tyrosinase behaviors of C10orf11 remain an enigma. The on an uncommon clinical entity to assist with early that maps the mouse c-albino locus. Proc Natl C10orf11 gene encodes a protein containing three diagnosis and management. Acad Sci USA. 1988 Sep;85(17):6352. leucine-rich repeats (LRRs) that have a variety of functions including cell adhesion, extracellular- 10. Cooksey C, Garratt P, Land E, et al. Evidence matrix assembly, neuronal development and RNA of the indirect formation of the catecholic processing.11 The C10orf11 mutation was observed intermediate substrate responsible for the in patient A but is not sufficient for the diagnosis autoactivation kinetics of tyrosinase. J Bio Chem. of albinism. It is currently unknown what effect, if 1997 Nov;272(42):26226-35. any, this mutation will have on patient A’s clinical symptoms. It is our hope that case reports like 11. Bella J, Hindle K, McEwan P, et al. The leucine- this will inspire continued research to identify rich repeat structure. Cell Mol Life Sci. 2008 the relationships between genetic and phenotypic Aug;65(15):2307-33. variations in the development of OCA. Identifying the significance of unique genetic mutations 12. Ihn H, Nakamura K, Abe M, et al. Amelanotic causing OCA will be vital to the development of metastatic melanoma in a patient with personalized medicine for patients with albinism. oculocutaneous albinism. J Am Acad Dermatol. 1993 May 28;5(2): 895–900. An essential component of medical management for these individuals involves genetic counseling. 13. Okoro AN. Albinism in Nigeria. A clinical and As in all types of autosomal-recessive inheritance, social study. Br J Dermatol. 1975 May;92: 485–92. these sisters will pass on one non-working copy of the OCA1 gene to all of their offspring. At 14. Satoko M, Kaneko T, Matsuzaki Y, et al. Case minimum, their children will be carriers of the of Oculocutaneous Albinism Complicated with condition. Additional patient education and Squamous Cell Carcinoma, Bowen’s Disease and future partner genetic counseling should be Actinic Keratosis. J Dermatol. 2014;41(9):863-4. encouraged. The optimal time to determine genetic 15. Wu C, Gao H, Chiang C. Malignant amelanotic risk and clarification of carrier status is before 4 melanoma developing from an intradermal naevus pregnancy occurs. This case highlights the value in a patient with oculocutaneous albinism. Clin of a dermatology consultation in young patients Exp Dermatol. 2009;34: 590-9. with clinical features of hypopigmentation and/ or ocular findings. As in this case, the initial diagnosis of oculocutaneous albinism was delayed until confirmed by an ophthalmologist aware of the spectrum of its clinical features. Delays can result in years of unprotected solar exposure in

Page 39 OCULOCUTANEOUS ALBINISM, A FAMILY MATTER Porphyria Cutanea Tarda: A Case Presentation and Discussion Jordan Harris, DO,* Craig Parson,** Michael Eyre, DO, FAOCD***

*Dermatology Resident, 1st year, Aspen Dermatology/OPTI-West/WUHS, Spanish Fork, UT **Medical Student, 4th year, Midwestern University Arizona College of Osteopathic Medicine, Glendale, AZ ***Board-certified Dermatologist, Aspen Dermatology, Spanish Fork, UT

Disclosures: None Correspondence: Jordan Harris, DO; [email protected]

Abstract The porphyrias are metabolic disorders caused by altered activity of enzymes in the heme biosynthetic pathway. Porphyria cutanea tarda (PCT) is the most common subtype, with a prevalence of about 1 in 10,000 people,1 and is due to deficient activity of uroporphyrinogen decarboxylase (UROD), the fifth enzyme in the heme biosynthetic pathway. Cutaneous findings are common and include photosensitivity, bullae, skin fragility, erosions, scarring, and milia in sun-exposed areas. The cause of PCT may be multifactorial, related to genetic and environmental factors. Generally, there is a strong association with liver disease, and one should consider possible triggers including but not limited to alcohol abuse, iron overload including possible hereditary hemochromatosis, hepatitis C virus infection, and estrogen use.1 The diagnosis can be made through screening of serum, urine, and fecal porphyrin levels. We present a case of a 57-year-old female with PCT and secondary hemochromatosis.

fluorescent properties and ability to form free Introduction radicals, it results in a delayed photodermatitis Case Report Porphyria cutanea tarda (PCT) is a complex and 3,4 A 57-year-old white female presented to our multifactorial disease. PCT results from subnormal PCT. Porphyria cutanea tarda is the most outpatient dermatology clinic with complaints of activity of uroporphyrinogen decarboxylase common porphyria, presenting with various blisters and bumps on her hands for three months’ (UROD) in the liver, with subsequent cutaneous findings including painful blistering, duration. She stated the lesions would start out as atrophic scars, hypertrichosis, hyperpigmented decreased conversion of uroporphyrinogen to 1-6 little blisters that would easily break open, leave coproporphyrinogen in the heme biosynthetic macules, and milia in sun-exposed areas. Since it her with painful sores, and heal with “little white, pathway (Figure 1).1-2 Uroporphyrin, the oxidized was first described by Waldenstrom in 1937, there pimple-like” bumps. The patient reported she had form of uroporphyrinogen, circulates in plasma, has been increasing interest in the relationship not developed any new blisters for a few weeks. between PCT, iron overload, UROD activity, and accumulates in various organs including the skin, 1 She didn’t recall any inciting triggers and denied and is excreted in urine. Due to uroporphyrin’s the possible link to hereditary hemochromatosis. any other affected areas. She reported starting nabumetone a few months earlier for arthritis Figure 1. The heme biosynthetic pathway. but admitted taking it only as needed. She denied any other medications. Past medical and family histories were unremarkable. She reported a long history of alcohol consumption, consuming five to six “shots” of whisky a night for 15 years.

Two weeks prior to our visit, she had previously been seen by a nurse practitioner who diagnosed her with dyshidrotic eczema. She was given an intramuscular corticosteroid injection, which she reported did not help.

On physical exam, there were multiple hyperpigmented macules, with areas of shallow scarring and multiple milia on her bilateral dorsal hands (Figures 2, 3). No onycholysis was noted. Her skin appeared bronze in nature, but she denied using tanning beds, and she reported having the darkest skin in her family. Examination of her face revealed noticeable hypertrichosis (Figure 4). The rest of her physical exam was unremarkable.

Given the lack of new bullae, no biopsy was performed, and she agreed to return for a biopsy if a new one arose. Based on history and clinical presentation, her case seemed most consistent with pseudoporphyria or porphyria cutanea tarda (PCT). She was instructed to hold her nabumetone, avoid other NSAIDS, and start decreasing her alcohol intake and sun exposure.

Laboratory workup, including a CBC, complete metabolic profile, iron studies, hepatitis B/C, HIV screen, HbA1C, CRP, and ANA, was unremarkable except for mildly elevated AST/ALT in a 2:1 ratio and a significantly elevated ferritin at 637 ng/ml (reference interval 15 ng/ml to 115 ng/ ml). A urinary porphyrin screen was performed, which showed considerably elevated uroporphyrins (uroporphyrin I – 794.0 mcg [normal 4.1 mcg

HARRIS, PARSON, EYRE Page 40

Made figure myself on Powerpoint. Figure 4 Many genetic and acquired susceptibility factors have been identified and studied in PCT patients. Most PCT patients have three or more precipitating factors.9,10 The most common are cigarette smoking, alcohol or estrogen use, iron overload, hemochromatosis, and viral infections.

Cigarette smoking has been found in 81% of patients with PCT.9,11 PCT patients who smoke tend to develop cutaneous symptoms at a younger age than non-smoking PCT patients.12 Smoking induces CYP1A2 synthesis that may in turn lead to 13 Figure 2 increased production of UROD inhibitor. Figure 3 Alcohol use has been reported in up to 80% of PCT patients.9 Although alcohol consumption is a common factor among PCT patients, it is uncommon for users of alcohol to develop PCT. There are several possible mechanisms by which alcohol consumption could cause PCT. Alcohol increases iron absorption, dissociates iron from its binding proteins, simulates ALA synthase, and inhibits UROD.6 Alcohol can also stimulate production of free radicals and reactive oxygen species, leading to oxidative changes that inhibit UROD.3 Figure 4. Clinical presentation showing notable facial hypertrichosis. Elevated estrogen levels have been found in Figures 2, 3. Clinical presentation revealing many PCT patients, with one study finding up numerous erosions and erythematous patches. Clinically, PCT presents with characteristic bullae to 66% of female PCT patients using exogenous 9 and skin fragility on sun-exposed areas such as the estrogen. Oral contraceptives, postmenopausal to 22.4 mcg] and uroporphyrin III – 962.5 mcg dorsal hands, forearms, ears and face. Women may hormone replacement, and tamoxifen are common 12 [normal 0.7 mcg to 7.4 mcg]), as well as mildly also develop bullae on the legs and dorsal feet.4 precipitating factors for PCT in women. elevated coproporphyrins (coproporphyrin I – 86.0 The bullae in PCT are filled with clear fluid and Infrequently, PCT has also been stimulated by 6 mcg [normal 7.1 mcg to 48.7 mcg]), consistent are formed by sun exposure or minor trauma.5 The pregnancy and childbirth. A possible mechanism with the diagnosis of porphyria cutanea tarda. fragile bullae rupture, creating erosions and shallow by which estrogen might cause PCT is via increased While she had significantly elevated ferritin, her ulcers that heal slowly and lead to scarring, milia estrogen quinone formation leading to increased 12 transferrin saturation was on the higher end of and/or altered pigmentation. Facial hypertrichosis free-radical production. normal at 44%. Given these findings and her can be the first clinical presentation of PCT bronzed skin, hemochromatosis gene mutation and is most often noted in women.3,6 Hyper- or Hepatic iron overload is found in nearly all patients studies for C282Y and H63D were done, which with PCT, but the mechanism is somewhat hypopigmentation in a wide variety of coloration 5,6 were negative. is common in sun-exposed areas. Sclerodermatous unclear. Iron may increase production of lesions can be found in up to 30% of patients.6,7 peroxides and free radicals, leading to oxidation The patient was referred to Hematology and of uroporphyrinogen in the cell, liver damage, Dystrophic calcification, non-healing ulcers, and 3,6 Gastroenterology for further evaluation. Further fingernail onycholysis are less-common findings. inhibition of UROD or enzyme modification. workup, including liver ultrasound and abdominal Most patients with iron overload have HFE gene 5,14 CT scan, showed a fatty liver. Smooth muscle PCT has been classified into three types, all of mutations, and HFE mutations are found more antibodies, liver-kidney microsomal antibodies, which reduce the activity of uroporphyrinogen commonly in PCT patients than in the general 21 mitochondrial (M2) antibodies, alpha-1- decarboxylase (UROD). Type 1, the most common, population, so gene testing should be considered antitrypsin, and ceruloplasmin levels were all within is sporadic and non-familial. The sporadic form if clinical suspicion is high. The two most common 5,15 normal limits. Hematology started the patient on accounts for 75% to 80% of PCT cases.4 UROD types of mutations are C282Y and H63D. phlebotomy every other week. At the patient’s two- levels are normal, but enzymatic activity in the liver, Homozygous C282Y mutation causes iron overload 5 month follow-up, she reported no new flares. Her exclusively, is reduced by at least 50%. Many factors in an estimated 50% of patients. Heterozygous 5 liver enzymes and ferritin had returned to normal can lead to the enzymatic deficiency, including C282Y causes iron excess in about 20% of patients. despite continuing, though reportedly decreasing, smoking cigarettes, alcohol or estrogen use, iron H63D mutation is a very common mutation in the her alcohol intake. overload (hemochromatosis), and viral infections Caucasian population, but it rarely develops into (HIV and HCV). hemochromatosis. Even though hemochromatosis Discussion is a common precipitating factor for PCT, most Porphyria cutanea tarda (PCT) is the most common Type II is familial. Familial PCT is inherited patients with hemochromatosis never develop the form of porphyria worldwide.2 Like all forms of autosomal-dominantly and accounts for 15% to 20% disease. porphyria, PCT is caused by abnormalities in of PCT cases. UROD enzymatic activity is reduced the heme biosynthesis pathway leading to the by at least 50% in both the liver and red blood cells. Hepatitis C and HIV infection have both been 16 accumulation of porphyrins in the body. Patients Multiple mutations have been found that produce found to precipitate PCT. HCV is a very common usually present with cutaneous symptoms in sun- the same phenotype.4,8 Familial PCT usually presents precipitating factor. Two possible mechanisms exposed areas in their fourth or fifth decades.3 UV in a clinically similar manner to sporadic PCT, but by which HCV causes PCT are its triggering of radiation with absorption of the Soret band (400 usually earlier in life, and is precipitated by similar increases in free hepatocellular iron and free radical 3,17 nm to 410 nm wavelength) by porphyrins that factors (e.g., alcohol, estrogen). Co-inheritance of oxidation due to increased oxidative stress. HIV accumulate in blood vessels of the upper dermis cause UROD and HFE mutations can cause accelerated can play an independent role in the development of 18 the photosensitivity found in PCT.4,5 Destabilization presentation of PCT.8 PCT, but it is often found with HCV coinfection. of porphyrins by sun exposure leads to creation of The mechanisms by which HIV produces PCT reactive oxygen species that cause tissue damage. A type III PCT has been observed in which a are altered porphyrins, direct hepatic damage, PCT porphyrin buildup is specifically induced genetic predisposition leads to decreased UROD impaired cytochrome oxidase, and increased by abnormal activity of the uroporphyrinogen activity in the liver alone.2 Also, exposure to estrogen levels.3 PCT has been associated with decarboxylase (UROD) enzyme, the fifth enzyme in polyhalogenated hydrocarbons can produce a form many other conditions such as diabetes mellitus, the heme biosynthetic pathway.6 of PCT known as toxic PCT. dialysis-dependent chronic renal failure, discoid

Page 41 PORPHYRIA CUTANEA TARDA: A CASE PRESENTATION AND DISCUSSION lupus erythematosus, myeloproliferative diseases, (100 mg) or chloroquine (125 mg) given twice a lymphoproliferative diseases, and hepatic disease.6,19 week has shown similar results as phlebotomy.27 While treating with antimalarials, monitor urine Clinical presentation usually provides strong and plasma porphyrin levels.2,4,6,16 Therapy is evidence to suspect PCT, and a variety of studies discontinued when porphyrin levels are normal. help improve diagnostic accuracy. Total plasma Treat underlying HCV and/or HIV infection if or urine porphyrin is the initial exam to confirm found to be present.18 Iron chelation can be used if porphyria. A 24-hour urine specimen with other treatments are contraindicated, but is not as fractionation reveals elevated uroporphyrins effective as phlebotomy or antimalarials. and a uroporphyrin-to-coproporphyrin ratio of 3:1 to 5:1, which distinguishes PCT from other Conclusion cutaneous porphyria’s, including pseudoporphyria, Porphyria cutanea tarda should be suspected in which would have normal urinary porphyrins.3,20 patients with bullae and increased skin fragility in Urinary delta-aminolevulinic acid (ALA) sun-exposed areas. The diagnosis can be confirmed and porphobilinogen (PBG) levels also aid in biochemically by characteristically elevated differentiating between porphyrias.21 PCT has uroporphyrins and coproporphyrins in the urine. normal urinary ALA and PBG levels. In office, Given the diagnosis of PCT, investigations may the urine sample examined under Wood’s light will include, but are not limited to, liver function tests, fluoresce pink or coral-red.4 Normal erythrocyte iron studies, HCV and HIV serology, alcohol intake, total porphyrins help distinguish PCT from and current medication review. With the possible hepatoerythropoietic porphyria (HEP), which association of hereditary hemochromatosis, one has markedly elevated erythrocyte porphyrins.20 may consider gene screening if PCT is clinically Decreased measured erythrocyte UROD activity suspected. The patient should continue to be points to familial PCT, as sporadic PCT has monitored closely, both clinically and biochemically, normal erythrocyte UROD activity.3 A detailed to ensure response to treatment and monitor for history will help reveal some possible precipitating possible relapse. Of the various treatment options factors such alcohol consumption, oral estrogen available, the preferred modality is phlebotomy use, or smoking. Liver studies, including serum combined with avoidance of sunlight and other bilirubin, prothrombin time, and hepatic enzymes, precipitating factors. should be performed. Complete blood count, metabolic panel with creatinine, and iron studies with an emphasis on serum ferritin levels will help in management. HFE genetic testing looking specifically at C282Y and H63D mutations should be used for hemochromatosis diagnosis.2,5,12 UROD mutation testing improves diagnostic accuracy for PCT type. Viral serology will help find the possible precipitating presence of HCV or HIV infection.2,16,22

Histopathology of PCT reveals a subepidermal bulla with little to no inflammatory infiltrate and an undulating, festooning dermal papilla projecting into the bulla.3,4,23 Thickened blood-vessel walls in the dermis occur due to deposition of PAS-positive material.4,6,23 Caterpillar bodies, a common, but not diagnostic, characteristic of PCT consist of PAS-positive eosinophilic, elongated, wavy structures usually found in the epidermis above the bulla.4,6,23 Direct immunofluorescence shows IgG, IgM, fibrinogen, and complement (C3) in the basement membrane and around vessels of the upper dermis.3,4,6,23

Management of PCT begins with avoidance of all possible precipitating factors like alcohol and estrogen.2,24 Physical barriers and sun protection, such as clothing and sunscreens containing zinc oxide, and avoiding skin trauma protect against worsening skin disease. This initial approach may be sufficient to treat PCT.

Phlebotomy is the preferred treatment for PCT. Phlebotomy of 450 mL (one unit) at two-week intervals is performed until serum ferritin falls below 25 ng/mL, or until hemoglobin falls below a preset point, to prevent anemia.2,25 Clinical improvement may take several months. Skin fragility and bullous formation will be the first clinical symptoms to improve. More chronic symptoms such as hypertrichosis and sclerosis will improve at a slower rate.26 Antimalarial medications (chloroquine and hydroxychloroquine) can be used as an alternative to phlebotomy. Low-dose treatment with hydroxychloroquine

HARRIS, PARSON, EYRE Page 42 References 14. Mehrany K, Drage LA, Brandhagen DJ, 1. Frank J, Poblete-Gutierrez P. Porphyria cutanea Pittelkow MR. Association of porphyria cutanea tarda – when skin meets liver. Best Pract Res Clin tarda with hereditary hemochromatosis. J Am Gastroenterol. 2010;24:735–45. Acad Dermatol. 2004;51(2):205-11.

2. Caballes FR, Sendi H, Bonkovsky HL. Hepatitis 15. Bonkovsky HL, Poh-Fitzpatrick M, Pimstone C, porphyria cutanea tarda and liver iron: an update. N, Obando J, Di Bisceglie A, Tattrie C, Tortorelli Liver Int. 2012 Jul;32(6):880-93. K, LeClair P, Mercurio MG, Lambrecht RW. Porphyria cutanea tarda, hepatitis C, and HFE 3. Horner ME, Alikhan A, Tintle S, Tortorelli S, gene mutations in North America. Hepatology. Davis DMR, Hand JL. Cutaneous porphyrias 1998;27(6):1661-9. part I: epidemiology, pathogenesis, presentation, diagnosis, and histopathology. Int J Dermatol. 16. Quansah R, Cooper CJ, Said S, Bizet J, 2013;52:1464-80. Páez D, Fernández GT. Hepatitis C- and HIV- induced porphyria cutanea tarda. Am J Case Rep. 4. James WD, Berger TG, Elston DM, eds. Andrews’ 2014;15:35-40. Diseases of the Skin: Clinical Dermatology. 11th ed. Philadelphia: Saunders/Elsevier; 2011. Chapter 26, 17. Korenaga M, Okuda M, Otani K, Wang Errors in Metabolism; p. 511-512. T, Li Y, Weinman SA. Mitochondrial dysfunction in hepatitis C. J Clin Gastroenterol. 5. Bulaj ZJ, Phillips JD, Richards AS, Franklin MR, 2005;39(2):S162-S166. Griffen LM, Guinee DJ, et al. Hemochromatosis genes and other factors contributing to the 18. Mansourati FF, Stone VE, Mayer KH. pathogenesis of porphyria cutanea tarda. Blood. Porphyria cutanea tarda and HIV/AIDS: a review 2000;95(5):1565-70. of pathogenesis, clinical manifestations and management. Int J STD AIDS. 1999;10:51. 6. Bleasel NR, Varigos A. Porphyria cutanea tarda. Australas J Dermatol. 2000;41:197-208. 19. Shieh S, Cohen JL, Lim HW. Management of porphyria cutanea tarda in the setting of chronic 7. Stevens HP, Ostlere LS, Black CM, Rustin MHA. renal failure: a case report and review. J Am Acad Generalized morphoea secondary to porphyria Dermatol. 2000;42(4):645-52. cutanea tarda. Br J Dermatol. 1993;129:455-7. 20. Deacon AC, Elder GH. Front line for the 8. Brady JJ, Jackson HA, Roberts AG, Rhian RM, investigation of suspected porphyria. J Clin Pathol. Whatley, SD, Rowlands LR, Darby C, Shudell E, 2001;54:500-7. Watson R, Paiker J, Worwood MW, Elder GH. Co- inheritance of mutations in the uroporphyrinogen 21. Sassa S. Modern diagnosis and management of decarboxylase and hemochromatosis genes the porphyrias. Br J Haematol. 2006;135:281-92. accelerates on the onset of porphyria cutanea tarda. 22. Pellicelli AM, Morrone A, Barbieri L, Andreoli J Invest Dermatol. 2000;115:868-74. A. Porphyria cutanea tarda in an HCV-positive 9. Jalil S, Grady JJ, Lee C, Anderson KE. Associations liver transplant patient: a case report. Ann Hepatol. among behavior –related susceptibility factors 2012;11(6):951-4. in porphyria cutanea tarda. Clin Gastroenterol 23. Maynard, B; Peters, MS. Histologic and Hepatol. 2012;8:297-302. immunofluorescence study of cutaneous porphyrias. 10. Egger NG, Goeger DE, Payne DA, Miskovsky J Cutan Pathol. 1992;19:40-7. EP, Weinman SA, Anderson KA. Porphyria 24. Deen K, Wu J. Porphyria cutanea tarda cutanea tarda: multiplicity of risk factors including masquerading as epidermolysis bullosa acquisita: HFE mutations, hepatitis C, and inherited a report of two cases. Case Rep Dermatol. uroporphyrinogen decarboxylase deficiency. Dig 2015;7:129-35. Dis Sci. 2002;47(2):419-26. 25. Ratnaike S, Blake D, Campbell D, Cowen 11. Fontanellas A, Martínez-Fresno M, P, Varigos G. Plasma ferritin levels as a guide Concepcion Garrido-Astray M, Perucho T, to the treatment of porphyria cutanea tarda by Moran-Jiménez MJ, Garcia-Bravo M, Mendez venesection. Australas J Dermatol. 1988;29:3-8. M, Poblete-Gutierrez P, Frank J, Henriques-Gil N, Enriquez de Salamanca R. Smoking but not 26. Sweeney GD, Jones KG. Porphyria cutanea homozygosity for the CYP1A2 g-163A allelic tarda: clinical and laboratory features. Can Med variant leads to earlier disease onset in patients Assoc J. 1979;120:803-7. with sporadic porphyria cutanea tarda. Exp Dermatol. 2010;19:e326-28. 27. Singal AK, Kormos-Hallberg C, Lee C, Sadagoparamanujam VM, Grady JJ, Freeman Jr 12. Barton JC, Edwards CQ. Porphyria cutanea DH; Anderson KE. Low-dose hydroxychloroquine tarda associated with HFE C282Y homozygosity, is as effective as phlebotomy in treatment of patients iron overload, and use of contraceptive vaginal with porphyria cutanea tarda. Clin Gastroenterol ring. J Community Hosp Intern Med Perspect. Hepatol. 2012;10:1402-9. 2016;6:30380.

13. Phillips JD, Bergonia HA, Franklin MR, Kushner JP. A porphomethene inhibitor of uroporphyrinogen decarboxylase causes porphyria cutanea tarda. Proc Natl Acad Sci U S A. 2007;104(12):5079-84.

Page 43 PORPHYRIA CUTANEA TARDA: A CASE PRESENTATION AND DISCUSSION A Rare Case of SCC in a Pediatric Patient with NF-1 Christopher Mancuso, DO,* Mojgan Hosseinipour, BA,** Craig Austin, MD,*** Charles Gropper, MD,**** Cindy Hoffman, DO*****

*Resident, 2nd year, Saint Barnabas Hospital Dermatology Residency, Bronx, NY **Medical Student, 4th year, Lake Erie College of Osteopathic Medicine, Erie, PA ***Pathology Associate, Fishkill, NY ****Chief of Dermatology, St. Barnabas Hospital, Bronx, NY *****Program Director, St. Barnabas Hospital Dermatology Residency, Bronx, NY

Disclosures: None Correspondence: Christopher Mancuso, DO; [email protected]

Abstract We present a case of a pre-adolescent female with neurofibromatosis type 1 (NF1) who developed squamous cell carcinoma (SCC) on the dorsum of the nose. This rare presentation has been reported in the literature only twice, and both instances involved adult patients. SCC itself is very rare in children and is usually seen in those with a predisposing condition like immunosuppression, radiation exposure or genodermatoses, none of which our patient had. We also discuss the possible pathogenesis of epithelial tumor development in patients with NF1, a historically non-epithelial tumor-producing disorder.

clinic with the lesion having grown since the last are at increased risk of developing non-epithelial Introduction visit. The patient then had a shave biopsy ofthe tumors including optic gliomas, astrocytomas and Neurofibromatosis type 1 is an autosomal- 2 dominant genetic disorder characterized by the nasal lesion, which showed atypical squamous cell malignant peripheral nerve sheath sarcomas. presence of cafe-au-lait macules (CALMs), proliferation invading the dermis, consistent with The NF1 gene codes for neurofibromin, a protein neurofibromas, nerve sheath tumors, Lisch nodules SCC (Figures 2, 3). that acts as a GTPase-activating protein. This leads and freckling in the axillary or inguinal region. Our patient underwent Mohs micrographic surgery to negative regulation of Ras-mitogen-activated Almost every organ system in the body can be for complete surgical removal, full examination protein kinase, which is involved in cell survival affected by renal dysfunction, from essential of tumor margins and best cosmetic outcome. and proliferation. Neurofibromin acts as a tumor hypertension and learning difficulties to scoliosis. After several months, she has shown no signs suppressor by hastening the transition from GTP Skin manifestations like CALMs and plexiform 9 of recurrence and is happy with the appearance to GDP, causing Ras to be nonfunctional. With neurofibromas will usually appear congenitally of her nose. The patient is being followed by Ras nonfunctional, tumor formation does not occur. or within the first year of life, whereas other skin Ophthalmology, Neurology and Dermatology, and findings, like simple neurofibromas, appear later she has been offered genetic counseling for her While evidence linking NF1 to epithelial tumors in childhood. Generally, all criteria for diagnosis underlying NF1. We recommended yearly follow- is scant, there have been some studies investigating of NF1 are met in 97% of patients by age 8 and up for full skin exams to monitor for further skin a possible role for the gene in their carcinogenesis. in 100% of patients by age 20. Patients are at cancer development. It is known that neurofibromin can be found increased risk of developing a number of different 9 in normal human epidermis. A Finland study central nervous and non-epithelial neoplasms. Discussion by Hermonen et al. used reverse transcriptase It is very rare for patients with NF1 to develop NF1 is an autosomal-dominant genetic disorder PCR, immunohistochemistry, and molecular cutaneous squamous cell carcinoma. resulting from mutations in the NF1 gene at hybridizations to characterize the expression of chromosome 17q11.2. Tumors in NF1 are NF within keratinocytes. They found evidence Case Report predominantly derived from connective tissue, that neurofibromin acts as a regulator of the basal An 11-year-old female with a past medical history and neurofibromas are the most common type of keratinocytes in normal skin and that dysregulation of NF1 and positive family history of NF1, 1 benign tumor in these patients. Patients with NF1 could potentially cause the development of including mother and sibling, presented to the epithelial tumors like basal cell carcinoma and dermatology clinic for evaluation of a lesion on 4 Figure 2 squamous cell carcinoma. Another study in mice her nose that was present for the past six months. by Atit et al. showed further evidence for NF1’s There was no bleeding, pain or change in size. role in epithelial carcinogenesis. They studied She denied similar lesions elsewhere. On physical mice who were heterogeneous for null mutations examination, the patient had a smooth, pink papule in NF1 and exposed them to known carcinogens. measuring 7 mm in diameter on the dorsum of Heterogeneous mice developed papillomatous the nose with overlying scale-crust (Figure 1), as growths as well as sustained increases in well as multiple well-defined brown patches and keratinocyte proliferation, while wild types with macules on the trunk and extremities. Differential the same exposure did not. In addition, all mice diagnosis included: verruca vulgaris, irritated with papillomas were shown to have activation of molluscum contagiosum, and pyogenic granuloma. Ras, a crucial step in the process of carcinogenesis, Cryotherapy using liquid nitrogen was performed 5 supporting its involvement in epidermal tumors. on the lesion for presumed verruca vulgaris. Three weeks later, the patient returned to the dermatology Figure 2. Low magnification. There are very few reported cases of epithelial tumors, specifically cutaneous squamous cell Figure 1 carcinoma (SCC), in patients with NF1. Ishida and Okabe reported a case of SCC of the forehead in an 80-year-old female patient with a history of NF1.2 Friedrich et al. reported a case of SCC arising on the sole of the foot in a 67-year-old male patient with NF1.3

Squamous cell carcinoma is the second most common cutaneous malignancy in adults. Classically, it occurs in older adults on chronically sun-exposed areas as well as in those with radiation Figure 3 exposure, chronic wounds, arsenic exposure and immunodeficiency. Children rarely develop any Figure 3. High magnification. cutaneous cancers, with an incidence of 1.4 per

MANCUSO, HOSSEINIPOUR, AUSTIN, GROPPER, HOFFMAN Page 44 1,000 patients. One study by a large pediatric References hospital showed that out of about 36,000 1. Seminog OO, Goldacre MJ. Risk of benign dermatology patients, 53 cutaneous malignancies tumours of nervous system, and of malignant were diagnosed. Of that number, 6% were squamous 6 neoplasms, in people with neurofibromatosis: cell cancer. In children, cutaneous malignancies population-based record-linkage study. Br J Cancer. are mainly seen in association with underlying skin 2013;108:193-8. conditions like albinism, xeroderma pigmentosum, nevus sebaceous, and Gorlin syndrome, although 2. Ishida M, Okabe H. Cutaneous squamous cell all of the classic predisposing factors can come into 7 carcinoma in a patient with neurofibromatosis type play. According to one article, pediatric squamous 1: A case report. Oncol Lett. 2013;6(4):878-80. cell cancer of all types appears to have increased in prevalence over the past two decades. They believe 3. Friedrich RE, Al-Dam A, Hagel C. it to be caused by multiple factors, including Squamous cell carcinoma of the sole of the foot recurrence of SCC after radiation treatments years 8 in neurofibromatosis type 1. Anticancer Res. later and increased HPV infection prevalence. 2012;32:2165-8.

Cutaneous malignancy should be considered early 4. Hermonen J, Hirvonen O. Neurofibromin: on in any child with predisposing factors and 10 expression by normal human keratinocytes in vivo atypical presentation. It is important to use a and in vitro and in epidermal malignancies. Lab dermatopathologist comfortable with diagnosing Invest. 1995;73(2):221-8. pediatric lesions. Clinicians may also consider performing a second, wider biopsy, so as not to 5. Atit RP, Mitchel K, Nguyen L, Warshawsky D, miss or delay diagnosis. Treatment of these lesions Ratner N. Neurofibromatosis type 1 and Tumor is recommended, and full excision is warranted, suppressor is a modifier of carcinogen induced as squamous cell cancers in children have poor pigmentation and papilloma formation in C57BL/6 8 prognoses. mice. J Invest Dermatol. 2000;114(6):1093–1100. Conclusion 6. De la Luz Orozco-Covarrubias M, et al. This is the third reported case of cutaneous SCC in Malignant cutaneous tumors in children. J Am a patient with NF1, and the first reported case in Acad Dermatol. 1994 Feb;30(2 Pt 1):243-9. a pre-adolescent patient. To our knowledge, this is also the first documented case of SCC of the nose 7. Hamm H, Höger PH. Skin tumors in childhood. diagnosed in a patient with NF1. Due to the rarity Dtsch Arztebl Int. 2011;108(20):347–53. of the condition, there are no clear guidelines for management of pediatric squamous cell cancer; 8. Chow CW, Tabrizi S, Tiedemann K, Waters with its increasing incidence, this issue may be K. Squamous carcinomas in children and young addressed in the future. Our case, along with prior adults: a new wave of a very rare tumor? J Pediatr studies, suggest a potential increase in risk for Surg. 2007;42:2035-9. developing epithelial tumors in patients with NF1, 9. Bolognia JL, Jorizzo JL, Rapini RP. Dermatology. warranting further study. With this knowledge, rd clinicians can be more informed about all the risks 3 Edition. Philadelphia: Elsevier; 2012. Chapter pertaining to NF1 and consider SCC when they 61, Neurofibromatosis & Tuberous Sclerosis. p. come across any abnormal lesions in predisposed 925-7. individuals. 10. Kotwal A, Watt D. Cutaneous squamous carcinoma in a child. J Plast Reconstr Aesthet Surg. 2009 Jul;62(7):e194-e195.

Page 45 A RARE CASE OF SCC IN A PEDIATRIC PATIENT WITH NF-1 Sclerotic-Type Chronic Graft-Versus-Host Disease: A Case Presentation and Discussion Madeline Tarrillion, DO,* Jenifer Lloyd, DO**

*Dermatology Resident, 2nd year, University Hospitals Regional Medical Center, Cleveland, OH **Program Director, University Hospitals Regional Medical Center Dermatology Residency, Cleveland, OH

Disclosures: None Correspondence: Madeline Tarrillion, DO; [email protected]

Abstract Background: Hematopoietic stem cell transplants (HSCT) are becoming more common; therefore, graft-versus-host disease (GVHD) is becoming a more prevalent dermatologic condition. Objective: To educate current dermatologists on the most current recommendations for chronic GVHD (cGVHD), specifically sclerotic-type chronic GVHD (ScGVHD). Methods: A patient with ScGVHD is presented. A literature review was performed for ScGVHD. Results: A discussion is provided on the presentation, treatment, and management of ScGVHD. Limitations: This is a case report of one patient. The mechanism of action of ScGVHD is not well-known, and there are no FDA-approved therapies with indications for cGVHD. Conclusion: Due to the increased morbidity and mortality of ScGVHD patients, research on the mechanism of action and optimization of currently used therapies is imperative. Introduction and stretching regimen to maintain his upper and In the past, acute and chronic GVHD were Hematopoietic stem cell transplants (HSCT) lower extremity range of motion, uses compression distinguished by time of onset following HSCT, are becoming more common for treatment of stockings to assist with his chronic lymphedema, multiple medical conditions. One of the most and receives wound care for his chronic plantar Figure 3 common complications of HSCT is graft-versus- wounds. host disease (GVHD). GVHD is distinguished as either acute or chronic, and both types frequently Discussion In 1968, the first successful allogeneic bone affect the skin. Due to the increased prevalence marrow transplant was performed. There are now of GVHD patients, dermatologists need to be approximately 25,000 allogeneic hematopoietic aware of the multiple presentations and the current stem cell transplants (HSCT) performed recommendations for treatment and management. 1 worldwide each year. One of the most severe This case presentation and discussion focus on sequela of HSCT is graft-versus-host disease, chronic GVHD (cGVHD), specifically sclerotic- specifically chronic GVHD, which occurs in 30 type chronic GVHD (ScGVHD), and the 2 percent to 70 percent of HSCT patients. The skin difficulties of its treatment and management. is the most frequently affected organ in both acute 1 Case Presentation and chronic GVHD. A 61-year-old male presented with a past medical history of multiple myeloma, status post Figure 1 autologous stem cell transplant with subsequent allogeneic sibling peripheral stem cell transplant. One year later, the patient was diagnosed with acute graft-versus-host disease (aGVHD) of the Figure 4 esophagus and small and large intestines. Two years after the aGVHD, the patient presented with symmetrical diffuse, bound down, woody plaques with hypopigmentation and alopecia of the upper and lower extremities (Figure 1). Involving the bilateral anterior lower legs were multiple pink- colored papules (Figure 2). On the plantar surface of the left foot, there were punched-out ulcerations with yellow adherent film Figure ( 3). There was decreased capillary refill of the fingers and toes. Wrist dorsiflexion was 15 degrees, and hand grasp was 75 percent of normal. Pathology revealed mild epidermal changes, thickening of dermal collagen bundles, and dermal fibrosis extending into the subcutis resulting in septal hyalinization (Figure 4). These findings were consistent with sclerotic- type chronic graft-versus-host disease.

The patient has been treated aggressively by Oncology with multiple immunosuppressive therapies, including topical ointments (tacrolimus and triamcinolone), oral corticosteroids, imatinib, cyclosporine, sirolimus, narrow-band UVB phototherapy, extracorporeal photopheresis, intravenous immunoglobulin (IVIG), and rituximab infusions. Long-term oral corticosteroids and cyclosporine usage resulted in adrenal Figure 4. Mild epidermal changes, thickening insufficiency and hypertension, respectively. The of dermal collagen bundles, and dermal fibrosis patient is currently receiving rituximab infusions. extending into the subcutis resulting in septal In addition, the patient follows a strict exercise Figure 2 hyalinization.

TARRILLION, LLOYD Page 46 with acute appearing in fewer than 100 days, and the chest and abdominal wall secondary to sclerosis chronic presenting more than 100 days after HSCT. may lead to decreased lung vital capacity and References 3 1. Hymes SR, Alousi AM, Cowen EW. Graft- However, this changed with the NIH consensus therefore decreased survival. Although cGVHD is versus-host disease: Part I. Pathogenesis and conference on cGVHD in 2005, where the acute not generally viewed as an acute, life-threatening clinical manifestations of graft-versus-host disease. and chronic GVHD definitions were reclassified condition, it can be lethal for ScGVHD patients. J Am Acad Dermatol. 2012 Apr;66(4):515.e1-18. based on clinical and histologic findings.1 The NIH definitions can now better indicate prognosis, guide 2 Conclusion 2. Jagasia MH, Greinix HT, Arora M, et al. National treatment, and define eligibility for clinical trials. As cGVHD becomes a more common dermatologic Institutes of Health Consensus Development condition, resulting from the increased prevalence Project on Criteria for Clinical Trials in Chronic Cutaneous cGVHD is a polymorphic condition of HSCTs, dermatologists must be aware of Graft-versus-Host Disease: I. The 2014 Diagnosis that often has multiple presentations within one the diverse presentations of cGVHD, as early and Staging Working Group report. Biol Blood patient. Non-sclerotic cGVHD can resemble lichen involvement can greatly decrease the sequelae of Marrow Transplant. 2015 Mar;21(3):389-401.e1. planus, poikiloderma, psoriasis or papulosquamous cGVHD. However, due to the unknown exact lesions, subacute cutaneous lupus, and keratosis mechanism of action of cGVHD, it is very difficult 2 3. Martires KJ, Baird K, Steinberg SM, et al. pilaris. Sclerotic-type cGVHD manifestations to treat. There are no FDA-approved therapies Sclerotic-type chronic GVHD of the skin: clinical appear more bound down, and can resemble lichen with indications for cGVHD, and most steroid- 3 risk factors, laboratory markers, and burden of sclerosus, morphea, and eosinophilic fasciitis. refractory treatments are approached through disease. Blood. 2011 Oct;118(15):4250-7. trial and error. Therefore, it is imperative that our Although sclerotic-type cGVHD is not an acute, community supports increased research on the 4. Hymes SR, Alousi AM, Cowen EW. Graft- life-threatening condition, widespread involvement mechanism of action and optimization of currently 3 versus-host disease: Part II. Management of may lead to significant disability and morbidity. used therapies for cGVHD. cutaneous graft-versus-host disease. J Am Acad Deep-seated fibrosis of the subcutaneous tissue Dermatol. 2012 Apr;66(4):535.e1-16. and fascia may result in loss of range of motion. Longstanding fibrosis may result in skin ulceration 5. Wolff D, Schleuning M, von Harsdorf S, et and proliferation of benign angiomatous nodules. al. Consensus Conference on Clinical Practice Due to the increased risk of developing cutaneous in Chronic GVHD: Second-Line Treatment of malignancies secondary to immunosuppression, Chronic Graft-versus-Host Disease. Biol Blood chronic scarring, and potentially photosensitizing Marrow Transplant. 2011;17(1):1-17. agents, the importance of sun protection and regular skin examinations should be emphasized.4

Because the exact mechanism of action of cGVHD is unknown, it is difficult to treat. Cutaneous sclerotic type cGVHD is particularly resistant to systemic immunotherapy.4 First-line therapy for chronic GVHD includes systemic corticosteroids with or without a calcineurin inhibitor, which is based on controlled trials; however, at least 50 percent of these patients will not respond adequately.5 For steroid-refractory cGVHD, there are no therapies with level I evidence from randomized, controlled trials. There are a few with level II evidence from clinical trials without randomization, including photopheresis, rituximab, pentostatin and thalidomide. Steroid-refractory cGVHD therapies all have level C recommendations, where evidence is insufficient to support for or against treatment, or evidence may not outweigh adverse consequences or cost of treatment.5 The second-line therapies for steroid-refractory cGVHD are generally approached through trial and error. More than 10 years after the initial NIH Consensus Conference in 2005, there are still no FDA-approved agents with indication for cGVHD. Therefore, there is a strong need for clinical trials to optimize the currently used therapies or to develop new agents.

A recent study using the new NIH cGVHD definitions revealed a possible association between ScGVHD and the presence of total body irradiation (TBI) conditioning prior to transplantation. It also suggested that elevated C3 may stimulate fibrotic processes, and that increased platelets may act as acute-phase reactants, triggering synthesis of collagens and other matrix proteins.3 These predictors were either unknown or absent in our patient. Of note, previous acute or chronic GVHD did not predispose patients to an increased risk of ScGVHD.3

This study also revealed that ScGVHD patients with a body surface area (BSA) sclerosis greater than the median 37.4 percent had poorer survival than those with less than median BSA sclerosis. In this population, it is possible that restriction of

Page 47 SCLEROTIC-TYPE CHRONIC GRAFT-VERSUS-HOST DISEASE: A CASE PRESENTATION AND DISCUSSION Secondary Syphilis: The Great Masquerader: A Case Presentation and Discussion Gina Caputo, DO,* Roxanne Rajaii, MS, DO,** Gary Gross, MD,*** Daniel S. Hurd, DO****

*Dermatology Resident, 2nd year, LewisGale Hospital Montgomery/Edward Via College of Osteopathic Medicine, Blacksburg, VA **Osteopathic Intern, Northeast Regional Medical Center, Kirksville, MO ***Clinical Dermatologist, LewisGale Hospital Salem, Salem, VA ****Program Director, Dermatology Residency Program, LewisGale Hospital Montgomery/Edward Via College of Osteopathic Medicine, Blacksburg VA

Disclosures: None Correspondence: Gina Caputo, DO; [email protected]

Abstract Syphilis has been called “the great imitator” due its wide range of variable symptoms that often mimic other disease processes. The painless syphilis chancre can easily go unnoticed, or be mistaken for a folliculitis, abrasion, or benign papule. The non-pruritic, diffuse rash that develops in secondary syphilis, characterized by dissemination and multiplication of the microorganism in different tissues, typically presents anywhere from simultaneously to six months after the healing of the primary chancre.1 We present a challenging case of secondary syphilis that masqueraded as connective-tissue disease, granuloma annulare, and tinea corporis for years despite initial treatment. Introduction and the importance of accurate diagnosis and performed with a clinical suspicion of a gyrate Syphilis, an entity with origins dating back to the early treatment to prevent progression of syphilis erythema or granuloma annulare. Biopsy showed 1530s, was first formally described in 1905. It is a to cardiovascular and neurologic sequelae. A high superficial and deep perivascular dermatitis with chronic disease with varying presentations and a clinical suspicion of disease, coupled with clinical, abundant perivascular lymphocytes and plasma waxing and waning course. Sexual contact is the serologic, and histologic evidence, is optimal for cells. There was focal patchy vacuolar interface main mode of transmission, with the causative diagnosis and early management of syphilis. change and increased reticular dermal mucin organism being Treponema pallidum, a spirochete. confirmed with Alcian blue/PAS stain (Figures 5 The gold standard of diagnosis is serologic testing, Case Report [4x], 6 [20x]). A 63-year-old Caucasian male with no documented past and penicillin G remains the treatment of choice. medical history presented in April 2015 for evaluation With further interrogation of the patient and review The condition’s varying presentations, along of a pruritic, diffuse rash of seven months’ duration. of the medical record, the patient had been seen with late manifestations of disease that involve The patient denied any constitutional symptoms. in 2010 for a similar rash, also treated with oral numerous organ systems, explain its distinction as 1,2 The patient had diffuse annular, granulomatous, terbinafine and biopsied, with results indicating drug the “great imitator.” erythematous papules coalescing into plaques with eruption versus arthropod-bite reaction. At that Syphilis is commonly misdiagnosed as connective- central clearing on the trunk, back, bilateral biceps and time, an ANA, Lyme titer and RPR were performed. tissue disease, granuloma annulare, lupus vulgaris, forearms (Figures 1-4). The rash was treated with oral The RPR came back positive for syphilis, and the psoriasis, tinea corporis, and other dermatological terbinafine and steroids and initially improved. patient was referred to Infectious Disease. He had diseases. Several case reports in the literature undergone an extensive workup at that time for Four weeks later, the patient returned without highlight the similarities between these diseases Histoplasma, HIV, ANA, Lyme, Blastomyces, and significant improvement, and a punch biopsy was Cryptococcus. The patient was started on cefuroxime 500 mg twice a day for the syphilis. Figure 3 Figure 1 Upon further questioning in 2015, the patient reported he may have been partially treated by the Centers for Disease Control (CDC) for syphilis. Figure 5

Figure 4

Figure 2 Figure 6

CAPUTO, RAJAII, GROSS, HURD Page 48 The patient denied any extramarital affairs. We approximately one-third of patients with untreated non-caseating granulomas on skin biopsy, whose performed another RPR, with a result of 1:128. The primary syphilis develop tertiary syphilis.1,4 lesions were exacerbated by treatment with topical patient was referred to Infectious Disease for work- Cardiovascular symptoms usually present between corticosteroids. Further investigation revealed this up of tertiary syphilis and treatment. Infectious 10 years and 30 years after the initial infection. was not a case of GA but rather tertiary syphilis Disease treated the patient with ceftriaxone 2 g IV The most common cardiovascular manifestation of with neurologic and cardiovascular manifestations.4 every 24 hours for two weeks, and he was worked up disease is syphilitic aortitis, typically involving the again for HIV and hepatitis. He also underwent a ascending aorta.2 Clinical signs and symptoms of Bittencourt et al. report a different case of secondary lumbar puncture to rule out neurosyphilis. Results neurosyphilis include “focal central nervous system syphilis in an HIV patient with palmoplantar from the HIV and hepatitis labs and the lumbar ischemia and stroke, tabes dorsalis (progessive lesions masquerading as palmoplantar psoriasis. puncture were negative. The patient was treated ataxia, bladder incontinence), and general paresis They present a 32-year-old male with “bilateral successfully for secondary syphilis. (altered mental status, depression, forgetfulness, asymptomatic erythematous-scaly plaques on confusion).”4 Cutaneous tertiary syphilis typically palms and soles for three months, associated with Discussion presents with nodular lesions that can easily mimic periungual erythema, subungual hyperkeratosis Syphilis is a chronic disease with varying other dermatologic diseases such as granuloma and onychodystrophy of toenails.” This case presentations and a waxing and waning course. annulare, lupus vulgaris, psoriasis, and sarcoid.4 demonstrates the challenge of diagnosing syphilis, While sexual contact is the main mode of in that clinically, it can mimic psoriasis and transmission, with the causative organism being Diagnosis of syphilis is based on both clinical dermatophytosis. However, the ungual alterations Treponema pallidum, a spirochete, transmission and laboratory findings. The gold standard for typical of syphilis in the case by Bittencourt et across the placenta is thought to be the second the diagnosis of primary syphilis continues to al., coupled with a negative result of mycological most common mode.2,3 Numerous studies have be visualization of spirochetes under dark-field examination and improvement after treatment, led investigated the transmission probability among microscopy. For secondary, latent, and tertiary to the actual diagnosis of syphilis over its mimickers. partners and have estimated it to be around 60 syphilis, serologic testing is the method of choice This validates the importance of clinical suspicion, percent. Three stages of syphilis have been described: for diagnosis. Nontreponemal tests, including particularly in the case of atypical manifestations of The primary stage, presenting with a painless VDRL, are often indicated for screening, while secondary syphilis.3,4 chancre at the site of inoculation; the secondary treponemal tests, including RPR, FTA-ABS (the stage, characterized by a polymorphic rash; and the serum fluorescent treponemal antibody absorption Conclusion tertiary stage, characterized by cardiovascular and test), and MHA-TP (microhemagglutination test Syphilis is a disease that skillfully mimics other neurologic sequelae and gumma formation. The for T. pallidum), are used to confirm the diagnosis. dermatological diseases in both clinical and 6 tertiary stage is the most destructive. Nontreponemal tests, however, can lack sensitivity histologic features. Furthermore, it is a disease with and can give a high rate of false-positive reactions. multisystem effects, one that allows a dermatologist Syphilis is divided into early (< 1 year) and late This is particularly true in patients of increased “to highlight the relationship of skin diseases to the 7 (> 1 year) stages, with the early stages (primary, age, patients who are pregnant or drug-addicted, rest of the body.” The cases by Wu and Bittencourt secondary, and early latent) believed to be infectious. and those with malignancy, autoimmune diseases et al., along with the present case, exemplify this Late manifestations of disease involving all organ (SLE), and viral (EBV and hepatitis), protozoal mimicry and the need for a high clinical index 3,4 systems have given syphilis its name as the “great or mycoplasmal infections. Neurosyphilis is often of suspicion for syphilis. Although a variety of imitator,” with the key to diagnosis remaining a diagnosed based on a combination of results from diagnostic tools are available for accurate diagnosis, 2 high index of suspicion. serologic testing, abnormalities of CSF cell count the incidence of false-negative laboratory tests as and protein levels, or a reactive CSF VDRL. well as clinical features resembling other etiologies A single, painless, indurated ulcer with a clean make it one of the most commonly misdiagnosed base characterizes primary syphilis. These primary The first-line therapy for syphilis remains entities in the field of dermatology. The tragic chancres also typically present with a sharply intramuscular benzathine penicillin G.2,5 Due to the outcomes that can result from misdiagnosis of marginated border. Up to 80 percent of patients devastating sequelae of syphilis, it is recommended syphilis, including but not limited to cardiovascular with primary syphilis have painless regional that patients allergic to penicillin be desensitized and neurologic sequelae, demonstrate the lymphadenopathy. The incubation period for primary and subsequently treated with penicillin therapy.5 importance of early and accurate diagnosis.6 syphilis ranges from three to 90 days. In men, the penis is the most common site affected, while in Despite serologic testing for the diagnosis of women, it is the labia majora. Anorectal chancres syphilis, atypical clinical presentations and false- are common in homosexuals. Extragenital chancres negative laboratory tests, particularly in HIV- involving the fingers, tongue, anus, and mouth are positive individuals, complicates accurate and rare, but when affected, they are typically painful early diagnosis of disease. This, in turn, has led lesions. The most common extragenital chancre to an increase in dermatopathological specimens location is the mouth, most specifically the lip.2 for the diagnosis of syphilis. In addition to the variability in clinical presentation and mimicry Secondary syphilis is often subtle and is a of other disease processes, the histopathological cutaneous manifestation of the disease. A primary features of syphilis also exhibit a wide spectrum, chancre can be found in up to one-third of with features ranging from interface dermatitis to patients with secondary syphilis. Skin lesions can granulomatous diseases. However, several well- often mimic other dermatologic diseases, making recognized histologic patterns characteristic of the syphilis easy to misdiagnose. The rash can have papulosquamous eruption of secondary syphilis variable morphology, ranging from macular to have been described. These include interstitial maculopapular, follicular, and occasionally pustular. inflammation, endothelial swelling, irregular Classically, however, lesions are non-pruritic acanthosis, and elongated rete ridges. Although not and are universally distributed with a “raw ham” diagnostic, they should raise suspicion for syphilis, or copper-colored appearance. The palms and particularly in the absence of clinical features.6 soles are typically involved. In up to 7 percent of patients, a patchy, “moth-eaten” pattern of Although a variety of diagnostic modalities alopecia has been reported. Systemic symptoms of exists for syphilis, the disease itself can present secondary syphilis may include malaise, prostration, variably and mimic other dermatologic conditions cachexia, headache, low-grade fever, asymptomatic including connective-tissue disease, granuloma meningitis, cranial nerve palsies, gastrointestinal annulare, lupus vulgaris, psoriasis, sarcoid, and symptoms, painless adenopathy, and vague bone tinea corporis. Wu et al. present a case of nodular and joint pain, among others.1,2 tertiary syphilis masquerading as granuloma annulare (GA). They describe a 47-year-old man Tertiary syphilis consists of cardiovascular and with annular plaques on the arms and torso, based neurologic involvement. It is estimated that on clinical and histopathological findings and

Page 49 SECONDARY SYPHILIS: THE GREAT MASQUERADER: A CASE PRESENTATION AND DISCUSSION References 1. Bolognia JL, Jorizzo JL, Schaffer JV. Dermatology. 3rd ed. Philadelphia: Elsevier Saunders; 2012. 2776 p.

2. Singh AE, Romanowski B. Syphilis: review with emphasis on clinical, epidemiologic, and some biologic features. Clin Microbiol Rev. 1999;12(2):187-209.

3. Bittencourt MDJS, Brito ACD, Nascimento BAMD, Carvalho AH, Nascimento MDD. A case of secondary syphilis mimicking palmoplantar psoriasis in HIV infected patient. An Bras Dermatol. 2015;90(3):216-9.

4. Wu SJ, Nguyen EQ, Nielsen TA, Pellegrini AE. Nodular tertiary syphilis mimicking granuloma annulare. J Am Acad Dermatol. 2000;42(2):378-80.

5. Czelusta A, Yen-Moore A, Van der Straten M, Carrasco D, Tyring SK. An overview of sexually transmitted diseases. Part III. Sexually transmitted diseases in HIV-infected patients. J Am Acad Dermatol. 2000;43(3):409-36.

6. Flamm A, Parikh K, Xie Q, Kwon EJ, Elston DM. Histologic features of secondary syphilis: A multicenter retrospective review. J Am Acad Dermatol. 2015;73(6):1025-30.

7. Chu MB, Tarbox M. The Role of Syphilis in the Establishment of the Specialty of Dermatology. JAMA Dermatol. 2013;149(4):426.

CAPUTO, RAJAII, GROSS, HURD Page 50 Segmental Speckled Lentiginous Nevus Exacerbated by Pregnancy in an Otherwise Healthy Female: A Case Report Logan Kolb, DO,* Jessica Schweitzer, DO,* Mary Veremis-Ley, DO***

*Traditional Rotating Intern, Larkin Community Hospital, South Miami, FL **Dermatology Resident, PGY-2, St. Joseph Mercy Hospital, Ann Arbor, MI ***Faculty, Department of Dermatology, St. Joseph Mercy Hospital, Ann Arbor, MI

Disclosures: None Correspondence: Logan Kolb, DO; [email protected]

Abstract Speckled lentiginous nevi (SLN), or nevus spili, are seen in 0.2% to 2.3% of the population, presenting as tan patches with overlying hyperpigmented macules or papules in a speckled arrangement. Segmental SLN represent a small subset of SLN, with the segmental type comprised of larger, unilateral lesions that may rarely give rise to melanomas and have been reported to proliferate in response to ultraviolet light exposure. We present the case of a 40-year-old woman who presented with dark brown macules and papules scattered in a sharp, unilateral distribution on her back, chest, and abdomen. The lesions had been present for 10 years but had enlarged and darkened during her previous pregnancies. A clinical diagnosis of segmental speckled lentiginous nevus was made, and the patient was given appropriate instructions for sun protection and proper follow-up. This is the second reported case of segmental SLN with morphologic changes during pregnancy, suggesting an underlying hormonal component in its pathogenesis. Introduction some authors to categorize SLN as a congenital characteristics of melasma, a hyperpigmentation Speckled lentiginous nevus (SLN), also referred to melanocytic nevus, while others believe it to be disorder that commonly affects women’s faces as nevus spilus, is a relatively common skin lesion, an acquired process because the characteristic secondary to hormonal changes, including those 1 speckled hyperpigmentation may take years associated with pregnancy or oral-contraceptive occurring in 2.3% of adults. SLN lesions present 6 as numerous, hyperpigmented macules and papules to develop. Segmental or “zosteriform” use. Melasma occurs more frequently in darker over tan-brown patches.2 SLN has recently been presentations of SLN are also believed to be pigmented individuals (Fitzpatrick III-V), may categorized into macular and papular subtypes, caused by somatic mosaicism, which consists of be triggered by sun exposure and pregnancy – known as nevus spilus maculosus and nevus spilus genetically distinct populations of cells that result suggesting hormones may have played a role in papulosus, respectively.3 Segmental SLN are large from post-zygotic somatic mutations. Recently, the hyperpigmentation component our patient’s lesions that present in a unilateral or zosteriform activating mutations of HRAS were identified SLN -- and has a genetic component, with 40% of distribution. Such cases typically present at birth or in smaller SLN lesions, whereas an activating affected patients reporting relatives also affected by missense NRAS mutation was identified in a the disease.11 in infancy and may worsen secondary to ultraviolet 8,9 (UV) light exposure.4 These have been reported to case of congenital segmental SLN. A meticulous physical examination can give give rise to single or multiple melanomas, although 4,5 Environmental factors also influence established the clinician several important clues for the this is rare. In this case report, we present a SLN lesions. Ultraviolet (UV) light exposure has diagnosis of SLN and associated disorders. The 40-year-old female with adult-onset segmental been reported to darken the lentiginous background underlying patch, a key finding in SLN, is absent SLN that worsened during pregnancy, review hyperpigmentation and cause proliferation of in clinically similar disorders like agminated nevus the disease’s pathogenesis and management, and 4 the speckled macules and papules. Additionally, and partial unilateral lentiginosis (also known as provide diagnostic pearls. 5 in one case series, melanomas arising within segmental lentiginosis). Macular versus papular segmental SLN occurred only in sun-exposed areas, Case Report which may be explained by epigenetic modification A 40-year-old, otherwise healthy woman presented 4 Figure 2 with a 10-year history of dark brown macules and of tumor suppressor genes in lesional skin. Our papules on the right side of her torso. The lesions patient reported darkening and enlargement of her SLN during pregnancy, which to our knowledge were asymptomatic but were noted to become 10 darker and larger during past pregnancies. No has been reported in only one other case. Of note, previous workup or treatments had been attempted. the other case of SLN worsened by pregnancy had A full review of systems, including visual changes, a congenital onset, whereas our patient reported hearing loss, neurologic abnormalities, and adult-onset of her SLN. There are similarities musculoskeletal changes, was negative. between the SLN in our patient and general

Physical examination revealed a female with Fitzpatrick type IV skin with a unilateral distribution of brown macules and papules in a speckled arrangement with background hyperpigmentation over the right side of the back, chest, and abdomen (Figures 1, 2). No epidermal nevi or port wine stains were noted. Due to the asymptomatic nature of the lesions and their clinical presentation, a clinical diagnosis of segmental speckled lentiginous nevus was made. The patient was educated on the importance of sun protection and close monitoring of her skin lesions with annual skin examinations. Figure 1 Discussion Despite continuing debate over the nosology of speckled lentiginous nevi (SLN) among melanocytic lesions, the etiology is likely Figure 1. Dark brown macules and papules Figure 2. Dark brown macules and papules in multifactorial, with genetic and environmental in a speckled, unilateral distribution overlying a speckled distribution overlying background factors playing a role.6 Approximately 80% background hyperpigmentation with two hyperpigmentation on the right side of the are present at birth or shortly after,7 leading associated café-au-late macules. back.

Page 51 SEGMENTAL SPECKLED LENTIGINOUS NEVUS EXACERBATED BY PREGNANCY IN AN OTHERWISE HEALTHY FEMALE: A CASE REPORT presentations of SLN are also important clinical References distinctions. Macular SLN are more likely to 1. Kopf AW, Levine LJ, Rigel DS, Friedman RJ, have an evenly spaced distribution, and they have Levenstein M. Prevalence of congenital-nevus- a higher likelihood of malignant changes, whereas like nevi, nevi spili, and café au lait spots. Arch nevus spilus papulosis more often presents in Dermatol 1985;121:766-9. an uneven, “star map” distribution and may be 3 associated with phakomatosis pigmentokeratotica. 2. Stewart DM, Altman J, Mehregan AH. SLN have also been associated with phakomatosis 12 Speckled lentiginous nevus. Arch Dermatol. pigmentovascularis (PPV) types III and IV and 1978;114(6):895-6. speckled lentiginous nevus syndrome, which is characterized by SLN along with ipsilateral muscle 13 3. Vidaurri-de la Cruz H, Happle R. Two distinct weakness, hyperhidrosis, or sensory changes. types of speckled lentiginous nevi characterized Type III PPV may be associated with multiple 14 by macular versus papular speckles. Dermatology granular cell tumors. Therefore, a thorough 2006;212(1):53-8. skin examination for port wine stains or nevus flammeus, an additional finding of PPV, should 4. Ly L, Christie M, Swain S, Winship I, Kelly be performed. Other differential diagnoses to be JW. Melanoma (s) arising in large segmental considered for SLN-like lesions include café au speckled lentiginous nevi: A case series. J Am Acad lait macules, congenital nevi, lentigo simplex, and Dermatol. 2011;64(6):1190-3. melanoma. 5. Torchia D. Segmentally grouped melanocytic

The diagnosis of SLN is often clinical, and nevi and melanoma risk. J Am Acad Dermatol management is similar to that of other large 2012;66(2):324-5. melanocytic nevi. On biopsy, the macules and papules are consistent with small junctional and 6. Schaffer J V, Orlow SJ, Lazova R, Bolognia JL. compound nevi, respectively, with histology of Speckled lentiginous nevus: within the spectrum background hyperpigmentation representing of congenital melanocytic nevi. Arch Dermatol. lentigo simplex.2 The darkening of SLN lesions in 2001;137(2):172-8. response to UV exposure may be explained by these lentiginous features. Management of segmental 7. Lazova R. Speckled Lentiginous Nevus. SLN patients is similar to that of patients with large Medscape [Internet]. Updated 19 Oct 2015 [cited or numerous nevi. Patients should be followed with 2 Mar 2016]. Available from: http://emedicine. annual skin examinations and be educated on the medscape.com/article/1061990-overview. importance of sun protection to prevent malignant changes within the lesion. Further treatment of 8. Sarin KY, McNiff JM, Kwok S, Kim J, Khavari lesions is often for cosmetic purposes and has been PA. Activating HRAS mutation in nevus spilus. J performed using Q-switched (QS) Nd:YAG, QS Invest Dermatol. 2014;134(6):1766-8. ruby, and QS alexandrite lasers.15 9. Kinsler VA, Krengel S, Riviere JB, Waelchli Conclusion R, Chapusot C, Al-Olabi L, Vabres P. Next- SLN typically present as smaller patches, generation sequencing of nevus spilus-type though they may also have larger, segmental or congenital melanocytic nevus: exquisite genotype- zosteriform distributions. Such segmental cases phenotype correlation in mosaic RASopathies. J are believed to be the result of somatic mosaicism Invest Dermatol. 2014;134(10):2658-60. affecting RAS proteins in the skin. SLN may worsen secondary to UV light exposure and have 10. Aloi F, Tomasini C, Pippione M. Agminated been reported to give rise to melanoma, which is Spitz nevi occurring within a congenital speckled more common in macular subtypes. We presented lentiginous nevus. Am J Dermatopathol. a case of segmental SLN in an otherwise-healthy, 1995;17(6):594-8. 40-year-old woman whose disease worsened during pregnancy; to our knowledge, this is 11. Handel AC, Miot LDB, Miot HA. Melasma: only the second reported case in the literature of a clinical and epidemiological review. An Bras segmental SLN worsened by pregnancy. Dermatol. 2014;89(5):771-82. 12. Fernández-Guarino M, Boixeda P, de las Heras E, Aboin S, García-Millán C, Olasolo PJ. Phakomatosis pigmentovascularis: clinical findings in 15 patients and review of the literature. J Am Acad Dermatol. 2008;58(1):88-93.

13. Happle R. Speckled lentiginous nevus syndrome. Delineation of a new distinct neurocutaneous phenotype. Eur J Dermatol. 2002;12:133–5.

14. Guiglia MC, Prendiville JS. Multiple granular cell tumors associated with giant speckled lentiginous nevus and nevus flammeus in a child. J Am Acad Dermatol. 1991;24(2):359-63.

15. Polder KD, Landau JM, Vergilis-Kalner IJ, Goldberg LH, Friedman PM, Bruce S. Laser eradication of pigmented lesions: a review. Dermatol Surg. 2011;37(5):572-95.

KOLB, SCHWEITZER, VEREMIS-LEY Page 52 Introducing New ULTRAVATE® Lotion HELP YOUR PATIENTS TAME THE BEAST OF PLAQUE PSORIASIS

ULTRAVATE Lotion offers class 1 effi cacy in a moisturizing lotion formulation.1

INDICATIONS AND USAGE: ULTRAVATE® (halobetasol propionate) antimicrobial agent should be used. If a favorable response does not Lotion, 0.05% is indicated for the topical treatment of plaque psoriasis occur promptly, the use of ULTRAVATE® Lotion should be discontinued in patients 18 years of age and older. until the infection has been adequately treated. Treatment beyond 2 weeks is not recommended, and the total dosage The treated skin area should not be bandaged, covered, or wrapped with should not exceed 50 grams per week because of the potential for the occlusive dressings, unless directed by the physician. drug to suppress the hypothalamic-pituitary-adrenal (HPA) axis. The safety and effectiveness of ULTRAVATE® Lotion in patients younger Discontinue therapy when control is achieved. If no improvement is seen than 18 years of age have not been established. within 2 weeks, reassessment of the diagnosis may be necessary. ULTRAVATE® Lotion is for external use only. Avoid use on the face, IMPORTANT SAFETY INFORMATION scalp, groin, or axillae. PRECAUTIONS: In a study of 20 adult subjects with moderate to severe ADVERSE REACTIONS: In controlled clinical trials, the most frequent plaque psoriasis, ULTRAVATE® Lotion produced HPA axis suppression adverse events reported for ULTRAVATE® Lotion included telangiectasia, when used twice daily for 2 weeks in 5 out of 20 (25%) patients. If HPA application site atrophy, and headache in 1% of patients. Less frequently axis suppression is documented, attempt to gradually withdraw the reported adverse reactions were application site discoloration, herpes drug, reduce the frequency of application, or substitute a less potent zoster, infl uenza, nasopharyngitis, otitis media acute, throat infection, steroid. Manifestations of adrenal insuffi ciency may require supplemental wound, and increased blood pressure. systemic corticosteroids. Recovery of HPA axis function is generally This preparation is not for ophthalmic, oral, or intravaginal use. prompt and complete upon discontinuation of topical corticosteroids. For external use only. Allergic contact dermatitis with corticosteroids is usually diagnosed Please see Brief Summary of full Prescribing Information by observing failure to heal, rather than noting a clinical exacerbation. on following page. Consider confi rmation of a clinical diagnosis of allergic contact dermatitis If you experience any Adverse Events you are encouraged to by appropriate patch testing. Discontinue ULTRAVATE® Lotion if allergic report them to the Drug Safety Department at 1-800-406-7984 contact dermatitis is established. or email [email protected]. You can also report to the If concomitant skin infections are present or develop, an appropriate FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Reference: 1. Ultravate® Lotion. Data on File; Jacksonville, FL: Ranbaxy Laboratories Inc; January 2015. ULTRAVATE is a registered trademark of Ranbaxy Laboratories Inc.

Ranbaxy Laboratories Inc. Jacksonville, FL 32257 Copyright © 2016 Ranbaxy Laboratories Inc, a SUN PHARMA company. Printed in USA ULL0008 3/16

SPTS1608A_Ultravate Lotion JA_JAOCD_FINAL2.indd 1 10/20/16 1:44 PM ULTRAVATE (halobetasol propionate) lotion 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy BRIEF SUMMARY: Risk Summary See package insert for full prescribing information. There are no data on topical halobetasol propionate use in pregnant women to inform any 1. INDICATIONS AND USAGE drug-associated risks for birth defects or miscarriage. In animal reproduction studies, halobetasol ULTRAVATE lotion is indicated for the topical treatment of plaque psoriasis in patients eighteen (18) propionate administered systemically during organogenesis to pregnant rats at 13 and 33 times the years of age and older. human topical dose and to pregnant rabbits at 3 times the human topical dose resulted in 2. DOSAGE AND ADMINISTRATION teratogenic and embryotoxic effects [see Data]. The clinical relevance of the animal findings is not Apply a thin layer of ULTRAVATE lotion to the affected skin twice daily for up to two weeks. Rub in clear. gently. Discontinue therapy when control is achieved. If no improvement is seen within two weeks, The background risk of major birth defects and miscarriage for the indicated population are reassessment of diagnosis may be necessary. unknown. In the U.S. general population, the estimated background risk of major birth defects and Treatment beyond two weeks is not recommended and the total dosage should not exceed miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. 50 grams (50 mL) per week because of the potential for the drug to suppress the hypothalamic-pi- 8.2 Lactation tuitary-adrenal (HPA) axis [see Warnings and Precautions 5.] . Risk Summary Do not use with occlusive dressings unless directed by a physician. There are no data on the presence of halobetasol propionate or its metabolites in human milk, the ULTRAVATE lotion is for external use only. effects on the breastfed infant, or the effects on milk production after topical application to women Avoid use on the face, scalp, groin, or axillae. who are breastfeeding. Systemically administered corticosteroids appear in human milk and could suppress growth, ULTRAVATE lotion is not for ophthalmic, oral, or intravaginal use. interfere with endogenous corticosteroid production, or cause other untoward effects. It is not 4. CONTRAINDICATIONS known whether topical administration of corticosteroids could result in sufficient systemic None. absorption to produce detectable quantities in human milk. The developmental and health benefits 5. WARNINGS AND PRECAUTIONS of breastfeeding should be considered along with the mother's clinical need for ULTRAVATE lotion 5.1 Effects on Endocrine System and any potential adverse effects on the breastfed infant from ULTRAVATE lotion or from the ULTRAVATE lotion is a topical corticosteroid that has been shown to suppress the hypothalamic-pi- underlying maternal condition. tuitary-adrenal (HPA) axis. Clinical Considerations Systemic effects of topical corticosteroids may include reversible HPA axis suppression, with the Advise breastfeeding women not to apply ULTRAVATE lotion directly to the nipple and areola to avoid potential for glucocorticosteroid insufficiency. This may occur during treatment or upon withdrawal direct infant exposure. of treatment of the topical corticosteroid. 8.4 Pediatric Use The potential for hypothalamic-pituitary adrenal (HPA) suppression with ULTRAVATE lotion was Safety and effectiveness of ULTRAVATE lotion in patients younger than 18 years of age have not evaluated in a study of 20 adult subjects with moderate to severe plaque psoriasis involving ≥ 20% been established. of their body surface area. ULTRAVATE lotion produced HPA axis suppression when used twice daily Because of higher skin surface area to body mass ratios, pediatric patients are at a greater risk for two weeks in 5 out of 20 (25%) adult patients with plaque psoriasis. Recovery of HPA axis than adults of HPA axis suppression and Cushing's syndrome when they are treated with topical function was generally prompt with the discontinuation of treatment [see Clinical Pharmacology corticosteroids. They are therefore also at greater risk of adrenal insufficiency during or after (12.2)]. withdrawal of treatment. Adverse reactions including striae have been reported with use of topical Because of the potential for systemic absorption, use of topical corticosteroids, including corticosteroids in infants and children [see Warnings and Precautions (5.1)]. ULTRAVATE lotion, may require that patients be evaluated periodically for evidence of HPA axis HPA axis suppression, Cushing's syndrome, linear growth retardation, delayed weight gain, and suppression. Factors that predispose a patient using a topical corticosteroid to HPA axis intracranial hypertension have been reported in children receiving topical corticosteroids. suppression include the use of more potent corticosteroids, use over large surface areas, prolonged Manifestations of adrenal suppression in children include low plasma cortisol levels and an absence use, occlusive use, use on an altered skin barrier, concomitant use of multiple corticosteroid-con- of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging taining products, liver failure, and young age. An ACTH stimulation test may be helpful in evaluating fontanelles, headaches, and bilateral papilledema [see Warnings and Precautions (5.1)]. patients for HPA axis suppression. 8.5 Geriatric Use If HPA axis suppression is documented, attempt to gradually withdraw the drug, reduce the Clinical studies with ULTRAVATE lotion included 89 subjects aged 65 years and over. No overall frequency of application, or substitute a less potent steroid. Manifestations of adrenal insufficiency differences in safety or effectiveness were observed between these patients and those younger may require supplemental systemic corticosteroids. Recovery of HPA axis function is generally than 65 years. Clinical studies of ULTRAVATE lotion did not include sufficient numbers of subjects prompt and complete upon discontinuation of topical corticosteroids. aged 65 and over to determine whether they respond differently from younger subjects. Systemic effects of topical corticosteroids may also include Cushing's syndrome, hyperglycemia, 10. OVERDOSAGE and glucosuria. Use of more than one corticosteroid-containing product at the same time may Topically applied ULTRAVATE lotion can be absorbed in sufficient amounts to produce systemic increase the total systemic exposure to topical corticosteroids. effects [see Warnings and Precautions (5.1)]. Pediatric patients may be more susceptible than adults to systemic toxicity from the use of topical 13. NONCLINICAL TOXICOLOGY corticosteroids due to their larger surface-to-body mass ratios [see Use in Specific Populations 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility (8.4)]. Long-term animal studies have not been performed to evaluate the carcinogenic potential of 5.2 Local Adverse Reactions halobetasol propionate. In a 90-day repeat-dose toxicity study in rats, topical administration of Local adverse reactions from topical corticosteroids may include atrophy, striae, telangiectasias, halobetasol propionate lotion at dose concentrations from 0.05% to 0.1% or from 0.25 to 0.5 burning, itching, irritation, dryness, folliculitis, acneiform eruptions, hypopigmentation, perioral mg/kg/day of halobetasol propionate resulted in a toxicity profile consistent with long-term dermatitis, allergic contact dermatitis, secondary infection, and miliaria. These may be more likely exposure to corticosteroids including adrenal atrophy, histopathological changes in several organ to occur with occlusive use, prolonged use, or use of higher potency corticosteroids, including systems indicative of severe immune suppression, and opportunistic fungal and bacterial infections. ULTRAVATE lotion. Some local adverse reactions may be irreversible. A no observable adverse effect level (NOAEL) could not be determined in this study. Although the 5.3 Concomitant Skin Infections clinical relevance of the findings in animals to humans is not clear, sustained glucocorticoid-related Use an appropriate antimicrobial agent if a skin infection is present or develops. If a favorable immune suppression may increase the risk of infection and possibly the risk of carcinogenesis. response does not occur promptly, discontinue use of ULTRAVATE lotion until the infection has been Halobetasol propionate was not found to be genotoxic in the Ames/Salmonella assay, in the Chinese adequately treated. hamster CHO/HGPRT assay, in the mouse micronucleus test, in the sister chromatid exchange test 5.4 Allergic Contact Dermatitis in somatic cells of the Chinese hamster, or in the chromosome aberration test in somatic cells of Allergic contact dermatitis with corticosteroids is usually diagnosed by observing failure to heal Chinese hamsters. Positive mutagenicity effects were observed in two genotoxicity assays: Chinese rather than noting a clinical exacerbation. Consider confirmation of a clinical diagnosis of allergic hamster nuclear anomaly test and mouse lymphoma gene mutation assay in vitro. contact dermatitis by appropriate patch testing. Discontinue ULTRAVATE lotion if allergic contact Studies in the rat following oral administration at dose levels up to 50 µg/kg/day indicated no dermatitis is established. impairment of fertility or general reproductive performance. 6. ADVERSE REACTIONS 17. PATIENT COUNSELING INFORMATION 6.1 Clinical Trials Experience This information is intended to aid in the safe and effective use of this medication. It is not a Because clinical trials are conducted under widely varying conditions, adverse reaction rates disclosure of all administration instructions or all possible adverse or unintended effects. observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of Advise patients using ULTRAVATE lotion of the following information and instructions: another drug and may not reflect the rates observed in practice. Important Administration Instructions During randomized, controlled, blinded clinical trials 277 adults with plaque psoriasis were treated Instruct patients to discontinue ULTRAVATE lotion when psoriasis is controlled. ULTRAVATE lotion with ULTRAVATE lotion twice daily for up to two weeks (up to approximately 50 grams/week). should not be used for longer than 2 weeks. Advise patients to contact the physician if no Table 1 presents adverse reactions that occurred in at least 1% of subjects treated with ULTRAVATE improvement is seen within 2 weeks. Inform patients that total dosage should not exceed 50 grams lotion twice daily for up to two weeks, and more frequently than in vehicle-treated subjects. per week [see Dosage and Administration (2)]. Table 1. Adverse Reactions Occurring in ≥ 1% of Subjects Treated with ULTRAVATE Lotion Instruct patients to avoid bandaging, wrapping or otherwise occluding the treatment area(s), unless for up to Two Weeks directed by physician. Advise patients to avoid use on the face, scalp, groin, or axillae [see Dosage ULTRAVATE Lotion (N=277) Vehicle Lotion (N=259) and Administration (2)]. Adverse Reaction % % Inform patients that ULTRAVATE lotion is for external use only. Advise patients that ULTRAVATE lotion Teleangiectasia 1% 0% is not for ophthalmic, oral, or intravaginal use [see Dosage and Administration (2)]. Breastfeeding women should not apply ULTRAVATE lotion directly to the nipple and areola to avoid Application site atrophy 1% <1% directly exposing the infant [see Lactation (8.2)]. Headache 1% <1% Rx Only Less common adverse reactions (incidence less than 1% but greater than 0.1%) that occurred in subjects treated with ULTRAVATE lotion included application site discoloration, herpes zoster, ULTRAVATE is a trademark of Ranbaxy Laboratories, Inc. influenza, nasopharyngitis, otitis media acute, throat infection, wound, and increased blood Manufactured for Ranbaxy Laboratories, Inc., Jacksonville, FL 32257 pressure. By: Ferndale Laboratories, Inc., Ferndale Ml 48220 U.S. Patent 8,962,028

Ranbaxy Laboratories Inc. Jacksonville, FL 32257 Copyright © 2016 Ranbaxy Laboratories Inc., a SUN PHARMA company. Printed in USA ULL0008 03/16

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