sign in sign up
<<
Home , Alopecia areata, Alopecia mucinosa, Alopecia totalis, Alopecia universalis, Contact dermatitis, Drug eruption

Volume 33

JAOCDJournalJournal OfOf TheThe AmericanAmerican OsteopathicOsteopathic CollegeCollege OfOf DermatologyDermatology

FocusFocus onon FlushingFlushing TriggersTriggers AA NeuralNeural LinkLink toto UnderstandingUnderstanding RosaceaRosacea

Also in this issue: Adult-onset Multisystemic Langerhans Cell Histiocytosis Review of Secukinumab Phase III Testing: A New Hope for Plaque ? Concurrent Unilesional Follicular and Syringotropic last modified on September 11, 2015 10:08 AM

JOURNAL OF THE AMERICAN OSTEOPATHIC COLLEGE OF Page 1 Journal of the American Osteopathic College of Dermatology

2014-2015 AOCD OFFICERS

PRESIDENT Rick Lin, DO, FAOCD

PRESIDENT-ELECT Alpesh Desai, DO, FAOCD

FIRST VICE-PRESIDENT Karthik Krishnamurthy, DO, FAOCD

SECOND VICE-PRESIDENT Daniel Ladd, DO, FAOCD

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

Editor-in-Chief SECRETARY-TREASURER Karthik Krishnamurthy, DO Jere J. Mammino, DO, FAOCD TRUSTEES Danica Alexander, DO, FAOCD (2012-2015) Reagan Anderson, DO, FAOCD (2012-2015) Michael Whitworth, DO, FAOCD (2013-2016) Tracy Favreau, DO, FAOCD (2013-2016) Sponsors: David Cleaver, DO, FAOCD (2014-2017) Amy Spizuoco, DO, FAOCD (2014-2017)

AuroraDx Immediate Past-President Ranbaxy Suzanne Sirota Rozenberg, DO, FAOCD EEC Representatives Valeant James Bernard, DO, FAOCD Michael Scott, DO, FAOCD

Finance Committee Representative Donald Tillman, DO, FAOCD

AOBD Representative Stephen Purcell, 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 from the author(s), inclusion of acknowledgment 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 Print and layout by: S&S Printing and Graphics LLC, 701 N. Marion St., Kirksville, MO 63501 Copy editing by: Julia Layton, Freelance Writing and Editing

Page 2 JOURNAL OF THE AMERICAN OSTEOPATHIC COLLEGE OF DERMATOLOGY Journal of the American Osteopathic College of Dermatology Table of Contents Volume 33 JAOCD Editors...... 4 Letter from the President...... 5 Letter from the Executive Director...... 6 Letter from the Editor-in-Chief...... 7 FEATURE ARTICLE: A Neural Link to Understanding : Focusing on Triggers...... 11 B.D. Gray, DO, K. Metzler-Wilson, PT, PhD, K.W. Dawes, MD, T.E. Wilson, PhD EDITOR’S PICKS: Adult-onset Multisystemic Langerhans Cell Histiocytosis: A Case Presentation and Discussion...... 17 Shahrzad Akbary, BS, Adam Sorensen, DO, Richard Bernert, MD, FASDP, Joseph Machuzak, DO, FAOCD, Stephen Kessler, DO, FAOCD A Rare Case of Unilesional Follicular and Syringotropic Mycosis Fungoides: A Case Report and Review of the Literature...... 20 Kevin Svancara, DO, Vernon T. Mackey, DO, FAOCD, FASMS Secukinumab for the Treatment of Plaque Psoriasis: A Review of Phase III Testing...... 23 Aline Babikian, DO, Kourosh Beroukhim, BS, Catherine Nguyen, BS, John Koo, MD ORIGINAL ARTICLES AND CASE REPORTS: Case of Persistent Regrowth of Blond in a Previously Brunette Totalis Patient...... 28 Karla Snider, DO, John Young, MD A case of chronic lichenoid manifesting as hypopigmented, flat-topped ...... 31 Ann Mazor Reed, DO, Jennifer David, DO, Stanley Skopit, DO, MSE, FAOCD Diffuse Dermal Angiomatosis of the : A Case Presentation and Discussion...... 33 Gina M. Caputo, DO, Roxanne Rajaii, MS, DO, Gary Gross, MD, Daniel S. Hurd, DO Laser Improvement of Permanent-makeup : A Case Report...... 35 Jonathan Crane, DO, FAOCD, David George Jackson, PhD Graham-Little-Piccardi-Lassueur Syndrome: A Case Report...... 36 Christopher Hixon, DO, Collin M. Blattner, BS, Daniel Hurd, DO Topical for the Treatment of Papulopustular Rosacea: A Review...... 38 Sean McGregor, PharmD, John Minni, DO, FAOCD Lymphoepithelioma-like Carcinoma of the : A Case of One Patient Presenting with Two Primary Cutaneous ...... 40 Jacqueline C. Fisher, DO, Rachel M. White, BA, Daniel S. Hurd, DO, FAOCD Primary Cutaneous Carcinosarcoma: A Case Report and Discussion of a Histological “Chimera”...... 43 Joseph Dyer, DO, Kaylan Pustover, DO, Prasanna Sinkre, MD, Richard Miller, DO, FAOCD Case report: Eccrine porocarcinoma of the in an immunosuppressed patient...... 45 Claire Otteni, BS, Richard Limbert, DO, Joseph Dyer, DO, Richard A. Miller, DO, FAOCD En Coup De Sabre: A Case Report...... 47 Ashvin Garlapati, DO, Ramya Tripuraneni, MBBS, Stanley Skopit, DO, MSE, FAOCD Sickle Cell-Associated Leg Ulcers: A Case Presentation and Discussion...... 50 Jessica Bernstein, DO, Kristen Stewart, MD, FAAD, Stanley Skopit, DO, MSE, FAOCD Twenty- Dystrophy in a 42-year-old Woman: A Case Report...... 53 Chelsea Duggan, DO, Kristin Rongstad, BS, Matthew Elias, DO, FAOCD Urticaria Pigmentosa: A Case Report and Review of Current Standards in the Diagnosis of Systemic ...... 55 Riddhi J. Shah, DO, Mark A. Kuriata, DO, FAOCD

JOURNAL OF THE AMERICAN OSTEOPATHIC COLLEGE OF DERMATOLOGY Page 3 Editor-In-Chief Founding Editor Assistant Editor Karthik Krishnamurthy, DO Jay Gottleib, DO Julia Layton, MFA

Associate Editors

Derrick Adams, DO Aaron Bruce, DO Jonathan Crane, DO Michael Scott, DO Scott Wickless, DO Red Bluff, CA Bozeman, MT Wilmington, NC Seattle, WA Dallas, Texas Editorial Board Sami Abbasi, DO Michelle Foley, DO Angela Leo, DO John Perrotto, DO Brownstown, MI Ormond Beach, FL New York, NY West Palm Beach, FL

Brett Bender, DO Marcus Goodman, DO Scott Lim, DO Andrew Racette, DO Farmington Hills, MI Roswell, GA Erie, PA Phoenix, AZ

Ryan Carlson, DO Melinda Greenfield, DO Chava Lustig, DO Richard Rudnicki, DO Hilliard, OH Albany, GA Weston, FL Mesquite, TX

Igor Chaplik, DO Denise Guevara, DO Jere Mammino, DO Amara Sayed, DO Aventura, FL Weston, FL Winter Springs, FL San Marcos, TX

Michael P. Conroy, MD Andrew Hanly, MD John Minni, DO Joseph Brant Schneider, DO Columbus, OH Miami, FL Port St. Lucie, FL Shawnee Mission, KS

John Coppola, DO Joel Harris, DO Tony Nakhla, DO Gregg Severs, DO Ormond Beach, FL Madison Heights, MI Orange County, CA Scranton, PA

David Dorton, DO Heather Higgins, DO Navid Nami, DO Sean Stephenson, DO Spring Hill, FL Troy, MI Newport Beach, CA Troy, MI

Matthew Elias, DO David Horowitz, DO Jon Keeling, DO Jacqueline Thomas, DO Lighthouse Point, FL Torrence, CA Lexington, KY Fort Lauderdale, FL

Merrick Elias, DO Mark Lebwohl, MD Dimitria Papadopoulos, DO Jim Towry, DO Delray Beach, FL New York, NY Bellmore, NY Ocala, FL

Page 4 JAOCD EDITORS Letter from the President

Rick Lin, DO, MPH, FAOCD President, AOCD Dear Readers, Welcome to another issue of the JAOCD. This publication has become one of the cornerstones of our organization. I want to thank Dr. Karthik Krishnamurthy for another fine issue and for his hard work and dedication. I also want to extend my thanks to Dr. Jay Gottlieb for his vision in starting the JAOCD. In addition, the national office staff, led by Executive Director Marsha Wise, has helped make this scientific publication a reality. Many things have happened since the last issue of the JAOCD was published. The AOCD Delegation to the AOA, led by Drs. Lloyd Cleaver and David Grice, represented the College at the AOA House of Delegates this summer in Chicago. There was a lively discussion on the House floor on resolutions concerning gun control, mental healthcare for medical students and physicians, rules for prescribing pain to the elderly, and adopting a reversal for a federal ban on sperm donation by homosexual men. I want to thank Drs. Cleaver and Grice for representing our college at such an important event. As my presidency comes to a close, I want to use this as an opportunity to thank all my mentors and advisors for guiding me through the year. I look forward to Dr. Alpesh Desai continuing to lead our beloved College and taking it to great heights. Although I will be stepping down from the presidency, I look forward to serving as the Immediate Past President and continuing my contribution to the Board of Trustees. In addition, I will be focusing on the next stage of my professional and academic career. I have assumed the position of Program Director for the recently established Rio Grande Valley Dermatology Residency that is part of the Corpus Christi Medical Center. I am excited and humbled to be able to contribute to the education of future osteopathic dermatologists during this turbulent time of the Accreditation Council for Graduate Medical Education merger. I sincerely believe that with the continued contributions of our members, we will thrive as a profession in this era of uncertainty. As an organization, we will never lose sight of our goals to provide osteopathic dermatologic care and education to patients and physicians. We will always strive to do what is best for our patients. Looking back to the vision of Dr. Gottlieb and the continued efforts of Dr. Krishnamurthy, I am touched and moved by the contributions of our members in bringing this journal to fruition. I can only imagine what the future holds for the AOCD. I look forward to seeing our future leadership in action and the increased active participation of our membership.

Rick Lin, DO, MPH, FAOCD President, American Osteopathic College of Dermatology

LETTER FROM THE PRESIDENT Page 5 Letter from the Executive Director

Marsha Wise Executive Director, AOCD

Hello, Everyone, In June, the AOCD Office welcomed a new member to the staff. Ms. Kristin Ayer was hired as our Administrative Assistant. She takes over for Jami Johnson, who left in May 2014. Look for Kristin’s article of introduction in the next issue of Dermline. The AOA House of Delegates recently met in Chicago. Meeting news can be found on the AOA website at http://www. osteopathic.org/inside-aoa/events/annual-business-meeting/house-resolutions/Pages/default.aspx. An update on the Single Accreditation System was presented to the House, which you can read here: http://www.osteopathic.org/inside-aoa/single- gme-accreditation-system/Documents/single-gme-update.pdf We had a very successful and well-attended Spring Conference in Charlotte, NC. We were most appreciative of Dr. Nicole Owens, Immediate Past Chair of the ACGME Dermatology Review Committee. Dr. Owens gave a presentation on the Single Accreditation system as well as took the time to sit down with our program directors to discuss the system and listen to their concerns. Exciting changes are in store for our Fall Conference. Our meeting is scheduled for October 16-19, 2015, in Orlando at the Loews Royal Pacific Resort. An information packet with further details was mailed to our members about the changes happening with this meeting. Hotel Reservations can be made online at http://uo.loewshotels.com/en/Royal-Pacific-Resort/ GroupPages/AOCD. If you will be attending the Sunday session at the Orange County Convention Center, you will need to register through the AOCD office for a Day Pass. Please register by September 30, 2015. Please also let us know if you will be taking advantage of our shuttle service from Loews to the convention center. The new CME cycle will begin on January 1, 2016. The AOA is updating the CME Guide for Physicians. As soon as the AOA makes it available to us, we will forward it to you. Please monitor your CME report, as the AOA will no longer provide this information to the AOCD office due to the AOA’s privacy policy. Many AOCD members have been inquiring about OCC and OCAT. For those whose board certificates expire in 2020, you will need to complete two PPA Modules prior to sitting for the exam. One module must be completed in this CME cycle ending December 31, 2015, and one in the next CME cycle. If you have not already done so, you must register at https://www. osteopathic-cat.com/register.php. This is all mandatory for recertification. If you have any questions, please refer to the website at http://aobd.org/aobd/occ/aobd-occ-faqs. There are OCC updates at the annual AOCD meeting as well, where you can ask questions. As always, should you have questions or concerns, please do not hesitate to call the AOCD office (800-449-2623). If we cannot answer your question, we will direct you to the person(s) who can. Thank you for allowing me to be your Executive Director. I hope to see you in Orlando. Sincerely, Marsha Wise Executive Director, American Osteopathic College of Dermatology

Page 6 LETTER FROM THE EXECUTIVE DIRECTOR Letter from the Editor-in-Chief

Karthik Krishnamurthy, DO, FAOCD Editor-in-Chief

Dear Readership, I am proud to report that the JAOCD continues to flourish thanks to our hard-working editorial board and all of the submissions from our members and residents. We are committed to publishing quality manuscripts, and I think everyone can agree that we take meaningful pearls away from each issue. During the ACGME/AOA single-accreditation transition, it remains important for us to be vigilant in incorporating those core Osteopathic Practices and Principles that we trained with. It is this identity that will ensure our survival as a unique profession within dermatology and protect our ability to deliver osteopathic care to our patients. This is why the journal has been showcasing osteopathy-focused articles on our covers whenever possible. The JAOCD’s Volume 29 original feature article, “An osteopathic approach to Raynaud’s Phenomenon,” was the No. 1 most-accessed article in 2014 by osteopathic physicians (not just dermatologists) across all journals (osteopathic and non-osteopathic), according to the American Academy of Osteopathy. Osteopathic dermatologists represent about 10% of the graduating dermatologists in the United States, mirroring the overall percentage of all osteopathic physicians among all U.S. physicians from all specialties. Osteopathy-focused literature will be especially vital in establishing the uniqueness of our core values during the merger, and the JAOCD is distinctive in addressing this need. The journal may also eventually play a role in endowing required osteopathic credits toward continued certification. We already offer AOA Cat 2-B CME credit for readership. I ask, then, that our members start incorporating osteopathic principles into more submissions. In addition to reflecting the uniqueness of our profession, it will contribute to a successful bid for Medline indexing, as we can fill a significant void in Medline’s current offerings. Indexing is paramount in validating the hard work of our students and residents. With your help, we look forward to publishing more osteopathy-focused articles in the future. Fraternally, Karthik Krishnamurthy, DO, FAOCD Editor-in-Chief, Journal of the American Osteopathic College of Dermatology

LETTER FROM THE EDITOR -IN-CHIEF Page 7 Aurora Diagnostics’ dermatopathology laboratories are focused on providing unsurpassed dermatopathology DISCOVER services to our referring physicians. Our network A NEW LEVEL OF of expertise consists of DERMATOPATHOLOGY SERVICES over forty board-certified dermatopathologists that are based locally throughout the country providing advanced technology and unparalleled customer support.

We believe that the practice of and the delivery of healthcare are both personal EXPERTS IN DERMATOPATHOLOGY and best served locally.

LABORATORY LOCATIONS: BIRMINGHAM, AL Cunningham

TAMPA, FL DermDX Tampa

MIAMI, FL ACCESS TO ADVANCED DIAGNOSTICS DermDX Miami Global Pathology Laboratory

JACKSONVILLE, FL DermDX Jacksonville

BOSTON, MA DermDX New England

MONROE, MI Pinkus Dermatopathology Laboratory

PLYMOUTH, MN Aurora Diagnostics CONVENIENT LOCAL SERVICE Twin Cities Dermatopathology EATONTOWN, NJ Aurora Diagnostics Pathology Solutions

LAS VEGAS, NV LMC Pathology Services

WOODBURY, NY Aurora Diagnostics Laboratory of Dermatopathology

GREENSBORO, NC Aurora Diagnostics A PARTNER FOR YOUR PRACTICE GPA Laboratories RIDGELAND, SC Aurora Diagnostics Biopsy Diagnostics

SAN ANTONIO, TX DISCOVER, CALL 866.420.5512 Aurora Diagnostics South Texas WWW.AURORADX.COM Dermatopathology Laboratory Aurora Diagnostics’ dermatopathology laboratories are focused on providing unsurpassed dermatopathology DISCOVER services to our referring physicians. Our network A NEW LEVEL OF of expertise consists of DERMATOPATHOLOGY SERVICES over forty board-certified dermatopathologists that are based locally throughout the country providing advanced technology and unparalleled customer support.

We believe that the practice of medicine and the delivery of healthcare are both personal EXPERTS IN DERMATOPATHOLOGY and best served locally.

LABORATORY LOCATIONS: BIRMINGHAM, AL Cunningham Pathology

TAMPA, FL DermDX Tampa

MIAMI, FL ACCESS TO ADVANCED DIAGNOSTICS DermDX Miami Global Pathology Laboratory

JACKSONVILLE, FL DermDX Jacksonville

BOSTON, MA DermDX New England

MONROE, MI Pinkus Dermatopathology Laboratory

PLYMOUTH, MN Aurora Diagnostics CONVENIENT LOCAL SERVICE Twin Cities Dermatopathology EATONTOWN, NJ Aurora Diagnostics Pathology Solutions

LAS VEGAS, NV LMC Pathology Services

WOODBURY, NY Aurora Diagnostics Laboratory of Dermatopathology

GREENSBORO, NC Aurora Diagnostics A PARTNER FOR YOUR PRACTICE GPA Laboratories RIDGELAND, SC Aurora Diagnostics Biopsy Diagnostics

SAN ANTONIO, TX DISCOVER, CALL 866.420.5512 Aurora Diagnostics South Texas WWW.AURORADX.COM Dermatopathology Laboratory Designed “to Intrigue”

RETIN-A MICRO ® () Gel microsphere 0.08% Exclusively available in a 50g pump

®/TMs are trademarks of Valeant Pharmaceuticals International, Inc. or its affiliates. Any other product or brand names and logos are the property of their respective owners. © 2015 Valeant Pharmaceuticals North America LLC. DM/RAM15/0007 Printed in USA. A Neural Link to Understanding Rosacea: Focusing on Flushing Triggers

B.D. Gray, DO,* K. Metzler-Wilson, PT, PhD,** K.W. Dawes, MD,*** T.E. Wilson, PhD****

*Intern, OhioHealth O’Bleness Hospital, Athens, OH **Assistant Professor of Neuroscience & Pharmacology, Marian University College of Osteopathic Medicine, Indianapolis, IN ***Dermatologist, Dawes Fretzin Clinical Research Group & Dawes Fretzin Dermatology Group, Indianapolis, IN ****Professor of Physiology, Marian University College of Osteopathic Medicine, Indianapolis, IN

Abstract Facial in rosacea can be triggered by events that do not normally cause sustained flushing. This review discusses why flushing was evolutionarily conserved, how facial flow increases, and how the process can go awry in rosacea. Known mechanisms of increased facial-skin blood flow associated with thermal/environmental, social/emotional, pharmaceutical/topicals, dietary, and physical-exercise trigger events are explored. Flushing triggers begin with neural (sympathetic, cranial , axon reflex, or sensory afferent) responses inducing (active vasodilation and/or reduced tonic vasoconstriction), fluid extravascularization, and increased vascular volume. Local inflammatory mediators can augment responses, but it is neural responses that initiate the process. We theorize that mechanistically understanding erythema will allow rosacea to be better tolerated and controlled.

Introduction are important, it is the neural events (sympathetic, which decrease associated with Rosacea is a chronic skin disorder most cranial nerve, axon reflex, and sensory afferent) rosacea but do not generally improve the that initiate the trigger. We refer the reader erythema. In contrast, neural (ganglionic, commonly characterized by erythema and α inflammatory in the central region, to a number of excellent reviews and source cholinergic, and -adrenergic) antagonism which affects many people worldwide, including material that cover general information about strategies have been reported to reduce rosacea rosacea, inflammatory and pathological changes erythema.13-15 One interesting approach is the an estimated 16 million people in the United 6-12 α States.1 Disease classification often includes associated with it, and its potential treatment. use of an 2-adrenergic agonist ( gel), both subtypes and variants. Subtypes include Although etiology is unknown, current FDA- which has recently been approved for treatment of approved treatments in the United States include rosacea erythema. This class of drug can directly erythematotelangiectatic, papulopustular, α phymatous, and ocular rosacea; variants include , gel, and , cause some vasoconstriction via post-synaptic 2- granulomatous and neurogenic rosacea.2,3 Regardless of classification or whether all patients Table 1. Common rosacea triggers can be adequately classified, most patients present Category Examples Stimulus/Mechanism at some point with induced or permanent facial Sun UV,* local and whole-body heating flushing.4 Hot weather Local and whole-body heating Rosacea erythema, especially in the erythematotelangiectatic subtype, can change Wind Local heating and cooling, , in intensity and is activated by trigger events. AVAs,** blood-pressure effect Erythema triggers vary among patients but can Thermal/ Hot bath, sauna Local and whole-body heating be grouped into categories related to thermal/ Environmental environmental, social/emotional, pharmaceutical/ Cold Local and whole-body cooling, AVAs, topicals, dietary, and exercise (Table 1). In a recent blood-pressure effect National Rosacea Society survey, more than 50% Indoor heat Local and whole-body heating of North American participants reported that Humidity Whole-body heating hot weather and baths, sun and wind exposure, emotional , consumption, and Embarrassment Mental stress exercise all trigger flushing and associated Psychological stress Arousal, blood-pressure effect symptomatology.5 Besides acute erythema, these Social/Emotional Mental stress, blood-pressure effect episodes can cause local inflammation, , and painful burning or stinging sensations. Arousal, whole-body heating Chronic and repeated bouts of flushing and Variable associated inflammation can induce structural Skin-care products Irritation, allergic changes in the vasculature (e.g., ) Pharmaceutical/Topical and connective , which add to disease signs Irritation, allergic and symptoms. Alcohol Direct effect, gustatory reflex This review addresses what is known about Spicy food Gustatory reflex the neural mechanisms underlying rosacea Heated foods and beverages Gustatory reflex erythema trigger events. We discuss why flushing Dietary was evolutionarily conserved, how blood flow Certain fruits and vegetables Variable, unknown mechanistically increases in facial skin, and how it Dairy Unknown can go awry in disorders such as rosacea. A review Aerobic exercise Whole-body heating with this particular focus, neural mechanisms of Exercise rosacea erythema triggers, has not been previously Resistance exercise Arousal, blood-pressure effect completed. Most mechanistic evaluations of * UV - rosacea have almost exclusively focused on the **AVA - arteriovenous anastomosis inflammatory aspects of the disease; while these

GRAY, METZLER-WILSON, DAWES, WILSON Page 11 adrenergic receptors on vascular smooth muscle face during an embarrassing task corresponds to which includes neurovascular dysregulation but also reduces the release of neurotransmitters an increase in an index of skin blood flow in that and inflammation.12 The subsequent sections α 22 and modulators from these via 2- area. It is thought that embarrassment, and in of the review discuss the neural origins of these adrenergic receptors located presynaptically part , may be a remnant of appeasement erythema triggers based on patient-frequency on the adrenergic axon terminals. Our central display that is observed in some social animals.23 data and trigger categorization. theory is that if rosacea erythema triggers are In sum, flushing should be considered a normal mechanistically understood, better avoidance and physiological response that can aid in providing treatment plans as well as prevention strategies social cues and conveying emotion. Rosacea Erythema Trigger for those more susceptible to this disease state Facial flushing can also participate to a minor Mechanisms can evolve. In rosacea, no erythema trigger is universal.5 In extent in heat dissipation. Humans can lose heat the current review, we refer to triggers as having from the face and head but primarily rely on hairy major (>50% of survey respondents), moderate skin of the rest of the body for heat dissipation. Skin Blood Flow (25%-50%), and minor (<25%) incidence rates To understand the erythema associated with Both in glabrous skin (e.g., nose, ears) and other and will discuss only the major and moderate rosacea, an understanding of the physiology facial areas (e.g., , cheek), blood flow can triggers.5 Rosacea erythema triggers can be of skin blood flow and its measurement is increase during times in which heat dissipation is roughly categorized into five groups (Table 1), required. The advent of many noninvasive necessary, but because of hairy skin’s sheer surface with varied mechanisms of induction of facial indices of skin blood flow (e.g., laser-Doppler area and large blood flow capacity (up to 8 L/min), flushing and associated symptomatology. The flowmetry with both fixed probes and scanners, there is a much greater potential to offload heat 24-26 study of facial blood flow is made more difficult transcutaneous tissue oxygenation, in vivo video in hairy skin. In addition to differences in skin because certain mechanistic pharmacological microscopy, photoplethysmography) has allowed blood flow, there are also neural, anatomical, and 16- procedures (e.g., intradermal microdialysis) measurements of indices of facial blood flow. functional differences between the types of skin 18 cannot be completed in the human face for safety The ease of use of these devices has allowed (Table 2). Notably, there is vasomotor cranial- and ethical reasons. Glabrous skin also suffers for increased utilization, but most dermatology- nerve involvement in facial mucosa and skin but 27 transcutaneous drug delivery difficulties due focused studies do not appropriately control for not in peripheral glabrous and hairy skin. Thus, to its thick epidermal layer. Thus, the majority factors that affect skin blood flow independent for primary heat dissipation, humans rely not on of mechanistic in vivo studies are completed of their treatment paradigm. For instance, not facial flushing but on blood-flow changes in non- in the hairy skin of the , , or thigh. expressing laser-Doppler measures as cutaneous facial hairy skin. Nonetheless, a discussion of erythema triggers as vascular conductance (flux/mean arterial blood If facial flushing is normal during embarrassment they relate to forearm, leg, and palm skin with the pressure) is problematic because and heat-stress conditions, what constitutes a inclusion of face skin when available provides a increases flow independent of changes in luminal flushing disorder? There are a number of factors framework to investigate flushing mechanisms in diameter of the . This is especially 28 and disorders that can cause flushing. The the face and in individuals with rosacea. important as arterial blood-pressure-to-flow of the rosacea patient who relationships are dissimilar between glabrous presents with flushing, sensitive skin and facial Thermal/Environmental and non-glabrous skin, and many trigger events 7 edema can be difficult. Rosacea’s most visible sign, Whole-body heat stress is a major rosacea flushing are sympathetic nervous system stimulants that facial erythema that fluctuates in intensity with trigger that induces a number of physiological increase arterial blood pressure.19, 20 trigger events, is defined by its pathophysiology, changes to improve the body’s ability to dissipate Also problematic is comparing groups and sites without skin-blood-flow standardization, as Table 2. Characteristic differences between types of absolute values are uninterpretable unless density Type Neural Anatomical Functional of blood vessels and other parameters are known – and in non-invasive studies, these are always Adrenergic vasoconstrictor Surface loops Heat dissipation unknown. Combined with the neural and trigger foci Cholinergic-related discussed above, understanding the physiological vasodilator Hairy mechanisms of skin blood flow, its assessment, Cholinergic sudomotor Tissue insulation and the control factors that govern responses and then applying these concepts to rosacea will provide new insights into this complex disease Adrenergic pilomotor whose etiology is still for the most part unknown. Adrenergic vasoconstrictor Surface capillary loops Grip and dexterity Facial Flushing Facial flushing is common in many mammals for Glabrous Cholinergic sudomotor Arteriovenous display (act of attracting attention or showing anastomoses (AVAs) emotion) and heat dissipation. Humans have retained the capacity to increase blood flow to Cranial nerves Surface capillary loops Display show emotion, such as flushing (blushing) in response to an embarrassing event or in response Adrenergic vasoconstrictor to frustrating circumstances. The questions of where, when, and why blushing occurs are difficult to answer. Charles Darwin said of blushing, “…a Cholinergic-related Arteriovenous Heat dissipation Facial rather curious question why, in most cases the face, vasodilator? anastomoses (AVAs) ears, and alone redden.”21 He hypothesized Cholinergic sudomotor that blushing could be due to generations of focus on the human face, possibly because of its role in communication. Highlighting this Adrenergic pilomotor? phenomenon, focused attention on a part of the

Page 12 A NEURAL LINK TO UNDERSTANDING ROSACEA: FOCUSING ON FLUSHING TRIGGERS 5 α heat. Notably, there are sympathetically proinflammatory photoproducts, such as DNA- conditions, 2C-adrenergic receptors are located mediated increases in rate and cardiac repair enzymes, TNF-α, and other .52,53 in the Golgi apparatus membrane. Then, with output; vasoconstriction of renal, splanchnic, and Photoproducts associated with tryptophan, mitochondrial ROS stimulation, such as during vasculatures; and vasodilation of another chromophore, increase expression of local cooling, the Golgi apparatus migrates to the skin to facilitate environmental heat transfer.29 COX-2 and thereby catalyze erythema, producing the cell surface and fuses with the existing cell 52 α Glabrous, hairy, and facial skin are under tonic PGE2 and PGE3 during UVB exposure. UVA membrane. This increases 2-adrenergic receptor sympathetic vasoconstrictor tone, as evidenced travels deeper into the skin and thus affects the density, which allows for greater vasoconstrictor by the release of vasoconstriction with ganglionic dermal layer to a greater extent. UVA damage per quanta of norepinephrine released from blockade or presynaptic release inhibitor and is perfusion- and O2-dependent, which heavily sympathetic nerves. To our knowledge, the local the existence of basal skin sympathetic nerve implicates a reactive oxygen species (ROS) cooling response in facial skin has not been activity.20,30-37 All skin types appear to utilize a mechanism.54 Finally, both UVB and UVA described. Facial skin could be different in that release of vasoconstrictor tone to increase skin exposures upregulate both vascular endothelial it has a higher density of sensory afferents, which blood flow during a whole-body heat stress. growth factor and toll-like receptor (TLR) could lead to an augmented counteracting of Peripheral hairy but not glabrous skin also pathways, which could mediate and vasodilation depending on pain and other sensory employs a cholinergic-related active vasodilator synthesis and secretion.55,56 This latter afferent vasoactive releases.42,59,60 Whether system.32,38 Although peripheral hairy skin has effect may sensitize the skin for subsequent UV- sensory afferent or other neural control of facial functional β-adrenergic receptors, it appears that exposure responses. Whether these UV processes blood flow during local cold stress is altered in facial skin may be more reliant on these receptors are altered in facial compared to peripheral hairy rosacea needs further clarification. during stress.39- 41 It is unknown if facial skin and glabrous skin or in rosacea, however, remains Wind is listed as a distinct and major rosacea also relies on the same cholinergic-related active to be determined. flushing trigger, but the specific temperature is vasodilator mechanism that peripheral hairy skin 5 Whole-body cold stress, a moderate rosacea not accounted for in most surveys. Cold-wind does. Schwab and colleagues identified marked flushing trigger, induces a number of physiological responses may be related to local and whole- vasodilation in affected areas in all subtypes changes to increase tissue insulation and decrease body cooling responses. Wind causes direct skin- of rosacea but did not resolve the vasoactive 5 environmental heat loss. Passive cold stress temperature changes via convective cooling and 42 Additional substance(s) or the origin(s) thereof. does not change cardiac output but causes may also cause irritation and thus induce sensory research is needed to determine whether changes systemic vasoconstriction, thereby increasing afferent responses similar to local cooling. Wind in facial vasodilator mechanisms are implicated in 57,58 vascular resistance and arterial blood pressure. may also dry superficial skin layers, leading to rosacea during whole-body heating. Despite this pressure increase, both peripheral a disruption of the skin barrier. If a hot or cold Local skin heating, also a major rosacea flushing hairy and glabrous skin undergo pronounced wind causes a great enough skin-temperature trigger, induces vasodilation that is sympathetic- decreases in cutaneous vascular conductance change, it may locally exacerbate or attenuate independent but requires adrenergic innervation during whole-body cooling. Peripheral hairy skin skin-blood-flow responses per change in internal for complete expression.5,43-45 This vasodilation normally remains vasoconstricted throughout temperature.61 Another possible cold-wind occurs in a biphasic manner in peripheral hairy a cold stress; however, skin with arteriovenous outcome, if applied directly to the face, is a skin, where the initial vasodilation is primarily anastomoses (e.g., glabrous skin) can oscillate “diving” reflex response that results in decreased due to an axon reflex and the later vasodilation to a between constricted and relaxed states. This heart rate and increased arterial blood pressure.62 nitric-oxide-mediated response.46 Local-heating- cyclical response has been termed the “hunting Experimental “diving” reflex procedures decrease induced vasodilation occurs in facial skin but is reaction,” as it is thought to increase flow to aid skin sympathetic nerve activity to peripheral not consistently observed in peripheral glabrous in dexterity and prevent tissue freezing without glabrous and hairy skin; this reduction in skin.47 Facial (i.e., forehead and cheek) axon reflex losing extraordinary amounts of heat.26 Thus, in vasoconstriction coupled with increased arterial responses follow hairy skin’s biphasic vasodilation response to whole-body cooling, arteriovenous pressure could lead to increased skin blood pattern but are unique in that standard topical anastomosis-rich areas such as the nose, ears, and flow.63,64 Little is known about wind or convective anesthetic protocols are not successful in blunting lips can increase blood flow, although responses cooling, outside the “diving” reflex, in facial skin. the initial, axon-reflex-associated vasodilation.47 in other areas of the face are less clear. Facial Similarly, possible changes in rosacea have yet to Guzman-Sanchez identified increased local heat skin’s absolute vasoconstriction in response to be determined. sensitivities in both erythematotelangiectatic and cooling may also be blunted or absent because papulopustular rosacea.48 This result is consistent many facial locations such as the forehead do not Social/Emotional with an upregulation of the heat-activated appear to contain a high density of cutaneous Emotional stress and anxiety are both major 5 transient receptor potential vanilloid-1 (TRPV1) vasoconstrictor nerves.36 Thus, it is possible that rosacea flushing triggers. Embarrassment is channel in erythematotelangiectatic rosacea and there are regional arteriovenous anastomosis often not precisely delineated in rosacea surveys, greater nerve-fiber densities in all subtypes of responses and less opposition to the increases in but it is a very common cause of increased rosacea.42,49 Thus, it is possible that the face has arterial blood pressure. This could be a mechanism blood flow in facial skin (see Facial Flushing a greater axon-reflex component compared to to decrease blood flow in some facial skin while section) and is likely related to emotional peripheral hairy and glabrous skin and that this increasing skin blood flow to other facial areas stress. The precise mechanisms of emotional- response is heightened in rosacea-affected areas.50 during whole-body cooling. It is possible that the stress-induced flushing are poorly understood. arteriovenous anastomosis response is altered in One theory relates to a catecholamine surge Ultraviolet (UV) exposure associated with 5 patients with rosacea, possibly due to changes in (likely neural due to timing) and associated sunlight is another major rosacea flushing trigger. the neural control of this response. b-adrenergic vasodilation. Peripheral hairy skin This stimulus is likely multifactorial, involving also possesses β-adrenergic receptors but not in whole-body and local heating mechanisms Local cooling can also be a moderate rosacea 5 a great enough density to induce erythema in resulting from UV-induced heat gain in addition flushing trigger. In peripheral hairy skin, locally 39 these areas. Sudomotor activity to peripheral to the unique activity of UV radiation itself. It is applied cold produces biphasic vasomotor glabrous skin increases during embarrassment, unclear whether UVA (320-400) or UVB (290- responses. An initial vasoconstriction is followed but less is known about the response in skin 320 nm) triggers symptoms. Although UVA by a transient vasodilation and then a prolonged blood flow. Validating these observations, mental 46 The mechanisms by which is the dominant component of solar radiation, vasoconstriction. stress increases peripheral glabrous and hairy local cooling causes these vascular changes, 65,66 it requires greater energy to induce a minimal skin sympathetic nerve activity. Mental stress 51 with the exception of α erythema dose. DNA is a chromophore, a 2C-adrenergic receptor also increases supraorbital-skin sympathetic UV-photon absorber, and in response to UVB- translocation, are unclear but likely involve nerve activity, and this increase is accentuated photon bombardment it creates a number of local sensory afferents. Under thermoneutral 67 in those with erythematotelangiectatic rosacea. GRAY, METZLER-WILSON, DAWES, WILSON Page 13 However, Drummond and Su did not observe Spicy-food consumption is also classified as a rosacea, often resulting in exaggerated responses; differences in an index of forehead-skin blood moderate rosacea flushing trigger and may utilize over time, persistent erythema, inflammation, flow in those with rosacea while performing a TRPV1-channel mechanism similar to that of and can develop. Highlighting embarrassing tasks; this is despite those with the oral sensation of heat.5 The classic response these blood-vessel changes, using capillaroscopy, rosacea reporting greater embarrassment and to spicy products is capsaicin-mediated, although Rosina and colleagues described increases in vessel 68 diameters, vessel tortuosity, and telangiectasia intensity of blushing compared to controls. other chemicals that are perceived as spicy could 86 There may be differences in neural responses also be involved. Kashima and Hayashi observed in rosacea-affected areas. Flushing triggers to mental stress vs. embarrassing tasks, but it is increases in an index of skin blood flow throughout are numerous and individualized but can be possible that rosacea symptoms are due in part to the face with oral capsaicin administration.74 grouped into thermal/environmental, social/ emotional, pharmaceutical/topical, dietary, and supraorbital-nerve overactivity or altered issues of Capsaicin-induced vasodilation occurs via exercise-related items. These erythema triggers perception. TRPV1-receptor stimulation, which causes begin with neural events such as sympathetic flushing through the gustatory parasympathetic Pharmaceutical/Topical 30 nervous system, cranial nerve, axon reflex, or vasodilator pathway. This reflex response via a sensory afferent responses. The nervous system, in Certain cosmetics, skin care products, and topical cranial nerve is different from acute or chronic addition to affecting inflammation, both directly medications applied to the face are classified as topical capsaicin administration75,76 As described 5 and indirectly controls blood-vessel diameter moderate rosacea flushing triggers. Defining previously, the increase in TRPV1-receptor gene and thus blood flow. The facial vasculature is this category’s mechanism of action is difficult expression in erythematotelangiectatic rosacea innervated by post-synaptic sympathetic fibers because of the plethora of potential skin care could provide a potential mechanism whereby and cranial nerves and is affected by axon reflexes, products, but it most likely results from either rosacea may result in hyperactive gustatory-reflex sensory nerves, and locally released paracrine skin irritation or an allergic reaction to the responses.49 substances. Because ganglionic blockade, product. Sensory afferent nerves sense skin intradermal botulinum toxin A, and adrenergic irritation, while the wheal and flair response Physical Exercise blockade have been reported to reduce flushing, of a typical allergic reaction involves an axon Physical exercise is another major rosacea flushing potential roles for the sympathetic nervous reflex. It is also possible that these trigger.5 On surveys, this concept is often referred system are implicated.15,30,31,87-89 Individuals with could not only increase skin blood flow but also to as “carrying and lifting” (resistive exercise) or rosacea appear to have overactive supraorbital compromise the skin barrier, leading to increased “walking, running, bicycling” (aerobic exercise). sympathetic responses to mental and physical transepithelial water loss and inflammation. This Physical stress increases arousal, which increases stress, which further implicates this mechanism. disrupted and inflamed facial skin barrier in skin sympathetic-nerve activity to peripheral Cranial nerves participate in cutaneous vasodilation via such responses as axon and rosacea appears to be involved in the increased glabrous and hairy skin as well as facial areas 27 susceptibility to and a more independent of changes in metabolism.36,65,77-80 gustatory reflexes. Individuals with rosacea vigorous response to cutaneous irritation.69 Issues The level of effort, but not the amount of muscle may also have altered facial axon reflexes, which could contribute to these augmented reflex associated with rosacea-induced disruption of the mass engaged in the effort, determines the increase 50 responses. When activated, sensory nerves facial skin barrier and how this relates to topicals in peripheral skin sympathetic-nerve activity 79,81,82 release local vasodilator agents (e.g., CGRP and require further research. in response to resistive exercise. Exercise ATP) and can stimulate , sweat task visualization and direct motor-cortex Dietary glands, and mast cells, releasing substances such stimulation increase peripheral skin sympathetic- as prostaglandins, bradykinin, and . Consumption of alcohol (ethanol) is a major nerve activity, indicating that feedback from 5 Prostaglandins, bradykinin, and histamine are rosacea flushing trigger. Alcohol is associated the exercising muscle is not needed to increase potent vasodilators, increase vascular permeability, with small amounts of cutaneous vasodilation, sympathetic activity.83,84 Individuals with rosacea 70 and produce edema. Although still unknown, it especially in the face and periphery. The have augmented supraorbital skin sympathetic- is possible that individuals with rosacea release vasodilation effect is thought to be due to the direct nerve activity to resistive exercise.67 Thus, it is more of these or are sensitized to inflammatory 71 effect of ethanol on vascular smooth muscle. possible that this sympathetic-outflow increase is substances. The current understanding of the Facial flushing is pronounced in individuals with part of the reason for erythema in these patients. pathophysiology of rosacea, including the aldehyde dehydrogenase inactivation due to a The responses of peripheral skin sympathetic- inflammatory cascade involving TLR2 and serine point , but this mutation likely does not nerve activity in rosacea are unknown, and thus protease KLK5 expression and abnormal forms account for alcohol’s potential trigger effect in it is unknown if the augmented responses are of peptides (LL-37 and FA-29), is 72 9,42,90 most individuals with rosacea. It is possible that limited to the face or reflect a global response. described in detail elsewhere. While this either individuals with rosacea are more sensitive inflammatory cascade is important, the neural to cutaneous vasodilation or that the ethanol Aerobic exercise causes an internally generated events initiate these processes. Over time, these induces a gustatory flushing response similar to heat stress. Thus, similar to whole-body heat erythema triggers can also lead to structural that of hot drinks or spicy foods. stress, widespread sympathetically mediated and functional adaptations that characterize the increases in skin blood flow conduct heat to the disease. Understanding these neural links and Hot drinks are classified as a moderate rosacea skin for dissipation. A few caveats associated physiological responses to erythema triggers 5 flushing trigger. Originally it was thought that with aerobic exercise-induced heat stress vs. may help to focus future rosacea treatments on the trigger was related to the in coffee environmental or passive heat stress: 1) There is mechanistically stopping disease progression or tea, but more recent investigations identified an anticipatory or feed-forward aspect of exercise, earlier and potentially in a more individualized 73 an oral-cavity heat effect. Wilkin suggested where peripheral skin sympathetic-nerve activity manner by targeting mechanisms of each that heat draining from the oral cavity into increases prior to the generation and sensation patient’s specific triggers, allowing rosacea to be the jugular heats carotid-artery blood via of heat stress; and 2) internally generated heat better tolerated and controlled. 73 a countercurrent system. While some heat (exercise heat stress) can occur more rapidly than 84,85 exchange occurs between vessels, it is more likely passive heat stress. Further research is needed Acknowledgements that the very warm temperatures (60 °C) cause to determine whether changes in sympathetic or Pilot work67 was conducted through funding a reflex vasodilation as occurs in other gustatory other neural responses during aerobic exercise are 27 from the National Rosacea Society. reflexes. This level of heat stimulates TRPV1 implicated in rosacea. receptors on warm sensory afferents, which could lead to a cranial-nerve reflex response. It is unclear to what extent individuals with rosacea Perspectives and Conclusions Flushing is a normal facial physiologic process have abnormal gustatory reflexes. that becomes hyperactive in individuals with

Page 14 A NEURAL LINK TO UNDERSTANDING ROSACEA: FOCUSING ON FLUSHING TRIGGERS into methods. . 2012;19:47-64. treatment regimen for rosacea: onabotulinumtoxin A. References J Drugs Dermatol. 2012;11:e76-9. 1. National Rosacea Society [Internet]. Barrington, 18. Yvonne-Tee GB, Rasool AH, Halim AS, IL: National Rosacea Society; c1996-2015. If you Rahman AR. Noninvasive assessment of cutaneous 35. Bini G, Hagbarth KE, Hynninen P, Wallin have rosacea, you’re not alone; 2014 [cited 2015 Feb vascular function in vivo using capillaroscopy, BG. Regional similarities and differences in 27]; [about 2 screens]. Available from http://www. plethysmography and laser-Doppler instruments: thermoregulatory vaso- and sudomotor tone. J rosacea.org/patients/index.php. its strengths and weaknesses. Clin Hemorheol Physiol. 1980;306:553-65. Microcirc. 2006;34:457-73. 2. Pelle MT. Rosacea. In: L. A. Goldsmith, S. I. 36. Nordin M. Sympathetic discharges in the human Katz, B. A. Gilchrest, A. S. Paller, D. J. Leffell and K. 19. Durand S, Zhang R, Cui J, Wilson TE, supraorbital nerve and their relation to sudo- and Wolff, editors. Fitzpatrick’s Dermatology in General Crandall CG. Evidence of a myogenic response in vasomotor responses. J Physiol. 1990;423:241-55. Medicine. New York City, NY: The McGraw-Hill vasomotor control of forearm and palm cutaneous 37. Cui J, Zhang R, Wilson TE, Crandall CG. Companies, Inc; 2012. microcirculations. J Appl Physiol. 2004;97:535-9. Spectral analysis of muscle sympathetic nerve activity 3. Scharschmidt TC, Yost JM, Truong SV, Steinhoff 20. Wilson TE, Zhang R, Levine BD, Crandall in heat-stressed humans. Am J Physiol Heart Circ M, Wang KC , Berger TG. Neurogenic rosacea: a CG. Dynamic autoregulation of cutaneous Physiol. 2004;286:H1101-6. distinct clinical subtype requiring a modified approach circulation: differential control in glabrous versus 38. Kellogg DL Jr., Pergola PE, Piest KL, Kosiba WA, to treatment. Arch Dermatol. 2011;147:123-6. nonglabrous skin. Am J Physiol Heart Circ Physiol. Crandall CG, Grossmann M, et al. Cutaneous active 2005;289:H385-91. 4. Del Rosso JQ, Thiboutot D, Gallo R, Webster vasodilation in humans is mediated by cholinergic G, Tanghetti E, Eichenfield L, et al. Consensus 21. Darwin C. The expression of the emotions in nerve cotransmission. Circ Res. 1995;77:1222-8. recommendations from the American & man and animals [Internet]. New York: D. Appleton Rosacea Society on the management of rosacea, part 39. Crandall CG, Etzel RA, Johnson JM. Evidence and Company; 1899 [cited May 1, 2015]. Available 1: a status report on the disease state, general measures, of functional beta-adrenoceptors in the cutaneous from: http://www.gutenberg.org/files/1227/1227- and adjunctive skin care. Cutis. 2013;92:234-40. vasculature. Am J Physiol. 1997;273:H1038-43. h/1227-h.htm. 5. National Rosacea Society [Internet]. Barrington, 40. Drummond PD. Adrenergic receptors in 22. Drummond PD, Mirco N. Staring at one side of IL: National Rosacea Society; c 1996-2015. Rosacea the forehead microcirculation. Clin Auton Res. the face increases blood flow on that side of the face. triggers survey; 2013 [cited 2015 Feb 27]; [about 2 1996;6:23-7. screens]. Available from http://www.rosacea.org/ Psychophysiology. 2004;41:281-7. 41. Drummond PD. The effect of adrenergic blockade patients/materials/triggersgraph.php. 23. Keltner D, Buswell BN. Embarrassment: its on blushing and facial flushing. Psychophysiology. distinct form and appeasement functions. Psychol 6. Chauhan N, Ellis DA. Rosacea: pathophysiology 1997;34:163-8. and management principles. Facial Plast Surg Clin Bull. 1997;122:250-70. 42. Schwab VD, Sulk M, Seeliger S, Nowak P, Aubert North Am. 2013;21:127-36. 24. Hertzman AB, Randall WC. Regional differences J, Mess C, et al. Neurovascular and neuroimmune in the basal and maximal rates of blood flow in the 7. Elewski BE, Draelos Z, Dreno B, Jansen T, aspects in the pathophysiology of rosacea. J Invest skin. J Appl Physiol. 1948;1:234-41. Layton A, Picardo M. Rosacea - global diversity and Dermatol Symp Proc. 2011;15:53-62. optimized outcome: proposed international consensus 25. Hertzman AB, Randall WC, Peiss CN , 43. Minson CT, Berry LT, Joyner MJ. Nitric oxide from the Rosacea International Expert Group. J Eur Seckendorf R. Regional rates of evaporation from the and neurally mediated regulation of skin blood flow Acad Dermatol Venereol. 2011;25:188-200. skin at various environmental temperatures. J Appl during local heating. J Appl Physiol. 2001;91:1619- Physiol 1952;5:153-61. 8. Webster GF. Rosacea. Med Clin North Am. 26. 2009;93:1183-94. 26. Johnson JM, Brengelmann GL, Hales JR, 44. Wenger CB, Stephenson LA, Durkin MA. Effect Vanhoutte PM, Wenger CB. Regulation of the 9. Steinhoff M, Schauber J, Leyden JJ. New insights of nerve block on response of forearm blood flow to cutaneous circulation. Fed Proc. 1986;45:2841-50. into rosacea pathophysiology: a review of recent local temperature. J Appl Physiol. 1986;61:227-32. findings. J Am Acad Dermatol. 2013;69:S15-26. 27. Drummond PD. Autonomic disorders affecting 45. Hodges GJ, Johnson JM. Adrenergic control of cutaneous blood flow. In: C. J. Mathias and R. 10. Layton A, Thiboutot D. Emerging therapies in the human cutaneous circulation. Appl Physiol Nutr Bannister, editors. Autonomic failure: A textbook of rosacea. J Am Acad Dermatol. 2013;69:S57-65. Metab. 2009;34:829-39. clinical disorders of the autonomic nervous system. 11. Yamasaki K, Gallo RL. The molecular pathology 46. Johnson JM, Minson CT, Kellogg DL Jr. of rosacea. J Dermatol Sci. 2009;55:77-81. New York City, NY: Oxford University Press; 1999. Cutaneous vasodilator and vasoconstrictor 28. Wilkin JK. The red face: flushing disorders. Clin 12. Del Rosso JQ, Gallo RL, Tanghetti E, Webster G mechanisms in temperature regulation. Compr Dermatol. 1993;11:211-23. , Thiboutot D. An evaluation of potential correlations Physiol. 2014;4:33-89. between pathophysiologic mechanisms, clinical 29. Crandall CG, Wilson TE. Human cardiovascular 47. Metzler-Wilson K, Kellie LA, Tomc C, Simpson manifestations, and management of rosacea. Cutis. responses to passive heat stress. Compr Physiol. C, Sammons D, Wilson TE. Differential vasodilatory 2013;91:1-8. 2015;5:17-43. responses to local heating in facial, glabrous and hairy 13. Schram AM, James WD. Neurogenic rosacea 30. Drummond PD. Mechanisms of physiological skin. Clin Physiol Funct Imaging. 2012;32:361-6. treated with endoscopic thoracic sympathectomy. gustatory sweating and flushing in the face. J Auton 48. Guzman-Sanchez DA, Ishiuji Y, Patel T, Arch Dermatol. 2012;148:270-1. Nerv Syst. 1995;52:117-24. Fountain J, Chan YH, Yosipovitch G. Enhanced skin 14. Del Rosso JQ. Management of facial erythema of 31. Fox RH, Goldsmith R, Kidd DJ. Cutaneous blood flow and sensitivity to noxious heat stimuli rosacea: what is the role of topical alpha-adrenergic vasomotor control in the human head, neck and in papulopustular rosacea. J Am Acad Dermatol. receptor agonist therapy? J Am Acad Dermatol. upper chest. J Physiol. 1962;161:298-312. 2007;57:800-5. 2013;69:S44-56. 32. Johnson JM, Pergola PE, Liao FK, Kellogg DL 49. Sulk M, Seeliger S, Aubert J, Schwab VD, 15. Yuraitis M , Jacob CI. Botulinum toxin for Jr., Crandall CG. Skin of the dorsal aspect of human Cevikbas F, Rivier M, et al. Distribution and the treatment of facial flushing. Dermatol Surg. and fingers possesses an active vasodilator expression of non-neuronal transient receptor 2004;30:102-4. system. J Appl Physiol. 1995;78:948-54. potential (TRPV) ion channels in rosacea. J Invest Dermatol. 2012;132:1253-62. 16. Berardesca E, Leveque JL, Masson P. 33. Kellogg DL Jr., Johnson JM, Kosiba WA. EEMCO guidance for the measurement of skin Selective abolition of adrenergic vasoconstrictor 50. Drummond PD, Su D. Endothelial and axon microcirculation. Skin Pharmacol Appl Skin Physiol. responses in skin by local iontophoresis of bretylium. reflex vasodilatation to acetylcholine in rosacea- 2002;15:442-56. Am J Physiol. 1989;257:H1599-606. affected skin. Arch Dermatol Res. 2012;304:133-7. 17. Roustit M, Cracowski JL. Non-invasive assessment 34. Dayan SH, Pritzker RN, Arkins JP. A new 51. Diffey BL, Farr PM, Oakley AM. Quantitative of skin microvascular function in humans: an insight

GRAY, METZLER-WILSON, DAWES, WILSON Page 15 studies on UVA-induced erythema in human skin. Br in Guillain-Barre syndrome: a microneurographic handgrip exercise. Circulation. 2003;108:2329-35. J Dermatol. 1987;117:57-66. study. J Neurol Neurosurg Psychiatry. 1997;63:537- 84. Silber DH, Sinoway LI, Leuenberger UA, 41. 52. Kochevar IE, Taylor CR, Krutmann J. Amassian VE. Magnetic stimulation of the human Fundamentals of Cutaneous Photobiology and 67. Wilson TE, Toma K, Metzler-Wilson K, Sammons motor cortex evokes skin sympathetic nerve activity. J Photoimmunology. In: L. A. Goldsmith, S. I. D. Augmented supraorbital skin sympathetic nerve Appl Physiol. 2000;88:126-34. Katz, B. A. Gilchrest, A. S. Paller, D. J. Leffell and activity responses to symptom trigger events in 85. Vissing SF, Hjortso EM. Central motor command K. Wolff, editors. Fitzpatrick’s Dermatology in rosacea patients. FASEB J. 2012;26:1092.10. activates sympathetic outflow to the cutaneous General Medicine, 8th ed. New York: McGraw-Hill 68. Drummond PD, Su D. Blushing in rosacea circulation in humans. J Physiol. 1996;492(Pt 3):931- Professional; 2012. sufferers. J Psychosom Res. 2012;72:153-8. 9. 53. Angst MS, Clark JD, Carvalho B, Tingle M, 69. Jappe U, Schnuch A, Uter W. Rosacea and contact 86. Rosina P, Zamperetti MR, Giovannini A, Schmelz M, Yeomans DC. Cytokine profile in human to cosmetics and topical medicaments-- Chieregato C, Girolomoni G. Videocapillaroscopic skin in response to experimental inflammation, retrospective analysis of multicentre surveillance data alterations in erythematotelangiectatic rosacea. J Am noxious stimulation, and administration of a COX- 1995-2002. Contact Dermatitis. 2005;52:96-101. Acad Dermatol. 2006;54:100-4. inhibitor: a microdialysis study. Pain. 2008;139:15- 27. 70. Kalant H, Le AD. Effects of ethanol on 87. Hsu CC, Lee JY. Pronounced facial flushing and thermoregulation. Pharmacol Ther. 1983;23:313-64. persistent erythema of rosacea effectively treated by 54. Auletta M, Gange RW, Tan OT, Matzinger E. carvedilol, a nonselective beta-adrenergic blocker. J Effect of cutaneous hypoxia upon erythema and 71. Altura BM, Altura BT. Microvascular and vascular Am Acad Dermatol. 2012;67:491-3. pigment responses to UVA, UVB, and PUVA (8- smooth muscle actions of ethanol, acetaldehyde, and MOP + UVA) in human skin. J Invest Dermatol. acetate. Fed Proc. 1982;41:2447-51. 88. Fowler J, Jarratt M, Moore A, Meadows K, Pollack A, Steinhoff M, et al. Once-daily topical brimonidine 1986;86:649-52. 72. Jung JG, Kim JS, Oh MK. The role of the tartrate gel 0.5% is a novel treatment for moderate 55. Brauchle M, Funk JO, Kind P, Werner S. flushing response in the relationship between alcohol to severe facial erythema of rosacea: results of two Ultraviolet B and H2O2 are potent inducers of consumption and insulin resistance. Alcohol Clin multicentre, randomized and vehicle-controlled vascular endothelial growth factor expression in Exp Res. 2010;34:1699-704. studies. Br J Dermatol. 2012;166:633-41. cultured keratinocytes. J Biol Chem. 1996;271:21793- 73. Wilkin JK. Oral thermal-induced flushing in 89. Shanler SD, Ondo AL. Successful treatment of 7. erythematotelangiectatic rosacea. J Invest Dermatol. the erythema and flushing of rosacea using a topically 56. Lee Y, Kim H, Kim S, Shin MH, Kim YK, Kim 1981;76:15-8. applied selective alpha1-adrenergic receptor agonist, KH et al. Myeloid differentiation factor 88 regulates 74. Kashima H, Hayashi N. Facial skin blood flow . Arch Dermatol. 2007;143:1369-71. basal and UV-induced expressions of IL-6 and responses to irritant stimuli in the oral cavity. Auton 90. Yamasaki K, Kanada K, Macleod DT, Borkowski MMP-1 in human epidermal keratinocytes. J Invest Neurosci. 2013;174:61-5. Dermatol. 2009;129:460-7. AW, Morizane S, Nakatsuji T, et al. TLR2 expression 75. Charkoudian N, Fromy B, Saumet JL. Reflex is increased in rosacea and stimulates enhanced 57. Hess KL, Wilson TE, Sauder CL, Gao Z, Ray control of the cutaneous circulation after acute and serine protease production by keratinocytes. J Invest CA, Monahan KD. Aging affects the cardiovascular chronic local capsaicin. J Appl Physiol. 2001;90:1860- Dermatol. 2011;131:688-97. responses to cold stress in humans. J Appl Physiol. 4. 2009;107:1076-82. Correspondence: Thad E. Wilson, PhD; Marian 76. Stephens DP, Charkoudian N, Benevento JM, University College of Osteopathic Medicine; 58. Wilson TE, Sauder CL, Kearney ML, Kuipers NT, Johnson JM, Saumet JL. The influence of topical Michael A. Evans Center for Health Sciences; 3200 Leuenberger UA, Monahan KD, et al. Skin-surface capsaicin on the local thermal control of skin blood Cold Spring Rd; Indianapolis, IN, 46222; 317-955- cooling elicits peripheral and visceral vasoconstriction flow in humans. Am J Physiol Regul Integr Comp 6256; [email protected] in humans. J Appl Physiol. 2007;103:1257-62. Physiol. 2001;281:R894-901. 59. Nolan MF. Two-point discrimination assessment 77. Iwase S, Ikeda T, Kitazawa H, Hakusui S, in the upper limb in young adult men and women. Sugenoya J, Mano T. Altered response in cutaneous Phys Ther. 1982;62:965-9. sympathetic outflow to mental and thermal stimuli 60. Nolan MF. Quantitative measure of cutaneous in primary palmoplantar . J Auton Nerv sensation. Two-point discrimination values for the Syst. 1997;64:65-73. face and trunk. Phys Ther. 1985;65:181-5. 78. Saito M, Naito M, Mano T. Different responses 61. Wenger CB, Bailey RB, Roberts MF, Nadel in skin and muscle sympathetic nerve activity to static ER. Interaction of local and reflex thermal effects muscle contraction. J Appl Physiol. 1990;69:2085-90. in control of forearm blood flow. J Appl Physiol. 79. Wilson TE, Dyckman DJ, Ray CA. Determinants 1985;58:251-7. of skin sympathetic nerve responses to isometric 62. Gooden BA. Mechanism of the human diving exercise. J Appl Physiol. 2006;100:1043-8. response. Integr Physiol Behav Sci. 1994;29:6-16. 80. Nordin M, Thomander L. Intrafascicular multi- 63. Fagius J, Sundlof G. The diving response in man: unit recordings from the human infra-orbital nerve. effects on sympathetic activity in muscle and skin Acta Physiol Scand. 1989;135:139-48. nerve fascicles. J Physiol. 1986;377:429-43. 81. Vissing SF, Scherrer U, Victor RG. Stimulation 64. Fagius J, Traversa R. Human sympathetic nerve of skin sympathetic nerve discharge by central activity to glabrous skin does not increase during command. Differential control of sympathetic simulated diving. Acta Physiol Scand. 1994;152:249- outflow to skin and skeletal muscle during static 58. exercise. Circ Res. 1991;69:228-38. 65. Muller MD, Sauder CL, Ray CA. Mental 82. Ray CA, Wilson TE. Comparison of skin Stress Elicits Sustained and Reproducible Increases sympathetic nerve responses to isometric arm and leg in Skin Sympathetic Nerve Activity. Physiol Rep. exercise. J Appl Physiol. 2004;97:160-4. 2013;1:e00002. 83. Leuenberger UA, Mostoufi-Moab S, Herr M, 66. Yamamoto K, Sobue G, Iwase S, Nagamatsu M, Gray K, Kunselman A, Sinoway LI. Control of skin Mano T, Mitsuma T. Skin sympathetic nerve activity sympathetic nerve activity during intermittent static

Page 16 A NEURAL LINK TO UNDERSTANDING ROSACEA: FOCUSING ON FLUSHING TRIGGERS Adult-onset Multisystemic Langerhans Cell Histiocytosis: A Case Presentation and Discussion

Shahrzad Akbary, BS,* Adam Sorensen, DO,** Richard Bernert, MD, FASDP,*** Joseph Machuzak, DO, FAOCD,**** Stephen Kessler, DO, FAOCD*****

*Medical student, 4th year, Midwestern University Arizona College of Osteopathic Medicine, Glendale, AZ ** Dermatology resident, 3rd year, Alta Dermatology/LECOMT, Mesa, AZ *** Board-certified Dermatopathologist, Arizona Dermatopathology, Scottsdale, AZ **** Board-certified Dermatologist, MacKenzie Dermatology, Prescott, AZ *****Program Director, Dermatology Residency, Alta Dermatology/LECOMT, Mesa, AZ

Abstract Langerhans cell histiocytosis (LCH) is a rare, characterized by the clonal proliferation of bone-marrow-derived epidermal dendritic cells. Though more commonly a disease of the pediatric population, LCH can manifest at any age and involve any organ system. As may mimic other disease processes, diagnosis is often delayed. Prognosis is variable and largely based on the severity of systemic involvement, with treatment being determined on a case-by-case basis. Herein, we present a case of adult-onset multisystemic LCH with high-risk organ involvement, followed by a brief discussion of its unique presentation and the management of this rare disease. Introduction Previous treatments had included use of clobetasol Langerhans cell histiocytosis (LCH) is a , oral , and betamethasone rare histiocytic disorder characterized by the valerate cream off and on over many years, none clonal proliferation and infiltration of CD207- of which had resulted in long-term relief of scalp positive (Langerin) dendritic cells in various changes. Past medical history was significant for organ systems.1 Historically, LCH has been long-standing central diabetes insipidus, type-II classified into several categories based on clinical diabetes mellitus, , , presentation, including Letterer-Siwe disease, low , iatrogenic -Schüller-Christian syndrome, eosinophilic secondary to papillary carcinoma of the thyroid, , and Hashimoto-Pritzker disease. The anti-mitochondrial antibody (AMA)-negative current understanding, however, describes these primary biliary , and primary sclerosing entities merely as possible presentations on the cholangitis. Of note, the patient denied any spectrum of the LCH disease process.2 history of smoking or pulmonary symptoms. Figure 2. Dense mononuclear infiltrate positioned beneath a hemorrhagic, The etiology of LCH is incompletely Physical exam showed multiple scattered, crusted papules and several vesicles over a nearly impetiginized scale, situated primarily within understood. While the pathologic Langerhans the papillary, perifollicular . cells in LCH are known to be clonal, there has confluent erythematous, scaly base distributed long been a debate in the literature regarding diffusely over the scalp; there was also evidence whether LCH is a neoplastic or a reactive of some follicular dropout and alopecia (Figure proliferation. However, the recent discovery in 1). Due to the progressive and prolonged 2010 of oncogenic BRAF-V600E in 57% of archived LCH specimens lends support to the idea that LCH may in fact be a neoplastic process and may respond to antineoplastic therapy such as BRAF-pathway inhibitors.3 Due to the rarity of the disease, much that is known about LCH is a result of individualized case studies. More commonly recognized in the pediatric population, LCH affects children at a rate of one in 200,000, usually occurring between 1 and 3 years of age.4 In adults, the Figure 3. Infiltrate consisting mostly of large, incidence is roughly one to two cases per million, rather monomorphic histiocytic cells with high predominantly affecting those between the ages nuclear-to-cytoplasmic ratios, conspicuous of 20 and 35 years.5 Here, we present a rare case Figure 1. Multiple scattered papules and nucleoli, and irregular nuclear profiles with vesicles with accompanying yellow-tinged of LCH presenting in a patient well outside the ridges and grooves; few eosinophils distributed crusting on scalp; extensive flaking also unevenly. typical age of onset. evident. infiltrate diagnostic of Langerhans cell Case Presentation histiocytosis (Figures 2, 3). Extensive positivity A 60-year-old Caucasian male presented to the nature of his disease as well as its refractoriness for Langerin (CD-207), staining for CD-31, dermatology clinic with a chief complaint of a to prior treatments, two 4-mm punch biopsies and lack of immunoreactivity for CD-83 further pruritic, mildly tender scalp along with flaking of the left and right parietal regions were confirmed the diagnosis. and scabbing of 10 years’ duration. During that obtained. Differential diagnosis at the time time, he had been evaluated by several physicians, included decalvans and another Multisystemic Work-up including dermatologists, with diagnoses ranging cicatricial alopecia. In light of the patient’s history of central diabetes insipidus and hepatobiliary disease, we from eczema and seborrheic dermatitis to Both biopsies revealed a neoplastic, suspected multisystemic LCH. Systemic work- folliculitis and alopecia. folliculocentric, extensive Langerhans cell up revealed normal CBC and CMP with the AKBARY, SORENSEN, BERNERT, MACHUZAK, KESSLER Page 17 6 lesions, the patient was initiated on a regimen of Table 1. Clinical Classification of LCH methotrexate at Mayo Clinic, Scottsdale, where Type Involvement treatment is ongoing. Bone: unifocal (single bone) or multifocal (>1 bone) Skin Discussion Single-system LCH In order to better classify LCH, the Histiocyte node (not the draining of another LCH ) Society stratifies disease based the number of (one organ/system involved, uni- or multifocal) organ systems involved (single-system versus Hypothalamic-pituitary/central nervous system multi-system) and whether or not disease activity is unifocal or multifocal in each organ Other (e.g., thyroid, thymus) system (Table 1). They also classify disease Multisystem LCH With or without involvement of “risk organs” (hematopoietic, , spleen, based on involvement of high-risk organs, (two or more organs/systems ) defined as the hematopoietic system, liver, involved) spleen, and lungs. Reproduced with permission of the Royal College of Physicians of Edinburgh Once a biopsy-proven diagnosis of cutaneous LCH is made, investigation into exception of known and chronically elevated cell histiocytosis with involvement of high- multisystemic manifestations is of utmost alkaline phosphatase and transaminases. A risk organs, the patient was referred to the importance to determine prognosis and chest radiograph concerning for bibasilar Mayo Clinic in Scottsdale, Arizona for further guide treatment.7 Guidelines for diagnosis changes prompted a high-resolution chest evaluation and treatment. There, a follow- and treatment are well established for the CT without contrast to be ordered. This up bone-marrow biopsy and PET scan were pediatric population;8 however, the approach revealed severe coalescing fibrotic and cystic not found to be consistent with hematologic to management for adult patients is less well lung disease in bilateral lower lobes with malignancy. defined. In 2009, the Histiocyte Society mild centrilobular emphysema and bilateral published guidelines for recommended baseline upper-lobar pulmonary fibrosis. Tiny calcified Treatment laboratory and radiographic evaluation (Table and uncalcified nodules were also noted For scalp symptoms, the patient was prescribed 2). This proposed work-up investigates the throughout. A skeletal radiographic survey 0.05% clobetasol spray and instructed to use hematopoietic system, liver, bone, lung, and showed several tiny punctate lucencies scattered it twice daily. After one month, he reported endocrine system. in the right and left humeral heads as well as significant improvement in symptoms (Figure While Langerhans cell histiocytosis can affect the humeral shafts. As these findings were 4). However, seven months after initial consistent with multisystemic Langerhans any organ system, the skin is often the first presentation the patient presented with new, identifiable manifestation of disease. In adults, scattered erythematous papules on bilateral cutaneous involvement is extremely variable cheeks and jawline; these were biopsied and in presentation.10 Lesions may present as found to be consistent with LCH (Figure small papules, pustules, and/or vesicles with 5). It is interesting and gratifying to note accompanying yellow crusting and erythema; that despite the above multisystemic findings, these classically occur in intertriginous areas the patient insists he feels healthy and is not or, as with our patient, on the scalp.7,10 On experiencing any , bone examination, the cutaneous manifestations can pain, or a lessened quality of life other than be easily mistaken for common dermatologic his skin complaints. However, due to the conditions such as eczema, seborrheic dermatitis, severe findings on imaging and persistent skin

Table 2: Recommended baseline evaluation upon diagnosis/reactivation of LCH9

Figure 4. Scalp after one month of treatment Full blood count with 0.05% clobetasol spray; note near- resolution of papules and vesicles, persistent Hemoglobin, white-blood-cell and differential count, platelet count erythema. Blood chemistry Total , albumin, bilirubin, ALT, AST, alkaline phosphatase, GGT , creatinine, electrolytes Ferritin Coagulation studies INR/PT, APTT/PTT, fibrinogen Early-morning sample Specific gravity and osmolality Abdominal ultrasound Size and structure of liver and spleen Chest radiograph (CXR) Figure 5. Erythematous papules on right Skeletal radiograph survey* cheek presenting seven months after initial diagnosis; biopsy consistent with Langerhans *Functional imaging such as bone scan is optional and can be performed in addition to skeletal survey. PET scan cell histiocytosis. has proven to be the most sensitive functional test used in the identification of LCH lesions and in evaluating patient response to therapy. However, PET scan is currently expensive and not widely available.

Page 18 ADULT-ONSET MULTISYSTEMIC LANGERHANS CELL HISTIOCYTOSIS: A CASE PRESENTATION AND DISCUSSION dermatophytosis, and folliculitis. This mimicry, may include a combination of systemic histiocytosis limited to the skin. Dermatology. coupled with the rarity of adult LCH, often along with a single-agent chemotherapeutic 2003;207(2):157-161. leads to a delay in biopsy and diagnosis. -- either vincristine or vinblastine. For these 11. Grana N. Langerhans cell histiocytosis. patients, response during the six-week induction Control. 2014;21(4):328-334. Central diabetes insipidus (DI) is the most phase with these therapies has been shown to be common endocrine manifestation of LCH and 12. Suri HS, Yi ES, Nowakowski GS, Vassallo the single most important long-term prognostic is caused by Langerhans cells infiltrating the R. Pulmonary Langerhans cell histiocytosis. indicator.14 posterior pituitary. A retrospective analysis by Orphanet J Rare Dis. 2012;7:16. Arico et al. reported DI to occur in 29.6% of 13. Morimoto A, Oh Y, Shioda Y, et al. Recent patients;5 however, incidence as high as 40% in Conclusion 7 Adult multisystemic Langerhans cell Advances in Langerhans cell histiocytosis. adult patients has been reported. Magnetic Pediatr Int. 2014;56:451-461. resonance imaging (MRI) is the most sensitive histiocytosis is a rare, though likely under- diagnostic tool for LCH-associated DI and will recognized, disease that requires a high index 14. Satter EK, High WA. Langerhans often show thickening of the pituitary stalk with of clinical suspicion to diagnose. LCH should cell histiocytosis: a review of the current “loss of bright spot,” which corresponds to loss be considered in adults with refractory lesions recommendations of the histiocyte society. of antidiuretic (ADH)-containing on the scalp. Once diagnosed, it requires an Pediatr Dermatol. 2008;25(3):291-295. 11 appropriate multisystemic work-up both for granules. Once this infiltration occurs, it results Correspondence: Shahrzad Akbary, BS; risk stratification and to guide subsequent in the irreversible sequelae of central DI, and [email protected] patients must receive lifelong supplementation therapeutic decision-making. While patients with desmopressin acetate. Diabetes insipidus often first present to the dermatologist, presents with polydipsia and polyuria and adults with multisystemic LCH require a may predate the diagnosis of LCH or develop multidisciplinary approach to manage disease subsequently.7 Our patient exemplifies this, as manifestations and guide treatment. he was diagnosed with central DI in 1994 and insists his scalp changes did not occur until the References early 2000s. 1. Berres ML, Lim KP, Peters T, et al. BRAF- V600E expression in precursor versus In adults, pulmonary LCH is more commonly differentiated dendritic cells defines clinically seen as an isolated disease rather than a distinct LCH risk groups. J Exp Med. manifestation of multisystemic LCH, and it is 2014;211:669–83. strongly associated with smoking.7 When the lungs are affected in adult multisystemic LCH, 2. Chu T, D’Angio GJ, Favara B, Ladisch S, as in our patient, the disease is classified as high- Nesbit M, Pritchard J. The Writing Group of the risk.6 The pathogenesis of pulmonary LCH is Histiocyte Society. Histiocytic syndromes in thought to be the infiltration and excessive children. Lancet. 1987;1:208–9. activation of Langerhans cells in the lung 3. Badalian-Very G, Vergilio JA, Degar BA, et parenchyma. While definitive diagnosis cannot al. Recurrent BRAF mutations in Langerhans be established without a biopsy demonstrating cell histiocytosis. Blood. 2010;116:1919-23. these abnormal Langerhans cells, imaging 4. Howarth DM, Gilchrist GS, Mullan BP, et al. modalities can be highly suggestive of disease in Langerhans cell histiocytosis: diagnosis, natural the proper clinical context. Presence of nodules, history, management, and outcome. Cancer. cystic changes, and honeycombing on high- 1999;85(10):2278- 2290. resolution CT are signs of advanced disease and increase the risk of pneumothorax, which occurs 5. Aricò M, Girschikofky M, Généreau T, et al. in up to 15% of patients.12 Dyspnea and a non- Langerhans cell histiocytosis in adults: report productive may also occur; however, as in from the International Registry of the Histiocyte our case, many patients may be asymptomatic, Society. Eur J Cancer. 2003;39(16):2341- 2348. making imaging and subsequent pulmonary- 6. Munir A, Leech N, Windebank KP, et al. function testing vital for patient prognosis and Langerhans cell histiocytosis: a multisystem monitoring. disorder. J R Coll Physicians Edinb. As exemplified in our case, hepatobiliary 2012;42:311-3. and splenic involvement in Langerhans cell 7. Girschikofsky M, Arico M, McClain KL. histiocytosis is not uncommon, occurring in Management of adult patients with Langerhans up to 20% of patients. As Langerhans cells cell histiocytosis: recommendations from an progressively infiltrate these organs, they cause expert panel on behalf of Euro-Histio-Net. bile-duct destruction and can lead to sclerosing Orphanet J Rare Dis. 2013;8:72. cholangitis, biliary cirrhosis, and subsequent 8. Haupt R, Minkov M, Astigarraga I, et portal hypertension.13 Therefore, a metabolic al. Langerhans Cell Histiocytosis (LCH): panel with work-up of any abnormalities is Guidelines for Diagnosis, Clinical Work-Up, always warranted in this patient population. and Treatment for Patients Till the Age of 18 Treatment for adult LCH is variable and Years. Pediatr Blood Cancer. 2013;60:175-184. depends largely on the extent of disease and its 9. Minkov M, Grois N, McClain K, et al. impact on the patient’s quality of life. Typically, Histiocyte Society Evaluation and Treatment patients with skin-limited disease will respond Guidelines. Histiocyte Society; 2009. to high-potency topical steroids and require no further treatment. However, in patients with 10. Singh A, Prieto VG, Czelusta A, McClain multisystemic disease, approach considerations KL, Duvic M. Adult Langerhans cell

AKBARY, SORENSEN, BERNERT, MACHUZAK, KESSLER Page 19 A Rare Case of Unilesional Follicular and Syringotropic Mycosis Fungoides: A Case Report and Review of the Literature

Kevin Svancara, DO,* Vernon T. Mackey, DO, FAOCD, FASMS**

*Dermatology Resident, 1st year, Advanced Desert Dermatology/Midwestern University, Peoria, AZ **Program Director, Dermatology Residency Program, Advanced Desert Dermatology/Midwestern University, Peoria, AZ

Abstract Mycosis fungoides (MF) is the most common cutaneous . It has three newly classified variations, one of which is follicular mycosis fungoides. Follicular mycosis fungoides (FMF) can further be divided into the rare variants unilesional follicular mycosis fungoides and syringotropic mycosis fungoides. We present a case with overlapping unilesional follicular mycosis fungoides and syringotropic mycosis fungoides. These rare variants can often appear clinically as benign inflammatory skin conditions and are frequently misdiagnosed for years. Close follow-up with repeated biopsies can lead to a diagnosis as the disease progresses. The disease has a poor prognosis compared to similar-staged diseases of classic mycosis fungoides. This is attributed to the location of the pathology, deep in the dermis and , which requires more aggressive treatments to reach the depth of the disease.

Introduction Table 1. Comparison of overall 5-year and 10-year survival rates1,2,4,18 Mycosis fungoides (MF) is the most common cutaneous lymphoma, estimated to occur in Classification Overall survival rates (%) 1 approximately 0.55 per 100,000 person-years. 5 year 10 year This cutaneous T-cell lymphoma (CTCL) is characterized by a T-cell lymphocytic infiltrate Mycosis fungoides (MF)* 97-98 in the papillary dermis, the presence of atypical with cerebriform nuclei, and Folliculotropic mycosis fungoides (FMF) 62-68 26 evidence of epidermotropism.2 MF has multiple Syringotropic mycosis fungoides (SMF) 100 83-97 variants presenting with different clinical and *Limited patch/plaque stage vastly different histologic presentations. The etiology of MF is unclear, with infectious, occupational, and genetic mutations presenting can be found with multiple plaques throughout Case Report possible causes.1,3 It has been noted to be a the body. There have been few published cases 8 A 45-year-old Caucasian male presented to challenging diagnosis histologically, as there can of FMF to date. Infiltrated plaques of the our office for a second opinion of a localized, be significant overlap between MF and benign eyebrows with alopecia are common and highly indurated plaque over the right with 1,4 1,4 inflammatory conditions. Many of the clinical characteristic findings with severe pruritus. In alopecia (Figure 1). The patient had no significant and histopathological features of MF can be multiple cases, infiltration of the eccrine sweat 1 past medical or family history. The lesion started absent in early disease, often causing a delay of glands is also present. four months prior as a with symptoms of 1 diagnosis and treatment. While many clinical Further classifications exist within each variant, itching and burning. The lesion progressed over and histological variants have been described over including rare forms of unilesional FMF and the next two months into a firm plaque with the years, MF has recently been divided into three syringotropic MF.8,9 Unilesional FMF is alopecia. No or further plaques variants. The World Health Organization and characterized by a single area of involvement of were noted on physical exam. World Health Organization for Research and less than 5% body surface area. Syringotropic The lesion was biopsied prior to presenting Treatment of Cancer held consensus meetings MF is characterized by prominent involvement at our office and read as follicular . in 2003 and 2004 to align the classifications of of the eccrine glands with syringolymphoid Prominent adnexal involvement within the cutaneous by resolving controversy 9 . There is significant overlap between follicular epithelium was noted. Superficial and over definitions and terminology between the folliculotropic and syringotropic MF, causing 5 deep perivascular infiltrates were also present. two organizations. difficulty for clinicians as the two have shown 8,10 Follicular mucin was noted within the follicular MF variants reclassified during the meeting variations in prognosis (Table 1). We report epithelium, as well as prominent eosinophils. No include the most common Aliber-Bazin type a complicated case of unilesional follicular and significant lymphoid atypia was noted at that and three variants including folliculotropic MF, syringotropic MF. time. The patient was informed that the T-cell pagetoid reticulosis, and granulomatous slack dyscrasia had the potential to be attributed to 5 skin. Folliculotropic mycosis fungoides (FMF) benign as well as malignant causes. is characterized by the presence of medium to The patient presented to our office, and two large, hyperchromatic T-cell infiltrates within the further biopsies were performed. The patient’s lab follicular known as folliculotropism. work showed a mild leukocytosis with all other The disease most often spares the epidermis labs within normal limits. The patient was started of the surrounding skin. While classic MF is on clobetasol 0.05% cream twice a day after the often reported with follicular manifestations initial visit. The slides (Figures 2, 3, 4) were representing follicular mucinosis, FMF reveals reviewed by multiple dermatopathologists as well involvement of the hair follicles and eccrine glands 5-7 as a dermatopathologist specializing in cutaneous by lymphoma cells. Clinically, the lymphoma is 1 lymphomas. A marked atypical, cerebriform, most commonly found on the head and neck. lymphocytic infiltrate was noted surrounding Patients often present with acneiform lesions, as well as permeating the hair follicles. Eccrine indurated plaques, or follicular-centered papules, Figure 1. Right supraorbital plaque with ducts and glands were also affected, with sparing with occasional tumors. Most often, patients alopecia, two months after onset.

Page 20 A RARE CASE OF UNILESIONAL FOLLICULAR AND SYRINGOTROPIC MYCOSIS FUNGOIDES: A CASE REPORT AND REVIEW OF THE LITERATURE Figure 2. Atypical lymphocytes infiltrating Figure 3. Atypical cerebriform lymphocytes Figure 4. Atypical lymphocytes permeating the follicular epithelium (folliculotropism) permeating the . the eccrine ducts. and dermis with sparing of the surrounding epidermis. treatment, the lesion had no further progression, and cases of SMF demonstrating follicular but the plaque persisted. The site was again involvement.9 Our case demonstrates an overlap of the surrounding epidermis. Close examination biopsied, demonstrating persistence of the of FMF with SMF. follicular and eccrine involvement. The patient of the infiltrate demonstrated marked nuclear FMF has multiple differences from MF, including was then referred for radiotherapy with follow- irregularity with hyperchromasia. An admixture head and neck involvement, which is typically up pending. 4 of histiocytes and eosinophils were present. spared in MF and often SMF. The pathogenesis The lymphocytic infiltrate was also present in and cause of accumulating lymphocytes within the intrafollicular dermis and subcutaneous fat. Discussion and around the follicular epithelium and eccrine An Alcian blue stain confirmed the presence of Our patient presents a rare case of unilesional glands, and sparing of the surrounding epidermis, mucin within the hair follicles. The findings were follicular and syringotropic mycosis fungoides. is poorly understood. However, multiple studies suspicious for incipient tumor-stage development. The diagnosis of FMF or SMF can be very difficult, have noted an increased expression of ICAM-1 Phenotypic studies were performed, often requiring multiple biopsies over time. The within follicular keratinocytes, which is thought clinical and histopathological presentation is to be induced by neoplastic T lymphocytes. This demonstrating a T-cell infiltrate represented 4,7,11 by an almost exclusive CD4+, CD8-, CD7- often mistaken for follicular mucinosis (FM). is hypothesized to lead to the obstruction of 15-17 phenotype. This pattern is characteristic of FMF Some debate exists on whether FM represents follicular orifices by neoplastic T-cells. Pereyo 9 a precursor to FMF or a benign variant of MF explains the relationship of FMF to MF as one as well as MF. Other positive T-cell markers 4,11,12 included CD3 and CD5. A CD68+ marker with a non-aggressive clinical course. It similar to that of lichen planopilaris to lichen 14 representing macrophages was also present. should be noted that follicular mucinosis in planus. The immunohistochemical analysis PD-1 was negative and most often found in younger patients most often is characterized by of FMF and MF are similar, most commonly spontaneous regression after two months to two demonstrating a CD4+ T-cell dyscrasia with a small/medium-sized (pleomorphic) T-cell 11 lymphomas. Contradictory data on PD-1+ T-cells years, without any further progression to MF. common loss of CD7 and often clonal T-cell 1 in FMF have been reported, with anywhere from Cerroni attempted to review the clinical and gene rearrangements. However, T-cell gene 9% to 80% of cases harboring positive T-cells.9,13 histopathologic differences between FM and rearrangements can be conflicting, as they The proliferative index was found to be low at malignant FMF. He noted that despite looking can be negative in many malignant cases and 15% to 20%. The CD 4/8 ratio was noted to have at the age of the patient, location of lesions, positive in benign conditions such as spongiotic 1,4,14 an absence of CD8 within the hair follicles and number of lesions, amount of mucin deposited dermatitis, further confusing the diagnosis. eccrine glands. However, an admixture of CD8 within the follicles, as well as gene rearrangement A few studies have required positive monoclonal lymphocytes was noted within the intrafollicular studies, significant overlap exists between the two gene rearrangements to make the diagnosis of disease states.11 This leads most often to delays FMF. Cerroni demonstrated that monoclonal dermis, adnexal dermis, and subcutaneous fat. 1,4 Gene rearrangement studies were negative for in diagnosis averaging two to five years. Early gene rearrangements were noted in six out of 11 both the biopsy specimen and peripheral blood. diagnosis is important considering the poor five- cases of idiopathic FM and only nine out of 19 year overall survival rate of 62%.4 The overlap cases of lymphoma-associated FM.7,10 This shows Considering the extent of lymphoid atypia, between FM and FMF shows the importance that gene rearrangements, although helpful if degree of lymphocytic infiltration of the dermis of close follow-up and the need for multiple found, cannot be heavily relied upon to make the and subcutaneous tissue, and the abnormal biopsies for persistent and changing lesions not diagnosis. phenotypic profile, the patient was diagnosed responding to conventional treatments.13 with unilesional follicular and syringotropic FMF was reclassified as a separate entity from mycosis fungoides. He was referred to a tertiary The of our patient’s lesion also MF due to its distinctive clinical and histological clinic that specializes in cutaneous lymphomas demonstrated prominent involvement of the features, as well as its worse prognosis and 5 for treatment. The lesion had slightly decreased eccrine-duct epithelium, known as syringotropic resistance to standard treatments. Fewer than with topical clobetasol 0.05% cream. The patient mycosis fungoides (SMF). SMF is described as 10% of patients with classic MF will progress was continued on clobetasol twice daily on atypical lymphocytes surrounding the eccrine to more advanced stages, and less than one third Tuesday, Thursday, Saturday and Sunday. He ducts and glands and infiltrating the eccrine of those patients will develop extracutaneous was also instructed to apply bexarotene 1% gel, a epithelium, with associated syringolymphoid disease with disease-related death in the first 10 9 1,5 synthetic that binds to the RXR ligand, hyperplasia. Some authors consider SMF and years after diagnosis. Most FMF patients are FMF to be closely related, but with separate clinically classified as stage IA or IB; however, on Monday, Wednesday, and Friday mornings. 6 This was paired with clobetasol in the evenings. disease processes. Other authors believe it they demonstrate worse five- and 10-year survival to be a variation or progression of the same rates, more similar to survival rates of patients After six weeks, the lesion had decreased in 4,14 vertical growth. The patient was instructed to disease process. The current WHO-EORTC with tumor-stage MF. Multiple studies have guidelines place SMF and FMF in the same noted disease-specific survival rates at five years replace the clobetasol with 0.1% 5 for six weeks, and then 2.5% group as a single variant of MF. Many articles and 10 years averaging 68% and 26%, respectively 18 for an additional six weeks. After 18 weeks of describe FMF also affecting the eccrine ducts (Table 1). Many studies stress the importance

SVANCARA, MACKEY Page 21 of treating all FMF patients as tumor-stage 15. Pereyo N, Requena L, Galloway J, 18 References regardless of the clinical appearance. This 1. Ahn C, ALSayyah A, Sangueza Sangüeza O. Follicular mycosis fungoides: demonstrates the need for early diagnosis with A clinicohistopathologic study. J Am Acad 17 O. Mycosis Fungoides: an Updated Review of more aggressive treatments. Clinicopathologic Variants. Am J Dermatopathol. Dermatol. 1997;36(4):563-568. Effective treatment options for FMF vary 2014;36(12):933-948. 16. Grau F, Point V, Matarredona J, et al. compared to classic MF, which often responds 2. De Masson A, Battistella M, Vignon- Follicular mycosis fungoides: presentation of to photochemotherapy (PUVA) and topical Pennamen MD, et al. Syringotropic Mycosis a case and review of the literature. J Eur Acad creams including mechlorethamine, nitrogen Fungoides: Clinical and histologic features, Dermatol Venereol. 1999;13(2):131-136. mustard, and steroids.5,18 Although response to treatment, and outcome in 19 17. Monopoli A, Annessi G, Lombardo G, et no standard treatment exists, many case reports patients. J Am Acad Dermatol. 2014;71(5):926- al. Purely follicular mycosis fungoides without have demonstrated the ineffectiveness of these 934. mucinosis: Report of two cases with review of the more superficial treatments.14,17 It is thought that literature. J Am Acad Dermatol. 2003;48(3):448– deep follicular involvement allows the disease 3. Carrington P. Follicular mycosis fungoides. J 452. to persist beyond their reach. Common, more Am Acad Dermatol. 1998;38(3):502-503. aggressive treatments with beneficial results 4. Lehman J, Cook-Norris R, Weed B, et al. 18. Van Doorn R, Scheffer E, Willemze R. include radiotherapy for localized lesions and Folliculotropic Mycosis Fungoides: Single- Follicular Mycosis Fungoides, a Distinct total-skin electron-beam therapy (TSEBT) for Center Study and Systematic Review. Arch Disease Entity With or Without Associated diffuse lesions, leading many to claim them as the Dermatol. 2010;146(6):607-613. Follicular Mucinosis: A Clinicopathologic treatment of choice.10,17,19 and Follow-up Study of 51 Patients. Arch 5. Willemze R, Jaffe E, Burg G, et al. Dermatol. 2002;138(2):191-198. WHO-EORTC classification for cutaneous Conclusion lymphomas. Blood. 2005;105(10):3768-3785. 19. Thein M, Ravat F, Orchard G, et al. Our case demonstrates a rare presentation of Syringotropic cutaneous T-cell lymphoma: an MF with unilesional follicular and syringotropic 6. Lacour JP, Castanet J, Perrin C, et al. Follicular immunophenotypic and genotypic study of five mycosis fungoides. Debate continues regarding Mycosis Fungoides. J Am Acad Dermatol. cases. Br J Dermatol. 2004;151(1):216-226. 1993;29(2):330-334. whether FMF and SMF are distinct entities Correspondence: Kevin Svancara, DO; 9191 W. or variations of the same disease process. Our 7. Rongioletti F, Reboro A. Cutaneous mucinoses: Thunderbird Rd, D-101, Peoria, AZ 85381; Fax: patient had prominent, marked follicular microscopic criteria for diagnosis. Am J (623) 977-6771; Ph: (623)977-6700; involvement as well as eccrine-duct involvement Dermatopathol. 2001;23(3):257-267. [email protected] with syringohyperplasia. As noted, FMF has a 8. Kempf W, Kazakov D, Schermesser M, et al. worse prognosis compared to classic MF. This is Unilesional follicular mycosis fungoides: report in contrast to SMF, which has a prognosis similar of two cases with progression to tumor stage to early-stage classic MF.10 Both FMF and SMF and review of the literature. J Cutan Pathol. have higher fail and recurrence rates with topical 2012;39(9):853-860. and superficial treatments, as was noted in this case. The case demonstrates the importance of 9. Pileri A, Facchetti F, Rutten A, et al. follow-up in patients presenting with plaques Syringotropic mycosis fungoides: a rare variant or consistent with benign inflammatory of the disease with peculiar clinicopathologic conditions that fail to respond to conventional features. Am J Surg Pathol. 2011;35(1):100-109. treatments. Oftentimes, these processes can 10. Yost J, Thy T, Kovalszki K, et al. Two cases represent early stages of MF, requiring repeated of syringotropic cutaneous T-cell lymphoma and biopsies with further cytological and serum review of the literature. J Am Acad Dermatol. testing in order to make the diagnosis. Most cases 2009;61(1):133-138. with unilesional plaques are associated with an indolent course; however, our case demonstrates 11. Cerroni L, Fink-Puches R, Bäck B, et al. that rarely they can be due to more aggressive Follicular Mucinosis: A Critical Reappraisal of forms such as FMF, requiring aggressive Clinicopathologic Features and Association With treatments. Further studies and case reports are Mycosis Fungoides and Sézary Syndrome. Arch required to better classify the differences and Dermatol. 2002;138(2):182-189. similarities between FMF and SMF. 12. Bonta M, Tannous Z, Demierre MF. Rapidly progressing mycosis fungoides presenting as follicular mucinosis. J Am Acad Dermatol. 2000;43(4):635-640. 13. Iorizzo M, El Shabrawi Caelen L, Vincenzi C, et al. Mycosis fungoides masquerading as alopecia areata. J Am Acad Dermatol. 2010;63(2):50-52. 14. DeBloom J, Severson J, Gaspari A, et al. Follicular mycosis fungoides: a case report and review of the literature. J Cutan Pathol. 2001;28(6):318-324.

Page 22 A RARE CASE OF UNILESIONAL FOLLICULAR AND SYRINGOTROPIC MYCOSIS FUNGOIDES: A CASE REPORT AND REVIEW OF THE LITERATURE Secukinumab for the Treatment of Plaque Psoriasis: A Review of Phase III Testing

Aline Babikian, DO,* Kourosh Beroukhim, BS,** Catherine Nguyen, BS,*** John Koo, MD****

* Intern, San Antonio Military Medical Center, Fort Sam Houston, TX ** Medical Student, 4th Year, University of California, Los Angeles, CA *** Medical Student, 4th Year, University of California, Irvine, CA **** Director, Psoriasis, Phototherapy and Skin Treatment Clinic, Professor and Vice Chair, Department of Dermatology, University of California San Francisco Medical Center, San Francisco, CA Abstract IL-17 is the newest cytokine implicated in the pathogenesis of psoriasis. Preclinical and phase II testing to pharmaceutically block this cytokine has proved promising. The results of phase III clinical trials using secukinumab were reviewed to evaluate safety and efficacy profiles for this medication. By week 12, the percentages of patients achieving 75% improvement in Psoriasis Area and Severity Index (PASI 75) and the investigator’s global assessment scores of 0 or 1 were superior with doses of secukinumab 300 mg and 150 mg over placebo. In a head-to-head study, secukinumab also performed superiorly compared to ustekinumab, an anti-interleukin-12/23 agent. The safety profile of secukinumab was favorable, with nasopharyngitis, upper respiratory tract , , and diarrhea being the most common adverse events. , to include especially mild candida infections, were more prevalent over placebo, and few patients experienced asymptomatic neutropenia. Overall, secukinumab exhibited a strong efficacy clinically, with a good safety profile.

Introduction Results Secukinumab is the most recent biologic medication to gained U.S. Two major clinical trials were conducted to investigate efficacy and safety Food and Drug Administration (FDA) approval for the treatment of of different doses of secukinumab. The first study compared secukinumab moderate-to-severe plaque psoriasis.1 Psoriasis patients, especially those against placebo, and the other against placebo and etanercept. In addition, with moderate-to-severe disease, are substantially undertreated, leading to two minor studies evaluated the efficacy of two different delivery methods a severe impairment of social and occupational wellbeing.2 The advent of of the medication. Another study directly compared secukinumab to biologic agents significantly increased the dermatologist’s ability to treat ustekinumab with a head-to-head design. moderate-to-severe psoriasis.3 Secukinumab is currently the only FDA approved biologic that acts by ERASURE inhibiting the interleukin (IL)-17 cytokine.1 IL-17 is a proinflammatory Study design. In this clinical trial, a total of 737 patients were randomized cytokine that has been detected in psoriatic lesions and is strongly implicated 1:1:1 to either secukinumab 300 mg, secukinumab 150 mg, or placebo. in psoriasis pathogenesis.4-10 It is a downstream product of interleukin-23, The two co-primary endpoints were achievement of PASI 75 and IGA which is targeted by another currently approved biologic, ustekinumab.9,11,12 0 or 1 at week 12. Patients who received secukinumab 300 mg and 150 In particular, IL-17A, one of the six homodimers of IL-17, is considered the mg were followed for another 40 weeks of maintenance. Those assigned to most important in this family for psoriasis development.13-15 Secukinumab secukinumab received dosages at baseline, and then weekly for four weeks, is a fully human monoclonal IgG1 antibody that specifically binds to and followed by every four weeks for the remainder of the study. inhibits IL-17A, which normally acts on keratinocytes to promote changes 16,17 Efficacy. By week 12, significantly higher percentages of those in both culminating in the clinical manifestation of psoriasis. Additionally, IL- secukinumab 300 mg and secukinumab 150 mg groups achieved PASI 17 plays a role in the recruitment and activation of , the blockade 14,18-21 75 (81.6% and 71.6%, respectively) and IGA 0 or 1 (65.3% and 51.2%, of apoptosis, and the stimulation of psoriasis angiogenesis. respectively) than those who took placebo, of whom 4.5% reached PASI 75 In addition to treating psoriasis, secukinumab is currently under investigation and 2.4% reached IGA 0 or 1 (P<0.001). Additionally, greater efficacy was for the treatment of psoriatic , , ankylosing demonstrated with 300 mg than with 150 mg. Similar patterns were also spondylitis, , Crohn’s disease, and non-infectious uveitis.22-27 noted for PASI 90 during the maintenance period and improvements of QoL, as assessed by the Dermatology Life Quality Index (P<0.001) (Table The purpose of this article is to review the five phase III studies for 1). secukinumab. Two clinical trials assessed the clinical response to secukinumab, with co-primary end points of at least 75% reduction in Adverse events. There was an overall higher incidence of adverse events with Psoriasis Area and Severity Index (PASI 75) and scores of 0 (clear) or 1 the secukinumab 300 mg and 150 mg groups than with placebo (55.1%, (almost-clear) based on a five-point investigator’s global assessment (IGA) 60.4%, and 47.0%, respectively). Infections were more prevalent with the by week 12 of treatment. IGA is a tool used by clinicians to document secukinumab 300 mg and 150 mg groups versus placebo (29.4%, 26.9%, and their impression of disease severity, with scores ranging from 0 (clear) to 4 16.2%, respectively). The most common adverse events were nasopharyngitis, (severe disease).28-30 An additional phase III trial compared secukinumab to headache, and upper respiratory tract infection. The clinical presentations ustekinumab in a head-to-head study, with a primary end point of PASI 90 and rates of serious adverse events were similar with secukinumab 300 mg, at week 16.31 150 mg, and placebo (6.3/100, 6.4/100 and 7.4/100, respectively, in patient- years). Methods We reviewed the published phase III clinical trial results involving the clinical FIXTURE efficacy of secukinumab. An English language literature search was carried Study design. A total of 1,305 patients were randomized 1:1:1:1 to either out on PubMed with the following word combinations: “secukinumab” and secukinumab 300 mg, secukinumab 150 mg, etanercept 50 mg, or placebo. “psoriasis” or “IL-17” and “psoriasis.” Citations within these publications This clinical trial evaluated secukinumab against placebo with co-primary were also reviewed for pertinent data. Additionally, information on these endpoints of PASI 75 and IGA 0 or 1 at week 12. Those assigned to topics was collected from oral presentations from the 73rd Annual Meeting secukinumab received dosages at baseline, and then weekly for four weeks, of the American Academy of Dermatology. followed by every four weeks for the remainder of the study; etanercept was

BABIKIAN, BEROUKHIM, NGUYEN, KOO Page 23 Table 1. Primary and secondary end points in ERASURE, FIXTURE, FEATURE, and JUNCTURE* End Point (category) STUDY Secukinumab Secukinumab Placebo Etanercept 300 mg 150 mg 50 mg**

PASI 75 ERASURE 81.6% (200/245) 71.6% (174/243) 4.5% (11/246) -- Week 12 (1°) FIXTURE 77.1% (249/323) 67.0% (219/327) 4.9% (16/324) 44.0% (142/323) FEATURE 75.9% (44/58) 69.5% (41/59) 0% (0/59) -- JUNCTURE 86.7% (52/60) 71.7% (43/60) 3.3% (2/61) --

IGA 0 or 1 Week 12 (1°) ERASURE 65.3% (160/245) 51.2% (125/244) 2.4% (6/246) -- FIXTURE 62.5% (202/323) 51.1% (167/327) 2.8% (9/324) 27.2% (88/323) FEATURE 69.0% (40/58) 52.5% (31/59) 0% (0/59) -- JUNCTURE 73.3% (44/60) 53.3% (32/60) 0% (0/61) --

PASI 90 ERASURE 59.2% (145/245) 39.1% (95/243) 1.2% (3/246) -- Week 12 (2°) FIXTURE 54.2% (175/323) 41.9% (137/327) 1.5% (5/324) 20.7% (67/323) FEATURE 60.3% (35/58) 45.8% (27/59) 0% (0/59) -- JUNCTURE 55% (33/60) 40% (24/60) 0% (0/61) --

PASI 75 ERASURE 80.5% (161/200) 72.4% (126/174) -- -- Weeks 12-52 (2°) FIXTURE 84.3% (210/249) 82.2% (180/219) -- 72.5% (103/142) FEATURE ------JUNCTURE ------

DLQI Absolute Change ERASURE -11.4 -10.1 -1.1 -- (2°) FIXTURE -10.4 -9.7 -1.9 -7.9 FEATURE ------JUNCTURE ------

*These studies were not conducted head-to-head. Studies had P<0.001 for ERASURE and FIXTURE and P<0.0001 for FEATURE and JUNCTURE. **PASI 75 and IGA data for etanercept are considered secondary end points but are included for comparison.

PASI: Psoriasis Area and Severity Index; values indicate percentage improvement of cutaneous symptoms. IGA: Investigator’s global assessment. DLQI: Dermatology Life Quality Index; an absolute decrease notes an improved individual assessment of a disease’s impact on life. administered twice at baseline, twice a week until Infections were noted for secukinumab 300 mg 26.7%, 30.9%, 24.5% and 19.3%, respectively. week 12, and then weekly through week 51. and 150 mg, etanercept and placebo as follows: While more patients with secukinumab (33 out Efficacy. By week 12, the percentages of patients taking secukinumab 300 mg and 150 mg that achieved PASI 75 (77.1% and 67.0%, respectively) and IGA 0 or 1 (62.5% and 51.1%, respectively) were greater than with placebo (4.9% reached PASI 75 and 2.8% reached IGA 0 or 1) (P<0.001). Secukinumab at 300 mg produced superior results compared to 150 mg (P<0.001). Additionally, secukinumab 300 mg showed superiority over etanercept for the percentage of patients achieving PASI 75 (77.1% and 44.0%, respectively) and PASI 90 (54.2% and 20.7%, respectively) (Figure 1). Adverse events. Overall, the incidence of adverse events was similar among secukinumab 300 mg and 150 mg and etanercept during induction (55.5%, 58.4%, and 57.6%, respectively), and was higher than placebo (49.8%). However, statistical analysis for significance was not performed. The most common adverse events with secukinumab Figure 1. Percentages of patients achieving PASI 75, IGA 0 or 1, and PASI 90 at week 12. were nasopharyngitis, headache and diarrhea. P<0.001 for all comparisons. Studies were not conducted in a head-to-head manner.

Page 24 SECUKINUMAB FOR THE TREATMENT OF PLAQUE PSORIASIS: A REVIEW OF PHASE III TESTING Table 2. Primary and secondary end points of secukinumab vs. ustekinumab phase III head-to- phase III clinical trials. Total incidents of head study* adverse events were similar for secukinumab and ustekinumab, 64.2% and 58.3%, respectively, and End Point (category) Secukinumab Ustekinumab infection rates were 29.3% and 25.3%, respectively. PASI 90 at Week 16 (1°) 79.0% (264/334) 57.6% (193/335) Both groups were notable for 3% serious adverse PASI 100 at Week 16 (2°) 44.3% (148/334) 28.4% (95/335) events. Headache, nasopharyngitis, diarrhea, arthralgia, and fatigue were the most common PASI 75 at Week 4 (2°) 50.0% (167/334) 20.6% (69/335) 31 events for both groups. *P<0.0001 for all comparisons. PASI values indicate percent improvement of cutaneous lesions. Discussion The clinical efficacy of IL-17 inhibitors such as secukinumab in phase III clinical trials further supports the importance of IL-17 (particularly IL-17A) in the pathogenesis of plaque psoriasis. A significant portion of patients who received this anti-IL-17 medication achieved PASI 75 and IGA scores of 0 or 1 – far greater than the portion that received placebo. Secukinumab performed considerably better than etanercept and ustekinumab, which were used as active comparators in these studies. Within the confines of these studies, there was no substantial difference noted in the safety profiles of these three medications. Two other biologic agents targeting IL-17 are currently in development. While IL-17A is thought to be the most important of the IL-17 homodimers involved with psoriasis, IL-17F Figure 2. Percentages of patients achieving PASI 90 and 100 at week 16 and PASI 75 at week is also thought to play at least a small part.15,32 4. P<0.0001 for all comparisons. Dosage of ustekinumab depended on a patient’s body weight: Brodalumab, a humanized antibody that blocks Patients <100 kg (220 lbs) received 45 mg, whereas patients >100 kg (220 lbs) received 90 mg. the receptor subunit (IL-17RA) to which both IL-17A and IL-17F bind, is thought to have a of 946) over etanercept (4 out of 333) developed Adverse events. Nasopharyngitis was a common more powerful effect against psoriasis because candida infections, none of those associated with adverse event. There were no new safety concerns of a wider blockage of IL-17 subsets. While secukinumab were classified as “severe,” while two of note that deviated from the former major there has been no head-to-head comparison, cases associated with etanercept were classified studies.28,30 and dosages and schedules of administration as “severe.” Nine patients in both secukinumab were noted to be different, in phase II trials groups were determined to have Grade 3 Head-to-head Against Ustekinumab the percentage achieving PASI 90 was higher neutropenia without associated infection, while Study design. In this head-to-head phase III with brodalumab 210 mg (75%) than with one patient on etanercept was diagnosed with trial, 676 patients were randomized 1:1 to either secukinumab 150 mg (52%), while the PASI Grade 4 neutropenia. Serious adverse events 34 secukinumab 300 mg or to either 45 mg or 90 75 was comparable (P<0.001). Similar to the were numerically lower with secukinumab 300 mg of ustekinumab, depending on their weight. studies on secukinumab, the most common side mg, secukinumab 150 mg and etanercept than In line with FDA dosage guidelines, ustekinumab effects in studies involving brodalumab were with placebo (6.8/100, 6.0/100 7.0/100, and dosing was based on each patient’s weight such infectious in nature – though there was one 8.3/100, respectively, in patient-years), though that patients weighing <100 kg (220 lbs) received case of serious neutropenia with brodalumab, significance was not calculated. There was one 45 mg, and patients weighing ≥100 kg (220 leading to discontinuation of the medication suicide with placebo. 34 lbs) received 90 mg at each appropriate visit. in this patient. One potential concern with Secukinumab was administered once at baseline FEATURE and JUNCTURE brodalumab is that the broader blockage might and then weekly at weeks 1, 2, 3, and 4, and then Study design. In the first study, 177 patients prove to have negative clinical implications. For every four weeks through week 48. Ustekinumab were randomized 1:1:1 to secukinumab 300 mg, instance, in studies, IL-17F deficiency was also administered at baseline, then at weeks secukinumab 150 mg or placebo. Medication (which would occur with brodalumab targeting 4, 16, 28, and 40. The primary end point for this administration was carried out using a pre-filled the IL-17 receptor) led to higher expression study was achievement of PASI 90 at week 16. syringe (FEATURE). In a second study, 182 of T helper type 2 (Th2) cytokine with more Secondary end points included PASI 100 at week 35 patients were randomized 1:1:1 to the same eosinophil function. The clinical relevance of 16 and PASI 75 at week 4. groups, but medication was administered by this information was not established. autoinjector/pen ( JUNCTURE). Primary end Efficacy. Of 334 secukinumab and 335 Another drug in development is ixekizumab, points were again achievement of PASI 75 and ustekinumab patients evaluated, 79.0% and a humanized IgG4 monoclonal antibody that IGA 0 or 1 among the three groups, whereas 57.6%, respectively, reached PASI 90 at week also specifically targets 17A.36 Secukinumab, on secondary end points included medication- 16. Secukinumab was shown to be superior the other hand, is fully human. An increased administration dynamics. to ustekinumab in all secondary end points, humanness score is theoretically associated with including: PASI 100 at week 16 (44.3% and Efficacy. Efficacies of the three treatment groups a decreased extent of immunogenicity, as there 28.4%, respectively), PASI 75 at week 4 (50.0% 37 were similar to former studies, despite small is less deviation from the recipient species. and 20.6%, respectively), and PASI 75 and IGA 0 sample sizes (Table 1). Both the pre-filled syringe Therefore, the fully human secukinumab may or 1 at week 16 (Table 2, Figure 2). and autoinjector/pen delivery methods were pose less of an immunologic risk than the shown to be successfully learned and employed Adverse events. There were no new substantial humanized ixekizumab. However, studies by the first week of use (Table 1). safety findings that deviated from other major suggest that the fully human and high-scoring humanized antibodies share relatively similar BABIKIAN, BEROUKHIM, NGUYEN, KOO Page 25 immunogenicity.37,38 In the FIXTURE study, 7 of 1. Sanford M, McKeage K. Secukinumab: first IL-17F/IL-17A heterodimeric cytokine signals 19 patients who had anti-secukinumab antibodies global approval. Drugs. 2015 Feb;75(3):329-338. through the IL-17RA/IL-17RC receptor complex. J Immunol. 2008;181(4):2799-2805. at baseline continued to test positive for the 2. Lebwohl MG, Bachelez H, Barker J, et al. antibodies. There were no associated decreases in Patient perspectives in the management of 16. Gisondi P, Dalle Vedove C, Girolomoni G. efficacy or adverse events noted in these patients. psoriasis: results from the population-based Efficacy and safety of secukinumab in chronic Additionally, two patients on placebo and four Multinational Assessment of Psoriasis and plaque psoriasis and therapy. patients on etanercept in the FIXTURE study, Psoriatic Arthritis Survey. J Am Acad Dermatol. Dermatol Ther. 2014;4(1):1-9. and two of 702 patients receiving secukinumab 2014 May;70(5):871-881 e871-830. in the ERASURE study, tested positive for anti- 17. Hueber W, Patel DD, Dryja T, et al. Effects of secukinumab antibodies following the initiation 3. Feldman SR, Malakouti M, Koo JY. Social AIN457, a fully human antibody to interleukin- of treatment.29 impact of the burden of psoriasis: effects on 17A, on psoriasis, rheumatoid arthritis, and patients and practice. Dermatol Online J. 2014 uveitis. Sci Transl Med. 2010;2(52):52ra72. Likewise, there is a difference in the isotype used by Aug;20(8). 18. Kao CY, Chen Y, Thai P, et al. IL-17 the two medications. Ixekizumab uses the isotype markedly up-regulates beta-defensin-2 IgG4, which has been shown to act as a bispecific 4. Ariza ME, Williams MV, Wong HK. expression in human airway epithelium via JAK molecule in vivo, with the ability to interact Targeting IL-17 in psoriasis: from cutaneous and NF-kappaB signaling pathways. J Immunol. with two separate antigens. This bispecificity immunobiology to clinical application. Clin 2004;173(5):3482-3491. may potentially lead to unknown drug reactions. Immunol. 2013 Feb;146(2):131-139. However, this isotype is thought to be functionally 5. Chan JR, Blumenschein W, Murphy E, et 19. Laan M, Cui ZH, Hoshino H, et al. monovalent. IgG1, used for secukinumab, is al. IL-23 stimulates epidermal hyperplasia via Neutrophil recruitment by human IL-17 via the most common isotype that is selected for TNF and IL-20R2-dependent mechanisms with C-X-C chemokine release in the airways. J the manufacture of therapeutic antibodies. This implications for psoriasis pathogenesis. J Exp Immunol. 1999;162(4):2347-2352. isotype is of particular interest when an active Med. 2006 Nov;203(12):2577-2587. 20. Liang SC, Tan XY, Luxenberg DP, et al. antibody is necessary for complement activation 6. Di Cesare A, Di Meglio P, Nestle FO. The Interleukin (IL)-22 and IL-17 are coexpressed and antibody-dependent effector-mediated cell IL-23/Th17 axis in the immunopathogenesis of by Th17 cells and cooperatively enhance killing, in the cases of certain cancer treatments. psoriasis. J Investig Dermatol. 2009;129(6):1339- expression of peptides. J Exp Med. In contrast, IgG4 does not activate complement 1350. 2006;203(10):2271-2279. -- though when these criteria are not pertinent, 21. Numasaki M, Fukushi J, Ono M, et al. as with these anti-psoriatic medications, studies 7. Lowes MA, Kikuchi T, Fuentes-Duculan J, Interleukin-17 promotes angiogenesis and tumor have noted either choice (IgG1 and IgG4) may et al. Psoriasis vulgaris lesions contain discrete growth. Blood. 2003;101(7):2620-2627. be considered acceptable theoretically, especially populations of Th1 and Th17 T cells. J Investig since the isotypes may be modified to improve Dermatol. 2008;128(5):1207-1211. 22. Novartis Pharmaceuticals. Secukinumab 39 function. It would be prudent to follow long- 8. Martin DA, Towne JE, Kricorian G, et al. Efficacy and Safety Study in Patients With term outcomes to see if these molecular design The emerging role of IL-17 in the pathogenesis Rheumatoid Arthritis and Inadequate Response details convey any clinical difference. of psoriasis: preclinical and clinical findings. J to Anti-TNFα Agents. (REASSURE2). In: Investig Dermatol. 2013;133(1):17-26. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2012 Conclusions 9. Pappu R, Ramirez-Carrozzi V, Sambandam [cited 2015 April 3]. Available from: https:// The phase III trials of secukinumab have A. The interleukin-17 cytokine family: critical clinicaltrials.gov/ct2/show/NCT01770379 demonstrated positive results in the treatment players in host defence and inflammatory NLM Identifier: NCT01770379. of plaque psoriasis. While the drug has a diseases. Immunol. 2011;134(1):8-16. satisfactory initial safety profile, long-term phase 23. Novartis Pharmaceuticals. Efficacy and Safety 10. Raychaudhuri SP. Role of IL-17 in psoriasis IV surveillance and registries are needed. of AIN457 (Secukinumab) in Patients With and psoriatic arthritis. Clin Rev Allergy Immunol. Relapsing Multiple Sclerosis. In: ClinicalTrials. 2013;44(2):183-193. gov [Internet]. Bethesda (MD): National 11. Tang C, Chen S, Qian H, Huang Library of Medicine (US). 2013 [cited 2015 W. Interleukin-23: as a drug target for April 3]. Available from: https://clinicaltrials. autoimmune inflammatory diseases. Immunol. gov/ct2/show/NCT01874340 NLM Identifier: 2012;135(2):112-124. NCT01874340. 12. Ritchlin C, Rahman P, Kavanaugh A, et al. 24. Dick AD, Tugal-Tutkun I, Foster S, et al. Efficacy and safety of the anti-IL-12/23 p40 Secukinumab in the treatment of noninfectious monoclonal antibody, ustekinumab, in patients uveitis: results of three randomized, controlled with active psoriatic arthritis despite conventional clinical trials. Ophthalmol. 2013;120(4):777-787. non-biological and biological anti-tumour 25. Hueber W, Sands BE, Lewitzky S, et al. necrosis factor therapy: 6-month and 1-year Secukinumab, a human anti-IL-17A monoclonal results of the phase 3, multicentre, double-blind, antibody, for moderate to severe Crohn’s disease: placebo-controlled, randomised PSUMMIT 2 unexpected results of a randomised, double-blind trial. Ann Rheum Dis. 2014;73(6):990-999. placebo-controlled trial. Gut. 2012;61(12):1693- 13. Weaver CT, Hatton RD, Mangan PR, 1700. Harrington LE. IL-17 family cytokines and the 26. Novartis Pharmaceuticals. 16-week Efficacy expanding diversity of effector lineages. and 3-year Safety, Tolerability and Efficacy of Annu Rev Immunol. 2007;25:821-852. Secukinumab in Active Ankylosing Spondylitis 14. Krueger JG, Fretzin S, Suarez-Farinas M, Patients (MEASURE 3). In: ClinicalTrials. et al. IL-17A is essential for cell activation gov [Internet]. Bethesda (MD): National and inflammatory gene circuits in subjects Library of Medicine (US). 2013 [cited 2015 April 3]. Available from: https://clinicaltrials. with psoriasis. J Allergy Clin Immunol. gov/ct2/show/NCT02008916 NLM Identifier: 2012;130(1):145-154 e149. NCT02008916. References 15. Wright JF, Bennett F, Li B, et al. The human Page 26 SECUKINUMAB FOR THE TREATMENT OF PLAQUE PSORIASIS: A REVIEW OF PHASE III TESTING 27. Novartis Pharmaceuticals. Extension Study up to 3 Years for Secukinumab in Psoriatic Arthritis (FUTURE 1 ext). In: ClinicalTrials. gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2013 [cited 2015 April 3]. Available from: https://clinicaltrials. gov/ct2/show/NCT01892436 NLM Identifier: NCT01892436. 28. Blauvelt A, Prinz JC, Gottlieb AB, et al. Secukinumab administration by pre-filled syringe: efficacy, safety and usability results from a randomized controlled trial in psoriasis (FEATURE). Br J Dermatol. 2015;172(2):484- 493. 29. Langley RG, Elewski BE, Lebwohl M, et al. Secukinumab in plaque psoriasis--results of two phase 3 trials. New Engl J Med. 2014;371(4):326- 338. 30. Paul C, Lacour JP, Tedremets L, et al. Efficacy, safety and usability of secukinumab administration by autoinjector/pen in psoriasis: a randomized, controlled trial ( JUNCTURE). J Eur Acad Dermatol Venereol. 2014; 29(6):1082- 90. 31. Thaci D, Blauvelt A, Reich K, et al. Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate to severe plaque psoriasis: 16-week results from the CLEAR study. Oral presentation at: the 73rd Annual Meeting of the American Academy of Dermatology; March 20- 24, 2015; San Francisco, California. 32. Gaffen SL. Structure and signalling in the IL-17 receptor family. Nat Rev Immunol. 2009;9(8):556-567. 33. Lonnberg AS, Zachariae C, Skov L. Targeting of interleukin-17 in the treatment of psoriasis. Clin Cosmet Investig Dermatol. 2014;7:251-259. 34. Brown G, Malakouti M, Wang E, Koo JY, Levin E. Anti-IL-17 phase II data for psoriasis: A review. J Dermatolog Treat. 2015;26(1):32-36. 35. Yang XO, Chang SH, Park H, et al. Regulation of inflammatory responses by IL-17F. J Exp Med. 2008;205(5):1063-1075. 36. Dyring-Andersen B, Skov L, Zachariae C. Ixekizumab for treatment of psoriasis. Expert Rev Clin Immunol. 2015;11(4):435-442. 37. Gao SH, Huang K, Tu H, Adler AS. Monoclonal antibody humanness score and its applications. BMC Biotechnol. 2013;13:55. 38. Harding FA, Stickler MM, Razo J, DuBridge RB. The immunogenicity of humanized and fully human antibodies: residual immunogenicity resides in the CDR regions. MAbs. 2010;2(3):256-265. 39. Salfeld JG. Isotype selection in antibody engineering. Nat Biotechnol. 2007;25(12):1369- 1372.

Correspondence: Aline Babikian, DO; [email protected]

BABIKIAN, BEROUKHIM, NGUYEN, KOO Page 27 Case of Persistent Regrowth of Blond Hair in a Previously Brunette Alopecia Areata Totalis Patient

Karla Snider, DO,* John Young, MD**

*PGYIII, Silver Falls Dermatology/Western University, Salem, OR **Program Director, Dermatology Residency Program, Silver Falls Dermatology, Salem, OR

Abstract We present a case of a brunette, 64-year-old female with no previous history of alopecia areata who presented to our clinic with diffuse over the scalp. She was treated with triamcinolone acetonide intralesional injections and experienced hair re-growth of initially white hair that then partially re-pigmented to blond at the vertex. Two years following initiation of therapy, she continued to have blond hair growth on her scalp with no dark hair re-growth and no recurrence of alopecia areata. Introduction (CBC), comprehensive metabolic panel (CMP), along the periphery of the occipital, parietal and Alopecia areata (AA) is a fairly common thyroid stimulating hormone (TSH) test and temporal scalp), sisaipho pattern (loss of hair in autoimmune disorder of non-. antinuclear antibody (ANA) test. All values were the frontal parietotemporal scalp), patchy hair unremarkable, and the ANA was negative. The loss (reticular variant) and a diffuse thinning The disease commonly presents as hair loss from 2 any hair-bearing area of the body. Following patient declined a biopsy. variant. Often, “exclamation point ” can be hair loss, it is not rare to see initial growth of A clinical diagnosis of alopecia areata was seen in and around the margins of the hair loss. depigmented or hypopigmented hair in areas made. The patient was treated with 5.0 mg/mL The distal ends of these hairs are thicker than the proximal ends, and they are a marker of active of regrowth in the first anagen cycle. However, intralesional triamcinolone injections that were 1 sustained and widespread hypopigmented hair repeated every four to six weeks for 24 months. inflammation. regrowth in a patient with alopecia areata totalis She concurrently used OTC 5% A high percentage of patients experience is a rare phenomenon. solution as well as B12 and biotin supplements. remission of the disease and have hair re-growth. She reported no side effects of treatment. It is common to have initial hypopigmentation Case Report During the course of treatment, she began or de-pigmentation of hair re-growth during the A 64-year-old Caucasian, brunette female to see steady scalp regrowth of white hair first anagen phase. Most patients experience re- presented to our office complaining of two within six months. Following initial growth of pigmentation to original hair color or even slight weeks of diffuse loss of hair from her scalp. completely depigmented hair, she began to see hypopigmentation of original hair color with The patient denied previous history of alopecia growth of blond hair. Two years after treatment subsequent growth. areata, , recently beginning was initiated, complete scalp-hair regrowth new medications, , or a precipitating had occurred, with blond-colored hair on the Epidemiology adverse event. The patient denied any history scalp vertex. Visual inspection demonstrated Alopecia areata is one of the most common of dermatological diseases and had no family no demarcation line of color change, but blond autoimmune diseases, with a lifetime risk of history of AA or autoimmune disease. She hair was observed down to the root of the hair 1.7 percent. AA affects both sexes equally. It admitted to attempting treatment with OTC in a patchy distribution (Figure 2). She denied is commonly encountered by dermatologists, treatment regimens for her hair loss but was application or use of chemical colorants or dyes. representing from 0.7 percent to 3.8 percent of unable to recall specific details. Her past medical dermatological patient visits.3 history was significant for hypertension and As with many autoimmune diseases, there tends hypercholesterolemia, treated with atenolol and Figure 2 to be a higher predilection of occurrence in simvastatin, respectively. patients afflicted with other autoimmune disease. Physical exam revealed diffuse thinning of In particular, thyroid disease, including Grave’s, hair over the entire scalp without scarring. No Hashimoto’s thyroiditis and simple goiter has other body areas were affected. Over the next a high disease association with AA, with a co- six months, her alopecia worsened to involve presence of 8 percent to 28 percent.4 is complete hair loss over her scalp (Figure 1). also seen in a higher percentage of AA patients 5 Initial workup included a complete blood count compared to the general population. It should be noted that there is often no concurrent Figure 1 vitiligo in distinct areas affected by alopecia areata because melanocytes within the epidermis express different antigens than those expressed by melanocytes within the hair follicle.6 In patients with alopecia areata, there is also Discussion a high association with psychiatric morbidity, Alopecia areata is a fairly common autoimmune especially anxiety and . AA patients disease. It can affect any hair-bearing area have a lifetime risk of 74 percent of developing 7 but typically presents on the scalp in well- one or more psychiatric illnesses. circumscribed, circular or ovoid patches.1 It can present with total scalp hair loss (alopecia Etiology totalis), loss of all scalp and (alopecia Hair color is determined by the type and amount universalis), in an pattern (loss of hair of melanin within the keratinocytes of the hair.

Page 28 A CASE OF PERSISTENT REGROWTH OF BLOND HAIR IN A PREVIOUSLY BRUNETTE ALOPECIA AREATA TOTALIS PATIENT The injection of intralesional , Table 1. Alopecia Areata Therapies namely triamcinolone acetonide, is one of the First-line Therapies Second-line Therapies Third-line Therapies most commonly used therapies for alopecia areata, resulting in hair regrowth in 64 percent Intralesional corticosteroids Sulfasalazine Systemic corticosteroids to 97 percent of treated areas.4 To date, this Topical corticosteroids Photochemotherapy Methotrexate is considered a first-line therapy in adult AA patients with less than 50% scalp involvement. Minoxidil Excimer laser Cyclosporine 10,14,15 The most commonly utilized concentration is 5 mg/ml, with no more than 3 mL injected into Anthralin Azathioprine the scalp every four to six weeks to minimize side 13 Topical Biologics effects. Common side effects are atrophy of tissue at injection sites, skin hypopigmentation at Fractional photothermolysis laser Prostaglandin analogs injection sites, and telangiectasias. Relapse rates vary based on the type of AA being treated. In Topical retinoids limited alopecia areata, the reported relapse rate Capsaicin at three months following therapy is 29%, while the reported rate in is 72%.13 Melanocytes situated in close proximity to the diffuse form of AA affecting only pigmented Patients with AA often experience significant hair bulb transfer melanosomes containing hairs is the underlying etiology of our patient’s psychological and psychosocial impacts. melanin to newly formed keratinocytes within presentation. In the “overnight whitening” Treatment should be aimed at alleviating these the hair bulb. The amount, type and density of phenomenon, a patient loses all pigmented effects. As mentioned previously, AA patients pigment found within the keratinocytes in the hairs rapidly, leaving behind only hairs that were tend to have high rates of psychological cortex of the hair determine the color and tone already white or grey. Historical figures such as comorbidities such as anxiety and depression, of the hair.1 Pigmented hair in alopecia areata Mary, Queen of Scotts and Marie Antoinette and practitioners should be sure to screen for and is targeted over depigmented hair, often with are rumored to have experienced “overnight address these issues. characteristic sparing of white and grey hair.1,2 whitening.”11 This phenomenon only describes The underlying etiology and pathophysiology are the underlying etiology of total scalp whitening. Conclusion still unclear, but it is known that alopecia areata Our patient suffered alopecia areata totalis of the Alopecia areata is a common autoimmune occurs due to an autoimmune assault to the hair scalp and then grew back depigmented hair that condition that causes non-scarring hair loss follicle that results in hair loss.8 Hair follicles eventually gained some pigmentation, resulting in any hair-bearing area. Most patients under non-pathological conditions have immune in blond hair. experience hair regrowth, and it is common privilege, meaning there is an environment for hair growth in the first anagen cycle to be Histopathology around the hair follicle that protects it from the hypopigmented or depigmented. Our patient Histologically, the acute phase of AA is . One of the first steps in the demonstrated an unusual case of AA totalis in characterized by an infiltrate of mononuclear development of alopecia areata is loss of hair- which previously dark-pigmented hair regrew T-cells (both CD8+ and CD4+) and eosinophils follicle immune privilege. Some individuals are as blond hair. The exact etiology of this rare around the lower portion of anagen follicles. genetically predisposed to loss of hair-follicle occurrence remains unknown, but we speculate It has been described histopathologically as a immune privilege due to expression of specific 1,3 a loss of hair-follicle autoimmune privilege and “swarm of bees.” HLA class II alleles.3 Genetic studies have autoantibody production against melanocytes 8 Chronically, there is a decrease in the number linked HLA-DQ3 to alopecia areata. Once may be responsible. This may have led to of mononuclear cells with miniaturization of immune privilege is lost, inflammatory cells reduced numbers of melanoblasts, incomplete hair follicles within the superficial dermis. attack pigment-producing anagen hair bulbs, and melanogenesis and partial destruction of the Melanocytes are found within the hair bulb in autoantigens are produced through autoreactive mechanism of melanin production and/or transfer decreased numbers, and they contain a decreased T cells with a TH1 cytokine profile (both CD4+ of melanin to keratinocytes within the hair amount of melanin.12 and CD8+). That pigmented hairs are targeted follicle. in alopecia areata suggests that melanocytes Differential Diagnosis or melanogenesis-associated within The differential diagnosis for alopecia areata melanocytes around the hair follicle are the target 1.References Bolognia J, Jorizzo JL, Rapini RP (eds). 9 includes other non-scarring alopecias such as of these autoantigens. androgenic alopecia, , telogen Dermatology. 2nd ed. Vol. 2. St. Louis: Mosby/ Decreased numbers of melanoblasts and effluvium, , secondary Elsevier; 2008. Chapter 68: Alopecias; p. 992-95. abnormal melanogenesis have been demonstrated (consider RPR) and non-active cicatricial 2. Alkhalifah A, Alsantali A, Wang E, et al. 10 1 in areas of hair regrowth. This promotes alopecia. Alopecia areata update: part I. Clinical picture, hypopigmented regrowth. It is possible that in histopathology and pathogenesis. J Am Acad patients with permanent hypopigmentation, Treatment/Management Dermatol. 2010 Feb;62(2):177-88. such as our patient, a cytotoxic event may have Several therapeutic modalities have been utilized occurred that either partially or fully destroyed in the treatment of alopecia areata. To date, there 3. Ito T. Recent Advances in the Pathogenesis of the melanocytes responsible for hair color. is no cure or prevention method for AA, and Autoimmune Hair Loss Disease Alopecia Areata. Therefore, the continued hypopigmentation of current therapies are aimed at ceasing hair loss Clin Dev Immunol. 2013;2013:348546. Epub hair in the patient in this case may be explained and inducing hair re-growth. Therapy should be 2013 Sep 18. doi: 10.1155/2013/348546. by a persistent decrease of pigment transfer by tailored and adjusted to the patient’s response. 4. Cho H, Jo S, Paik S, Jeon H, Kim K, Eun H, melanocytes produced by damaged melanoblasts It is not uncommon for practitioners to utilize Kwon O. Clinical Characteristics and Prognostic to the hair-fiber keratinocytes. This may account multiple therapies concurrently. Factors in Early-Onset Alopecia Totalis and for the re-pigmentation, though decreased, that First-, second- and third-line therapies are . J Korean Med Sci. 2012 occurred in a patchy distribution on the vertex of listed in Table 1. Our patient responded well to Jul;27(7):799-802. the scalp in this patient. intralesional injections, so we will 5. Kumar S, Mittal J, Mahajan B. Colocalization It is unlikely that an acute episode of the rapid, discuss this treatment modality in detail. of vitiligo and alopecia areata: coincidence or

SNIDER, YOUNG Page 29 consequence? Int J Trichology. 2013 Jan;5(1):50- 2. 6. Tobin DJ, Bystryn JC. Different populations of melanocytes are present in hair follicles and epidermis. Pigment Cell Res. 1996 Dec;9(6):304- 10. 7. Colón EA, Popkin MK, Callies AL, Dessert NJ, Hordinski MK. Lifetime prevalence of psychiatric disorders in patients with alopecia areata. Compr Psychiatry. 1991 May-Jun;32(3):245-51. 8. Gilhar A, Kalish R. Alopecia areata: a tissue specific autoimmune disease of the hair follicle. Autoimmun Rev. 2006 Jan;5(1):64-9. 9. Ramot Y, Sinclair R, Zlotogorski A. Regrowth of black hair in two red-haired alopecia areata patients. Australas J Dermatol. 2012 Nov;53(4):e91-2. 10. Madani S, Shapiro J. Alopecia areata update. J Am Acad Dermatol. 2000 Apr;42(4):549-66. 11. Tan S, Weller R. Sudden whitening of the hair in an 82-year-old woman: the “overnight graying” phenomenon. Clin Exp Dermatol. 2012 Jun:37(4):458-9. 12. Wade MS, Sinclair RD. Persistent depigmented regrowth after alopecia areata. J Am Acad Dermatol. 2002 Apr;46:619-20. 13. Alsantali A. Alopecia areata: a new treatment plan. Clin Cosmet Investig Dermatol. 2011 July;4:107-15.

14. Shapiro J. Alopecia Areata: Update on therapy. Dermatol Clin. 1993;11:35–46. 15. Alkhalifah A, Alsantali A, Wang E, McElwee KJ, Shapiro J. Alopecia Areata update: Part II: Treatment. J Am Acad Dermatol. 2010;62:191– 202.

Correspondence: Karla Snider, DO; 1430 Commercial Drive SE, Salem, OR 97302; Ph: (503) 362-8385; Fax: (503) 362-8435; karla. [email protected]

Page 30 A CASE OF PERSISTENT REGROWTH OF BLOND HAIR IN A PREVIOUSLY BRUNETTE ALOPECIA AREATA TOTALIS PATIENT A case of chronic lichenoid dermatitis manifesting as hypopigmented, flat-topped papules

Ann Mazor Reed, DO,* Jennifer David, DO,** Stanley Skopit, DO, MSE, FAOCD***

* Dermatology resident, 2nd year, NSU-COM/Larkin Community Hospital, Miami, FL ** Dermatology resident, 1st year, NSU-COM/Larkin Community Hospital, Miami, FL *** Program Director, Dermatology Residency, NSU-COM/Larkin Community Hospital, Miami, FL

Abstract We report a case of a 65-year-old African American female with chronic lichenoid dermatitis that manifested as hypopigmented, flat-topped papules. The lesions were initially thought to be flat based on their clinical appearance. Histology of a lesion revealed resolving lichenoid dermatitis with some features suggesting a possible histological differential diagnosis of cutaneous T-cell lymphoma. However, molecular studies showed oligoclonal results, which was insufficient to meet the criteria of a clonal process. We present a possible new subtype of , the hypopigmented variant. After previous therapy with topical corticosteroid cream, our patient improved with clobetasol ointment twice daily, an intramuscular triamcinolone injection and narrowband UVB (NB-UVB) three times a week for six weeks. Introduction for this condition included a “ cream” with features raised the possibility of a histological Lichen planus (LP) is an idiopathic inflammatory no improvement. The patient’s past medical and differential diagnosis of cutaneous T-cell disease of the skin, nails, hair, and mucous surgical history were non-contributory. She had lymphoma. However, molecular studies showed 1 no known drug or environmental and oligoclonal results, which was insufficient to meet membranes. The pathogenesis and etiology of denied taking any medications, including over- the criteria of a clonal process. The patient’s lipid LP is uncertain, although many believe it occurs the-counter medications. panel, complete metabolic panel, and complete secondary to T-cell-mediated autoimmune blood count were all within normal limits. These damage. Classical LP is characterized by small, The findings on physical exam included multiple, findings along with her clinical presentation pruritic, violaceous, flat-topped papules that white, hypopigmented, flat-topped papules on were highly suggestive of a long-standing and favor the flexor surfaces of the extremities.2 the bilateral dorsal hands, , and lateral (Figure 1). resolving lichenoid inflammatory process such as Typically, the lesions are symmetric and resolving lichen planus. bilateral.1 LP is a common inflammatory cause of 3 The patient had no oral or nail lesions nor did she . The hypopigmented variant exhibit any lymphadenopathy. The treatment plan included clobetasol 0.05% of lichen planus has been hypothesized as a new ointment twice daily to affected areas on hands, subtype of lichen planus. A shave biopsy was obtained from a on her forearms and ankles for two weeks per month, an right elbow and sent for histologic examination. intramuscular injection of 40 mg triamcinolone, Analysis of the biopsy revealed a focally lichenoid and narrow-band UVB three times a week for Case Report infiltrate with thinning of the epidermis, some six weeks. On two-month follow-up, the patient A 65-year-old African American female presented irregular, jagged epidermal retia, and prominent admitted to improvement of her . to our outpatient dermatology clinic complaining fibrosis in the papillary dermis (Figure 2). of asymptomatic “white bumps” on her hands and Immunohistochemical studies were performed feet that began three years prior to presentation. to further characterize the process. Lesional cells Discussion She stated that these lesions first developed on the Lichen planus has numerous variants, including showed a CD3+, CD5+ and CD7+ phenotype dorsal surface of her hands and gradually spread actinic LP, acute LP, annular LP, atrophic LP, (Figures 3, 4). The CD4 to CD8 ratio was to her forearms and elbows, eventually affecting bullous LP, LP pemphigoides, hypertrophic LP, approximately 1:1. CD20 staining was very focal her ankles as well. The patient had been under inverse LP, LP pigmentosus, lichen planopilaris, and CD30 staining essentially negative. Melan-A the care of another dermatologist for the past staining highlighted focal loss of melanocytes at linear LP, LP- erythematosus overlap three years. Per patient history, prior treatment the dermoepidermal junction (Figure 5). Some syndrome, nail LP, oral LP, ulcerative LP,

A B C

Figure 1. Numerous scattered, hypopigmented, flat-topped papules involving the dorsal hand (A), extensor surface of forearm and elbows (B), and lateral (C).

REED, DAVID, SKOPIT Page 31 with topical clobetasol ointment twice daily for two weeks per month, one intramuscular corticosteroid injection, and NB-UVB therapy three times a week for six weeks. Conclusion Lichen planus has many variants, but a hypopigmented variant has not been described. The numerous subtypes of LP are differentiated from classic LP by distribution and morphology. The morphology of the lesions in our patient was hypopigmented, whereas the most commonly described lesions of LP are violaceous or hyperpigmented. The clinical differential for the Figure 2. H&E (4x): Histopathology of lesional skin of right elbow demonstrating a focal described lesions included flat warts, but there lichenoid infiltrate with thinning of the epidermis and some irregular, jagged epidermal retia (A). were no koilocytes on histology. In our patient, Higher-power magnification (10x) visualizes the prominent fibrosis in the papillary dermis (B). clinical findings and histopathologic clues pointed to a case of hypopigmented LP. vulvovaginal LP, and lichenoid .3 lesions without additional treatment. Topical However, a hypopigmented variant has not been corticosteroids remain the first-line therapy 3 References described. There is a subset of vitiligo patients that for localized LP. For severe cases, immune- 1. Gorouhi F, Davari P, Fazel N. Cutaneous have some “lichenoid characteristics,” including modulating therapies such as cyclosporine may and Mucosal Lichen Planus: A Comprehensive analogous locations and, in the initial phase, be effective. In our case, the patient improved Review of Clinical Subtypes, Risk Factors, 4 pathological features similar to those of LP. Diagnosis, and Prognosis. ScientificWorldJournal, This subtype of vitiligo is termed “lichen planus c2014; 2014, Article ID 742826, 22 pages. depigmentosus” and is considered by some to be 2. Boyd AS, Neldner KH. Lichen planus. J Am the counterpart of lichen planus pigmentosus.4 Acad Dermatol. 1991;25:593-619. Due to the normal melan-A stain and clinical findings, we do not believe our patient had lichen 3. Bolognia JL, Jorizzo JL, Rapini RP. nd planus depigmentosus. Dermatology. 2 ed. Vol. 1. Spain: Elsevier; c2008. Chapter 12, Lichen planus and lichenoid Although the pathogenesis and etiology of LP dermatoses; p. 159-180. remain unknown, it is thought to be related to an autoimmune process in which CD8+ T 4. Patel AB, Kubba R, Kubba A. lymphocytes attack basal keratinocytes.5 There Clinicopathological correlation of acquired are various triggers thought to be associated with hypopigmentary disorders. Indian J Dermatol Figure 3. Immunohistochemical stain showing the initiation of lichen planus. These include but Venereol Leprol. 2013 May 1;79 (3):376-382. CD3+ phenotype. are not limited to infections, vaccines, drugs, and 5. Wagner, G, Rose, C, Sachse, MM. Clinical contact .3 Exposure to these triggers variants of lichen planus. J Dtsch Dermatol Ges. can initiate an autoimmune cascade and the 2013 April ;11(4):309–319. generation of effector T cells with cytotoxic potential.3 Correspondence: Ann Mazor Reed, DO; 4970 There are many drugs commonly implicated in W Atlantic Blvd., Margate, FL 33063; Ph: 954- lichenoid drug eruptions. The most common 977-0270; F: 954-977-6824; Amazorreed@ ones include ACE-inhibitors, , larkinhospital.com antimalarials, quinidine and gold. In its classical form, LP is characterized by small, polygonal, violaceous, flat-topped papules that favor the flexor surfaces of the extremities.2 Because lichen planus most commonly presents Figure 4. Immunohistochemical stain showing as hyperpigmented or violaceous papules, other CD7+ phenotype. diagnostic possibilities were considered for our patient as well. Part of the differential diagnosis for hypopigmented flat-topped papules includes flat warts. However, because the histopathology did not reveal characteristics consistent with a , hypopigmented lichen planus was favored as our diagnosis.

Treatment Formulating a treatment plan for lichen planus can be difficult, as there are some cases that remit spontaneously and others that are resistant to treatment. Additionally, it is important to rule Figure 5. Melan-A staining highlights focal out a drug-induced form, as withdrawal of the loss of melanocytes at the dermoepidermal offending agent may lead to resolution of the junction.

Page 32 A CASE OF CHRONIC LICHENOID DERMATITIS MANIFESTING AS HYPOPIGMENTED, FLAT-TOPPED PAPULES Diffuse Dermal Angiomatosis of the Breast: A Case Presentation and Discussion

Gina M. Caputo, DO,* Roxanne Rajaii, MS, DO,** Gary Gross, MD,*** Daniel S. Hurd, DO****

* Dermatology Resident, PGY-2, LewisGale Hospital Montgomery/VCOM, Blacksburg, VA ** Osteopathic Intern, Northeast Regional Medical Center, Kirksville, MO *** Clinical Dermatologist, LewisGale Physicians Salem, Salem, VA **** Program Director, Dermatology Residency Program, LewisGale Hospital Montgomery/VCOM, Blacksburg VA

Abstract Figure 3 Diffuse dermal angiomatosis (DDA), a rare dermatological disorder and variant of reactive cutaneous angioendotheliomatosis, is characterized clinically by the presence of erythematous and violaceous lesions that have the potential to ulcerate. Although it classically presents in the extremities, a few cases have been reported of DDA involving the breast (DDAB). DDA has often been linked to vaso-occlusive and cardiac co-morbidities, and treatment has therefore usually targeted these underlying conditions. This case presents a patient with DDAB who was successfully treated with therapy, supporting previous reports of its benefit in the management of this patient population. mammoplasty, and stent placement in extreme Introduction 1,8 In 1994, Krell et al. initially recognized cases of vaso-occlusive disease. In this case diffuse dermal angiomatosis (DDA) as a rare report, we present an adult patient with a classic but distinct variant of reactive cutaneous presentation of DDAB who was successfully angioendotheliomatosis.1,2 Clinically, it presents treated with isotretinoin for a duration of four Figure 4 as erythematous, violaceous, indurated plaques months. that are often ulcerated and tender. It generally involves the lower extremities, although only a Case Report total of 14 cases of DDA have been cited in the A 60-year-old Caucasian female presented current literature to date.1,2 A form of DDA has with a three-month history of exquisitely also been reported that is localized to the breast tender, ulcerating and bleeding , with a (DDAB). Only five documented cases of DDAB tremendous amount of exuded material bilaterally. have been cited.1 Patients with DDAB often This eruption started approximately six weeks present with intractable along with after cardiac . During the procedure, the these cutaneous lesions.1,3,4 patient received heparin, but was not placed on Due to its rarity, the pathogenesis of the disease coumadin. She denied exacerbating or alleviating is not fully understood, but it is thought to be a factors. Past medical history was significant for 1 cardiovascular disease, transient ischemic attack, result of tissue ischemia. Numerous studies have Figure 5 reported an association with severe peripheral hypertension, and hypercholesterolemia. The vascular disease among other co-morbidities.2,5,6 patient was a smoker when she was evaluated for Histologically, diffuse dermal vascular- and this eruption. Her medications upon evaluation endothelial-cell proliferation between collagen included atorvastatin, clopidogrel, lisinopril, bundles is seen, and uniform positivity is achieved metoprolol, and topical . Family history with immunoperoxidase stains CD31 and CD34, was noncontributory. All labs were found to be vascular markers characteristic of DDA.1,4,5 within normal limits. The management of DDA and DDAB Physical exam revealed reticularis on the is centered on improving the underlying breasts, bilaterally. The left breast (Figure 1) ischemia and achieving revascularization. The was much more affected than the right (Figure modalities in current practice include the use 2), with associated healed punctuate ulcerations of oral corticosteroids, isotretinoin, reduction and changes of healed infarcts. The rest of her Figure 1 Figure 2

CAPUTO, RAJAII, GROSS, HURD Page 33 cutaneous exam was negative. patient’s often having a significant clinical history of long-term tobacco use. Hypertension has also References Histologic sections of a punch biopsy from the 1. Tollefson MM, McEvoy MT, Torgerson RR, been reported to be associated with DDA.1,4 left breast revealed a diffuse capillary proliferation Bridges AG. Diffuse dermal angiomatosis of the within the dermis and extending into the As noted previously, the management of DDA and breast: Clinicopathologic study of 5 patients. J subcutis in a patchy distribution (Figures 3 [5x], DDAB is centered on improving the underlying Am Acad Dermatol. 2014;71(6):1212-17. 4 [10x], 5 [20x] p. 33). There was no evidence ischemia and achieving revascularization. Many 2. Yang H, Ahmed I, Mathew V, Schroeter AL. of vasculitits or a thrombotic vasculopathy to modalities have been implemented in the Diffuse dermal angiomatosis of the breast. Arch suggest either coumadin or heparin necrosis. treatment of DDA and DDAB, including the Dermatol. 2006;142(3):343-7. There was also no evidence of endothelial atypia use of oral corticosteroids, isotretinoin, reduction or malignancy. This pattern was consistent with mammoplasty, and stent placement in extreme 3. Krell JM, Sanchez RL, Solomon AR. Diffuse diffuse dermal angiomatosis, a form of reactive cases of vaso-occlusive disease.1,8 Morimoto et al., dermal angiomatosis: a variant of reactive angioendotheliomatosis. Treatment included as well as other authors, have described successful cutaneous angioendotheliomatosis. J Cutan pain control and isotretinoin at a dose of 40 mg revascularization procedures facilitating the Pathol. 1994;21(4):363-370. 9 PO twice daily for a duration of four months, to healing of DDA ulcers. In this case report, we 4. Sanz‐Motilva V, Martorell‐Calatayud A, which the patient responded positively. describe successful treatment with isotretinoin at Rongioletti F, Escutia‐Muñoz B, López‐Gómez a dose of 40 mg PO twice daily for a duration of S, Rodríguez‐Peralto JL, Vanaclocha F. Diffuse Discussion four months. Isotretinoin is a retinoid compound dermal angiomatosis of the breast: clinical First described in 1994 by Krell et al., diffuse dermal most often used to treat severe acne. Its and histopathological features. Int J Dermatol. angiomatosis (DDA) is a rare skin condition antiangiogenic properties, however, have proved 2014;53(4):445-449. to be beneficial in the treatment of DDAB as primarily affecting females and characterized by 10 5. McLaughlin ER, Morris R, Weiss SW, Arbiser erythematous, violaceous, indurated plaques that well. A similar response to isotretinoin therapy was reported by Mclaughlin et al. This study JL. Diffuse dermal angiomatosis of the breast: are often ulcerated and tender and are commonly response to isotretinoin. J Am Acad Dermatol. 1-3 found that treatment with a dose of 1 mg/kg of localized to the lower extremities. Although 2001;45(3):462-5. the pathogenesis is unknown, it is often noted in isotretinoin over two months resulted in complete resolution of the ulceration in this patient with 6. Bauer J, Maroon M, Rodenhaver T. Diffuse patients with severe peripheral vascular disease 5 among other co-morbidities.2,5 A few authors DDAB. Although the exact mechanism of dermal angiomatosis: Characterization of a rare have reported a correlation between DDA and action of isotretinoin in the treatment of DDAB and evolving proliferative vascular endothelial trauma, namely from surgery.1 While DDA is is unknown, it has been postulated that it may process. J Am Acad Dermatol. 2007;56(2):AB81. involve the inhibition of angiogenesis and/or rare, with 14 total cases reported, involvement 7. Sommer S, Merchant WJ, Wilson CL. Diffuse 1,2 protease production, stimulation of fibrinolysis, of the breast is even less frequently diagnosed. dermal angiomatosis due to an iatrogenic and possibly enhancement of To date, only five cases of DDA of the breast 5,10 arteriovenous fistula. Acta Derm Venereol. 1 migration. (DDAB) have been described. Although often 2004;84(3):251-2. affecting large pendulous breasts bilaterally, Although the use of isotretinoin in the treatment 8. Villa MT, White LE, Petronic-Rosic V, Song these patients presented in an otherwise atypical of DDAB has proved promising, the drug is not DH. The treatment of diffuse dermal angiomatosis fashion without relevant medical history or vaso- without risk. It must be highly regulated due of the breast with reduction mammaplasty. Arch occlusive disorder.2 Histologically, however, to its effect as a teratogen. Other possible side Dermatol. 2008;144(5):693-694. they demonstrated diffuse dermal vascular effects include dry skin, chapped lips, epistaxis, and endothelial cell proliferation between , severe depression, and suicidal ideation. 9. Morimoto K, Iioka H, Asada H, Kichikawa collagen bundles and uniform positivity with Therefore, although found to be effective in K, Taniguchi S, Kuwahara M. Diffuse immunoperoxidase stains CD31 and CD34, this patient population, all the risks and benefits dermal angiomatosis. Eur J Vasc Endovasc vascular markers characteristic of DDA.1,4,5 of isotretinoin therapy must be thoroughly Surg. 2011;42(3):381-383. 10 HHV-8 is also often used to aid in diagnoses and considered on a case-by-case basis. 1 10. Adams BJ, Goldberg S, Massey HD, Takabe is uniformly negative in DDA. K. A cause of unbearably painful breast, diffuse The exact process underlying the development Conclusion dermal angiomatosis. Gland Surg [Internet]. of DDA has yet to be determined, but tissue DDA is a rare variant of reactive cutaneous 2012 [cited 2015 June];1(2):[1 screen]. ischemia is often cited.1 According to Bauer et al., angioendotheliomatosis, classically described on Correspondence: Gina Caputo, DO; ginacap@ the current hypotheses regarding the pathogenesis the lower extremities but occasionally involving pcom.edu of the disease are as follows: “1) atherosclerotic the breast (DDAB) and presenting as unbearable plaques may embolize to distal small vessels and breast pain. Although few cases of DDAB have create endothelial hyperplasia; (2) vascular steal been reported, its recognition and discussion syndromes can give rise to ischemic necrosis with is paramount in identifying the appropriate subsequent ulceration; or (3) ischemia leads to treatment for this patient population. Evaluation increased vascular endothelial growth factor and of these patients should be focused on symptoms subsequent endothelial proliferation.”6 Given and relevant medical history, with particular this understanding, it is believed that reversing emphasis on vaso-occlusive and hypercoagulable ischemia and achieving revascularization can co-morbidities. Management should be patient- be beneficial in improving the clinical signs of dependent, and we believe that isotretinoin disease.6 Several associations have been made therapy should be considered in patients with a between DDA and other co-morbid conditions. classical clinical and histological presentation of Many authors have reported associations between DDAB. In addition, due to the strong correlation DDA and peripheral vascular atherosclerosis, of DDA and tobacco use, smoking cessation arteriovenous fistulas, anticardiolipin antibodies, should always be encouraged in conjunction hypercoagulable states, and breast ulceration.2,6,7 with medical treatment and strict control of The most common and widely accepted cardiovascular risk factors. association, however, has been with vascular occlusive disease.6 Smoking and DDA have also been found to be strongly associated, with Page 34 DIFFUSE DERMAL ANGIOMATOSIS OF THE BREAST: A CASE PRESENTATION AND DISCUSSION Laser Improvement of Permanent-makeup Eyebrows: A Case Report

Jonathan Crane, DO, FAOCD,* David George Jackson, PhD**

*Private Practice, DermOne, Wilmington, NC; Program Director, Dermatology Residency Program, Sampson Regional Medical Center, Clinton, NC; Co-course Director, Dermatology, Campbell University School of Osteopathic Medicine, Lillington, NC **University of Miami Miller School of Medicine, Coral Gables, FL

Abstract With the growing use of permanent cosmetics, dermatologists are increasingly seeing patients who want to fix or remove their treatments. Many permanent-cosmetics tattoos can be treated with laser. When selecting a laser, wavelength and pulse duration are important considerations. It is also important to inform the patient that permanent-cosmetics tattoo removal typically requires multiple treatments, that the tattoo may not completely resolve and that treatment may cause color alterations. This case demonstrates laser treatment of a black permanent-cosmetics eyebrow tattoo that ultimately resulted in a brownish color.

Figure 1 it ideal for darker and for patients with darker skin.2

Conclusion When selecting a laser to use for permanent- makeup removal, it is important to consider the ink color and select the laser wavelength that will be most effective with that pigment. The Figure 2 patient needs to be well informed that the color could change. Since we are seeing an increase in permanent makeup and tattooing as a beauty trend, we as dermatologists should be prepared for patients seeking alterations or removal.

References of the needle varies between 500 rpm and 3500 1. De Cuyper C. Permanent makeup: indications Case Report and complications. Clin Dermatol. 2008 Jan- A 31-year-old Caucasian female presented to the rpm. The needles of choice are entomological needles, which are 36 nm long and 0.36 mm or Feb;26(1):30-4. office stating she was unhappy with the appearance 4 of her permanent-makeup eyebrows. She felt 0.41 mm in diameter. Some permanent-makeup 2. Kilmer SL. Laser eradication of pigmented they were too black. Prior to presenting to our artists use an alternate procedure that entails lesions and tattoos. Dermatol Clin. 2002 office she had returned to the permanent-makeup using a tattoo pen to insert pigment drops into Jan;20(1):37-53. the superficial dermis.1 artist to have brown added to lighten them, but 3. Lee CN, Bae EY, Park JG, Lim SH. Permanent she felt they were still too dark and wanted them The inks and pigments are considered “cosmetics makeup removal using Q-switched Nd: YAG lightened further. We decided to treat her with a and color additives” and are not regulated by the laser. Clin Exp Dermatol. 2009 Dec;34(8): 1 1064-nm Q-switched Nd:YAG laser, a laser often FDA. Some are “not approved for skin contact.” e594-e596. used for tattoo removal. We treated the eyebrows The ink colors in permanent eyebrows are usually for a total of three treatments, with treatments of a darker hue.4 One issue is fading of the 4. Vassileva S, Hristakieva E. Medical spaced at three-month intervals. Settings were: dark brown tint to a color more similar to red. applications of tattooing. Clin Dermatol. 2007 2 1064-nm wavelength, 2-mm spot, 8 J/cm , 5 Hz, A chemical change in these inks may alter the Jul-Aug;25(4):367-374. and 5-ns pulse. By the end of the third treatment, compound from ferrous oxide (FeO) to ferric the patient felt she was 60% to 70% improved oxide (Fe O ), which results in a color change to 2 3 Correspondence: Jonathan Crane, DO, and was very happy with the results. brownish-red.4 FAOCD; [email protected] Various lasers may be employed to remove Discussion permanent makeup, including lasers with Many permanent-eyebrow procedures are wavelengths between 500 nm and 570 nm, which attempting to fill gaps or address thinning of are easily absorbed by red and pink colors.3 the eyebrows. They can be done by tattoo artists This 500-nm range works well for reds and or permanent-makeup artists and are primarily pinks but may actually darken some pigments, administered by two related techniques. One including those often used in permanent- method currently used by permanent-makeup eyebrow procedures. The longer-wavelength artists is a derivative of traditional Japanese (1064-nm) Q-Switched Nd:YAG laser has tattooing. The procedure, called “dermatography,” been demonstrated as more effective than the was developed by Dutch dermatologist Eddy van frequency-doubled Q-Switched Nd:YAG laser der Velden and involves applying varying colors in lightening permanent eyebrows.3 The 1064- in a small number of administration periods. The nm wavelength is both useful for removing apparatus used is the Van der Velden Derma- darker hues and less absorbed by melanin when injector, which has a needle holder that moves compared to its 532-nm counterpart, making up and down within a stainless-steel tube.4 Speed CRANE, JACKSON Page 35 Graham-Little-Piccardi-Lassueur Syndrome: A Case Report

Christopher Hixon, DO,* Collin M. Blattner, BS,** Daniel Hurd, DO***

*Dermatology Resident, 2nd year, Lewis Gale Hospital Montgomery/VCOM, Blacksburg, VA **Medical Student, 4th year, Des Moines University, Des Moines, IA ***Program Director, Dermatology Residency Program, Lewis Gale Hospital Montgomery/VCOM, Blacksburg, VA

Abstract Graham-Little-Piccardi-Lassueur syndrome is a variant of lichen planopilaris characterized by the triad of patchy cicatricial alopecia of the scalp, noncicatricial alopecia of the axilla and groin, and follicular spinous papules on the body, scalp, or both. The disease is most commonly seen in women 30 to 70 years of age. We present a case of this rare syndrome in a 68-year-old female with and provide a discussion about the disease and treatment options. infiltrate, and the absence of interface dermatitis Introduction Figure 1 Graham-Little-Piccardi-Lassueur syndrome in the overlying epidermis (Figures 4, 5). (GLPLS) is a rare subtype of lichen planopilaris Histologic findings were consistent with a (LPP) that presents with the triad of multifocal diagnosis of lichen planopilaris (LPP). The cicatricial alopecia of the scalp, noncicatricial clinical picture of LPP, noncicatricial alopecia alopecia of the axilla and groin, and a follicular and keratotic papules is consistent with the rare lichen planus (LP) eruption on the body, scalp, variant of LPP known as GLPLS. 1 or both. It is four times more likely to affect Treatment was initiated with topical high-potency women and is characteristically seen in those who steroids with consideration for systemic steroids 1 are middle-aged to post-menopausal. Although or antimalarials pending punch-biopsy results the exact etiology of GLPLS is unknown, it is and clinical course. At two-week follow-up, our thought to be an immune-mediated disorder patient demonstrated noticeable improvement that causes an inflammatory reaction against the in scalp erythema, scaling and pruritus. At one- 2 fish oil, and calcium with vitamin D. The only bulge region of hair follicles. The disease is non- month follow-up, scalp erythema was no longer medication change in the past 18 months familial, although one case with a familial origin present, scaling had improved, and hair loss had 3 was from lisinopril to losartan. Family history has been reported. ceased. Systemic medications were not initiated revealed hypothyroidism in the patient’s father given the significant clinical improvement, and and son. Social history revealed a 25 pack-year she will continue to be monitored regularly. Case Report smoking history but no tobacco use in the last 30 A 68-year-old female presented with a one-year years. She denied any alcohol or illegal drug use. history of a mildly pruritic, erythematous, scaly Dermatological exam revealed cicatricial Discussion frontal scalp and alopecia involving her head, The name GLPLS comes from the names of the alopecia of the frontal scalp and temples with eyebrows, , axillae, legs and arms. Her physicians who first described this condition. associated perifollicular scalp erythema and eyebrows and eyelashes experienced the most The disease was originally defined in 1913 by hyperkeratotic follicular scaling; also noted were rapid progression of hair loss, with complete Piccardi, who described a case of progressive a few residual tufts of black, normal-looking madarosis over six to eight months. However, her cicatricial scalp alopecia, noncicatricial alopecia in (Figure 1). Noncicatricial alopecia main areas of concern at the time of her initial the axillae and pubic area, and follicular spinous of the eyebrows, eyelashes, axillae, forearms, visit were the frontal scalp and temporal regions. papules on the trunk and extremities, to which and legs was present in addition to multiple The patient reported that her hair was previously he gave the name cheratosi spinulosa, or keratotic follicular, keratotic, and spinous papules over the 4 grey, but as her hairline receded, black pigmented spinulosa. In 1915, Graham-Little published remainder of the scalp (Figures 2, 3). Differential hairs developed despite never coloring her hair. a case of a similar condition in a 55-year-old diagnosis included GLPLS, classical LPP, frontal Previous treatment included triamcinolone woman who was referred by Lassueur, describing fibrosing alopecia (FFA), , 5 ointment prescribed by her primary care it as “ et atrophicans.” , discoid , physician for presumed scalp psoriasis, which In addition to the classical triad of cicatricial , , reduced scaling but failed to arrest the hair loss. alopecia of the scalp, noncicatricial alopecia of and sarcoidosis. Two 4 mm punch biopsies taken The patient then visited her beautician, who the axillae and groin, and a follicular keratosis from the frontal scalp revealed scarring alopecia recommended over-the-counter selenium-sulfide eruption, GLPLS can affect the eyebrows and with dermal fibrosis, a perifollicular lymphocytic 6,7 shampoo for seborrheic dermatitis and lateral face. shampoo and conditioner. These products caused mild reduction in scale, but she again noted an Figure 2 Figure 3 increasingly receding hairline. The patient had an otherwise unremarkable 12-point and had no known drug allergies except for gabapentin sensitivity, which caused nausea. Past medical history included hypothyroidism, aortic regurgitation, mitral regurgitation, hypertension, , depression, seasonal allergies, and toxoplasmosis that had been treated 58 years prior. The patient’s medications included levothyroxine, losartan, bupropion, sertraline, acetaminophen/butalbital/caffeine, sumatriptan,

Page 36 GRAHAM-LITTLE-PICCARDI-LASSUEUR SYNDROME: A CASE REPORT Figure 4 Figure 5 References 1. Pai VV, Kikkeri NN, Sori T, Dinesh U. Graham-Little Piccardi Lassueur syndrome: an unusual variant of follicular lichen planus. Int J Trichology. 2011 Jan;3(1):28-30. 2. Tchernev G, Nenoff P. Antigen mimicry followed by epitope spreading: a pathogenetic trigger for the clinical morphology of lichen planus and its transition to Graham Lassueur Piccardi Little Syndrome and keratosis lichenoides chronica - Medical hypotheses or reality? An GLPLS is a rare type of LPP that typically Bras Dermatol. 2009 Nov-Dec;84(6):682-8. presents in women who are 30 to 70 years old, Conclusion GLPLS is an uncommon entity that has been 3. Viglizzo G, Verrini A, Rongioletti F. Familial although the condition has been reported in reported fewer than 50 times in the literature. 1 Lassueur-Graham-Little-Piccardi syndrome. males and younger individuals. LPP can be It has a classical clinical presentation and is not Dermatology. 2004;208(2):142-4. subdivided into three clinical variants: classical associated with systemic disease. Although its 8 4. Piccardi G. Keratosis spinulosa of the scalp in LPP, FFA, and GLPLS. GLPLS may have a pathogenesis is unknown, the T-cell-mediated its relations with the pseudo-pelade of Brocq. Ital positive pull test for anagen hairs due to the immune response in GLPLS is similar to that J Skin Vener Dis. 1914;49:416. same altered integrin expression seen in active in LP. There is no universally effective treatment, 8 LP P. Histopathological findings of GLPLS are so therapy should be directed at halting disease 5. Graham-Little EG. Folliculitis decalvans et similar to those seen in LPP, but the absence of progression. atrophicans. Br J Dermatol. 1915;27:183–5. interface dermatitis of the overlying epidermis 6. Camacho F. Alopecias cicatriciales. In: can help differentiate the two. Early lesions Camacho F, Montagna W, eds. Tricología. of LPP reveal a perifollicular lymphocytic Madrid: Grupo Aula Médica; 1996. p. 537–551. infiltrate at the level of the infundibulum and the isthmus, along with vacuolar changes of the 7. Morillo M, Rodríguez Pichardo A, Herrera .10 More advanced cases show A, Camacho F. Síndrome de Piccardi-Lassueur- perifollicular fibrosis and epithelial atrophy at Graham Little. Estudio de seis casos. Actas the level of the infundibulum that give rise to Dermosifiliogr. 1998;89:392–395. 10 a characteristic hourglass configuration. As 8. Assouly P, Reygagne P. Lichen planopilaris: the disease progresses, vertically oriented elastic update on diagnosis and treatment. Semin Cutan 10 fibers replace the destroyed hair follicles. Med Surg. 2009 Mar;28(1):3-10. The exact etiology of GLPLS is unknown, 9. Bardazzi F, Landi C, Orlandi C, Neri I, Varotti but it is likely similar to the T-cell-mediated C. Graham Little-Piccardi-Lasseur syndrome immunological mechanism that triggers the following HBV vaccination. Acta Derm Venereol. 2 clinical expression of LP. GLPLS has not been 1999 Jan;79(1):93. associated with underlying systemic disease, 10. Vega Gutiérrez J, Miranda-Romero A, Pérez but it may cause stress and anxiety due to its Milán F, Martínez García G. Graham Little- presentation. Isolated cases describing a familial Piccardi-Lassueur syndrome associated with pattern (HLA DR1), association with hepatitis androgen insensitivity syndrome (testicular B vaccination, and a female (genetically XY) feminization). J Eur Acad Dermatol Venereol. patient with complete androgen insensitivity 2004 Jul;18(4):463-6. syndrome have been reported.3,9,10 11. George SJ, Hsu S. Lichen planopilaris treated Unless GLPLS is recognized early, treatment with thalidomide. J Am Acad Dermatol. 2001 is usually only mildly effective. Once scarring Dec;45(6):965-6. occurs, hair regrowth will not occur. Treatment is directed at halting the progression of disease, 12. Kubba R, Rook A. Graham Little syndrome: preventing further alopecia, and providing follicular keratosis with cicatricial alopecia. Br J symptomatic relief. Various therapies including Dermatol. 1975;93(suppl 11):53-55. intralesional and systemic corticosteroids, retinoids, PUVA therapy, topical , and Correspondence: Christopher Hixon, DO; antimalarials have all produced varying results.8 [email protected] Isolated reports have demonstrated anecdotal success with cyclosporine and thalidomide11,12 The disease is often progressive, with little potential for hair regrowth once complete destruction of the follicle occurs. Early, accurate diagnosis is imperative to prevent progression.

HIXON, BLATTNER, HURD Page 37 Topical Ivermectin for the Treatment of Papulopustular Rosacea: A Review

Sean McGregor, PharmD,* John Minni, DO, FAOCD**

*Medical Student, 4th year, Philadelphia College of Osteopathic Medicine - GA Campus, Suwanee, GA **Dermatologist, Waters Edge Dermatology, Port Saint Lucie, FL

Abstract Rosacea is a common inflammatory skin disorder that affects many Americans. Currently, oral and topical are among the most effective medications used. Ivermectin 1% cream was recently approved for the treatment of papulopustular rosacea. The primary objective of this article is to provide a clinical review of the efficacy and safety of ivermectin 1% cream. innate immune response to environmental and/ rosacea as defined by an IGA score of 3 (82% and Introduction 15 Rosacea is estimated to affect nearly 16 million or infectious stimuli. 72.9%). 1 Americans. Patients with lighter skin types are Oral and topical antimicrobials have been used Following 12 weeks of therapy, the percentage most often affected by rosacea. However, those successfully for the treatment of rosacea, and of patients able to achieve an IGA grade of clear of darker skin types are not entirely exempt from ivermectin 1% cream was recently approved for or almost clear in the ivermectin groups were 2 this diverse disorder. Rosacea is defined as an the treatment of papulopustular rosacea. The 38.4% and 40.1%, compared to 11.6% and 18.8% inflammatory skin disorder characterized by the primary objectives of this article are to review in the vehicle groups (p<0.001).15 Additionally, presence of inflammatory papules and pustules, the current literature surrounding the use of a significant difference in IGA scores was erythema, and telangiectases distributed in the topical ivermectin in the treatment of rosacea appreciated as early as four weeks in each study.15 3,4 central facial region. Phymatous and ocular and to provide further insight with regard to The mean reduction in inflammatory-lesion manifestations are also characteristic findings administration and adverse effects. counts were 75% and 76% with a mean difference 3,4 seen in rosacea. of -8.16 [-10.12, -6.13] and -8.22 [-10.18, The National Rosacea Society Expert Committee -6.25] in comparison to vehicle for each of the Mechanism of Action 15 classifies rosacea into four distinct subtypes.2,5 Ivermectin is an avermectin antiparasitic ivermectin groups (p<0.001). In comparison, However, patients do not always conform to one agent that is used orally for the treatment of a 50% reduction in inflammatory-lesion counts was observed in the vehicle groups from both specific subtype, and there may be significant strongyloidiasis, demodicidosis, pediculosis, 15 overlap between groups. Erythematotelangiectatic and , in addition to other parasitic/ trials (p<0.001). Additionally, quality-of-life rosacea (ETR) is characterized by flushing and helminthic infections. It exerts its effect by assessments, as measured by Dermatology Life erythema of the central facial region with or binding to parasite glutamate-gated ion channels, Quality Index (DLQI) and RosaQoL, were 5 significantly improved in the ivermectin group in without telangiectases. Papulopustular rosacea resulting in increased permeability to chloride 15 (PPR) is characterized by persistent central ions.12,13 Hyperpolarization of the cell ensues, comparison to vehicle. facial erythema with transient inflammatory ultimately resulting in the death of the parasite. Both trials were then extended for an additional 5 papules and pustules. Phymatous rosacea (PhR) Additionally, ivermectin has been shown to 40 weeks in order to assess long-term safety. is characterized by thickened, nodular skin and display anti-inflammatory properties through Patients initially allocated to receive ivermectin 5 . Finally, ocular rosacea (OR) is inhibition of lipopolysaccharide-induced 1% cream were continued on a once-daily topical- characterized by the presence of ocular dryness, inflammation. Specifically, a reduction in TNF- application regimen. Patients in the vehicle group conjunctivitis, and in addition to alpha and interleukin-1b (IL-1b) have been were then assigned to receive azelaic acid 15% gel 5 burning and stinging sensations in the eye. documented along with a corresponding increase applied topically twice daily. A total of 622 and Rosacea is hypothesized to be the result of vascular in interleukin-10 (IL-10), an anti-inflammatory 636 patients continued the trial into its extension cytokine.14 phase, and approximately 80% of the patients dysregulation and abnormal inflammatory 16 responses ultimately resulting in chronic completed the study. Dermatologic adverse vasodilation and inflammation.6 Additionally, Clinical Trials effects were noted in 7.8% and 9.8% of the a variety of triggers including stress, heat, hot The Ivermectin Phase III Study Group reported patients in the ivermectin groups in comparison liquids, spicy foods, and alcohol exacerbate the the results of two, 12-week, randomized, double- to 12.9% and 16.3% in the vehicle/azelaic-acid groups.16 Notably, no serious or severe adverse underlying vasodilation and inflammation and blind, parallel-group, vehicle-controlled studies 16 are associated with flares of rosacea.4 Innate in 2014. The primary objective of each study was events were related to either study medication. immune mechanisms like , to determine efficacy based on the improvement While it was not the primary objective of the serine proteases, and toll-like receptors (TLRs) in Investigator’s Global Assessment (IGA) of extension phases of the trials, efficacy at 52 have been implicated in the inflammatory and severity scores and the reduction in inflammatory weeks was addressed. A total of 71.1% and 76% 7 15 of patients in the ivermectin groups were able to vasodilatory processes responsible for rosacea. lesion count. Approximately 700 patients were 16 Specifically, elevated levels of (i.e. enrolled in each study, and patients were allocated achieve IGA grades of clear or almost clear. LL-37) and kallikrein 5 (KLK5) have been to receive either ivermectin 1% cream or vehicle Another 16 week, randomized, investigator- 8-10 found in the skin of patients with rosacea. in a 2:1 ratio.15 Patients were then instructed blinded, parallel-group study was conducted Additionally, patients with rosacea have been to apply either ivermectin 1% cream or vehicle on behalf of the Ivermectin Phase III study found to have an increased density of once daily. The patient population was primarily group in Europe. The study compared once- , specifically D. folliculorum and D. brevis, Caucasian (96.2% and 95.3%) and female (68.2% daily application of ivermectin 1% cream with associated with their pilosebaceous units, and and 68.7%) with an mean age of approximately twice-daily application of metronidazole 0.75% antigenic proteins from Bacillus oleronius isolated 50 years old (50.4 +/- 12.09 and 50.2 +/- 12.29).15 cream. The primary objective of this study was from Demodex mites may play a role in the Mean inflammatory lesion counts upon initiation to determine whether ivermectin 1% cream was 11 underlying pathophysiology of rosacea. As of the trial were 31 and 33 (SD +/- 14.33, 13.7), superior to metronidazole 0.75% cream with such, rosacea may be the result of an abnormal and the majority of patients had moderate regard to reductions in inflammatory-lesion

Page 38 TOPICAL IVERMECTIN FOR THE TREATMENT OF PAPULOPUSTULAR ROSACEA: A REVIEW counts in patients with papulopustular rosacea.17 of the trial. [Prescribing Information]. Fort Worth, TX: Laboratories, L.P. 2014. A total of 962 patients with moderate to severe As with all new medications that come to papulopustular rosacea and inflammatory-lesion market, cost will likely be the largest barrier to 14. Ci X, Li H, Yu Q, et al. Avermectin Exerts counts between 15 and 70 were randomized in a its use. However, ivermectin 1% cream should be Anti-inflammatory Effect by Down regulating 1:1 ratio to receive either ivermectin 1% cream or 17 considered in patients who fail or are unable to the Nuclear Factor Kappa-B and Mitogen- metronidazole 0.75% cream. The mean number tolerate more affordable modalities. activated Protein Kinase Activation Pathway. of inflammatory lesions at baseline was 32.46 +/- Fundam Clin Pharmacol. 2009;23(4):449-455. 13.36, and 83.3% of patients had moderate rosacea based on IGA scores.17 The percent reduction in References 15. Stein Gold L, Kircik L, Fowler J, et al. Efficacy inflammatory-lesion counts in the ivermectin 1. National Rosacea Society. Rosacea Riddle Now and Safety of Ivermectin 1% Cream in the group was 83% in comparison to 73.7% in the Threatens More Than 16 Million Americans Treatment of Papulopustular Rosacea: Results metronidazole group, with an absolute difference [Internet]. Chicago: National Rosacea Society; of Two Randomized, Double-Blind, Vehicle- of 9.3% (p<0.001).17 Additionally, 84.9% of 2010 Apr 1 [cited 2015 Mar 22]; [about 2 Controlled Pivotal Trials. J Drugs Dermatol. patients in the ivermectin group were able to screens]. Available from: http://www.rosacea.org/ 2014;13(3):316-323. press/archive/20100401.php. achieve IGA grade clear or almost clear in 16. Stein Gold L, Kircik L, Fowler J, et al. Long- comparison to 75.4% in the metronidazole group 2. Powell F, Raghallaigh S, eds. Rosacea and 17 Term Safety of Ivermectin 1% Cream vs Azelaic (p<0.001). Similar findings were observed Related Disorders. In: Bolognia J, Jorizzo J, Acid 15% Gel in Treating Inflammatory Lesions in each group with regard to patient-reported Schaffer J, eds. Dermatology, vol. 1. Philadelphia: 17 of Rosacea: Results of Two 40-Week Controlled, outcomes. WB Sauders; c2012. 561 p. Investigator-Blinded Trials. J Drugs Dermatol. 3. Tan J, Berg M. Rosacea: Current State 2014;13(11):1380-1386. Adverse Effects of Epidemiology. J Am Acad Dermatol. 17. Taieb A, Ortonne J, Ruzicka T, et al. Superiority The most commonly reported adverse effects 2013;69:S27-35. of Ivermectin 1% Cream over Metronidazole associated with ivermectin 1% cream were 4. Del Rosso JQ. Management of Cutaneous 0.75% Cream in Treating Inflammatory Lesions burning sensations, dry skin, skin irritation, of Rosacea: A Randomized, Investigator-Blinded pruritus, skin pain, and eye pain.15-17 Rosacea: Emphasis on New Medical Therapies. Expert Opin Pharmacother. 2014;15(14):2029- Trial. Br J Dermatol. 2014. [Epub Ahead of 2038. Print]. Administration 18. Van Zuuren E, Kramer S, Carter B, et al. Ivermectin 1% cream should be applied topically 5. Wilkin J, Dahl M, Detmar M, et al. Standard Classification of Rosacea: Report of the National Effective and Evidence-Based Management once daily to the affected areas of the face, Strategies for Rosacea: Summary of a Cochrane typically the forehead, nose, chin, and cheeks.13 A Rosacea Society Expert Committee on the Classification and Staging of Rosacea. J Am Acad Systematic Review. Br J Dermatol. 2011;165:760- pea-sized amount should be used and spread as a 781. thin layer, avoiding the eyes and mouth.13 Dermatol. 2002;46(4):584-587. 6. Feldman S, Huang W, Huynh T. Current 19. Del Rosso JQ, Thiboutot D, Gallo R, et Drug Therapies for Rosacea: A Chronic Vascular al. Consensus Recommendations from the Discussion American Acne and Rosacea Society on the Ivermectin 1% cream is a novel antimicrobial and Inflammatory Skin Disease. J Manag Care Pharm. 2014;20(6):623-629. Management of Rosacea, Part 2: A Status Report agent for the topical treatment of papulopustular on Topical Agents. Cutis. 2013;92:277-284. rosacea. Its efficacy and safety are well documented 7. Cribier B. Pathophysiology of Rosacea: in the aforementioned clinical trials. Additionally, Redness, Telangiectasia, and Rosacea. Ann it has favorable patient-reported outcomes and a Dermatol Venereol. 2011;138(S3):S184-91. Correspondence: Sean McGregor, PharmD; minimal side-effect profile. 8. Yamasaki K, DiNardo A, Bardan A, et [email protected] Metronidazole, azelaic acid, and doxycycline are al. Increased Serine Protease Activity and the most effective medications available for the Cathelicidin Promotes Skin Inflammation in 18 treatment of papulopustular rosacea. Their anti- Rosacea. Nat Med. 2007;13(8):975-980. inflammatory effects are the proposed mechanism 10,19 9. Del Rosso JQ, Gallo R, Kircik L, et al. Why of action in papulopustular rosacea. Likewise, is Rosacea Considered to be an Inflammatory ivermectin has been shown to possess anti- Disorder? The Primary Role, Clinical Relevance, inflammatory properties, in addition to and Therapeutic Correlations of Abnormal effectiveness against demodicidosis. This dual- Innate Immune Response in Rosacea-Prone action property might explain its effectiveness Skin. J Drugs Dermatol. 2012;11:694-700. in the treatment of papulopustular rosacea. However, the exact role that Demodex mites play 10. Del Rosso JQ, Thiboutot D, Gallo R, et in the underlying pathogenesis of rosacea has yet al. Consensus Recommendations from the to be fully elucidated. American Acne and Rosacea Society on the Management of Rosacea, Part 3: A Status Report Conclusion on Systemic Therapies. Cutis. 2014;93:18-28. There is documented evidence that ivermectin 11. O’Reilly N, Menezes N, Kavangh K. Positive 1% cream is superior to metronidazole 1% cream Correlation Between Serum Immunoreactivity with regard to percent reduction in inflammatory- to Demodex-associated Bacillus Proteins lesion counts. However, it is difficult to conclude and Erythematotelangiectatic Rosacea. Br J that this is a clinically significant difference. Dermatol. 2012;167(5):1032-1036. Additionally, it is difficult to determine whether 12. Wolstenholme A, Rogers A. Glutamate-gated this difference is applicable to metronidazole gel Chloride Channels and the Mode of Action of as well. Likewise, ivermectin 1% cream is likely the Avermectin/Milbemycin Anthelminthics. better tolerated than azelaic acid. However, it is Parasitology. 2005;131:S85-95. not possible to say that it is superior with regard to efficacy, as this was not the primary objective 13. Soolantra (Ivermectin) Topical Cream, 1%

MCGREGOR, MINNI Page 39 Lymphoepithelioma-like Carcinoma of the Skin: A Case of One Patient Presenting with Two Primary Cutaneous Neoplasms

Jacqueline C. Fisher, DO,* Rachel M. White, BA,** Daniel S. Hurd, DO, FAOCD***

*Dermatology Resident, PGY-2, VCOM/LewisGale Hospital Montgomery, Blacksburg, VA **Medical Student, OMS IV, Philadelphia College of Osteopathic Medicine, Philadelphia, PA ***Dermatology Residency Program Director, VCOM/LewisGale Hospital Montgomery, Blacksburg, VA

Abstract Lymphoepithelioma-like carcinoma of the skin (LELCS) is a rare cutaneous most frequently found on the head and neck of elderly patients. Debate exists regarding its histogenesis, but it’s believed to be of epithelial origin. Histologically, LELCS is remarkably similar to undifferentiated nasopharyngeal carcinoma, a neoplasm associated with Epstein-Barr virus (EBV) infection. EBV reactivity is the main distinguishing factor between these two cutaneous neoplasms, with LELCS rarely documented to test positive for EBV. In general, those diagnosed with LELCS are advised to undergo evaluation of the nasopharynx as well as other internal organ systems that may harbor a lymphoepithelioma-like carcinoma to exclude cutaneous metastasis. Current treatment guidelines recommend wide local excision or Mohs micrographic surgery to prevent local recurrence of LELCS. To the best of the authors’ knowledge, this case is the first to report a patient with two separate lymphoepithelioma-like carcinomas of the skin presenting simultaneously. Introduction Case Report neck and left parietal scalp neoplasms showed Lymphoepithelioma-like carcinoma of the skin An 83-year-old Caucasian female was referred a dermal proliferation of atypical epithelioid (LELCS) is a rare cutaneous neoplasm with low to our dermatology clinic for surgical excision cells forming well-defined nests invested by malignant potential. It is currently classified as of a previously biopsied lesion on her left a dense lymphocytic infiltrate (Figure 2). a variant of squamous-cell carcinoma (SCC), neck reported initially as a nodular basal-cell The atypical epithelioid cells were basophilic although historically, its etiology has been debated. carcinoma with focal morpheaform features. The and featured enlarged nuclei with prominent LELCS demonstrates nearly identical histologic patient also complained of an asymptomatic, nucleoli. A central ulceration was present under features to undifferentiated nasopharyngeal slowly enlarging lesion to her left parietal scalp microscopic examination of the cutaneous carcinoma, also known as metastatic believed to be present for at least three months. biopsy on the patient’s left parietal scalp. The lymphoepithelioma of the nasopharynx, classically The patient’s past medical history was non- overlying epidermis appeared uninvolved in differentiated from LELCS by positive reactivity contributory, and she denied any constitutional both samples. Each specimen stained positive for an associated infection with Epstein-Barr symptoms at the time of clinical presentation. for cytokeratin (CK) 5/6 and epithelial 1,2 Therefore, an evaluation of the virus (EBV). Clinical examination revealed a solitary, 2.0 cm x nasopharynx with an ear, nose, and throat (ENT) 2.2 cm, tan to pink, indurated ulcerative plaque examination is advised to exclude undifferentiated (Figure 1). There were no naso-oropharyngeal nasopharyngeal carcinoma.2-4 LELCS generally abnormalities or regional lymphadenopathy. A is a slow-growing neoplasm with a good overall shave biopsy was performed to the left parietal prognosis. However, due to multiple cases of scalp to exclude both basal-cell carcinoma and recurrence after initial surgical excision, the gold squamous-cell carcinoma. standard of treatment for LELCS is wide local excision or Mohs micrographic surgery.2,5 The histopathological findings for both the left

Figure 2. H&E staining of LELCS (20x).

Figure 3. In situ hybridization Epstein-Barr virus encoded RNA (ISH/EBER) of LELCS on parietal scalp. Demonstrates absence of blue staining; determined to be EBV negative Figure 1. Lymphoepithelioma-like carcinoma of the skin on parietal scalp. (20x).

Page 40 LYMPHOEPITHELIOMA-LIKE CARCINOMA OF THE SKIN: A CASE OF ONE PATIENT PRESENTING WITH TWO PRIMARY CUTANEOUS NEOPLASMS incidence is equal in men and women.8 LELCS the spindle-cell variant of .23 often presents as a solitary, flesh-colored to red, However, unlike LELCS, melanoma is positive firm papule, plaque, or nodule.2 The average size for S100 and other neuroectodermal markers is fairly large, measuring about 2 cm to 3 cm in such as HMB-45 and melan-A. LELCS should diameter.3 Typically, LELSC is asymptomatic be distinguished from malignant lymphoma and slowly enlarges over a period of months to by the absence of atypical lymphocytes in years.8 LELCS.1 Epithelial markers such as epithelial- membrane antigen and cytokeratins will react Histology positive in LELCS and negative in malignant On histology, LELCS presents as a dermal lymphoma. LELCS has shown the presence of proliferation of atypical polygonal epithelioid occasional binucleated cells resembling Reed- cells arranged in nests, cords, or sheets surrounded Sternberg cells; however, Hodgkin lymphoma is by a peripheral dense lymphocytic infiltrate.6 negative for cytokeratins and positive for CD30 Figure 4. Control slide demonstrating positive 1,2,21,23 Cellular atypia includes vesicular hyperchromatic and CD15. Basal-cell carcinoma will reaction to ISH/EBER immunohistochemical nuclei and prominent nucleoli with scant demonstrate neoplastic basophilic cells extending stain (20x). amphophilic-to-eosinophilic cytoplasm.2 The downward from the epidermis, whereas LELCS reactive lymphoid stroma is comprised of small does not typically have an epidermal connection membrane antigen (EMA), suggesting tumors B- and T-lymphocytes, staining positive for and lacks peripheral palisading. Inflamed, poorly differentiated squamous-cell carcinoma (SCC) of epithelial origin. Staining for CK7 and CD3 and CD20, with an occasional plasma cell 1,19 CK20 yielded negative results, excluding Paget’s present.2,8 LELCS generally extends into the strongly resembles LELCS. However, LELCS disease and Merkel-cell carcinoma (MCC), reticular dermis with occasional involvement into typically does not involve overlying epidermis, respectively, from the differential diagnosis. Due the subcutis and even skeletal muscle.6,10 LELCS and poorly differentiated SCC usually has an area of well-differentiated carcinoma or overlying to the concern for an underlying metastatic stains positively for pancytokeratin, CK5, CK6, 1,3,5 undifferentiated nasopharyngeal carcinoma or p63 and EMA reactivity, likely indicating a SCC in situ. Cutaneous lymphadenoma lymphoepithelioma-like carcinoma (LELC) of neoplasm of epithelial origin.2,7 These markers demonstrates a similar dense lymphocytic infiltrate as LELCS, but these lymphocytes another internal organ, an in situ hybridization also indicate that LELCS may derive from an 1,2 for Epstein-Barr virus-encoded RNA (ISH/ epidermal, follicular, glandular, sudoriferous appear benign and monomorphic. Follicular EBER) was performed for detection of an active origin.2,5,7,11-14 In fact, the histogenesis of LELCS dendritic-cell tumor (FDCT) is similar to or latent EBV infection (Figure 3). The patient’s is controversial. Historically, LELCS was thought LELCS by way of syncytial-appearing plump cells surrounded by reactive lymphoid cells, but histologic slides were compared to a control ISH/ to derive from adnexal origin, supported by the 2 EBER immunohistochemical stain (Figure 4). fact that LELCS is located in the dermis and FDCT stains negative for cytokeratin markers. 6,15 FDCT will demonstrate positive reactivity to Ki- The negative ISH/EBER stain for both lesions usually lacks a connection with the epidermis. 2 strongly favors two primary LELSC in our patient Also, within LELCS, there is often sebaceous, M4, CD21, and CD35. and does not favor a metastatic disease related to eccrine and trichilemmal differentiation.8 In Histologically, LELCS is remarkably similar an EBV-driven undifferentiated nasopharyngeal more recent literature, some consider LELCS to metastatic lymphoepithelioma of the carcinoma or internal LELC. to be a variant of squamous-cell carcinoma nasopharynx, also known as undifferentiated (SCC).2,4,16-20 For instance, Wang et al. presented 1,3,22 Our patient was referred to an oncologist for nasopharyngeal carcinoma. Epstein-Barr a case of LELCS occurring below a from medical evaluation to exclude cutaneous metastasis virus (EBV) reactivity is the main distinguishing removal of multiple recurrent, well-differentiated of an undifferentiated nasopharyngeal carcinoma factor between LELCS and undifferentiated and subsequent moderately differentiated 1,2,4,24 or lymphoepithelioma-like carcinoma of other nasopharyngeal carcinoma. In general, SCC.19 However, SCC is typically located in internal organs. Given the patient’s advanced LELCS is negative for EBV reactivity, whereas the superficial dermis and maintains connectivity age and frail status, the patient refused oncologic undifferentiated nasopharyngeal carcinoma will with the epidermis.4 Finally, others believe that 1,2,4,24 examination as she planned to decline systemic test positive for EBV. There has been only LELCS is a morphologic pattern as opposed to a treatment if an underlying internal malignancy one reported case, that of a Japanese woman, of distinct clinicopathologic entity.17,21,22 was discovered. Per initial consultation with LELCS in a patient who tested EBV positive, but no related neoplasms were found elsewhere the patient, the oncologist remarked that it was 22 highly unlikely that an internal carcinoma was Differential in the patient’s body. In situ hybridization for metastasizing to her skin. She was also referred The differential diagnosis is fairly extensive EBER, the most reliable, specific, and highly to a plastic surgeon for evaluation and surgical and includes cutaneous metastasis of sensitive method for detecting latent EBV, was used in this case report and yielded a negative removal of both LELCS. undifferentiated nasopharyngeal carcinoma, a 22,25 lymphoepithelioma-like carcinoma of another result for EBV in our patient. Metastatic Our patient plans to undergo surgical excision internal organ, basal-cell carcinoma, squamous- lymphoepithelioma of the nasopharynx is rare, of both cutaneous neoplasms and remains free 2,4,6 cell carcinoma, keratoacanthoma, Merkel-cell but aggressive when it does occur. LELCS from systemic symptoms, which supports the carcinoma, melanoma, malignant lymphoma, secondary to metastasis of undifferentiated diagnosis of two primary lymphoepithelioma- Hodgkin’s lymphoma, cutaneous lymphadenoma, nasopharyngeal carcinoma appears to be very rare, like carcinomas of the skin. 2,4 as there are fewer than 20 cases currently reported and follicular dendritic cell tumor. Histologic 2,6,11 features and immunohistochemical staining in the literature. Nonetheless, it is highly Discussion distinguish LELCS from the possible differential recommended to evaluate the patient for possible Lymphoepithelioma-like carcinoma of the skin diagnosis. undifferentiated nasopharyngeal carcinoma (LELCS) is a rare primary cutaneous neoplasm by a complete otolaryngologic exam including 6 Merkel-cell carcinoma (MCC) can present 4,26 initially described in 1988 by Swanson et al. indirect laryngoscopy of the nasopharynx. clinically similar to LELCS but will stain Since this first report, close to 80 cases have A review of symptoms is recommended when positive for neuroendocrine markers such as been described in the English literature. LELCS LELCS is confirmed to exclude metastasis synaptophysin, neuron-specific enolase, and from a variety of internal organ systems.2,4,5,22 occurs most often in elderly individuals on sun- 1 2 CK20. In addition, peripheral lymphocytic exposed areas, primarily the head and neck. Lymphoepithelioma-like carcinoma can be infiltrate is usually absent in MCC.2,14 Clarke However, there has been a report of LELCS found in many organs besides the skin, including 7-9 and Ioffreda report a case in which LELCS occurring on the trunk and upper extremity. The salivary glands, thyroid, thymus, lungs, stomach, demonstrates spindle-shaped cells that resemble FISHER, WHITE, HURD Page 41 , breasts, uterine cervix, prostate, , 2. Welch PQ, Williams SB, Foss RD, et al. of the skin. A case report with immunophenotypic and urinary bladder..6,7,16,17,23,27 Histologically, Lymphoepithelioma-like carcinoma of head and analysis and in situ hybridization for Epstein-Barr EBV reactivity has been associated only with neck shin: a systemic analysis of 11 cases and viral genome. Am J Surg Pathol. 1992;9:909-13. review of literature. Oral Surg Oral Med Oral lymphoepithelioma-like carcinoma of the 17. Lind AC, Breer WA, Wick MR. 4,7,22,24 Pathol Oral Radiol Endod. 2011;111:78-86. stomach, salivary glands, lungs, and thymus. Lymphoepithelioma-like carcinoma of the skin 3. Abedi SM, Salama S, Alowami S. with apparent origin in the epidermis-a pattern Treatment Lymphoepithelioma-like carcinoma of the skin: or an entity? A case report. Cancer. 1999;15:884- The prognosis for patients with LELCS is case report and approach to surgical sign out. 90. generally good despite its categorization as a Rare Tumors. 2013;5:157-9 18. Cassarino DS, DeRienzo DP, Barr R. poorly differentiated neoplasm.2,5,6,22,27 It is a low 4. Lassen CB, Lock-Anderson J. Cutaneous : a malignant tumor with rare reports of metastasis Lymphoepithelioma-like carcinoma of the skin: comprehensive clinicopathologic classification. J to lymph nodes at presentation and to internal a case with perineural invasion. Plast Reconstr Cutan Pathol. 2006;33:191-206. organs such as, liver, lung, and bone.9,27 There Surg Glob Open. 2014 Dec 5;2(11):e252 are only two reported deaths from metastatic 19. Wang G, Bordeaux JS, Rowe DJ, Honda KS. LELCS.4,6 There are multiple reports of local 5. Gille TM, Miles EF, Mitchell AO. Lymphoepithelioma-like carcinoma vs inflamed recurrence after incomplete excision.6 Therefore, Lymphoepithelioma-like carcinoma of the squamous cell carcinoma of the skin. JAMA most LELCS are treated by wide local excision skin treated with wide local excision and Dermatol. 2014;150:1367-8. chemoradiation therapy: A case report and or Mohs micrographic surgery to lower the risk 20. Bolognia JL, Jorizzo JL, Rapini RP, eds. 2,28 review of the literature. Case Rep Oncol Med. of recurrence. LELCS and undifferentiated Dermatology. Edinburgh: Mosby, Inc; 2008. p. 2012;2012:241816. nasopharyngeal carcinoma are both radiosensitive, 1782-1783. Print. and this treatment modality should be used for 6. Swanson SA, Cooper PH, Mills SE, Wick 21. Shek, TW, Leung EY, Luk IS, Loong F, recurrent cases, nonsurgical candidates, and MR. Lymphoepithelioma-like carcinoma of the 3,8 Chan AC, Yik YH, et al. Lymphoepithelioma- those with lymph-node metastasis. There skin. Mod Pathol. 1988;1:359-65. are also a few reports of perineural invasion, in like carcinoma of the skin. Am J Dermatopathol. which Mohs micrographic surgery, radiation, and 7. Robins P, Perez MI. Lymphoepithelioma 1996;6:637-44. like carcinoma of the skin treated by Mohs were used in combination therapy 22. Aoki R, Mitsui H, Karada K, et al. A case micrographic surgery. J Am Acad Dermatol. without evidence of recurrence on follow-up of lymphoepithelioma-like carcinoma of the skin 3-5,7 1995;32:814-16. evaluation. associated with Epstein-Barr virus infection. J 8. Glaich AS, Behroozan DS, Cohen JL, Goldberg Am Acad Dermatol. 2010;62(4):681-84. LH. Lymphoepithelioma-like carcinoma of the 23. Clarke LE, Ioffreda MD. Lymphoepithelioma- Conclusion skin: a report of two cases treated with complete In conclusion, lymphoepithelioma-like like carcinoma of the skin with spindle cell microscopic margin control and review of the carcinoma of the skin is a rare, slowly growing differentiation. J Cutan Pathol. 2005;6:419-23. neoplasm with low malignant potential. LELCS literature. Dermatol Surg. 2006:2:316-19. 24. Iezzoni JC, Gaffey MJ, Weiss LM. The role is believed to be of epithelial origin based on 9. Hall G, Duncan A, Azurdia R, Leonard N. of Epstein-Barr virus in lymphoepithelioma-like immunohistochemical reactivity, although its Lymphoepithelioma-like carcinoma of the skin: a carcinomas. Am J Clin Pathol. 1995;103:308. exact histogenesis remains debatable. There case with lymph node metastases at presentation. are multiple dermatologic neoplasms that can Am J Dermatopathol. 2006;3:211-5. 25. Chang YL, Wu CT, Shih JY, Lee YC. New clinically resemble LELCS. Therefore, it is aspects in clinicopathologic and oncogene 10. Wick MR, Swanson PE, LeBoit PE, Strickler important to conduct a histologic examination studies of 23 pulmonary lymphoepithelioma-like JG, Cooper PH. Lymphoepithelioma-like from a biopsied specimen to exclude other carcinomas. Am J Surg Pathol. 2002;26:715-23. carcinoma of the skin with adnexal differentiation. dermatologic entities. Undifferentiated J Cutan Pathol. 1991;18:93-102. 26. Dudley CM, Snow SN, Voytovich MC, nasopharyngeal carcinoma demonstrates identical Warner TF, Hartig GK. Enlarging facial nodule 11. Luk NM, Yu KH, Choi CL, Yeung WK. histologic characteristics, and although it rarely on an elderly patient. Lymphoepithelioma-like Skin metastasis from nasopharyngeal carcinoma occurs, it is a very aggressive neoplasm that carcinoma of the skin (LELCS). Arch Dermatol. in four Chinese patients. Clin Exp Dermatol. requires a thorough otolaryngologic examination 1998;134:1628-9, 1631-2. and CT scans of the head and neck if suspected. 2004;29:28-31. 27. Kazakov DV, Nemcova J, Mikyskova I, A thorough review of systems is recommended 12. Ng KF, Chen TC, Chang PL. Michal M. Absence of Epstein-Barr virus, to exclude other possible organ systems that Lymphoepithelioma-like carcinoma of the . human papillomavirus, and simian virus 40 may have a lymphoepithelioma-like carcinoma J Urol. 1999;161:1277-8. metastasizing to the skin. Wide surgical in patients of central European origin with excision or Mohs micrographic surgery are the 13. Gillum PS, Morgan MB, Naylor MF, lymphoepithelioma-like carcinoma of the skin. recommended treatments for non-aggressive Everett MA. Absence of Epstein-Barr virus in Am J Dermatopathol. 2007;4:365-9. lymphoepithelioma like carcinoma of the skin. forms of LELCS to prevent local recurrence. To 28. Jimenez F, Clark RE, Buchanan MD, Polymerase chain reaction evidence and review of the best of our knowledge, this is the first case Kamino H. Lymphoepithelioma-like carcinoma five cases. Am J Dermatopathol. 1996;5:478-82. demonstrating two primary lymphoepithelioma- of the skin treated with Mohs micrographic like carcinomas of the skin presenting in different 14. Abdelkrim SB, Dhouibi A, Moussa A, et al. surgery in combination with immune staining for anatomic locations on the same patient without Merkel cell carcinoma with lymphoepithelioma- cytokeratins. J Am Acad Dermatol. 1995;32:878- evidence of a metastatic source. like pattern: a case report of an exceedingly rare 81. variant of Merkel cell carcinoma with lymph References node metastases at presentation. Case Rep 1. Ferlicot S, Plantier F, Rethers L, Bui Pathol. 2011;2011:840575. Correspondence: Jacqueline C. Fisher, DO; [email protected] AD, Wechsler J. Lymphoepithelioma-like 15. Ko T, Muramatsu T, Shirai T. carcinoma of the skin: a report of 3 Epstein- Lymphoepithelioma-like carcinoma of the skin. Barr virus (EBV)-negative additional cases. J Dermatol. 1997;2:104-9. Immunohistochemical study of stroma reaction. J Cutan Pathol. 2000;6:306-11. 16. Carr KA, Bulengo-Ransby SM, Weiss LM, Nickoloff BJ. Lymphoepithelioma like carcinoma

Page 42 LYMPHOEPITHELIOMA-LIKE CARCINOMA OF THE SKIN: A CASE OF ONE PATIENT PRESENTING WITH TWO PRIMARY CUTANEOUS NEOPLASMS Primary Cutaneous Carcinosarcoma: A Case Report and Discussion of a Histological “Chimera”

Joseph Dyer, DO,* Kaylan Pustover, DO,** Prasanna Sinkre, MD,*** Richard Miller, DO, FAOCD****

*Dermatology Resident, 1st year, Largo Medical Center, Largo, FL **PGY-1, Largo Medical Center, Largo, FL ***Dermatopathologist, Cockerell Dermatopathology, Dallas, TX ****Dermatology Residency Program Director, Largo Medical Center, Largo, FL Abstract Primary cutaneous carcinosarcoma is a rare and aggressive biphasic malignant neoplasm that exhibits both epithelial and mesenchymal components. This malignancy is more commonly described arising from organs such as the , breast, bladder, and lung, and is rarely seen on the skin. The histopathogenesis of this neoplasm is unknown, but a prevailing divergence theory exists. It is imperative that this neoplasm be diagnosed and treated, as it can be fatal. Here we report a case of primary cutaneous carcinosarcoma presenting on the skin of an 86-year-old male. Introduction carcinoma. The mesenchymal component may be Immunohistochemical stains are important for Primary cutaneous carcinosarcoma (PCC) is of osseous, cartilaginous or, more rarely, skeletal- the diagnosis of carcinosarcoma. Cytokeratin or smooth-muscle lineage.5 highlights the epithelial elements, while vimentin a rare neoplasm not commonly found on the 1 skin. To our knowledge, fewer than 100 cases Although the histopathogenesis of PCC is highlights the mesenchymal elements. Two 1 of PCC have been reported in world literature. unknown, there are two common theories at studies emphasize the role of p63, a homologue Carcinosarcoma is most often observed in organs present. The prevailing hypothesis, also known of the tumor suppressor gene p53, in confirming epithelial derivation of poorly differentiated or other than the skin including the uterus, breast, as the divergence or monoclonal hypothesis, 6,7 1,2 It is thought that p63 is urinary bladder, and lungs. When it does occur states that a single stem cell undergoes metaplastic carcinomas. involved in the prevention of terminal squamous on the skin, it is typically found on an elderly divergent differentiation into separate epithelial 5 stem-cell differentiation and can be the key to male in sun-exposed areas of the head, neck, and and mesenchymal elements. The less likely 6 3 establishing an epithelial presence in a tumor. upper extremities. Clinically, the lesion is often convergence hypothesis proposes that the tumor 4 Pure sarcomas and carcinomas are negative exophytic and ulcerated and develops rapidly. arises from two or more stem cells of epithelial for p63, thus p63 staining is highly specific for and mesenchymal origin that independently 7 1,2,5 diagnosing metaplastic carcinomas like PCC. converge. Case Report Our tumor demonstrated positive staining for An 86-year-old male presented with a lesion on his left cheek of 3 months’ duration. On physical Figure 1 Figure 3 exam, there was a 1.0 cm x 1.2 cm, ill-defined, red, friable nodule on the patient’s left cheek. The clinical impression was of basal-cell carcinoma. After a shave biopsy, routine H&E stains of the lesion revealed a poorly differentiated, biphasic malignant neoplasm comprised of trabecular arrangement of pleomorphic cells with considerable cytoplasm juxtaposed with atypical cellular hyperchromatic malignant stroma (Figure 1). Immunohistochemical stains revealed the pleomorphic cells with considerable cytoplasm were positive for cytokeratin (Figure 2) and p63 (Figure 3), while the intervening atypical stromal cells were positive for vimentin (Figure 4) and CD10. Both cell populations were negative for neuroendocrine markers. Computed tomography of the neck and chest was negative for Figure 2 Figure 4 locoregional lymphadenopathy. This microscopic and radiographic analysis was consistent with primary cutaneous carcinosarcoma. The patient was treated with Mohs micrographic surgery and remains disease-free at three months.

Discussion Primary cutaneous carcinosarcoma is an aggressive tumor composed of carcinomatous and sarcomatoid cells. The epithelial component is most commonly a basal-cell carcinoma or squamous-cell carcinoma, but it can also be associated with adnexal-derived tumors including spiradenocarcinoma, porocarcinoma, proliferating trichilemmal cystic carcinoma, and metrical DYER, PUSTOVER, SINKRE, MILLER Page 43 CD10 in the mesenchymal component, but the References significance of this is unclear as this pattern 1. Kwan JM, Satter EK. Carcinosarcoma: is recognized in both basal-cell carcinomas a primary cutaneous tumor with biphasic (epithelial lineage) and atypical fibroxanthomas differentiation. Cutis. 2013;92:247-249. (mesenchymal lineage).2 2. Rose RF, Merchant W, Stables GI, et al. Basal Treatment of PCC is predominantly surgical cell carcinoma with a sarcomatous component with wide local excision or, as in the case of our (carcinosarcoma): a series of 5 cases and a patient, Mohs micrographic surgery. Adjuvant 4 review of the literature. J Am Acad Dermatol. radiotherapy is not currently recommended. 2008;59:627-632. Regular clinical follow-up is paramount. 3. Bellew S, Del Rosso JQ, Mobini N. Primary Cutaneous carcinosarcomas typically have a carcinosarcoma of the ear. J Clin Anesthet better prognosis than carcinosarcomas arising in Dermatol. 2009;2(8):33-35. visceral organs, but nonetheless these tumors can be aggressive. Prognosis seems to be most closely 4. Syme-Grant J, Syme-Grant NJ, Motta L, linked to the origin of the epithelial component. et al. Are primary cutaneous carcinosarcomas One meta-analysis found that PCCs containing underdiagnosed? Five cases and a review of a basal- or squamous-cell carcinoma had a five- the literature. J Plas Reconstr Aesthet Surg. year survival rate of 70%.8 Conversely, PCCs 2006;59:1402-1408. with an epithelial element of adnexal origin 5. Hong SH, Hong S-J, Lee Y, Kang E-Y. Primary have a poorer prognosis, with a 25% five-year cutaneous carcinosarcoma of the : case 5 disease-free survival rate. Other poor prognostic report and literature review. Dermatol Surg. factors include age younger than 65, tumor size 2013;39:338-40. greater than 2 cm, a recent growth pattern, longer duration of existing skin tumor, and metastasis 6. Romanelli P, Miteva M, Schwartzfarb E, et al. to lymph nodes.3,5 Even after surgical excision, p63 is a helpful tool in the diagnosis of a primary 7% to 19% of PCCs recur.1,9 Diagnosis and cutaneous carcinosarcoma. J Cutan Pathol. treatment is necessary, with locoregional and 2009;36:280-2. distant metastases documented in 19% and 26% 7. Suh K-Y, Lacouture M, Gerami P. p63 of cases, respectively.1 PCC can also be fatal, in primary cutaneous carcinosarcoma. Am J with one report documenting PCC with cerebral Dermatopathol. 2007;29:374. metastases resulting in death.10 8. Tran TA, Muller S, Chaudahri PJ, et al. Cutaneous carcinosarcoma. Adnexal vs epidermal Conclusion types define high and low-risk tumors. Results of PCC is an admixed malignancy of epithelial and a meta-analysis. J Cutan Pathol. 2005;32:2-11. mesenchymal components. The diagnosis of this 9. Brasanac D, Boricic I, Todorovic V, Tomanovic rare neoplasm is critical given its high rate of N. Primary cutaneous carcinosarcoma: case report recurrence, metastases, and occasional mortality. with expanded immunohistochemical analysis. These risks are especially notable when the lesion Int J Dermatol. 2008;47:496-501. clinically resembles an unexceptional basal- cell carcinoma, as in our case. It is necessary 10. Chittari K, Birnie AJ, Kulkarni KR, et al. to increase knowledge and awareness of this Sarcomatoid carcinoma of the hand: a clinical case uncommon and aggressive histologic “chimera.” with an aggressive and uncommon presentation. Clin Exp Dermatol. 2012;37:505-8.

Correspondence: Kaylan Pustover, DO; kaylan. [email protected]

Page 44 PRIMARY CUTANEOUS CARCINOSARCOMA: A CASE REPORT AND DISCUSSION OF A HISTOLOGICAL “CHIMERA” Case report: Eccrine porocarcinoma of the scalp in an immunosuppressed patient

Claire Otteni, BS,* Richard Limbert, DO,** Joseph Dyer, DO,*** Richard A. Miller, DO, FAOCD****

*Medical Student, 4th year, Philadelphia College of Osteopathic Medicine, Philadelphia, PA **Dermatology Resident, 3rd year, Nova Southeastern University College of Osteopathic Medicine, Largo Medical Center, Largo, FL ***Dermatology Resident, 1st year, Nova Southeastern University College of Osteopathic Medicine, Largo Medical Center, Largo, FL ****Program Director, Dermatology Residency Program, Nova Southeastern University College of Osteopathic Medicine, Largo Medical Center, Largo, FL

Abstract Eccrine porocarcinoma (EPC) is an extremely rare malignancy of the eccrine sweat glands. They arise from the intraepidermal portion of the eccrine glands and are locally aggressive, with a high propensity to metastasize. Compromised immunity may be a contributing risk factor for developing EPC. We report a case of EPC presenting on the scalp in a patient on immunosuppressive therapy for bilateral lung transplants. cell carcinoma was suspected, and excision were present (Figure 3) and were highlighted Introduction with Mohs micrographic surgery (MMS) was with both carcinoembryonic antigen (CEA) Eccrine porocarcinoma (EPC) was first described planned for the following week. The patient was (Figure 4) and cytokeratin 7 (CK7) (Figure 5). in 1963 by Pinkus and Mehregan. They used prophylaxed with cephalexin 500 mg twice daily No areas of lymphovascular or perineural invasion the term “epidermotropic eccrine carcinoma” due to his immunosuppression. The tumor was were identified. Depth of involvement was at least to describe this tumor due to its origin from first debulked with a flexiblade, and a specimen 6.5 mm, Clarks level IV. A diagnosis of eccrine the intraepidermal portion of the eccrine sweat was sent for permanent sections. Deep and porocarcinoma with squamous differentiation glands. EPC is a very rare type of skin cancer, peripheral margins were examined during MMS, was made. representing 0.005% to 0.01% of all skin and squamous cell carcinoma was present in 1-5 Subsequently, the patient was sent to medical tumors. EPC tumors occur most commonly in the first two stages. The tumor was cleared after oncology for evaluation and recommendations older age groups, with peak incidence at age 67, removal of the third stage. The resulting defect 3,4,6 for further workup. The consultant endorsed and have a slight female predominance. They was 4 cm, and the patient was sent to plastic only close clinical surveillance. At the time of have various clinical appearances, presenting as an surgery for closure immediately following MMS. ulcerated nodule, plaque, polypoid or verrucous publication, this patient has been recurrence-free papule.4 The most common location is the lower for two months. extremities, but EPC can occur on the upper Histopathological evaluation of the permanent extremities, trunk and . EPC arising in sections revealed additional findings beyond what Discussion the setting of immune compromise is rare. Here, was seen during MMS. Low-power microscopy Pinkus and Mehregan first described the tumor we report a case of EPC presenting on the scalp revealed a proliferation of atypical epithelium as epidermotropic eccrine carcinoma in 1963, and in a patient on immunosuppressive therapy for emanating from the intraepidermal portion of it was later termed eccrine porocarcinoma (EPC) bilateral lung transplants. the eccrine sweat glands, extending into the by Mishima and Morioka in 1969.2 dermis (Figure 2). Areas of epithelioid cells with Eccrine porocarcinoma (EPC) is an extremely Case Report intercellular bridges and keratinization were rare malignancy of the eccrine sweat glands. The A 49-year-old Caucasian male presented with a present. However, cells with ductal differentiation tumors arise from the intraepidermal portion of rapidly enlarging tumor on his left posterior scalp Figure 2 Figure 4 for five weeks. The lesion was mildly tender to but was otherwise asymptomatic. No regional lymphadenopathy was palpable. Past medical history was significant for cystic fibrosis resulting in bilateral lung transplant. Medications included mycophenolate mofetil 1.5 g twice daily, prednisolone 5 mg daily, and tacrolimus 1 mg twice daily. Family history was noncontributory. Clinical exam revealed a 2.7 cm, exophytic, pink, keratotic nodule on the left posterior scalp (Figure 1). Upon initial examination, squamous

Figure 1 Figure 3 Figure 5

OTTENI, LIMBERT, DYER, MILLER Page 45 the eccrine glands and are locally aggressive, with are used for EPCs and include wide local excision References a high propensity to metastasize. EPCs most (WLE), chemotherapy, and 1. Pal S, Jyoti P, Sengupta S, Anuradha S. Eccrine commonly occur in adult life, with various reports Mohs micrographic surgery (MMS). While most 2,3 Porocarcinoma of Scalp: A Rare Case Report. of peak incidence ranging from 67 to 74 years. cases have been treated with wide excision, Song Iran J Pathol. 2015;10(1):65-68. A majority of authors report no difference in et al. proposed that MMS has proven success incidence between genders; however, Riera-Leal and should be considered.4 MMS allows for 2. Vaz Salgado MA, Garcia CG, Lopez Martin et al. recently described a slight female bias (64%).6 examination of 100% of peripheral margins vs. JA, Guerra E, Benito A, Sepulveda JM, Carrato The most frequent location of presentation is the traditional bread-loaf sections with WLE. A. Porocarcinoma: Clinical Evolution. Dermatol lower extremities (50%), followed by the trunk Surg. 2010;36(2):264-67. 2-4 (24%), head (18%), and upper extremity (8%). Conclusion 3. Bhat W, Akhtar S, Khotwal A, Platt AJ. Our case involved an atypical presentation on the Eccrine porocarcinoma (EPC) is a rare skin Primary Eccrine Porocarcinoma of the Finger scalp in an immunosuppressed patient. malignancy presenting with a variety of clinical With Transit Forearm and Axillary Metastasis. Clinically, eccrine porocarcinomas can have a appearances, making identification difficult. In Ann Plast Surg. 2011;66(4):344-46. variety of appearances, such as ulcerated nodule, our case, an exophytic, pink, keratotic nodule 4. Song SS, Wu Lee W, Hamman MS, Jiang verrucous plaque, or polypoid papule. Due to was located on the scalp and initially thought to SI. Mohs Micrographic Surgery for Eccrine their protean clinical presentations, these tumors be squamous cell carcinoma. EPC recognition Porocarcinoma. Dermatol Surg. 2015;41(3):301- are often misdiagnosed preoperatively and can is important due to its aggressive growth, 06. be mistaken for pyogenic granuloma, basal cell propensity for recurrence and spread, and 5. Bolognia JL, Jorizzo JL, Schaffer JV. carcinoma, , amelanotic resultant poor prognosis. No concise guidelines rd melanoma, and, as in our case, squamous cell have been established for the treatment of EPC Dermatology. 3 edition. Philadelphia: Elsevier carcinoma.4 due to the paucity of reports in the literature. We Saunders, 2012. p. 539-544. report the 22nd case of EPC treated with MMS. Histologically, EPCs are located in the epidermis 6. Riera-Leal L, Guevara-Gutiérrez E, It is a unique case of eccrine porocarcinoma due and dermis, as they arise from the intraepidermal Barrientos-García JG, Madrigal-Kasem R, to its uncommon location on the scalp, as well as portion of the eccrine sweat glands. The tumor is Briseño-Rodríguez G, Tlacuilo-Parra A. its presentation in an immunosuppressed patient. characterized by epithelioid cells with ductal lumen Eccrine Porocarcinoma: Epidemiologic and To the best of our knowledge, there have been associated with pleomorphic, hyperchromatic Histopathologic Characteristics. Int J Dermatol. fewer than 10 cases of porocarcinoma involving nuclei and mitotic figures. When confined to the 2014;54(5):580-86. the scalp reported in the literature.1,7,8 Our epidermis, they are termed “in situ.” They can also 7. Permi HS, Bhat SP, Prasad H L K, Bhat VS. patient is also only the seventh reported case of invade the dermis with a pushing or infiltrative Eccrine Porocarcinoma of Scalp: An Uncommon EPC with compromised immunity, and, to our pattern. In our case, there was involvement of Tumor at an Unusual Site. Indian J Surg knowledge, the first case in a patient with lung atypical cells extending into the dermis. There was Oncol. 2011;2(2):145–147. transplantation. no evidence of cutaneous or systemic metastases 8. Rana RE, Verma SS, Puri VA, Baliarsing AS. (no palpable lymphadenopathy); however, due Sweat gland tumour (Eccrine porocarcinoma) to the aggressive nature of the lesion (and the of scalp: A rare tumour. Indian J Plast Surg. patient’s immunosuppressed state), our patient 2005;38(1):51-3. was referred to medical oncology. 9. Mak ST, Li KK. Eccrine Porocarcinoma of EPCs are locally aggressive with a high the in a Non-Caucasian Patient. Ophthal likelihood of metastasis. Twenty percent of cases Plast Reconstr Surg. 2014 May 19. [Epub ahead have reported local and lymph-node metastases of print] (even though margins were free on pathological exam), while 10% of cases have reported further 10. Jeon SP, Kang SJ, Jung SJ. Rapidly Growing metastases to viscera and bone.2,4 With metastases, Eccrine Porocarcinoma of the Face in a Pregnant prognosis is poor, with reports of mortality rates Woman. J Craniofac Surg. 2014;25(2):715-17. ranging from 67% to 80%. Prognosis has been 11. Jeon J, Kim JH, Baek YS, Kim A, Seo SH, Oh associated with clinical characteristics such as 2,4 CH. Eccrine Poroma and Eccrine Porocarcinoma multinodularity, ulceration, and rapid growth. in Linear Epidermal . Am J Dermatopathol. Histologic features also correlate with prognosis: 2014;36(5):430-32. A mitotic index of more than 14 mitotic cells/ hpf, lymphovascular invasion, and a tumor depth 12. Mahomed F, Blok J, Grayson W. The greater than 7 mm indicate a worse prognosis.2,4 Squamous Variant of Eccrine Porocarcinoma: High-risk features in our patient’s tumor included A Clinicopathological Study of 21 Cases. J Clin ulceration, rapid growth, and a possible depth of Pathol. 2008;61(3):361-365. greater than 7 mm. 13. Robson A, Greene J, Ansari N, Kim B, In addition, compromised immunity may be a Seed PT, McKee PH, Calonie E. Eccrine contributing risk factor for developing EPC. Six Porocarcinoma (Malignant Eccrine Poroma): A previous cases of EPC in immunosuppressed Clinicopathologic Study of 69 Cases. Am J Surg patients have been described: three patients Pathol. 2001;25:710-720. with renal transplants, two patients with human immunodeficiency virus (HIV), and one patient 4,12 Correspondence: Claire Otteni; with chronic lymphocytic leukemia (CLL). [email protected] Our patient, on treatment after bilateral lung transplant with cystic fibrosis, is the seventh reported case of EPC with immunosuppression. Due to the rarity of this lesion, as well its aggressive nature, an optimal treatment plan has not been defined. A variety of treatment options

Page 46 CASE REPORT: ECCRINE POROCARCINOMA OF THE SCALP IN AN IMMUNOSUPPRESSED PATIENT En Coup De Sabre: A Case Report

Ashvin Garlapati, DO,* Ramya Tripuraneni, MBBS,** Stanley Skopit, DO, MSE, FAOCD***

*Dermatology Resident, 3nd year, Larkin Community Hospital/NSU-COM, South Miami, FL **Traditional Rotating Intern, Fairview Hospital, a Cleveland Clinic Hospital, Cleveland, OH ***Program Director, Dermatology Residency Program - Larkin Community Hospital /NSU-COM, South Miami, FL

Abstract En coup de sabre is an unusual variant of localized defined by its distinct location involving the frontoparietal region of the forehead and scalp. We report a rare case of en coup de sabre in a 16-year-old female with vitamin D deficiency. The workup, management, and relationship between scleroderma and serum vitamin D concentrations will be discussed.

Figure 1 Figure 2

Figure 3

Introduction centromere, SS-A, SS-B, C3, and C4. Scleroderma is a rare connective-tissue disorder A biopsy was taken from the vertex of the scalp. of unknown etiology. It is characterized by Histopathology showed thick, dense hyalinized increased collagen production resulting in collagen bundles in the dermis (Figure 2). There dermal thickening and hardening of the skin. was a sparse, deep lymphocytic infiltrate that did Scleroderma involves a wide range of disease. It not extend into the subcutaneous fat (Figure 3). can include systemic involvement of the internal The patient’s clinical history, , Our patient received a taper, which organs, referred to as systemic sclerosis, or it laboratory results and histopathologic findings began at 60 mg daily and eventually tapered can be confined to the skin in a localized form, were consistent with linear scleroderma en coupe down to 10 mg daily over a period of one month. referred to as or localized scleroderma. de sabre, a rare subtype of localized scleroderma. Concurrently, the patient began methotrexate En coupe de sabre is a rare craniofacial subtype of localized scleroderma. Figure 4

Case Report A 16-year-old female presented to our clinic with a one-year history of hair loss involving the right side of her scalp. She denied any associated symptoms such as , vision changes or trauma to the scalp. The patient had no medical history and no significant family or drug history. On physical examination, there was a hyperpigmented, atrophic plaque extending from the vertex of her scalp down to the right side of her forehead (Figure 1). The patient’s complete blood count (CBC) and comprehensive metabolic panel (CMP) were unremarkable, but the vitamin D level was decreased at 16 ng/ml. Autoimmune serology was performed, and patient was negative for ANA, DSDNA, SSDNA, SCL-70, anti-

GARLAPATI, TRIPURANENI, SKOPIT Page 47 15 mg once a week with folic acid 1 mg every may be present in the area of involved scalp, which finding or reflects a true association between day except the day methotrexate was taken. can be the presenting complaint. Typically, the vitamin D levels and clinical manifestations Vitamin D supplementation was not given to lesions are confined to the skin and subcutaneous of scleroderma. Recent studies, however, have our patient. Our clinic did not have UVA/PUVA tissue; occasionally, underlying muscle, cartilage shown that individuals with vitamin D deficiency or narrowband UVB therapy available, but the and bone can also be involved, resulting in facial are at a higher risk of developing autoimmune patient was referred to a clinic that did have these atrophy. When hemifacial atrophy occurs, Parry diseases.16 It is postulated that the relationship modalities. The patient refused these therapeutic Romberg syndrome (PRS) should be in the between vitamin D and autoimmune disease options. This treatment plan yielded good results, differential diagnosis. It has been reported that has to do with vitamin D’s immunomodulating with the patient and physician both noting less PRS coexists in 20% to 37% of patients diagnosed activity on vitamin D receptors present on induration of the lesion after three months of with en coupe de sabre.8 There have been many antigen-presenting cells and activated T cells.17 methotrexate. The patient’s lesion did not show discussions as to whether these are two distinct In 2011, a study conducted in Hungary to much improvement visually (Figure 4, p. 47), but diseases or clinical variants of the same disease. find a link between scleroderma and serum on palpation there was significant softening of The ailments have comparable ages of onset and vitamin D levels concluded that patients with the plaque. disease progressions. PRS may have dermatologic scleroderma do have considerably lower serum findings similar to those seen in en coupe de concentrations of vitamin D when compared to sabre, but they are typically more prominent and controls, and that cutaneous fibrosis is inversely Discussion 18 Scleroderma is a rare connective-tissue disorder do not exhibit cutaneous sclerosis at any stage of related to serum vitamin D concentrations. This in which increased collagen production leads to the disease. relationship between vitamin D and autoimmune disease suggests that vitamin D may be a thickening and hardening of the skin. In systemic On rare occasions, localized scleroderma has modifiable environmental factor in patients with sclerosis, there is systemic involvement of internal been associated with multisystemic involvement, scleroderma. organs; in morphea, or localized scleroderma, the including rheumatologic, ophthalmologic disease is confined to the skin. Both localized and neurologic manifestations, which occur Treatment and Prognosis and systemic forms are characterized by fibrosis 9 Onset of cutaneous in about 20% of cases. En coupe de sabre is typically a self-limited of the skin. Localized scleroderma is further disease precedes extracutaneous manifestations. disease in children. There can be softening or divided into five main subtypes on the basis of Neurologic abnormalities occur most commonly regression of skin lesions, but complete resolution clinical appearance and distribution.1 These in association with en coupe de sabre, and of these, 10 seldom occurs and reactivation is always include plaque, bullous, generalized, deep, and complex partial seizures occur most frequently. 19 possible. The long-term prognosis of en coupe linear scleroderma. Radiologic anomalies are predominantly ipsilateral de sabre in children is generally excellent. In most The incidence of localized scleroderma ranges to the skin lesion. Neuroradiologic abnormalities cases, the cosmetic defect is minimal and can from 0.4 to 2.7 per 100,000 people.2 Though can involve white-matter lesions, cerebral atrophy, be covered by the patient’s hair. Adults tend to all races may be affected, there is an increased intraparenchymal calcification, meningocortical have a more variable course, with some patients 11 CT scan of the prevalence among Caucasians, accounting variations and skull atrophy. clinically deteriorating over time. This may result 2 brain can show thinning of the skull under the for 72% to 82% of patients. There is a female in severe contractures. predominance in all subtypes of localized cutaneous lesions. MRI of the brain may show Studies have found that early intervention during scleroderma except for linear scleroderma, in focal cerebral atrophy and blurring of the gray- 9 the active phase of the lesions is most beneficial. which males and females are equally affected.1 white matter. A gadolinium-enhanced MRI of For initial management, it has been recommended There is a similar distribution among children and the brain has been recommended for all patients 12 to use methotrexate and systemic glucocorticoids, adults. In adults, the incidence peaks in the fifth with neurologic symptoms. Amaral et al. suggest that all patients, regardless of symptoms, should followed by UVA1 with or without , decade of life. In children, 90% of patients are 20,21 narrow-band UVB, or mycophenolate mofetil. diagnosed between the ages of 2 and 14 years.3-6 be considered for neuroimaging studies at the time of diagnosis given that a subset of patients Other treatment options include topical and Though the pathophysiology of scleroderma will have neurological damage without displaying intralesional glucocorticoids, vitamins E and D3, has yet to be fully elucidated, it is postulated clinical signs.9 D-penicillamine, antimalarials, retinoids, and that the fibroblasts of patients with scleroderma immunosuppressive agents such as cyclosporine The pathogenesis of scleroderma is not entirely 11 produce increased levels of extracellular and cyclophosphamide. matrix components including collagen, elastin, known. Evidence suggests it is autoimmune in Ultraviolet A light (UVA), with or without fibronectin and glycosaminoglycans.7 This nature and initiated by a provocative event, most psoralens, is an effective therapeutic option. elevated fibroblast activity can also lead to commonly local trauma to the skin. Subsequent UVA1, which is a specific wavelength increased levels of signaling and transcription endothelial-cell damage leads to an increase range of UVA, offers particularly deep skin molecules, including IL-6, pro-IL-1 alpha in fibroblast activity and ischemia secondary penetration and is believed to soften the and ICAM-1.7 This culminates in increased to narrowing of the lumen and alteration in 11 plaques by two mechanisms: causing systemic deposition of extracellular matrix components, collagen production. There have been reports of immunosuppression, and inducing enzymes that resulting in hardening of skin. a positive association between Borrelia infection and scleroderma, but there has been no evidence degrade the collagen matrix in the skin. En coup de sabre is an unusual variant of 13 of Borrelia infection in scleroderma lesions. In cases where the lesions are disfiguring and the linear scleroderma and is defined by its distinct patient pursues cosmetic improvement, surgical location involving the frontoparietal region of the Patients may also have elevated autoantibodies, repair is a corrective option. Narrow lesions can be forehead and scalp. The term “en coup de sabre” most frequently anti-nuclear antibody and treated with simple excision followed by primary was originally coined by the French to depict the anti-single stranded DNA (ssDNA) antibody. closure. Wider lesions may necessitate a more inflicted on soldiers who were struck Rheumatoid factor, anti-histone antibody, anti- elaborate reconstruction, which can include an on the head with a sword, which resulted in a phospholipid antibody and anti-topoisomerase array of flaps, implants or autologous fat or bone thickened scar on one side of the forehead. IIα antibody may also be elevated, but these are seen more commonly in generalized morphea.13 transplantation. Due to the invasiveness of these Clinically, the lesion presents as a linear, band-like, There is no autoantibody that correlates with procedures, the use of fillers, such as hyaluronic 22 ivory-colored, sclerotic plaque with violaceous disease activity.14,15 acid, have been employed as an alternative. borders. The violaceous border often surrounds the indurated plaque and has been described as a It has also been noted that patients with scleroderma have lower serum levels of vitamin D. Conclusion lilac ring. En coup de sabre is also characterized En coupe de sabre is a rare connective-tissue by atrophy and furrowing of the skin. Alopecia It is not entirely clear whether this is an incidental

Page 48 EN COUP DE SABRE: A CASE REPORT disorder, identified by its distinct location on References Souberbielle JC, Benveniste O, Amoura Z, Piette the frontoparietal scalp and forehead. Early 1. Peterson LS, Nelson AM, Su WPD. JC, Cacoub P, Costedoat-Chalumeau N. Vitamin intervention during the active phase of the disease Classification of morphea (localized scleroderma). D and . Rev Med Interne. 2012 has shown maximum benefit in overall outcomes Mayo Clin Proc. 1995 Nov;70(11):1068-76. Feb;33(2):87-93. in these patients. Scleroderma has been associated 17. Vacca A, Cormier C, Mathieu A, Kahan with low levels of vitamin D. Further studies are 2. Peterson LS, Nelson AM, Su WPD, Mason A, Allanore Y. Vitamin D levels and potential needed to elucidate whether there is a causative T, O’Fallon WM, Gabriel SE. The epidemiology impact in systemic sclerosis. Clin Exp Rheumatol. relationship between vitamin D deficiency and of morphea (localized scleroderma) in Olmsted 2011;29(6):1024-31. scleroderma. This could give insight into whether County 1960–1993. J Rheumatol. 1997;24(1):73– normalizing vitamin D levels would modify the 80. 18. Amital H, Agmon-Levin N, Sanchez- disease progression, potentially presenting a new 3. Fett N, Werth VP. Update on morphea: Castanon M, Lopez-Hoyos M, Matucci-Cerinic therapeutic focus. part I. Epidemiology, clinical presentation, M, Szucs G, Arnson Y, Shapira Y, Szekanecz and pathogenesis. J Am Acad Dermatol. Z, Shoenfeld Y. Serum 25-OH vitamin D 2011;64(2):217–228. concentrations are linked with various clinical in patients with systemic sclerosis. Ann Rheum Dis. 4. Leitenberger JJ, Cayce RL, Haley RW, Adams- 2011;70(Suppl3):482. Huet B, Bergstresser PR, Jacobe HT. Distinct autoimmune syndromes in morphea: a review 19. Eubanks LE, McBurney EI, Galen W, Reed of 245 adult and pediatric cases. Arch Dermatol. R. Linear scleroderma in children. Int J Dermatol. 2009;145(5):545–550. 1996;35:330– 336. 5. Christen-Zaech S, Hakim MD, Afsar FS, Paller 20. Fett N, Werth VP. Update on morphea: part AS. Pediatric morphea (localized scleroderma): I and II. Outcome measures and treatment. J Am review of 136 patients. J Am Acad Dermatol. Acad Dermatol. 2011;64(2):231-42. 2008;59(3):385–396. 21. Brownell I. Familial linear scleroderma (en 6. Zulian F, Athreya BH, Laxer R. Juvenile coup de Sabre) response to antimalarials and localized scleroderma: clinical and epidemiological narrow band ultraviolet B therapy. Dermatol features in 750 children: an international study. Online J. 2007;13:11. Rheumatology. 2006;45(5):614–620. 22. Walls A, Goldberg D, Foley E, Makredes 7. Trojanowska M. What did we learn by studying M. Correction of morphea en coup de sabre scleroderma fibroblasts? Clin Exp Rheumatol. with filler. J Am Acad Dermatol. 2004;22(suppl. 33):S59-S63. 2012;66(4):AB209. 8. Kister I, Inglese M, Laxer RM, Herbert Correspondence: Ashvin Garlapati, DO; J. Neurologic manifestations of localized [email protected] scleroderma: a case report and literature review. Neurology. 2008;71(19):1538–1545. 9. Amaral T, Neto J, Lapa A, Peres F, Guirau C, Appenzeller S. Neurologic involvement in scleroderma en coup de sabre. Autoimmune Dis. 2012; 2012(Article ID 719685): 6 pages. 10. Flores-Alvarado DE, Esquivel-Valerio JA, Garza-Elizondo M, Espinoza LR. Linear scleroderma en coup de sabre and brain calcification: is there a pathologic relationship? J Rheumatol. 2003;30(1):193-195. 11. Holland K, Steffes B, Nocton J, Schwabe M, Jacobson R, Drolet B. Linear scleroderma en coup de sabre with associated neurologic abnormalities. Pediatrics. 2006;117(1):132-136. 12. Kister I. Neurologic manifestations of localized scleroderma: a case report and review of the literature. Neurology. 2008;71(19):1538. 13. Miller K, Lehrhoff S, Fischer M, Meehan S, Latkowski J. Linear morphea of the forehead (en coup de sabre). Dermatol Online J. 2012;18(12):22. 14. Marzano AV. Localized scleroderma in adults and children: clinical and laboratory investigations on 239 cases. Eur J Dermatol. 2003;13(2):171-6. 15. Takehara K, Sato S. Localized scleroderma is an autoimmune disorder. Rheumatology. 2005;44 (3):274. 16. Schoindre Y, Terrier B, Kahn JE, Saadoun D,

GARLAPATI, TRIPURANENI, SKOPIT Page 49 Sickle Cell-Associated Leg Ulcers: A Case Presentation and Discussion

Jessica Bernstein, DO,* Kristen Stewart, MD, FAAD,** Stanley Skopit, DO, MSE, FAOCD***

* Dermatology Resident, 2nd year, Larkin Community Hospital/NSUCOM, Miami, FL ** Dermatologist, Advanced Dermatology and Cosmetic Surgery, Jacksonville, FL *** Program Director, Dermatology Residency Program, Larkin Community Hospital/NSUCOM, Miami, FL

Abstract This case describes a 46-year-old female with a history of sickle-cell disease and a non-healing on her lateral malleolus. Etiology, clinical presentation, and management of sickle-cell ulcers are discussed. Introduction overlying the right lateral malleolus with white- Discussion Sickle-cell leg ulcers are a frequent yellow adherent discharge centrally, undermined Sickle-cell disease (SCD) is an autosomal- of sickle-cell disease. While the pathogenesis borders, and 1 cm of surrounding erythema recessive inherited blood disorder characterized by of these ulcers is not completely understood, (Figures 1, 2). The site was tender to palpation. bone-marrow production of red blood cells with many factors are believed to contribute, No edema was present, and dorsalis pedis pulses defective, sickled hemoglobin (hemoglobin S). including trauma, mechanical obstruction, were 2+ bilaterally. A biopsy was taken to rule This occurs due to a point mutation in the DNA venous incompetence, bacterial infections, out an underlying squamous-cell carcinoma and of the β-globin subunit of adenine for thymine.1 abnormal autonomic control, , anemia . The resulting translated protein contains a with decreased oxygen carrying capacity, and The pathology revealed vaso-occlusion of substitution of the amino acid valine for glutamic 2 decreased nitric oxide bioavailability. Although superficial dermal blood vessels with overlying acid in the beta-hemoglobin chain. When the management is often difficult, it should always epidermal necrosis (Figures 3, 4). A bacterial defective hemoglobin becomes deoxygenated, include three key objectives: treatment of current culture taken after the biopsy demonstrated polymerization occurs, leading to misshapen, ulcers, managing complications, and prevention Pseudomonas aeruginosa, which was treated sickled, rigid red blood cells. Leg ulcers are the of future lesions. with ciprofloxacin. The patient was prescribed most common cutaneous manifestation of SCD a trolamine emulsion for local care and are a long-recognized complication of SCD, and zinc-sulfate supplementation, and her dating back to the first documentation of a sickle- Case Report 3,4 A 46-year-old black female with a history of pain was adequately managed with a lidocaine cell patient by Herrick in 1910. Reported sickle-cell anemia treated with hydroxyurea patch and oral gabapentin. She was referred prevalence is 2.5% in the United States, 1.5% presented to the dermatology clinic complaining to vascular surgery for evaluation of possible to 13.5% in Africa, and >40% in Jamaica, with of a non-healing wound on her right ankle for venous insufficiency. Doppler ultrasound and homozygous SS and SS α-thalassemia patients MRI were negative for venous insufficiency and having the overall highest prevalence rate of all 10 to 12 weeks. She complained of a moderate, 3,5,6 dull, constant pain and recalled wearing an ill- , respectively. genotypes. Sickle-cell-associated leg ulcers (SCU) are often painful and disabling, with slow fitting shoe that had rubbed the area prior to Considering the patient’s history and negative healing times and frequent recurrence. Limiting the development of the wound. The patient supplementary tests, the differential diagnosis mobility, they often become a hindrance to had previously seen her internist, an infectious- included sickle-cell ulcer versus hydroxyurea- education and employment. For these reasons, disease physician, and a wound-care specialist for induced ulcer. Due to concern for potentially they have a profound effect on patients’ quality of this condition. Previous treatments, including severe vaso-occlusive crisis, discontinuation 7 life and can lead to mood disturbances. anti-gout medications, a six-day oral-prednisone of hydroxyurea was not recommended by taper, topical lidocaine and collagenase ointment, hematology. She was referred to wound care, The pathogenesis of these ulcers is not completely failed to improve symptoms. She was otherwise who reported positive improvement in size, depth understood, but it is generally believed to be healthy and had no history of tobacco use or and pain with a combination of weekly surgical a multifactorial process. Proposed potential previous non-healing skin lesions. debridement and alternating topical collagenase contributing factors include mechanical On physical exam, there was a 4 cm x 3 cm ulcer gel and a triple gel containing , obstruction by dense, sickled red cells, venous levofloxacin, and . incompetence, bacterial infections, abnormal

Figure 1 Figure 2

Page 50 SICKLE CELL-ASSOCIATED LEG ULCERS: A CASE PRESENTATION AND DISCUSSION Figure 3 Figure 4

autonomic control with excessive vasoconstriction restriction. Patients should be educated regarding Hydroxyurea (HU) is an antimetabolite that when in the dependent position, in situ these preventive measures as well as on how to inhibits ribonucleotide reductase, thereby thrombosis, anemia with decrease in oxygen recognize early signs of skin injury. Treatment inhibiting DNA synthesis. It increases fetal carrying capacity, and decreased nitric oxide of existing ulcers can be challenging, and thus hemoglobin levels and red-blood-cell water bioavailability leading to impaired endothelial far there is no general consensus as to the gold content while decreasing deformability and function.8 Trauma is also believed to contribute standard of therapy. Treatment options include adhesion to vascular . Its efficacy to the development of these ulcers by triggering local wound care, surgical interventions, and in treating SCD was first demonstrated in 1990 sickling of the red blood cells.9 Areas with systemic medications.9 Topical therapies for local and has decreased the number of vaso-occlusive less subcutaneous fat, thin skin, and decreased wound care include triple antibiotic ointment, crises in severe cases.19,20 It is currently the blood flow (such as the malleoli, anterior tibia, arginine-glycine-aspartic tripeptide bound to only FDA-approved drug for SCD. While dorsal foot, and Achilles tendon) are frequently hyaluronate, and topical oxygen with a tent.3 In some authors report improvement of leg ulcers involved, with the medial malleolus being the addition, various wound-care dressings have been with hydroxyurea, others state development or most common location for sickle-cell ulcers.8 used, such as wet-to-dry dressings, Unna boots, worsening of leg ulcers with this drug.3,13,21-23 Other risk factors include age greater than 20 hydrocolloid dressings, collagen matrix dressings, Theoretically, the increase in fetal hemoglobin years old, male gender, hemoglobin less than 6 hemodialysate, and hydrophilic polyurethane should be beneficial, as populations of sickle- g/dL, lower fetal hemoglobin, antithrombin III film.3,5,10-12 Compression and activity restriction cell patients with high spontaneous rates of deficiency, and HLA types B35 or Cw4.9 can be critical to healing. Surgical interventions hemoglobin F (such as in Saudi Arabia) have a 21 Clinically, SCU appear as round, punched- include debridement to remove non-viable tissue low incidence of leg ulcers. However, it has been hypothesized that the reduced susceptibility of out ulcers with raised borders, deep bases, as well as myocutaneous flaps and split-thickness 9 erythrocytes to deformation caused by HU may necrotic slough, and at times surrounding skin grafts for extensive or recalcitrant ulcers. Unfortunately, most allografts fail due to the impair blood flow in the microcirculation, leading hyperpigmentation and scaling. These preexisting circulatory problems. A bilayered to anoxia and consequent cutaneous ulceration surrounding changes are also frequently seen skin-equivalent graft manufactured from after a minor trauma.24 Average healing time with venous ulcers. Having an active ulcer neonatal foreskin was reported to cause rapid for a hydroxyurea ulcer after discontinuing the carries a 146-fold increased risk of developing healing without recurrence.13 drug is four months, which coincides with the further ulcers, so nearby additional ulcers or 3 known 120-day survival of the circulating red scarring from previous ulcers may be observed. Reported systemic treatments for SCU include 22 While definitive, randomized Biopsies are often nonspecific; however, vascular zinc sulfate, pentoxifylline, antithrombin III, blood cells. controls are still needed to further elucidate the obstruction of superficial dermal blood vessels L-carnitine, arginine butyrate, hydroxyurea, relationship between this drug and SCU, careful by the rigid, inflexible, sickled red blood cells erythropoietin, and transfusions. Oral zinc attention should be given to skin changes during with overlying tissue necrosis may be seen. sulfate improves the anemia of SCD and is also 21 14 HU treatment in patients with SCD. Adding Additional work-up of a patient with suspected a key element in . Pentoxifylline, recombinant human erythropoietin aided in ulcer SCU includes venous and arterial studies to an effective medication for decreasing vaso- healing in one case study and may be an option assess underlying peripheral vascular status, occlusive crises in SCD, was reported successful 25 15 for patients who are unable to discontinue HU. peripheral blood smear, complete blood count, in one case of SCU. It is thought to work by folate, iron, vitamin B12, homocysteine, liver decreasing sickling of red blood cells, increasing Transfusions of packed red blood cells are enzymes, renal function, urinalysis, D-dimer, and erythrocyte deformability, increasing leukocyte commonly used to prevent and treat many hemoglobin electrophoresis to measure the levels flexibility, inhibiting platelet aggregation, complications of SCD, including anemia, acute of hemoglobins A, S, and F.9 reducing blood viscosity, and decreasing plasma chest syndrome, and .26 9 Management of SCU includes three key fibrinogen levels. In a case of concomitant Despite a lack of controlled trials, they have also antithrombin III deficiency, heparin and points: treatment of current ulcers, managing been utilized as a mode of therapy for recalcitrant antithrombin III concentrate successfully treated complications, and prevention of future lesions. SCU. However, the procedure has several risks a patient’s ulcer.16 L-carnitine, an efficacious 27 Preventative measures include maintaining the including iron overload and alloimmunization. treatment for ischemic heart disease, peripheral skin barrier function with liberal use of emollients, Other recent, developing advances in therapy arterial disease, and vasculopathic leg ulcers, has evading trauma by wearing properly fitting shoes include topical granulocyte-macrophage colony- been demonstrated to aid in healing of SCU in and using insect repellent, and promoting good stimulating factor, negative-pressure therapy, case reports.17 Arginine butyrate, which increases venous drainage and minimizing stasis through low-level laser therapy, oral bosentan, and heparin fetal hemoglobin synthesis, rapidly healed one 28-32 , leg elevation, and salt sulfate. Additional randomized, controlled patient’s ulcer.18

BERNSTEIN, STEWART, SKOPIT Page 51 t rials are required to better assess their use in a References patients with sickle cell disease to treatment with more widespread population. 1. Rees DC, Williams TN, Gladwin MT. Sickle hydroxyurea. N Engl J Med. 1990;322:1037-45. Infections are a common complication of cell disease. Lancet. 2010;376:2018-31. 20. Charache S, Terrin ML, Moore RD, et sickle-cell ulcers. The most common organisms 2. Bunn HF. Pathogenesis and treatment of sickle al. Effects of hydroxyurea on the frequency of are and Pseudomonas cell disease. New Engl J Med. 1997;337:762-9. painful crises in sickle cell anemia. N Engl J aeruginosa.27 As bacteria may impair would Med. 1995;332:1317-22. healing, the use of appropriate antimicrobials is an 3. Eckman JR. Leg ulcers in sickle cell disease. 21. Chaine B, Neonato MG, Girot R, Aractingi important component of treatment. Additionally, Hematol Oncol Clin North Am. 1996;10:1333- S. Cutaneous adverse reactions to hydroxyurea in if underlying osteomyelitis is suspected, MRI, 44. patients with sickle cell disease. Arch Dermatol. bone scan or bone biopsy may be required to rule 4. Herrick JB. Peculiar elongated and sickle- 2001;137:467-70. out this severe complication. shaped red blood corpuscles in a case of severe 22. Velez A, Garcia-Aranda, JM, Moreno Pain management is another integral part of SCD anemia. 1910. Yale J Biol Med. 2001;74:179-84. JC. Hydroxyurea-induced leg ulcers: is therapy. Commonly used oral pain medications 5. Koshy M, Entsuah R, Koranda A, et al. Leg macroerythrocytosis a pathogenic factor. J Eur include acetaminophen, non-steroidal anti- ulcers in patients with sickle cell disease. Blood. Acad Dermatol Venereol. 1999;12:243-4. inflammatory drugs, cyclooxygenase-2 inhibitors, 1989;74:1403-8. , , antidepressants, and 23. Kersgard C, Osswald M. Hydroxyurea and .9 However, there are anecdotal 6. Nolan VG, Adewoya A, Baldwin C, et al. Sickle sickle cell leg ulcers. Am J Hematol. 2001;68:215- reports of topical opioids offering total pain relief cell leg ulcers: associations with hemolysis and 6. for SCUs. Ballas described two patients, one SNPs in Klotho, TEK and genes of the TGF- beta pathway. Br J Hematol. 2006;133:570-8. 24. Sirieix ME, et al. Leg ulcers and hydroxyurea: treated with one tablet of oxycodone dissolved in forty-one cases. Arch Dermatol. 1999;135:818- 1 mL to 2 mL of water mixed with debridement 7. Halabi-Tawil M, Lionnet F, Girot R, Bachmeyer 20. ointment, the other with one 100 mg tablet of C, Lévy PP, Aractingi S. Sickle cell leg ulcers: a meperidine dissolved in water and applied with frequently disabling complication and a marker 25. Al-Momen AK. Recombinant human xylocaine ointment. Both patients reported of severity. Br J Dermatol. 2008;158:339-44. erythropoietin induced rapid healing of a chronic almost immediate pain relief and an ability to leg ulcer in a patient with sickle cell disease. Acta 8. Minniti CP, Eckman J, Sebastiani P, Steinberg significantly reduce their consumption of oral Haematol. 1991;86:46-8. MH, Ballas SK. Leg ulcers in sickle cell disease. opioids.33 Am J Hematol. 2010;85:831-3. 26. Cho G, Hambleton IR. Regular long- term red blood cell transfusions for managing 9. Trent JT, Kirsner RS. Leg ulcers in sickle cell chronic chest complications in sickle cell Conclusion disease. Adv Skin Wound Care. 2004;17:410-6. Sickle-cell ulcers are a common and difficult disease. Cochrane Database Syst Rev. 2011 Sep complication of sickle-cell disease. They present 10. Cackovic M, Chung C, Bolton LL, Kerstein 7;(9):CD008360. as round, punched-out ulcers on areas with thin MD. Leg ulceration in sickle cell patient. J Am 27. Ladizinski B, Bazakas A, Mistry N, Alavi A, skin and decreased blood flow, most commonly Coll Surg. 1998;187:307-9. Sibbald RG, Salcido R. Sickle cell disease and leg the medial malleolus. Their pathogenesis is not 11. La Grenade L, Thomas PW, Serjeant GR. ulcers. Adv Skin Wound Care. 2012;25:420-8. yet fully elucidated but seems to be multifactorial. A randomized controlled trial of solcoseryl and 28. Mery L, Girot R, Aractingi S. Topical Management consists of prevention, controlling duoderm in chronic sickle-cell ulcers. West effectiveness of Molgramostim (GM-CSF) in complications, and treating existing wounds. Indian Med J. 1993;42:121-3. sickle cell leg ulcers. Dermatol. 2004;208:135-7. Treatment of the ulcers is difficult and often requires a combination of topical medications, 12. Fried M, Golan J. Treatment of leg ulcers in 29. Oliviera Paggiaro A, et al. Negative pressure dressings, compression, debridement and even sickle cell disease. Blood. 1990;75:2467. therapy for complex wounds in patients with systemic therapies. The role of hydroxyurea is 13. Gordon S, Bui A. Human skin equivalent sickle-cell disease: a case study. Ostomy Wound not yet fully determined; it could possibly help, in the treatment of chronic leg ulcers in sickle Manag. 2010;56:62-7. worsen, or have no effect on patients’ ulcers. The cell disease patients. J Am Podiatr Med Assoc. 30. Bonini-Domingos CR, Valente FM. Low- risk-to-benefit ratio must be considered when 2003;93:240-1. level laser therapy of leg ulcer in sickle cell anemia. initiating or discontinuing this medication in a 14. Serjeant GR, Galloway RE, Gueri MC. Rev Bras Hematol Hemoter. 2012;34:64-7. patient with sickle-cell disease. Oral zinc sulfate in sickle cell ulcers. Lancet. 31. Lionnet F, et al. Efficacy of the endothelin 1970;2:891-2. receptor blocker bosentan for refectory sickle cell 15. Frost ML, Treadwell P. Treatment of sickle leg ulcers. Brit J Haematol. 2008;142:991-2. cell leg ulcers with pentoxifylline. Int J Dermatol. 32. Hayek S, Dibo S, Baroud J, Ibrahim A, 1990;29:375-6. Barritault D. Refractory sickle cell leg ulcer: is 16. Cacciola E, Musso R, Giustolisi R, Alessi M. heparan sulphate a new hope? Int Wound J. 2014 Blood hypercoagulability as a risk factor for leg Feb 21. doi: 10.1111/iwj.12217. [Epub ahead of ulcers in sickle cell disease. Blood. 1990;75:2467- print] 8. 33. Ballas SK. Treatment of painful sickle cell leg 17. Serjeant BE, Harris J, Thomas P, Serjeant GR. ulcers with topical opioids. Blood. 2002;99:1096. Propionyl-L-carnitine in chronic leg ulcers of homozygous sickle cell disease: a pilot study. J Am Acad Dermatol. 1997;37:491-3. Correspondence: Jessica Bernstein, DO; [email protected] 18. Sher GD, Olivieri NF. Rapid healing of chronic leg ulcers during arginine butyrate therapy in patients with sickle cell disease and thalassemia. Blood. 1994;84:2378-80. 19. Rodgers GP, Dover GJ, Noguchi CT, Schecter AN, Niehuis AW. Hematologic responses of

Page 52 SICKLE CELL-ASSOCIATED LEG ULCERS: A CASE PRESENTATION AND DISCUSSION Twenty-nail Dystrophy in a 42-year-old Woman: A Case Report

Chelsea Duggan, DO,* Kristin Rongstad, BS,** Matthew Elias, DO, FAOCD***

* PGY-1 Traditional Intern, Garden City Hospital, Garden City, MI ** OMS III, Nova Southeastern University, Ft. Lauderdale, FL *** Dermatologist, Private Practice, Lighthouse Point, FL

Abstract Twenty-nail dystrophy is a nail disorder that commonly affects all 20 nails. We are report a case affecting a 42-year-old female with co-existing alopecia areata.

Introduction Figure 1 Twenty-nail dystrophy (TND), also known as trachyonychia, is a nail disorder commonly affecting all 20 nails. It may present as an idiopathic finding, a familial condition, or occurring in association with other dermatologic conditions, most commonly alopecia areata, psoriasis, or lichen planus. Here we present a case of a 42-year-old female with TND and co- existing alopecia areata (AA). Although TND is often self-limiting, many patients seek treatment secondary to the cosmetic appearance. There is not a well-known and universally accepted treatment for TND. Our patient was successfully treated with the daily application of flurandrenolide tape and urea 45% topical gel to all of her nails, along with biotin 5,000 mcg daily.

Case Report A 42-year-old female with an unremarkable past medical history originally presented with a chief complaint of hair loss to the scalp, onset four months prior. During this initial encounter, the patient also had a secondary complaint that all of her fingernails and toenails had been painful and Figure 2 thinning for the past year. She stated that she had tried treating the nail problem with terbinafine, as well as fluconazole ointment, neither of which had improved her symptoms. On physical exam, she was found to have an annular area to the scalp that was devoid of hair, as well as thinning of the nail plates to all of her fingernails (Figure 1) and toenails. The exam was otherwise unremarkable. After diagnosing the patient with alopecia areata (AA) of the scalp and discussing options with the patient, a 3 mm punch biopsy was performed to the third digit of the left hand to further investigate her nails. Dermatopathology results showed a diagnosis of with intraungual serum deposition (Figure 2). The changes in the sections were subtle and consistent with nail lichen planus. A dermatopathology consultation was also obtained, and again, nail changes most consistent with lichen planus were found. These findings, along with the concurrent AA, confirmed a diagnosis of trachyonychia and nail lichen planus. Had we not done a nail-matrix biopsy, it would have been assumed that the nail changes were secondary to the alopecia areata.

DUGGAN, RONGSTAD, ELIAS Page 53 The patient was instructed to take biotin 5,000 The pathology often shows these subtypes: mcg daily and apply flurandrenolide tape daily to eczematous/dermatitis, lichen planus-like, and/or References 1 1. Sehgal, VN. Twenty-nail dystrophy all of her nails. She was also prescribed urea 45% psoriasiform histopathology. The microscopic trachyonychia: an overview. J Dermatol. topical gel to be applied to the nails daily. She examination of the eczematous form may show 2007;34:361-6. opted to have triamcinolone acetonide injected spongiotic inflammatory changes of the nail to the annular area of the scalp. In her follow- matrix (most common), lymphocytic infiltrates, 2. Commons, C. Twenty nail dystrophy in up appointments, she reported that she had been or exocytosis of the lymphocytes in the nail identical twins. Pediatr Dermatol. 1988;5(2):117- compliant with our treatments and was found epithelia.1,9 The lichen planus-like morphology 119. to have marked improvement of the pain and sections may show widespread , 3. Gordon KA, Vega JM, Tosti A. Trachyonychia: thinning of the nails, as well as re-growth of hair hypergranulosis, or a lymphohistiocytic infiltrate A comprehensive review. Indian J Dermatol 1 to her scalp lesion. and degeneration of basal keratinocytes. Lastly, Venereol Leprol. 2011;77:640-5. the psoriasiform histology sections may show acanthosis and parakeratosis with grouping of 4. Pucevich B, Spencer L, English JC. Unilateral Discussion polymorphonuclear leukocytes along the nail trachyonychia in a patient with reflex sympathetic Twenty-nail dystrophy, also known as 1 dystrophy. J Am Acad Dermatol. 2008;58:320. trachyonychia, is a disorder that most commonly plate. affects all 20 nails. It is a well-known disease There is no generally accepted first-line treatment 5. Grover C, Khandpur S, Reddy BS, Chaturvedi, and diagnosed based on clinical features and for TND. Treatment modalities range from U. Longitudinal Nail Biopsy: Utility in 20-Nail confirmed via biopsy.1 The causes of twenty-nail intralesional injections to intramuscular injections Dystrophy. Dermatol Surg. 2003;29:1125–1129. dystrophy (TND) can either be congenital, as in as well as systemic and topical preparations. Some 6. Scheinfeld, NS. Trachyonychia: A case report familial TND, or acquired in association with of the treatment modalities that have been used and review of the manifestations, associations, various dermatologic conditions.2 It was first are PUVA ( plus ultraviolet A light), and treatment. Cutis. 2003;71:299-302. described in 1950 by Alkiewicz.3 Twenty-nail acitretin, tazarotene gel 0.1%, triamcinolone 7. Tosti A, Fanti AF, Morelli R, Bardazzi F. dystrophy is characterized by a rough, sandpaper- acetonide IM injection, triamcinolone Trachyonychia associated with alopecia areata: like, lackluster appearance of the nails. Other intralesional injections, oral prednisolone, topical A clinical and pathologic study. J Am Acad possible nail findings include elevation/pitting, 5-fluorouracil 5% cream, intra-matrix steroids Dermatol. 1991;25:266-270. splitting, thinness, brittleness and/or a musky- with or without griseofulvin (10mg/kg for six grayish color. A less common form of TND is months), and oral biotin therapy.1,3,8 Sakata et al. 8. Blanko FP, Scher RK. Trachyonychia: Case characterized mostly by pitting and a “shiny” found in a follow-up study of 12 trachyonychia report and review of the literature. J Drugs color.3 TND is usually bilateral and symmetric.1 patients that regardless of treatment modality, Dermatol. 2006;5:469-473. If unilateral nail changes are found, one should 50% of the patients had resolution or significant 9. Khandpur S, Bansal A, Sharma VK, Bhatti SS, investigate the possibility of reflex sympathetic improvement of their within six 4 12 Singh MK. Twenty nail dystrophy in vitiligo. J dystrophy. years. Dermatol. 2007;34:189-192. TND is thought to have an autosomal-dominant 10. Seval DK, Pinar O, Serap P. Coexistence of mode of inheritance and often presents during Conclusion psoriasis, and alopecia areata with trachyonychia childhood or at birth.1,5 The condition tends to In summary, trachyonychia is a nail disorder 1 in a pediatric patient with . have a slow progression. TND has been described commonly affecting all 20 nails. It may present Arch Argent Pediatr. 2014;112:5. occasionally in adults but most commonly affects as an idiopathic finding or along with other children 3 to 12 years of age.3,6 TND has an equal dermatologic conditions, most commonly AA, 11. Tosti A, Bardazzi F, Piraccini BM, Fanti PA, predilection for females and males.1,7 TND is psoriasis, or lichen planus. Our patient did have Cameli N, Pileri S. Is Trachyonychia, a variety often idiopathic, but occasionally an associated an associated etiology of AA. The most common of alopecia areata, limited to the nails? J Invest etiology is found.8 There is some question of a histopathological findings are spongiosis and Dermatol. 1995;104(5 Suppl):27S-28S. relationship with various other dermatologic lymphocytic exocytosis, although the disorder is 12. Sakata S, Howard A, Tosti A, Sinclair R. 3,13 conditions, such as vitiligo, psoriasis, eczema, usually diagnosed based on clinical appearance. Follow up of 12 patients with trachyonychia. lichen planus, alopecia areata/universalis, Many treatment modalities have been tried, Australas J Dermatol. 2006;47:166. vulgaris, sarcoidosis, immunoglobulin as there is not a universally accepted treatment 13. Tosti A, Bardazzi F, Piraccini BM, Fanti (Ig)A deficiency, sarcoidosis, and graft-versus- regimen. However, depending on the cause of 1,3,8,9 PA. Idiopathic trachyonychia (twenty-nail host disease, among others. The most the TND, treatment may not be necessary, as it dystrophy): a pathological study of 23 patients. common associations and causes of TND are is a self-limiting disease that usually improves 3 5 Br J Dermatol. 1994;131:866-872. alopecia areata, psoriasis, and lichen planus. The spontaneously, especially in children. strong association of TND with dermatologic conditions that have an autoimmune etiology Correspondence: Kristin Rongstad; kr734@ has raised the suspicion that the nail changes nova.edu could be immunologically mediated.10 In a study by Tosti et al., 40 of the 1,095 patients with AA had been diagnosed with trachyonychia.7,11 They found that trachyonychia occurs in approximately 3% of adults.7,11 Tosti et al. also noted that while nail changes may precede or follow the onset of alopecia, the two conditions often arise simultaneously.7,11 There was also found to be no association between the course of AA and the course of TND.7 In a study by Grover et al., AA was found to be the most common abnormality associated with trachyonychia.5 To confirm the diagnosis of TND, a nail biopsy is often performed. The specimen should be a longitudinal biopsy or a nail-matrix punch biopsy.1,3 Page 54 TWENTY-NAIL DYSTROPHY IN A 42-YEAR-OLD WOMAN: A CASE REPORT Urticaria Pigmentosa: A Case Report and Review of Current Standards in the Diagnosis of Systemic Mastocytosis

Riddhi J. Shah, DO,* Mark A. Kuriata, DO, FAOCD**

*Dermatology Resident, 2nd year, MSUCOM/Lakeland Regional Medical Center, St. Joseph, MI **Dermatology Residency Program Director, MSUCOM/Lakeland Regional Medical Center, St. Joseph, MI

Abstract Mastocytosis is a group of diseases that is characterized by mast-cell infiltration of the skin. The cutaneous forms of the disease are most identifiable, yet it is important to recognize the progression to systemic disease due to the eaffect on morbidity and mortality. We Our goal is to describe a case of cutaneous mastocytosis as well as review the current standards in diagnosis and management of systemic mastocytosis. Introduction patient had several bouts of loose stools. This and spleen did not reveal any organomegaly. Mast-cell disease is a rare disorder, primarily was accompanied by and indigestion, Muscle strength and tone appeared to be within of childhood, that is usually self-resolving. which occurred 30 minutes after a meal. A normal limits. There were no palpable lymph Approximately two-thirds of cases are limited to colonoscopy was performed one year prior at an nodes in the neck, axillae or groin regions. outside facility, and it was within normal limits. the skin. The most common forms of cutaneous Our differential diagnosis included systemic However, no biopsies were performed to look mastocytosis include: mastocytoma, urticaria mastocytosis as well as syndrome, for mast-cell infiltration of the digestive tract. pigmentosa, telangiectasia macularis eruptiva , inflammatory bowel disease, Our patient also had sharp, intermittent, left perstans, maculopapular cutaneous mastocytosis, urticaria, and myeloproliferative disorder. and diffuse cutaneous mastocytosis.1 Our upper quadrant abdominal pain that radiated to Through a collaborative effort between case report presents a patient with a history the left chest and shoulder. Remaining review of dermatology and hematology/oncology, an of urticaria pigmentosa (UP) that had not systems was negative except for occasional mild extensive workup to rule out SM was performed. resolved as expected. Furthermore, she started headaches and lightheadedness. She admitted Initially, punch biopsies of the right shin and to develop symptoms that raised concern for to mild generalized pruritus for which she left dorsal forearm revealed cutaneous mast-cell possible systemic mastocytosis (SM). Based took and cimetidine as needed. In disease. Stains were positive for mast-cell tryptase upon our literature search, systemic mastocytosis addition, she experienced easy flushing, which and CD117 (Figure 5, p. 56). Complete blood is an extremely rare diagnosis, but a potentially was more pronounced while exercising and count with differential, comprehensive metabolic life-threatening one. This paper will help Uthis drinking alcohol. profile, lactate dehydrogenase, fractionated dermatologists become more familiar with The patient had a past medical history of mild catecholamines, IgE level, and uric acid were worrisome signs/symptoms, diagnostic criteria, asthma and attention deficit hyperactivity all within normal limits. Serum tryptase level and treatments for systemic disease. disorder.. Social history included rare alcohol use, was 14.8. Additionally, she underwent imaging smoking one1 pack of cigarettes per day, and no studies including a CT scan of the chest, illicit drugs. She was also exposed to different abdomen, and , abdominal ultrasound, and Case Report cleaning daily as a carpet cleaner. Family A 20-year-old Caucasian female with a history skeletal survery, which were all unremarkable. history wasis non-contributory. of urticaria pigmentosa since childhood A bone-marrow biopsy was performed andthat presented to our office for initial evaluation of The physical examination revealed a subtle but showed at least 15 clusters of dense mast-cell worsening symptoms involving multiple organ diffuse, reddish-purple, mottled, reticular, macular aggregates (Figure 6, p. 56). However, flow systems. She complained of bone pain often discoloration involving the bilateral upper and cytometry did not reveal expression of CD2 or localized to the bilateral . In addition, the lower extremities, chest, abdomen, and back CD25 on CD117+ mast cells. Additionally, only (Figure 1-4, p. 55/56). about 10% of the mast cells were spindle-shaped Figure 1 The head and neck within the bone marrow smear as opposed to were uninvolved. Upon greater than 25%. Furthermore, our patient tested stroking lesions on the negative for KIT D816V mutation. bilateral forearms, the Taking into account the clinical presentation, areas became swollen, positive histopathology, and laboratory and itchy, and red, illiciting bone-marrow findings, our patient did not meet a positive Darier’s sign. the full criteria for the diagnosis of SM. For UP, Examination of the liver Figure 2

SHAH, KURIATA Page 55 Figure 3 Figure 4 cell mediators in cutaneous and extracutaneous tissues. Symptoms that may raise suspicion include , vomiting, abdominal pain, bloating, diarrhea, flushing, pruritus, bone pain, , chills, weight loss, , headaches, syncope, difficulty concentrating, anxiety, and depression. Physical assessment may reveal organomegaly, predominately involving the liver or spleen, lymphadenopathy, gastroduodenal ulcerations, and signs of end-organ such as elevated transaminases, , and portal hypertension in advanced disease forms.6 In addition, one should investigate for skin findings consistent with reddish-brown, maculopapular, plaque-like, bullous or nodular lesions, diffuse skin involvement, solitary mastocytoma, telangiectasias, and positive Darier’s sign. These findings may indicate a new or prior diagnosis of cutaneous mastocytosis and will help with the workup for systemic disease.7 The next step involves obtaining a . Special stains including Wright-Giemsa, Toludine blue, tryptase, and CD117 should be 8 the patient was started on histamine H2-receptor Mastocytosis is more common in children than ordered. In addition, laboratory investigation antagonists, ranitidine 150 mg by mouth twice adults. Over 50% of children are diagnosed prior should include complete blood count with daily and famotidine 20 mg by mouth daily, as to two years of age, and disease is usually limited to differential. The peripheral blood picture can show well as a mast-cell stabilizer, cromolyn 200 mg the skin. Most children will spontaneously resolve anemia, thrombocytopenia, and leukocytosis. by mouth three times daily to control mast- by . In contrast, initial diagnosis of Some patients with SM may also present with cell activation. Additionally, she was given an cutaneous mastocytosis as an adult increases elevated eosinophils, basophils, and/or platelets. epinephrine autoinjector in case of anaphylactic the likelihood of developing systemic disease. Myeloproliferative or myelodysplastic changes reactions. We suggested she also minimize The median age at diagnosis of SM in adults can also be seen. exposure to cleaning solvents as this may be a is 55 years, with a slight male predominance. Occasionally, it may be feasible to obtain imaging potential aggravating factor. On follow-up, our The incidence of systemic disease is extremely studies in order to identify the extent or stage of patient’s symptoms had improved. , a rare.4 Neither cutaneous nor systemic forms of disease. For example, computed tomography scan, histamine H1-, was also added mastocytosis appear to be inherited. endoscopy/colonoscopy, or abdominal ultrasound to the regimen. In addition, we are considering Mutations of KIT have been implicated in the may be considered in patients who present with phototherapy as an adjuvant treatment. pathogenesis of both cutaneous and systemic primarily gastrointestinal complaints. Skeletal The patient continues to be closely monitored mastocytosis. Mast cells express c-kit tyrosine surveys and dual-energy X-ray absorptiometry by both dermatology and oncology for potential kinase receptor on their surface, which serves as scans may be helpful in patients with suspected bone involvement such as osteoporosis, osteolysis, risk of full-blown SM in the future. There is a site for attachment of stem-cell factor (SCF). 8 a likelihood that her disease will continue to SCF is a growth factor needed for the normal and evaluation for pathological fractures. progress. As a result, the patient was advised to development and expansion of mast cells. In However, it is not necessary to evaluate follow up every four to six months for repeat labs. mastocytosis, there is a pathologic activation of extramedullary tissues for the presence of mast cells to make the diagnosis of SM if the bone There is also a possibility that the patient may the c-kit receptor, leading to unregulated clonal 6 exhibit a wild-type KIT mutation other than expansion and activation of mast cells. The most marrow is being examined. D816V, and it may be prudent to include the full common mutation in systemic mastocytosis is Bone-marrow analysis is of crucial importance KIT mutation-panel testing at a future visit. on codon 816 replacing aspartic acid for valine. in the diagnosis of SM. The presence of multiple This is seen in up to 93% percent of patients aggregates of mast cells in bone-marrow aspirate 5 Discussion with systemic mastocytosis. Recently, additional is the major diagnostic criterion for SM as Mastocytosis is a group of diseases that is mutations have been identified. determined by the World Health Organization characterized by mast-cell infiltration of the Initial workup for SM involves a thorough (WHO). Each aggregate should contain skin.¹ Mast cells originate from CD34- antigen- history and physical examination looking for greater than 15 mast cells. The cells are usually positive, pluripotent progenitor cells in the bone clinical clues to indicate an excess release of mast- located paratrabecularly, but they can also been marrow. From within their granules, tThey Figure 6 release from within their granules mediators Figure 5 such as histamine, heparin, chymase, tryptase, leukotrienes B4, C4, E4, platelet-activating factor, and prostaglandin D2.2 Mastocytosis was first discovered in 1869 by Nettleship and Tay, who recognized the classic cutaneous form of disease now known as urticaria pigmentosa. It was not until 1949 that Ellis discovered mast cells within a patient’s liver, spleen, lymph nodes, and bone marrow, suggesting that it may also be a systemic disease.3

Page 56 URTICARIA PIGMENTOSA: A CASE REPORT AND REVIEW OF CURRENT STANDARDS IN THE DIAGNOSIS OF SYSTEMIC MASTOCYTOSIS 6 seen around vessels and adnexal structures. In References addition, there are several bone-marrow findings 1. Lladó AC, Mihon CE, Silva M, Galzerano A. in the WHO minor criteria for SM, which Systemic mastocytosis - a diagnostic challenge. include the following: 1) more than 25% of Rev Bras Hematol Hemoter. 2014 May- mast-cell infiltrates demonstrating an abnormal Jun;36(3):226-9. spindle-shape; 2) flow cytometry of bone-marrow preparation demonstrating mast cells that 2. Gordon JR, Burd PR, Galli SJ. Mast cells as express CD2 and/or CD25; and 3) polymerase- a source of multifunctional cytokines. Immunol chain-reaction evaluation of bone-marrow cells Today. 1990; 11:458-464. 6,8 detecting a positive mutation of KIT D816V. 3. Metcalfe DD. Mast cells and mastocytosis. This mutation can also be evaluated via a blood Blood. 2008;112:946-956. test. Along with a serum tryptase level greater than 20 ng/mL, these four findings account 4. Lim KH, Tefferi A, Lasho TL, et al. Systemic for the WHO minor criteria for SM.9 In order mastocytosis in 342 consecutive adults: to make a diagnosis of SM, an individual must survival studies and prognostic factors. Blood. present with one minor and one major criterion 2009;113(23):5727-36. or three minor criteria. 5. Piao X, Paulson R, van der Geer P, Pawson The treatment of mast-cell disease is multifaceted. T, Bernstein A. Oncogenic mutation in the Kit First and foremost, patients should avoid triggers receptor tyrosine kinase alters substrate specificity such as excess heat, intense exercise, insect and induces degradation of the protein tyrosine and snake bites, medications like aspirin and phosphatase SHP-1. Proc Natl Acad Sci U S A. non-steroidal anti-inflammatory drugs, and 1996 Dec 10;93(25):14665-9. alcohol.6 In addition, some muscle relaxants and 6. Bains SN, Hsieh FH. Current approaches inducing agents used during surgery for general to the diagnosis and treatment of systemic anesthesia may cause mast-cell mediator release mastocytosis. Ann Allergy Asthma Immunol. and potentially cause anaphylactic reaction. 2010 Jan;104(1):1-10. Radiocontrast media may cause a similar 7. Soter NA. Mastocytosis and the skin. Hematol reaction.10 Oncol Clin North Am. 2000;14:537. H1 histamine- receptor antagonists (H1) such 8. Valent P, Horny HP, Escribano L, Longley as lorataidine and hydroxyzine are the first- line BJ, Li CY, Schwartz LB, Marone G, Nuñez treatments for symptoms caused by mast- cell R, Akin C, Sotlar K, Sperr WR, Wolff K, mediator release. These help control urticaria and Brunning RD, Parwaresch RM, Austen KF, pruritus. Psoralen plus ultraviolet A (PUVA) Lennert K, Metcalfe DD, Vardiman JW, Bennett therapy can also improve pruritus by reducing JM. Diagnostic criteria and classification of histamine release. Gastrointestinal symptoms mastocytosis: a consensus proposal. Leuk Res. respond better to H2 histamine-receptor 2001 Jul;25(7):603-25. antagonists (H2)like cimetidine and ranitidine.11 Cromolyn sodium helps decrease diarrhea, 9. Sperr WR, Jordan JH, Fiegl M, Escribano L, , and bloating.6 Bellas C, Dirnhofer S, Semper H, Simonitsch- Klupp I, Horny HP, Valent P. Serum tryptase Individuals who demonstrate signs of levels in patients with mastocytosis: correlation osteoporosis benefit from calcium and vitamin D with burden and implication for supplementation and may need bisphosphonates defining the category of disease. Int Arch Allergy depending on the severity of disease. In addition, Immunol. 2002 Jun;128(2):136-41. all patients should be given an epinephrine autoinjector and instructed on its use in case 10. Marone G, Stellato C, Mastronardi P, of . Patients with more aggressive Mazzarella B. Nonspecific histamine-releasing subvariants of SM may qualify for cytoreductive properties of general anesthetic drugs. Clin Rev therapies such as mesylate, interferon Allergy. 1991 Fall-Winter;9(3-4):269-80. 6 alpha, and cladribine. These treatments are not 11. Tebbe B, Stavropoulos PG, Krasagakis curative but are intended to improve symptoms K, Orfanos CE. Cutaneous mastocytosis in and quality of life. adults. Evaluation of 14 patients with respect to systemic disease manifestations. Dermatology. Conclusion 1998;197(2):101-8. This case highlights the important role that 12. Wilson TM, Metcalfe DD, Robyn J. dermatologists play in the recognition of Treatment of systemic mastocytosis. Immunol cutaneous mastocytosis progressing to systemic Allergy Clin North Am. 2006 Aug;26(3):549-73. disease. It is imperative to perform a thorough history, physical, and review of systems in all Correspondence: Riddhi J. Shah, DO; patients with cutaneous mastocytosis to help MSUCOM/Lakeland Regional Medical initiate a comprehensive work up. Systemic Center, 1234 Napier Ave., St. Joseph, MI disease can be quite aggressive and potentially 49085; Ph: (269)-429-7546; F: (269)-429-0807; life-threatening. Timely diagnosis and early [email protected] treatment can decrease morbidity and mortality.

SHAH, KURIATA Page 57 HALOG Cream and Ointment are designed for a difference your patients can truly feel.

BIPHASIC CREAM for sustained relief.1,2 PLASTIBASE® OINTMENT for enhanced spreadability and appeal.3

INDICATIONS AND USAGE: HALOG (Halcinonide, USP) 0.1% is indicated for the relief of the infl ammatory and pruritic manifestations of corticosteroid-responsive dermatoses. For topical use only. For Important Safety Information, please see Brief Summary on reverse. For full Prescribing Information see Product Package Insert at HalogRx.com REFERENCES: 1. Blecker, J. Double-blind comparison between two new topical steroids, halcinonide 0.1% and cream 0.05%. Curr Med Res Opin. 1975;3:225-228. 2. Bagatell FK. Halcinonide: a new potent anti-infl ammatory drug. Cutis. 1974:14:459-462. 3. Thau P, Fox C. A new procedure for the preparation of polyethylene- mineral oil gels. J Soc Cosmet Chem. 1965;16:359-363.

HALOG® is a registered trademark of Ranbaxy Laboratories Inc. All other trademarks are property of their respective owners. HLG0020B 07/15

1560 Sherman Avenue, Evanston, IL 60201-4808 Voice: (847) 328-2256 Fax: (847) 328-0509 Dermatology [email protected] Foundation dermatologyfoundation.org SHAPING THE FUTURE OF DERMATOLOGY

Ronald R. Brancaccio, M.D. Receives Dermatology Foundation Practitioner of the Year Award

At its recent annual meeting of membership in San Francisco, the Dermatology Foundation recognized the many contributions that Ron R. Brancaccio, M.D. has made to dermatology by honoring him with the 2014 Practitioner of the Year Award. The award honors the exemplary clinical care Brancaccio provides for his patients as well as his significant contributions to the field through leadership and teaching.

A close colleague lauds Dr. Brancaccio for his “years of service to his many grateful patients, and to our specialty for sharing his expertise in contact dermatitis.” For Dr. Brancaccio, it is primarily about his patients. “It is amazing how much personal satisfaction I experience every day from my patients. There is nothing comparable to it,” he says.

Dr. Brancaccio became interested in dermatology in medical school. “It is very visual, and just seemed to click with the way my brain processes information.” And after he traveled west from George Washington University School of Medicine to take dermatology electives at Stanford and then Oregon Health Sciences University (OHSU), “I knew this was the direction I wanted to go in.”

He completed his residency at OHSU where—he explains—he benefited tremendously from the mentorship of Dr. Frances Storrs, an early prime mover in contact dermatitis. Then Dr. Brancaccio returned to NYC and spent three years working with another early leader in contact dermatitis, Dr. Alexander Fisher.

Dr. Brancaccio’s overarching goal was to open his own practice while also maintaining an academic presence. He began in the late 1970s with a small office in Brooklyn in the neighborhood where he grew up. Then several years later he added a location in Greenwich Village in Manhattan, where he lived. Dr. Brancaccio has been affiliated with the NYU Medical School for nearly 40 years, where he is now Clinical Professor of Dermatology, teaching residents in the contact dermatitis clinic. Dr. Brancaccio has also shared his expertise through his many lectures and publications over the years, and ran patch testing courses at the AAD meetings until the technique finally became widespread.

Longtime friend and colleague, Dr. Frances Storrs, presented Dr. Brancaccio with this year’s award and noted that Dr. Brancaccio “has published 49 articles, almost always with a resident, young faculty member, or medical student. As a mentor and roll model, he is superb.”

Dr. Brancaccio has held a variety of leadership positions, including president of the New York Dermatological Society, the Dermatological Society of Greater New York, and the American Contact Dermatitis Society. Other honors have included Clinical Attending Physician of the Year in Dermatology at NYU (1994), and numerous appearances among the “Best Doctors in New York.”

For Dr. Brancaccio, his patients of all ages (his oldest is 106) have always been his central focus. “I try to bring to each one my expertise and compassion, and help them understand their problem. Some of the most satisfying moments in my career involved the successful detective work that identifies an elusive , which changes a patient’s life when they avoid it—and even when I can’t solve a case, it’s always an interesting journey. I love my work,” Dr. Brancaccio reiterates. “I am so proud and fortunate to be a dermatologist.”

The Dermatology Foundation was established in 1964 and is the leading private funding source for skin disease research. It pro- vides funding that helps develop and retain tomorrow’s teachers and researchers in dermatology, and enable advancements in patient care. For more information visit dermatologyfoundation.org

Page 60 1560 Sherman Avenue, Evanston, IL 60201-4808 Voice: (847) 328-2256 Fax: (847) 328-0509 Dermatology [email protected] Foundation dermatologyfoundation.org SHAPING THE FUTURE OF DERMATOLOGY

Alan M. Menter, M.D. Receives Dermatology Foundation Clark W. Finnerud Award

At its recent annual meeting of membership in San Francisco, the Dermatology Foundation presented Alan M. Menter, M.D. with the prestigious 2014 Clark W. Finnerud Award. The award recognizes Dr. Menter’s many contributions to the field as both an exceptional clinician and highly effective teacher and mentor to new generations of dermatologists.

“Alan Menter is an exemplary clinician, a leader in the world of psoriasis, and an exceptionally capable teacher,” a colleague observes. “I have benefitted directly from his wisdom.”

Dr. Menter is a noted practicing dermatologist in Dallas, a highly respected teacher, and a widely recognized psoriasis expert. He came to the U.S. from South Africa, where he grew up and completed medical school and then his residency. Ironically, neither dermatology nor a move to the U.S. had been his plan. But near the end of his medical studies, “I met a highly erudite Scottish professor of dermatology” with a forward-looking grasp of skin biology. Dr. Menter was hooked. After his residency at the University of Pretoria General Hospital and two dermatology fellowships in London, Dr. Menter returned to Johannesburg with plans to begin his practice. Unexpectedly, he was offered a two-year dermatology fellowship at the University of Texas Southwestern Medical Center. He accepted and, before his fellowship had ended, made Dallas his home.

Dr. Menter’s decision to dedicate his efforts to improving the understanding and care of psoriasis grew from his family’s history with this disease. “Psoriasis is a very tough disease that often shows up in people at a really young age,” he points out. “Imagine being 30 or 35, trying to make your way in the world, and having unsightly patches all over your body. It is really important to get these patients clear.” Dr. Menter has an extensive clinical practice, and is known for the attentive care he gives each of his many patients. His academic pursuits began at the University of Texas Southwestern Medical Center, where he is now clinical professor of dermatology. Dr. Menter began teaching at Baylor University Medical Center as well in the mid- 1980s, which became the focus of his academic activities. He was eventually appointed chair of dermatology. His research there has included more than a hundred clinical trials, and he has published extensively. Over his 40-year career in Dallas, Dr. Menter has worked continuously to stimulate solutions for psoriasis patients. He created the first gene bank for psoriasis and participated in identifying the first psoriasis gene. He also founded the International Psoriasis Council, a collaborative, innovative forum for those who work with psoriasis to improve knowledge and advance patient care. The Dermatology Foundation was established in 1964 and is the leading private funding source for skin disease research. It provides funding that helps develop and retain tomorrow’s teachers and researchers in dermatology, and enable advancements in patient care. For more information visit dermatologyfoundation.org

Page 61 Save the Dates for Upcoming AOCD Meetings

2016 Spring Meeting Ritz Carlton Battery Park New York, NY March 30 - April 3

2017 Spring Meeting Ritz Carlton Atlanta, GA March 29 - April 2

2016 Fall Meeting Loews Santa Monica Beach Hotel Santa Monica, CA September 15 - 18

LIVE IN COLORADO SPRINGS!

This area is the gem of the Rocky Mountain Front Range with over 300 days of sunshine, a dry climate, ready access to all outdoor activities, and a safe environment in which to enjoy life and raise a family. From the Garden of the Gods to the Olympic Training Center, this town is incredible, just an hour outside of Denver and a couple hours’ drive to numerous ski resorts including Breckenridge and Vail. Colorado Springs is a perfectly situated outdoor paradise.

Colorado Dermatology Institute (CDI) provides full-service medical, surgical (including Mohs micrographic surgery), and cosmetic care. CDI is designed to change patients’ expectations of the level of personalized care they can, and should, receive when seeking medical service. Our group currently consists of three dermatologists, three PAs, and three dermatology residents. We strive to remain on the leading edge of patient-centered medical care and to be actively involved in promoting the future of dermatology. Please visit our website at www.coderm.com.

We are looking to hire a BC/BE dermatologist, part- or full-time, with a demonstrated passion for excellence and patient care who wants a path to partnership in the rapidly expanding Colorado Dermatology Institute. We offer a relocation allowance, guaranteed salary, and comprehensive benefits package. Direct Contact Information For immediate consideration, please contact our practice manager: Jeff Anderson 719-531-5400 [email protected]