Journal of the American Osteopathic College of Dermatology

2011-2012 OFFICERS President: Bradley Glick, DO, FAOCD President-Elect: James Towry, DO, FAOCD First Vice-President: David Grice, DO, FAOCD Second Vice-President: Suzanne Rozenberg, DO, FAOCD Third Vice-President: Rick Lin, DO, FAOCD Secretary-Treasurer: Jere Mammino, DO, FAOCD (2010-2013) Immediate Past President: Leslie Kramer, DO, FAOCD Executive Director: Marsha Wise, BS Trustees: Reagan Anderson, DO, FAOCD (2011-2012) Alpesh Desai, DO, FAOCD (2010-2013) Karthik Krishnamurthy, DO, FAOCD (2011-2014) Editor Mark Kuriata, DO, FAOCD (2010-2013) Karthik Krishnamurthy, DO John Minni, DO, FAOCD (2011-2014) Andrew Racette, DO, FAOCD (2009-2012) Resident Coordinator: John Grogan Grants and Corporate Support Coordinator: Carmen Stanton AOCD Assistant: Rick Mansfield Sponsors: Global Pathology Laboratory

JAOCD Founding Sponsor Medicis JAOCD Founding Sponsor Ranbaxy Cover photo credit to NASA/European Space Agency. Dermatology Foundation Bayer AOCD • 1501 E. Illinois • Kirksville, MO 63501 800-449-2623 • FAX: 660-627-2623 www.aocd.org

COPYRIGHT AND PERMISSION: Written permission must be obtained from JAOCD the Journal of the American Osteopathic College of Dermatology for copying or Founding Sponsor 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 acknowledgement of the original source, and a payment of $15 per page, table or figure of reproduced material. Permission fees are waived for authors wishing to reproduce their own articles. Request for permission should be directed to JAOCD c/o AOCD, PO Box 7525, Kirksville, MO 63501. Copyright © 2003 by the Journal of the American Osteopathic College of Dermatology

Print and layout by: The Dimensional Group, Mason City, IA 50401 Proofreading: Julia Layton, Freelance Proofreading and Editing Journal of the American Osteopathic College of Dermatology Issue 23, August 2012 Journal of the

American Osteopathic College of Dermatology Contents aocd JAOCD Editors...... 4 Letter from the Departing Editor...... 5 Letter from the Executive Director...... 6 Letter from the President...... 7 Systemic Mastocytosis: A Case Report and Review of the Literature ...... 8 Jessica Garelik, MS IV, Aleksandra Brown, DO, Annette LaCasse, DO, FAOCD Endogenous Ochronosis within Melanocytic Nevi ...... 13 Kurt Grelck, DO, Vishala Sharma, MSIV, Les Rosen, MD, John Kartsonis, MD, FAAD, Layne Nisenbaum, DO, FAOCD Desmoplastic Melanoma: An Update on Diagnostic and Management Considerations ...... 21 Sadaf “Sabrina” Waqar, DO, MPH, Layne Nissenbaum, DO, FAOCD Erosive Papulonodular Dermatosis: A Case Report and Review of the Literature ...... 23 Jessica Newburger, DO, David B. Kessler, DO, FAOCD Regression of Cutaneous Melanocytic Lesions: A Diagnostic and Management Dilemma ...... 26 Brooke Blumetti, DO, Stephen Olsen, M.D., Howard Lipkin, DO, Annette LaCasse, DO, FAOCD Case Study: Psoriasis Clearing Post Stroke ...... 31 Jonathan S. Crane, DO, FAOCD, David G. Jackson, BS, Ronald P. Benjamin, M.D., Charlene Snyder, PA-C, Christine M. Cook, BS, CCRC Autoimmune Progesterone Dermatitis ...... 34 Leah Schammel, DO, Steven K. Grekin, DO, FAOCD Cutaneous Diffuse Large B-cell Lymphoma: A Case Report and Review of Literature ...... 36 Helen G. Kaporis, DO, Michael Kassardjian, DO, Donna D. Tran, MSIV, Bill V. Way, DO, FAOCD Keratoacanthoma-Like Dermatofibroma ...... 38 Zhi Zhong Wang, MD, MSc, Andrew Simone, MD Elastolytic Granuloma: A Case Report and Discussion...... 40 Mounir Wassef, DO, Layne Nisenbaum, DO, FAOCD A Case of a Cutaneous Sinus Tract of Dental Origin...... 42 Garrett R. Bohrnstedt, DO, Daniel S. Hurd, DO, FAOCD A Rubbery Pink-Blue Nodule on the Scalp of a 93-Year-Old Woman...... 44 Michael Centilli, DO, Peter Saitta, DO, Michael Whitworth, DO, FAOCD, Christopher Schwimer, DO, FAOCD, Jean Holland, MD, FAAD Essential Alopecia Syphilitica: A Case Report and Review of Literature...... 47 Stacy Rosenblum, DO, Mariel Bird, DO, Amanda Beehler, DO, Steven Alder, MD, Stephen Kessler, DO Syringofibroadenoma: A Case Report and Discussion...... 52 Steffany B. Steinmetz, DO, Ryan L. Owen, DO, Robert M. Law, M.D., Bill V. Way, DO, FAOCD A Case of Migrating Necrotic Ulcers...... 54 Kristin L. Regan, DO, Martin Diamond, DO Erosive Pustular Dermatosis of the Scalp Resembling Basal-cell Carcinoma in an Elderly Woman...... 56 Christine Moussa, MSIV, John Ebner, DO, FAAD, Keliegh Culpepper, MD Sunscreen: Filtering Fact From Fiction...... 58 Jessica L. Borowicz, DO, Cherise Khani, BS, Richard A. Miller, DO, FAOCD The Importance of Rapid Recognition and Management of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis in Adult Patients...... 71 Leah K. Shama, DO, Vienna Lowenbraun, DO, Kimball Silverton, DO, FAOCD Micronodular Juvenile Xanthogranuloma Versus Benign Cephalic Histiocytosis...... 78 Mari M. Batta, DO, Yoon Cohen, OMS IV, Stephen Kessler, DO, Ronald Hansen, MD Bullous Tinea Corporis Secondary to Trichophyton Tonsurans...... 80 Leah Kohler, DO, LT, MC/FS, USN, Tony Clinton, MD, CDR, MC/FS, USN Senior Editor Copy Editor Karthik Krishnamurthy, DO Julia Layton, BA, MFA Bronx, NY Lakewood, CO

Associate Editors

Sami Abbasi, DO Matthew Doppelt, DO Matt Leavitt, DO Shaheen Oshtory, DO Brownstown, MI Knoxville, TX Maitland, FL San Francisco, CA

Daniel Abraham, DO Merrick Elias, DO Mark Lebwohl, MD Dimitria Papadopoulos, DO Jacksonville, NC Delray Beach, FL New York, NY Bellmore, NY

Brad Abrams, DO Brad Glick, DO Angela Leo, DO John Perrotto, DO Sarasota, FL Margate, FL New York, NY West Palm Beach, FL

Derrick Adams, DO Marcus Goodman, DO Scott Lim, DO Stephen Purcell, DO Red Bluff, CA Roswell, GA Erie, PA Allentown, PA

Marcy Alvarez, DO Melinda Greenfield, DO Rick Lin, DO Andrew Racette, DO Miami, FL Albany. GA McAllen, TX Phoenix, AZ

Kevin Belasco, DO Denise Guevara, DO Deborah Longwill, DO Richard Rudnicki, DO Milwaukee, WI Weston, FL Miami, FL Mesquite, TX

Brett Bender, DO Andrew Hanly, MD Chava Lustig, DO Amara Sayed, DO Farmington Hills, MI Miami, FL Weston, FL San Marcos, TX

Joseph Brant Schneider, DO Aaron Bruce, DO Joel Harris, DO Megan Machuzak, DO Shawnee Mission, KS Loveland, CO Madison Heights, MI Mesa, AZ

Jennifer Bucci, DO Heather Higgins, DO Jere Mammino, DO Michael Scott, DO Greensboro, NC Troy, MI Winter Springs, FL Seattle, WA

Ryan Carlson, DO David Horowitz, DO Chris Manlio, DO Gregg Severs, DO Hilliard, OH Torrence, CA Loxahatchee, FL Scranton, PA

Igor Chaplik, DO David Kessler, DO John Minni, DO Jim Towry, DO Fort Lauderdale, FL Massapequa, NY Port St. Lucie, FL Ocala, FL

Mark S. Cheiken, DO Michael Krutchik, DO Jacqueline Thomas, DO Tony Nakhla, DO Fort Lauderdale, FL Palm Coast, FL Palm Harbor, FL Orange County, CA

Michael P. Conroy, MD Mark Kuriata, DO Navid Nami, DO Matthew Elias, DO Columbus, OH St. Joseph, MI Newport Beach, CA Lighthouse Point, FL

Jonathan Crane, DO Jocelyn LaRocque, DO Jon Keeling, DO Wilmington, NC Charlotte, NC Lexington, KY

4 JAOCD Editors Letter from the Departing Editor-in-Chief

Jay Gottlieb, DO, FAOCD Founding Editor

Dear AOCD Members and Resident Members,

I founded the Journal of the American Osteopathic College of Dermatology in 2002, and I have been Editor- in-Chief since its inception. I am as proud of the JAOCD as I am of the AOCD and the AOA, and as I leave the editorial helm I am confident our journal will continue to flourish. Karthik Krishnamurthy, DO, has taken over as Editor-In-Chief. I will be working closely with him and with Julia Layton, our Copy Editor, over the next six months to make this a smooth transition, and I will be available to offer input and guidance even after this transitional period. The didactic, clinical and teaching skills that Karthik brings to this position will ensure that the JAOCD continues to grow and improve as a scientific journal. At this time, I want to thank the membership, and in particular Stan Skopit, DO, Jon Keeling, DO, James Delrosso, DO, and Andrew Racette, DO, for all they have done to help get the journal to where it is today. Julia Layton continues to do a fantastic job working the day-to-day activities that are required to maintain this type of publication, and she will stay on as Copy Editor after my departure. I also want to thank Rick Mansfield for his excellent job in maintaining the journal's financial records. We always need to recognize and support the Sponsors of the JAOCD: Global Pathology, Medicis, Galderma, Ranbaxy and Bayer Healthcare, currently. Global Pathology, Medicis and Galderma are Founding Sponsors that have supported the JAOCD from even before the first issue went to press. It has been an honor and a privilege to serve as the Editor-in-Chief for a decade. I know that Karthik will pick up where I leave off, furthering the interests of our journal and our college as we move forward. All the best to you, Jay Jay Gottlieb, DO, FAOCD Founder, JAOCD

Letter from the DEPARTING EDITOR-IN-CHIEF 5 Letter from the Executive Director of the AOCD

Marsha Wise Executive Director

Greetings, everyone!

Our recent Midyear Meeting in Branson was a success. It was good to see everyone again. The Board of Trustees of the AOCD voted to recommend that the Journal of the American Osteopathic College of Dermatology be an officially recognized committee of the AOCD: JOURNAL of the AMERICAN OSTEOPATHIC COLLEGE OF DERMATOLOGY (JAOCD): This committee shall consist of the journal editor and a minimum of four additional members. This committee shall oversee the content and publication of the JAOCD. This will require a by-laws change, and AOCD members will have the opportunity to vote on this at the Annual Meeting held in San Diego, CA, on Monday, October 8, 2012. In 2013, in addition to our Midyear Meeting and Annual Convention, we are planning a weekend continuing- medical-education (CME) event in order to provide our members with an additional opportunity to obtain CME credit. This weekend event will be held in a location easily accessible from a major airport. We hope to provide a minimum of 12 CME credit hours during this event. Our 2014 Midyear Meeting will be held at the Ritz Carlton Dallas, and our goal is to provide 25 CME credit hours at that meeting.

Upcoming Meetings Information regarding our Annual Convention in San Diego will be available soon. Check our website for updated meeting information.

AOA Meetings At the recent Postdoctoral Training Review Committee meeting in Chicago on April 19, four new dermatology residency programs were approved. Additional information regarding these programs will be made available in the fall issue of the DermLine. The AOA also approved, with the help of Dr. Stephen Purcell and representatives from the AOCD, AOCP, NYCOM, and the Ackerman Academy, the first-ever Dermatopathology Fellowship with the Ackerman Academy and the New York College of Osteopathic Medicine (NYCOM). The AOCD continues to grow and evolve, and we are no longer considered a small organization. Moving forward, our operating procedures will be further fine-tuned in order to meet that growth and better serve our members. As always, thank you for your support of our College and the journal we're so proud of. Sincerely, Marsha Wise, BS Executive Director, AOCD

6let t er from the Executive Director Letter from the President of the AOCD

Brad Glick, DO, MPH, FAOCD President, AOCD

Dear AOCD members, program directors, residents, and students,

This 23rd issue marks the 10-year anniversary of the Journal of the American Osteopathic College of Dermatology (JAOCD). I would like to share some history of the journal, as some of you may not realize or recall the tremendous efforts on the part of a few that have made the journal what it is today. First, the founding editor, Dr. Jay Gottlieb, along with his original co-editors, Drs. James Q. Delrosso and Stanley Skopit, developed the journal from scratch, crafting its architecture and premise and summoning support from colleagues, residents, students and industry. After 10 years of hard work and dedication as Senior Editor, Dr. Gottlieb is stepping down. Congratulations and thank you, Dr. Gottlieb. You developed an academically sound periodical and a tremendous legacy for our college, as the JAOCD is one of only two journals representing the specialty colleges of the osteopathic profession. The journal will now be in the very capable hands of Dr. Karthik Krishnamurthy, who is taking over the Senior Editor position. Please continue to support the journal by maintaining regular appreciation and recognition of its sponsors and, most important, continuing to submit pertinent and academically sound articles. I hope all attendees enjoyed this year's mid-year AOCD meeting in Branson, MO. Dr. David Grice compiled a fantastic line-up of speakers as well as terrific social functions. As I have said previously, I welcome any comments you may have regarding our meetings. I am in constant contact with our board members and am working closely with the program chairs of our upcoming meetings, Dr. Rick Lin (Midyear Meeting in Winter Park, Colo.) and Drs. David Grice and Suzanne Rozenberg (Annual Meeting in San Diego). At the Annual Meeting, Dermpath Diagnostics is offering 10 $1,000 travel vouchers for outstanding resident research presented at the meeting. Final criteria will soon be made available to residents and program directors. In the meantime, your Board of Trustees and various committees continue to work to better our College. The Membership Committee is currently being reorganized, and a search is underway for a replacement for Dr. Monte Fox, who served as Committee Chair for more than five years. Thank you, Dr. Fox, for your service and dedication to the AOCD. Educationally speaking, the number of residency programs in the AOCD continues to grow, with four new programs approved this past year. Additional information regarding these programs will be made available in the fall issue of DermLine. The AOA also approved the first ever Dermatopathology Fellowship with the Ackerman Academy and NYCOM, the result of efforts by the AOCD, AOCP, NYCOM and the Ackerman Academy, and in particular Dr. Stephen Purcell. It is clear the American Osteopathic College of Dermatology is on solid ground. I am honored and privileged to serve as your AOCD President. Once again, thank you, and please feel free to email me directly at [email protected]. Fraternally yours, Brad P Glick, DO, MPH, FAOCD President, AOCD Letter from the President 7 Systemic Mastocytosis: A Case Report and Review of the Literature

Jessica Garelik, MS IV,* Aleksandra Brown, DO,** Annette LaCasse, DO, FAOCD***

*Michigan State University College of Osteopathic Medicine, Lansing, MI **Dermatology Resident, PGY II, Pontiac Osteopathic Hospital, Pontiac, MI ***Dermatology Residency Program Director, Pontiac Osteopathic Hospital, Pontiac, MI

ABSTRACT Mastocytosis is a rare, heterogeneous disorder characterized by abnormal mast cell proliferation and accumulation in one or more organ systems. There are many variants recognized by the World Health Organization (WHO), the most common of which presents as pruritic, tan colored macules that urticate when rubbed. While this disorder appears to be limited to the skin in children, patients diagnosed in adulthood usually possess a greater risk for systemic involvement and are more likely to have persistent disease. We present a case of clinically asymptomatic, bone marrow biopsy proven adult-onset systemic mastocytosis and review of the literature on the pertinent aspects of the disorder. Case Report She was advised to take fexofenadine in the morning and cetirizine in the evening. She A 23-year-old female presented also was given an epinephrine pen, and to our clinic for evaluation of multiple it was recommended that she be cautious hyperpigmented macules and papules with alcohol, NSAIDs, aspirin, bee stings, on her thighs, arms, chest and abdomen and local trauma to the skin lesions. (Figures 1 & 2). They had been present for approximately one year and were mildly pruritic. Review of systems revealed fatigue Discussion for two weeks. She had no significant past Mastocytosis is a clonal disorder medical history, and family history was characterized by abnormal proliferation non-contributory. She did report an allergy of mast cells leading to accumulation in to bee stings. various tissues.1,2 The World Health Physical exam revealed scattered 2.5 Organization currently recognizes seven mm orange-to-tan colored macules and subcategories of mastocytosis, including papules on her bilateral thighs, upper cutaneous mastocytosis, indolent systemic extremities, abdomen and chest. These mastocytosis, systemic mastocytosis lesions showed dermatographism with with an associated clonal, hematological positive Darier’s sign. Hyperpigmentation non-mast-cell lineage disease, aggressive of the lesions was persistent with systemic mastocytosis, mast cell leukemia, diascopy. No hepatosplenomegaly or mast cell sarcoma, and extracutaneous 2,3 lymphadenopathy was palpable. mastocytoma. These major categories are Figure 1 Systemic Mastocytosis on back further divided into additional variants, Labs were taken and revealed a serum of thighs where cutaneous mastocytosis, specifically, tryptase level of 70.3 ng/ml initially and can be separated into sub-variants including 57.1 ng/ml on repeat draw one week later urticaria pigmentosa/maculopapular (normal less than 11.5 ng/ml). CBC was cutaneous mastocytosis, typical urticaria within normal limits. pigmentosa, plaque form, nodular form, A site was biopsied with a 3 mm punch telangiectasia macularis eruption perstans, and demonstrated superficial perivascular diffuse cutaneous mastocytosis, and solitary infiltrate of lymphocytes around slightly mastocytoma of skin.4 The overall incidence ectatic vessels (Figure 3). A toluidine blue of mastocytosis is about 1/50,000-100,000 stain showed significantly increased mast per year.2 It affects males and females cells within the papillary dermis. The above equally. It occurs in all races, but is more was consistent with urticaria pigmentosa, common in whites.5 Mastocytosis affects macular type. more children (65%)6 than adults, where The patient was then referred to an 80% of children present with cutaneous 1 allergist for testing. She was found to be lesions before 6 months of age. Incidence significantly atopic with positive reactions of mastocytosis increases again from age 30 2 to ragweed, weeds, grass, dust mite and cats. to 50 years. Most cases of mastocytosis in Her elevated serum tryptase also indicated children are limited to the skin and resolve 2,7 systemic involvement, which prompted a spontaneously. Patients with adult or bone marrow biopsy. The patient’s bone adolescent-onset mastocytosis may present marrow biopsy further confirmed the with cutaneous lesions, but experience a diagnosis of systemic mastocytosis, greater risk for systemic involvement and 2 although she had no GI symptoms, bone are more likely to have persistent disease. Figure 2 Systemic Mastocytosis on pain, diarrhea, or other systemic symptoms. Mast cells originate from pluripotent back of thighs

8 Systemic Mastocytosis: A Case Report and Review of the Literature bone marrow cells that express CD34+, CD13+, CD 117+ and high affinity IgE receptor (FcεRI).4,8 They then travel to specific sites in the body pre-determined by expression of specific cell surface adhesion molecules.3,4 In this way, mast cells are broadly dispersed throughout the body, collecting in highest concentration in tissues that are directly exposed to the external environment, such as in the dermis, respiratory mucosa, gastrointestinal mucosa, and genitourinary mucosa.3,4 Mast cells may also surround blood vessels, lymphatics and Figure 3 Systemic Mastocytosis peripheral nerves.9 Upon reaching their final destination, expression as well.4 The discovery of these gastrointestinal system, or cardiovascular mast cells eventually mature and become mutations may explain the varied clinical system and may manifest as a pathological fully granulated cells.3,4 Under normal presentation and may be important in fracture; neuropsychiatric symptoms; regulation, both factors in bone marrow better understanding pathogenesis and nausea, vomiting, or malabsorption; and 2 and those in mast cells’ final residence play determining appropriate therapies and syncope or flushing, respectively. 6 a role in controlling mast cell number and prognosis. Mastocytosis is diagnosed based on differentiation.4 The major growth factor Patients with mastocytosis may present clinical characteristics, and it is confirmed for mast cell survival and differentiation with acute/chronic systemic symptoms or by histology.4 Biochemical data may also is stem cell factor.6 Stem cell factor links cutaneous lesions, where symptoms reflect help support a diagnosis of mastocytosis. to its related receptor, a tyrosine kinase, the extent of mast cell disease, mediator Cutaneous mastocytosis can be diagnosed known as KIT, which is encoded by the c-kit released, and other organs involved.2 by typical clinical skin lesions and a positive gene. It is postulated that a mutation in c-kit In about 90 percent of cases, the most Darier’s sign.2 In addition, a skin biopsy is may lead to enhanced receptor function common presentation of mastocytosis is necessary to confirm the diagnosis, and it and thus result in abnormal growth and limited to the skin and is characterized by may show multifocal aggregates of mast accumulation of mast cells in at least one or single or multiple lesions that are itchy.2,11 cells in the upper dermis as well as around more organ systems.3,4 The most common Seventy-five percent of patients with blood vessels.4,7 According to the World mutation identified in neoplastic mast cells cutaneous mastocytosis have a positive Health Organization diagnostic criteria is a mutation involving codon 816 of c-kit Darier’s sign, whereby rubbing the lesion for cutaneous mastocytosis, the skin lesion mRNA, where an A to T substitution leads leads to urtication.2 Additional specific must show focal dense infiltrates greater to an aspartic acid to valine substitution of findings may be present depending on than 15 mast cells per cluster or greater amino acids during protein synthesis.3,4,6,8 the variant of cutaneous mastocytosis.1 0 than 20 cells per high-power field in This mutation has been found in the Urticaria pigmentosa, the most common diffuse mast cell infiltrates on histology.13 peripheral blood of adult patients whose form of cutaneous mastocytosis and Cutaneous mastocytosis may also be mastocytosis has a hematologic component, the variant represented in this clinical diagnosed if a c-kit D815v mutation is and more currently in the skin and bone case, may present more specifically with discovered. In patients without skin lesions, marrow of a majority of adult patients symmetric, red-brown or tan macules or mastocytosis may be suspected if one or with systemic or cutaneous mastocytosis.4,6 papules, primarily located on the trunk and more of the following symptoms or findings Pediatric cutaneous mastocytosis has been extremities. It often spares the face, palms are present: unexplained ulcer disease or thought to signify a transient dysregulation and soles. In cases where patients present malabsorption, radiographic or 99mTc of local growth factors,10 but in rare with acute or chronic systemic symptoms, bone scan abnormalities, hepatomegaly, circumstances, an inactivating mutation at tissues such as those of liver, bone, spleen, splenomegaly, lymphadenopathy, peripheral codon 839 has been identified in children and gastrointestinal tract can be affected.2,11 blood abnormalities, or unexplained with cutaneous mastocytosis.4 Another Most common systemic symptoms include flushing or hypotension.4 While not genetic polymorphism identified, Q576R flushing,12 headache, or fatigue.2,7 Chronic diagnostic, elevated levels of plasma polymorphism, located in the interleukin-4 systemic symptoms may involve the or urinary histamine or metabolites of receptor alpha chain, may moderate disease skeletal system, central nervous system, histamine, prostaglandin D2 metabolites GARELIK, BROWN, LACROSSE 9 Galderma: we know skin outside and in.

Important Safety Information Oracea® (doxycycline, USP) is indicated for the treatment of only infl ammatory lesions (papules and pustules) of rosacea in adult patients. In clinical trials, the most common adverse events reported were gastrointestinal upsets, nasopharyngitis/pain, and nasal congestion/sinusitis. Oracea® should not be used to treat microbial infections, and should be used only as indicated. This drug is contraindicated in people who have shown hypersensitivity to any of the tetracyclines, and, like other tetracycline drugs, may cause fetal harm when administered to a pregnant woman. Oracea® should not be used during pregnancy, by nursing mothers, or during tooth development (up to the age of 8 years). Although photosensitivity was not observed in clinical trials, Oracea® patients should minimize or avoid exposure to natural or artifi cial sunlight. All contraindications, warnings, and precautions associated with tetracyclines must be considered before prescribing Oracea®. The safety of Oracea® treatment beyond 9 months has not been established.

Galderma is a registered trademark. ©2011 Galderma Laboratories, L.P. Galderma Laboratories, L.P., 14501 N. Freeway, Fort Worth, TX 76177 GEN-316 Printed in USA. 08/11 in the urine, or plasma mast cell be helpful in diagnosis, as it is a marker diarrhea and abdominal pain, although tryptase may also point to a diagnosis of mast cell degranulation and is released they may also help reduce bone pain and of mastocytosis. Other markers, such as with histamine. The plasma tryptase level disorders of cognitive function. Topical serum interleukin (IL)-6 levels, and soluble correlates with number of mast cells in the cromolyn sodium, leukotriene antagonists, SCF receptor (CD117) and IL-2 receptor lesions of urticaria pigmentosa in adults interferon, and cyclosporine have also (CD25) levels may indicate presence with systemic mastocytosis. Serum total proven to be effective. Calcium, vitamin of the disease.4 In the subset of patients tryptase in addition to skin biopsy should D, and bisphosphonates may be used to who present without skin lesions yet are be performed in a patient with complaints treat osteoporosis. In select patients with suspected to have mastocytosis, a bone of itchy cutaneous lesions, flushing, cutaneous mastocytosis, psoralen and marrow biopsy and aspirate is indicated or anaphylactic reactions to drugs or long-wave ultraviolet radiation (PUVA) for diagnosis and determination of the hymenoptera sting to rule out idiopathic and targeted laser therapy for managing type. To diagnose systemic mastocytosis anaphylaxis, where plasma tryptase levels widespread and discrete lesions have a patient must have certain bone marrow and mast cell proliferation would be normal been used successfully.11,13 In adult findings. In systemic mastocytosis, in between anaphylactic episodes.4 A 24-h patients with urticaria pigmentosa with or mast cells appear larger and fusiform in urine 5-hydroxyindoleacetic acid (5-HIAA) without systemic manifestations, PUVA morphology and have loosely scattered, and urinary metanephrines may be ordered photochemotherapy has been associated fine cytoplasmic granules, while normal in patients with suspected mastocytosis to with a decrease in whealing, lessening of bone marrow counterparts are round to rule out the possibility of carcinoid tumor Darier’s sign and pruritus, and fading of oval in shape, have densely packed, or pheochromocytoma.4 pigmentary changes in existing lesions.1 uniform cytoplasmic granules, and nuclei Overall therapy for mastocytosis These characteristic skin lesions, however, 14 that are non-lobulated. According to the is conservative, and most of the current may return three to six months after WHO criteria for diagnosis of systemic treatments will not permanently cure the discontinuing therapy. Due to its transient mastocytosis, a patient must present with skin or systemic lesions but may provide therapeutic benefits and possible side at least one major criterion and one minor considerable symptomatic relief.2,11 effects, it should be recommended for those criterion or else three minor criteria in the First-line treatment of mastocytosis patients who have extensive cutaneous 13 bone marrow or extracutaneous organs. includes counseling the patient, including disease and are unresponsive to other forms 1 Major criteria include multifocal dense parents of patients under age 18 and of treatment. Potent topical corticosteroids, infiltrates of mast cells where greater than other care providers. Patients should be such as 0.05% betamethasone dipropionate 15 mast cells are present in aggregates. instructed to avoid factors that elicit an ointment, applied with occlusion for 8 Minor criteria are as follows: greater than acute mediator release from mast cells, hours per day for 8-12 weeks, may also 25% spindle-shaped cells or other atypical such as heat, cold, friction, pressure, help decrease pruritus and number of 2,4 morphologic features in mast cell infiltrates; intense exercise, stress, anxiety, stinging mast cells. It may be recommended as c-KIT D 816V mutation; CD25 and/or insects and radiographic dyes.2,13 Drugs, treatment for patients who have extensive 4 CD2 expression on CD117+ mast cells; such as aspirin, non-steroidal anti- cutaneous disease. In addition, a single serum tryptase levels greater than 20 ng/ inflammatory drugs, codeine, morphine, intralesional injection of steroid, specifically ml devoid of an associated hematologic thiamine, and opiates should be avoided triamcinolone acetonide, 40 mg/ml, has 13 disorder. While bone marrow biopsy is as well. Patients and their care providers been associated with control of pruritus an important diagnostic tool in adults, it is should be informed of their increased and absence of Darier’s sign as well as 1 not recommended in children as systemic risk of anaphylactoid reactions, and in cutaneous atrophy after four weeks. It 2,13 symptoms are rare. Bone marrow biopsy, such cases, epinephrine is used to treat may also clear lesions for at least one year. however, is especially useful in those episodes of vascular collapse.2,4 Patients In a few cases, removing lesions through 13 adult patients who have severe systemic should be instructed to self-administer it surgery may be curative. For patients with 2 symptoms or anaphylactic episodes. It is subcutaneously. Additional treatment is systemic mastocytosis with an associated also helpful in adult patients with urticaria aimed at relieving an individual’s specific clonal hematologic non-mast cell lineage pigmentosa, especially if they have disease symptoms secondary to mediator disease (SM-AHNMD), treatment is based peripheral blood abnormalities, enlarged release. Antihistamines, including H1 and on the specific hematologic abnormality. liver or spleen, or lymphadenopathy to find H2 blockers, may both be utilized to treat Treatment with interferon-alpha 2b has out if they have an associated hematologic pruritus, flushing, and wheal formation, been used with mixed results in patients 4 disorder. Other tissue specimens may be yet newer-generation antihistamines are with SM-AHNMD or aggressive systemic 4 obtained as indicated to define the extent favored over older-generation for control mastocytosis (ASM). Chemotherapeutic 4 of mast cell involvement. For instance, if and anti-sedating properties.13 Common regimens have also been of limited lymphoma is considered, then lymph nodes H1 blockers utilized include hydroxyzine, success in patients with aggressive forms can be biopsied, and such is the case for dexchlorpheniramine or doxepin, of mastocytosis such as ASM, mast other organs. while H2 blockers include mequitazine, cell leukemia (MCL) and SM-AHNMD. Lab analysis proves to be useful in cetirizine, loratadine, and mizolastine.10 Cladribine, a nucleoside analogue, however, diagnosis of mastocytosis. Complete The class of H2 antihistamines, may have therapeutic benefits, as its blood counts may reveal anemia, including ranitidine or cimetidine, and ability to exercise its cytotoxic activity is thrombocytopenia, thrombocytosis, proton pump inhibitors may be used to not specific to cells that are active in the 4,7 leukocytosis, and eosinophilia in treat gastric hypersecretion.10,13 Oral cell cycle. Thus, it can slow progressing patients with systemic mastocytosis.2 disodium cromoglycate may improve neoplastic processes. Tyrosine kinase Subclinical malabsorption may present as these cutaneous symptoms as well while inhibitor, such as imatinib mesylate, may hypocholesterolemia or hypoproteinemia. also providing systemic relief, mostly act on the mutated kit tyrosine kinase Total tryptase level can be tested and may of gastrointestinal symptoms such as in mastocytosis, but it is thought to be of limited use as it fails to specifically

GARELIK, BROWN, LACROSSE 11 inhibit kit with codon 816 mutations common presenting symptom is an itchy, associated with the most common forms tan-colored macule that forms a wheal of systemic mastocytosis.4,7 Splenectomy after being scratched, systemic symptoms, may be indicated in patients with including flushing, dyspepsia, diarrhea or massive splenomegaly associated with hypotension, may occur as well. In order to hypersplenism or portal hypertension, and make a diagnosis of systemic mastocytosis, it may improve the survival in patients a patient must have at least one major who have grave prognoses.4,13 While long- criterion and one minor criterion or else term prognosis is unknown, bone marrow three minor criteria based on the World transplantation may be considered as well Health Organization’s criteria for diagnosis for this subset of patients. In advanced of systemic mastocytosis. In addition, disease, radiotherapy may prove to be a bone marrow biopsy helps confirm the beneficial in treating refractory bone pain. diagnosis. Treatment is based on reducing The patient’s age at time of symptoms and preventing mast cell presentation is important in determining degranulation. Histamine receptor blockers, prognosis.10 The majority of pediatric PUVA therapy, potent topical steroids, and patients with cutaneous mastocytosis interferon-alpha 2b have been used with experience improvement of symptoms some success. In general, patients with over time, and 50% of patients’ symptoms the indolent form of mastocytosis have a have completely resolved by adolescence. relatively good prognosis, whereas patients Patients with mastocytosis should be with more aggressive forms of mastocytosis followed depending on the type of systemic have a poorer prognosis with decreased mastocytosis, occurrence of mediator- five-year survival. related symptoms, coexisting disorders, and References 13 treatment. Patients with indolent systemic 1. Soter NA. The Skin in Mastocytosis. J Invest Dermatol. mastocytosis should have a follow-up 1991; 96 (3): 32S-39S once a year, where serum tryptase levels, 2. Vano-Galvan S, De la Hoz B, Nuňez R, Iaen P. Indolent Systemic Mastocytosis. IMAJ. 2010; 12: 185-188. complete blood cell count and complete 3. Johnson MR, Verstovsek S, Jorgensen JL, Manshouri T, metabolic panel are checked. Patients with Luthra R, et al. Utility of the World Health Organization more aggressive forms of mastocytosis Classification Criteria for the Diagnosis of Systemic Mastocytosis in Bone Marrow. Mod Pathol. 2009; 22: should be followed more frequently, and 50-57. if disease progression is suspected, a bone 4. Metcalfe, DD. The Mastocytosis Syndrome. Fitzpatrick’s Dermatology in General Medicine New York (NY) marrow examination should be performed. McGraw-Hill; 2003. p. 1603-1608. Overall, patients with indolent 5. Kennedy RJ, Scoffield JL, Garstin WIH. An Unusual Presentation of Systemic Mastocytosis. J Clin Pathol. systemic mastocytosis have minimal 1999; 52: 301-302. symptoms and should remain stable with a 6. Lanternier F, Cohen-Akenine A, Palmerini F, Feger F, normal life span. Patients with this form of Yang Y, et al. Phenotypic and Genotypic Characteristics of Mastocytosis According to the Age of Onset. PLoS disease do not commonly progress to severe ONE. 2008; 3(4): 1-6. disease. Patients with more aggressive forms 7. Akin C, Metcalfe DD. Systemic Mastocytosis. Annu Rev of systemic mastocytosis tend to have a Med. 2004; 55: 419-32. 8. Lim K, Tefferi A, Lasho TL, Finke C, Patnaik M, et al. poorer prognosis. In patients with systemic Systemic Mastocytosis in 342 Consecutive Adults: mastocytosis with associated clonal Survival Studies and Prognostic Factors. Blood. 2009; hematologic non-mast cell lineage disease, 113 (23): 5727- 5736. 9. Inamadar A, Palit A. Cutaneous Mastocytosis: Report five-year survival is reduced, and patients of Six Cases. Indian J Dermatol Venereol Leprol. 2006; with mast cell leukemia have expected 72(1): 50-53. survival duration of about six months.13 10. Briley LD, Phillips CM. Cutaneous Mastocytosis: A Review Focusing on the Pediatric Population. Clin Pediatr (Phila). 2008; 47 (8):757-761. 11. Peterson AH. Systemic Mastocytosis: Case Report Conclusion and Literature Review. J Natl Med Assoc. 1984; 76 (5): 469-473. This case describes a female patient 12. Metcalfe DD. Classification and Diagnosis of who presented with skin lesions consistent Mastocytosis: Current Status. J Invest Dermatol. 1991; with urticaria pigmentosa. While she 96(3): 2S-4S. 13. Bains SN, Hsieh FH. Current Approaches to the did not experience systemic symptoms Diagnosis and Treatment of Systemic Mastocytosis. Ann clinically, a bone marrow biopsy confirmed Allergy Asthma Immunol. 2010; 104: 1-10. the presence of systemic disease, and 14. Stevens EC, Rosenthal NS. Bone Marrow Mast Cell Morphologic Features and Hematopoietic Dyspoiesis her symptoms were controlled with oral in Systemic Mast Cell Disease. Am J Clin Pathol. 2001; antihistamines. Overall, mastocytosis 116: 177-182. represents a clonal disorder of mast cells affecting 1 in 50,000-100,000 new patients per year. In adults, mastocytosis is thought to result from a mutation in the kit receptor, and thus leads to abnormal growth of mast cells. While the most

12 Systemic Mastocytosis: A Case Report and Review of the Literature Endogenous Ochronosis Within Melanocytic Nevi

Kurt Grelck, DO,* Vishala Sharma, MSIV** Les Rosen, MD,*** John Kartsonis, MD, FAAD,**** Layne Nisenbaum, DO, FAOCD*****

*Second-year dermatology resident, Columbia Hospital, West Palm Beach, FL **NOVA Southeastern University, Ft. Lauderdale, FL ***Dermatopathologist, Dermpath Diagnostics, Pompano Beach, FL ****University of Florida College of Medicine, Jacksonville, FL *****Program Director, Columbia Hospital Dermatology Residency, West Palm Beach, FL

ABSTRACT Alkaptonuria is a rare autosomal recessive disease that manifests as a result of the deposition of homogenistic acid within connective tissues. Patients often present during infancy with darkening of diapers due to oxidation of homogenistic acid, or during adulthood with progressive arthritis. Skin manifestations are often subtle but may precede the onset of arthritis and be a clue to the underlying diagnosis. We describe a case of man with alkaptonuria with evidence of ochronotic pigment deposition within dermal melanocytic nevi, which has not yet been described in the literature. The epidemiology, clinical features, pathophysiology, histopathologic characteristics, and current therapies are reviewed. Introduction early in life; instead, it was identified after 14. Alkaptonuria (AKU) is a rare, autoso- he injured his knee 42. 7 10 mal-recessive disorder of tyrosine metabo- and underwent sub- lism. Originally recognized by Garrod in 5 42. 6 sequent orthopedic 5 1909, alkaptonuria has been with humanity surgery in December for far longer, as its signature deposition of of 2002. He had a 14 10 1 9 ochronotic pigment may have been found history of progres- 4.1 26 1.0 1,2,3 9 in several Egyptian mummies. Typically sive arthritic pain 5 6 0 manifesting clinically in the 3rd decade to the knees and Calcitonin: 13 [0.0-15.9 pg/mL] of life with progressive arthritis, most most of his joints TSH: 1.72 [0.40-4.00 mcIU/mL] patients tend to eventually be diagnosed and back. After FSH: 5 during joint replacement or repair.4 How- injuring his knee Alk Phos: 120 [37-116 U/L] ever, AKU can have a variety of cutaneous he was evaluated by manifestations that often go unrecognized ALT: 45 [6-41 U/L] an orthopedic sur- AST: 34 [9-34 U/L] by the patient and the uninitiated clini- geon and sent for Bilirubin, total: 0.7 [0.1-1.0 mg/dL] cian alike. The metabolic defects associ- arthroscopy. During Protein, total: 6.9 [6.0-7.6 g/dL] ated with this disease lead to the pathologic the procedure, the deposition of homogentisic acid (HGA) orthopedic surgeon HGA 744 [<10 mmol/mol] in various tissues such as the sclera, carti- was surprised to Table 1 lage, connective tissues, heart, bone, pros- find darkened black cartilage tate, and genitouretal system. This case and bone (Figure 1). Even- illustrates the possible role that the der- tually, the patient required matologist and dermatopathologist can bilateral knee and ankle play in the diagnosis of AKU, and the rec- replacements. Following the ognition of the fact that HGA may selec- diagnosis of AKU, the patient tively deposit in melanocytic nevi as well. was referred to the National Institutes of Health (NIH) Report of Case for evaluation and possible enrollment in a trial to evalu- A 54-year-old man with a history of ate the use of nitisinone. At AKU presented to his dermatologist for the time of his initial workup full body exam in February of 2011. Two at the NIH, he had a history biopsies of atypical nevi were taken and sent of darkening pigmentation for histopathologic evaluation. His medical to the ears, face, sclera and history was significant for hypothyroid- hands which had not pre- ism, but was otherwise unremarkable apart Figure 1 Darkened ochronotic bone and cartilage are vis- viously been diagnosed as from the diagnosis of AKU and history of ible during arthroscopy of the patellofemoral joint AKU. During his evaluation progressive generalized arthritis. He had at the NIH, a 24-hour urine specimen for taken off of the medication due to increased both knees and ankles replaced over the homogentisic acid level was significantly liver function test levels after five days of previous 10 years, worked as a truck driver elevated (see Table 1). The remainder of treatment. Following his diagnosis and and had a history of previous tobacco and his bloodwork, urine, CT scan of the chest workup at the NIH, his sister was also diag- alcohol use. He had no history of exposure and abdomen, MRI of the brain, and echo- nosed with AKU. Over the following years to depigmentary agents, antiarrhythmics, cardiogram findings were within normal the patient’s skin continued to darken in or antimalarials. He had no history of dark- limits. He was enrolled in a trial of nitisi- the aforementioned areas, and his arthritic ened urine and his diagnosis was not made none at 0.35mg twice a day, but had to be pain continued to increase. During his der- Grelck, Sharma, Rosen, Kartson is 13 matologic exam in 2011, the patient was the first few days of life as the enzymatic noted to have multiple macular, blue-gray pathway of tyrosine metabolism is not yet hyperpigmented areas on the nose, bilat- functioning and HGA may not be present in eral helices, and bilateral elbows (Figure the urine.16 Twenty-one percent of patients 2). Numerous hyperkeratotic, coalescing present before one year of age.4 The mean blue-gray papules were present over the age of diagnosis for AKU was 55.9 years bilateral dorsal hands, predominately over of age, and the incidence peaked between the metacarpal phalangeal joints, as well as the fourth to seventh decades of life in a the first web space between the thumb and review by Khaled et al.6 Skin manifesta- second digit and the ulnar hand (Figure tions usually present in the fourth decade 3). Also present was a slight macular blue- of life, often as blue-black macules on the gray pigmentation over the cheeks. Bilat- ears.6 Blue-black coloration is partly a result eral scleral pigmentation (“Osler’s sign”) of the Tyndall effect. Other skin sites are was also noted (Figure 4). The chest had a often involved, and these are most gener- hyperpigmented melanocytic nevus 6 mm ally in sun-exposed sites, cartilaginous sites, in diameter with varied dark coloration and and areas with apocrine glands.17,18 Axil- somewhat irregular borders, and the back lary skin pigmentation in the pattern of had a 7 mm irregularly hyperpigmented glandular orifices, as well as staining of papule, both of which were biopsied. undergarments, may be present late in the first decade. Other areas of skin find- Figure 2: Ochronosis of the external ear Histopathology ings include the nose, dorsa of the hands, palms and soles, teeth, buccal mucosa, nails, Two biopsies were examined. The fingers, cerumen, and abdomen.6,19 Pig- first (specimen A) was from the right chest, mented colloid milium on the dorsa of and the second (specimen B) was from the hands has also been reported.16 We the left upper back. In both cases, histo- believe that this case may be the first docu- pathologic analysis revealed dermal mela- mented deposition of ochronotic pigment nocytic nevi associated with fine granules within melanocytic nevi. Ocular involve- of brown ochronotic pigment interspersed ment also is common, mainly manifest- throughout the melanocytes (Figures 5 & ing as scleral pigmentation although it may 6). No ochronotic pigment was identi- also involve the conjunctiva, eyelids, tarsus fied within the normal skin that was not or cornea.6,16 Arthritis is likely the most part of the dermal nevi in both specimens. common clinical finding in patients and leads to the diagnosis of AKU in 45 per- Figure 3: Right hand first and second cent of patients.4 The earliest symptoms Diagnosis interdigital web space involvement. usually develop in the lumbar spine, hips, Endogenous ochronosis; alkaptonuria. knees and large weight bearing joints in the third to fourth decade.4,19 The clinical Discussion and Comment presentation of arthritis often is likened to that of rheumatoid arthritis.19 Ochro- Alkaptonuria is a rare metabolic dis- notic arthropathy usually involves the spi- order, with only approximately 1,000 cases nal joints first. The radiographic changes in the literature to date.5,6,7 The uncommon are similar to those of osteoarthritis but nature of this entity makes for a difficult instead are located in large joints, including early diagnosis even when clinical symp- the hip and shoulder joints, with sparing toms of darkened cartilage or arthritis begin of the sacroiliac joint and smaller periph- to appear in a patient’s 30s. The systemic eral joints.19 Narrowing of the joint spaces and progressive nature of this disease makes with calcification of the intervertebral disks early diagnosis a priority; however, treat- and eventual fusion of vertebral bodies are ment of this disease remains in its relative Figure 4: “Osler’s sign” of the sclera. seen in the lumbar spine and result in lim- infancy. ited range of motion and ankylosis.4,19 Fifty The rarity of alkaptonuria precludes a Santa Domingo, where a higher degree of percent of patients have a joint replaced specific incidence in the population, but it consanguinity may be a contributing fac- by the age of 55.4 Fifty-seven percent of is estimated to occur in 1:250,000-1,000,000 tor.8-11 It is possibly less common in India.12 patients have tendon-related findings, such people.4 The inheritance pattern of alkap- Alkaptonuria typically presents in a bimodal as thickened Achilles tendons, tears follow- tonuria is autosomal recessive, and it is manner, with recognition of the disease ing minor trauma, joint effusions, or syno- either distributed equally between males occurring after the observation of dark urine vitis.4 Magnetic resonance imaging (MRI) and females or has a male predominance in diapers as a child or later in life during has become the imaging modality of choice (1.3-2.5:1).6 As Garrod noted, consanguin- the investigation of progressive arthritis, for visualizing the specific bone, joint and ity often is a causative factor when detailed as was the case with the patient described ligament changes of AKU compared to con- pedigree analysis is performed. There herein. Alkaptonuric patients are usually ventional radiography.20 Cardiovascular seems to be some degree of geographic clus- asymptomatic as children and young adults manifestations of AKU relate to deposition tering, with a reported 10-fold higher inci- 4,13-15 apart from darkening of the urine, of ochronotic pigment (HGA polymers) dence in Slovakia (1:19,000 people) and which interestingly may not be seen during within heart valves, endocardium, aortic

14 Endogenous ochronosis within melanocytic nevi Figure 5: Dermal nevus with ochronotic pigment present on Figure 6: Higher-power view of ochronotic granules situated H&E (original magnification 50x) within the dermal nevus (original magnification 200x)

intima, and coronary arteries.21 The rate ally 20-30 mg per day.4,5 Depending on the (see histologic characteristics).44,45 The of aortic valve disease had a prevalence of patent’s genetic carrier status, levels may binding of benzoquinone acetic acid to col- over 40% by the fifth decade. There is con- be variable. Other laboratory findings in lagen leads to destabilization of collagen troversy regarding whether there is actually AKU patients are typically normal.16 DNA and to loss of periodicity and homogeniza- an increased rate of coronary heart dis- can be extracted from whole blood and tion of collagen fibers. This is thought to ease.4,21-23 Patients should be evaluated with analyzed for mutations in HGO on chro- occur through inhibition of lysyl hydroxy- echocardiography for evidence of valvu- mosome 3q21-q23 by polymerase chain lase, an enzyme whose function is to pro- lopathy and with CT scanning to screen reaction (PCR) on a research basis.18,27,28 vide sites for cross linkage between collagen for increased coronary calcium deposi- Alkaptonuria is associated with a deficiency fibers. Benzoquinone acetic acid is there- tion. The genitourinary system can also of homogentisate 1,2-dioxygenase (HGO) fore thought to be the actual cause of col- be involved, with development of kidney activity in the liver and kidney of homozy- lagen fiber degeneration.46 The mechanism and prostate stones in a portion of AKU gotes, resulting in a block of the metabolic underlying the development of arthritis is patients. Renal ultrasound or CT scan- pathway of tyrosine and phenylalanine (see not as well understood, but is suspected ning should be performed to rule out renal Figure 7).4,27,29 AKU was the first disease to result from oxidation products, matrix calculi.4 Incidental prostatic lithiasis com- to be discovered as a Mendelian autoso- microdamage, osteoporosis, and osteo- monly occurs due to the alkaline pH of mal-recessive single gene trait.1 Both com- clast viability.47 The hyaline cartilage has prostatic secretions, and if clinically indi- pound heterozygotes and homozygotes increased hardness and decreased elastic- cated, further investigation for obstruction have been found.28 This gene has now been ity, likely resulting from the inhibition of may be warranted.24,25 completely sequenced, and a large num- lysyl hydroxylase and eventual cartilaginous 48,49 The current standard in the diag- ber of AKU mutations have been identified degeneration. 27,30-41 nosis of alkaptonuria is based on quanti- in many different countries. Certain Within the skin, fine ochronotic pig- tative measurement of urinary HGA, as types of genetic sequences may represent a ment granules are seen free in the dermis, the clinically observed dark urine is not mutational hot spot (CCC or GGG repeats) 36 in the basement membrane, within elastic always present. Urine will discolor rap- in the HGO gene, perhaps leading to the 42 fibers, within endothelial cells of blood ves- idly when the pH is greater than 7.0, or graphic clustering seen in Slovakia. sels, in the secretory cells of sweat glands, when reducing substances such as ascorbic Homogentisic acid (2,5-dihydroxy- and within dermal macrophages.44,52 A mild acid (which normally protect HGA from phenylacetic acid, HGA) builds up as increase in basal layer melanin may also oxidation) are not present. Several other a consequence of HGO deficiency and is be seen.52 Occasional multinucleated giant tests apart from the measurement of HGA excreted by active tubular secretion of HGA cells can be seen.44 are available, such as the alkali test, pho- in urine. HGO is normally present in the Ochronotic pigment granule depo- tographic paper test, Benedict’s reagent kidneys and liver of unaffected individu- sition within collagen bundles causes test, and ferric chloride test.16,26 More als, but its activity is absent in those with homogenization and swelling; formation commonly, HGA in urine is oxidized by AKU. Although high levels of urinary HGA of a jagged, fractured, or pointed appear- the air to form a pigment-like polymeric excretion are seen in AKU patients (active ance; and a size sometimes over 100 material responsible for the black color of tubular excretion 400 to 500 mL/minute), μm.16,43,48 These bodies can be distinguished standing urine. However, if the urinary HGA gradually accumulates in tissues and from melanin by negative staining with sil- pH is too acidic, this reaction may never is oxidized, and polymerization leads to the ver nitrate and positive black staining with occur. Urinary and serum measurements 16,43 development of ochronotic polymers. In cresyl violet or methylene blue.50 Addition- of HGA are performed by chromatogra- tissues, HGA is oxidized to benzoquinone ally, ochronotic pigment cannot be bleached phy-mass spectrometry.27 HGA urinary acetic acid and binds irreversibly to collagen by 10% hydrogen peroxide after 72 hours levels are typically between 1 and 8 grams fibers as a polymer. On H&E, ochronotic as melanin can be.51 It is interesting that per day, whereas normal excretion is usu- pigment has a yellow or brown “ochre” color in this case of AKU, ochronotic granule

Grelck, Sharma, Rosen, Kartsonis 15 Phenylalanine symptoms, such as arthropathy. Pig- mentation secondary to antimalarial Phenylalanine hydroxylase agents usually is more prominent on mucosal surfaces, and may fluoresce under Wood’s lamp examination. Tyrosine Other causes of mucous membrane pigmentation include argyria, amal- gam tattoo, and chrysiasis.16 Ami- Tyrosine aminotransferase odarone typically exhibits a slate gray-blue coloration to sun-exposed areas. Exogenous ochronosis typi- 4-Hydroxyphenylpyruvic acid cally resolves with cessation of the inciting agent, although in some cases the hyperpigmentation or discolor- 4-hydroxyphenylpyruvic acid Nitisinone ation of tissues may last for many years.61 Other causes of dark urine include melanuria, porphyria, myo- Homogentisic acid globinuria, bilirubinuria, and hema- turia, which should be excluded with appropriate serologic and Homogenisate 1,2 dioxygenase Alkaptonuria urine studies.16 Ocular ochronotic manifestations have been misdiag- nosed as melanosarcoma, resulting Maleylacetoacetic acid in enucleation of the eye.62 Also in the differential for ocular ochrono- sis is melanoma, Addison’s disease, Succinylacetoacetic acid medications, exposure to silver, iron (siderosis), copper (chalcosis), arsenic (arsenic melanosis), gold (chrysiasis), Fumarylacetoacetic acid aluminum, quinones, aniline dyes, and eye cosmetics containing carbon Succinylacetone 63-67 Fumarylacetoacetic acid hydrolase black. The differential diagnosis of ochronotic arthritis includes ankylos- Fumaric acid + acetoacetic acid ing spondylitis,68 rheumatoid arthri- Figure 7: Tyrosine pathway in alkaptonuria tis, calcium pyrophosphate dihydrate deposition,69 herniated disc,70 and deposition is seen specifically within the tion and occupational history should be 71 dermis that is occupied by the dermal able to rule out a drug-induced history of osteoarthritis. These can be differentiated nevus, and not in the surrounding der- ochronosis-like pigmentation, with con- by radiographic studies (see clinical sec- mis. Electron microscopic analysis typically firmation by negative urinary HGA test- tion), as ochronotic arthropathy tends to shows smaller-sized homogeneous bodies ing. An interesting aspect of this case is its manifest with specific findings. A thorough amalgamating into larger, non-membrane- initial presentation from the histopathologic history combined with failure to demon- bound structures.51 Early lesions dem- perspective, with a dysplastic nevus on the strate the excretion of HGA in the urine onstrate the deposition of electron-dense chest being evaluated. As was apparent on should allow the clinician to rule out AKU amorphous ochronotic pigment around the initial biopsy (specimen A), ochronotic from these other aforementioned masquer- individual collagen fibrils within collagen pigment was present within the dermal aders of endogenous ochronosis. fibers.52 This deposition gradually causes nevus taken from the chest (see report of Despite the elucidation of the patho- individual collagen fibril degeneration and a case and histopathology). It is conceiv- physiology of AKU, there are no effec- eventual replacement by ochronotic pig- able for a patient to have applied prescrip- tive therapies available. The most ment throughout the entire collagen fiber.51 tion or over-the-counter topical lightening promising agent is 2-(2-nitro-4-trifluorom The differential diagnosis of AKU lies cream containing hydroquinone on the -ethylbenzoyl)-1,3-cyclohexanedione, or mainly with acquired exogenous ochrono- lesion in an effort to lighten it for cosmetic nitisinone. Nitisinone is a triketone her- sis. A variety of drugs, both topical and sys- improvement. However, after finding the bicide that inhibits 4-hydroxyphenylpyru- same ochronotic pigment granules within vate dioxygenase, the enzyme responsible temic, can mimic the darkening of the skin 7,72 and tissues seen in endogenous ochrono- the second biopsied nevus, which was from for production of HGA. Nitisinone can sis. Hydroquinone, phenol, carboxylic acid the back, the likelihood of a cosmetic appli- reduce HGA production while increas- cation of hydroquinone became less prob- ing levels of plasma tyrosine and phe- (component in cutaneous ulcer dressings), 73 resorcinol, antimalarials, tetracyclines, able, and a call to the clinician was made nylalanine. A three-year phase II trial phenothiazine, amiodarone, picric acid, for additional history. It is possible that has been completed as of 12/10/2010 benzene, heavy metals, chemotherapeutic dermal melanocytic nevi that are biopsied (NCT00107783). Interim analysis suggests agents, and minocycline are among those and contain ochronotic pigment on histo- positive results, but the final outcome data agents whose previous use of or exposure pathology could lead to a diagnosis of AKU remain unpublished. A previous study in to must be ruled out.44,50,53,56-60 A medica- in patients who have yet to manifest other two patients did show a reduced excretion

16 Endogenous ochronosis within melanocytic nevi Grelck, Sharma, Rosen, Kartsonis 17 18 Title rate of urinary HGA of 65%, with conse- commonly mitral and pulmonary valve McGraw-Hill Medical; 2008. p. 1224-1228. quential elevation in tyrosine levels.4 Ther- involvement) and CT scanning to screen 17. Turiansky GW, Levin SW. Bluish patches on the ears and axillae with dark urine: ochronosis and alkaptonuria. apy was discontinued as it was possible that for coronary artery calcification should be Int J Dermatol 2001; 40: 333–335. 7,82 neurologic symptoms analogous to those performed. Cardiovascular ochrono- 18. Spenny ML, Suwannarat P, Gahl WA, Cowen EW. Blue 82 pigmentation and arthritis in an elderly man. Am Acad seen in tyrosinemia type III could have sis usually runs a benign course; how- Dermatol 2005; 52: 122–124. 7 developed. A slightly larger study in nine ever, medical treatment of valvulopathy 19. Al Essa M, Al-Shamsan L, Rashed MS, Ozand PT. patients was conducted with lower doses or valve replacement may be warranted.83 Alkaptonuria: Case report and review of the literature. of nitisinone, and a 95% decrease in HGA Ann Saudi Med. 1998;18(5):442-4. 20. Perrone A, Impara L, Bruni A, Primicerio P, Marini M. was seen, without complications apart Conclusion Radiol Med (Torino). 2005 Oct;110(4):349-358. from increased liver function tests in two Alkaptonuria is an uncommon, inher- 21. Pettit SJ, Fisher M, Gallagher JA, Ranganath LR. patients.57 The patient described in this Cardiovascular manifestations of Alkaptonuria. J Inherit ited disease for which the pathogenesis and Metab Dis. 2011 Apr 20. case was enrolled in this trial but had to be mode of inheritance has been well known to 22. Vavuranakis M, Triantafillidi H, Stefanadis C, Toutouzas prematurely taken off of nitisinone due to medicine from the time of Garrod. Unfor- P. Aortic stenosis and coronary artery disease caused increased liver function tests. by alkaptonuria, a rare genetic metabolic syndrome. tunately, an effective treatment for this dis- Cardiology. 1998;90(4):302-4. The use of ascorbic acid has been ease remains an area for exploration. In 23. Ffolkes LV, Brull D, Krywawych S, Hayward M, Hughes SE. Aortic stenosis in cardiovascular ochronosis. J Clin shown to reduce the urinary levels of the case described herein, deposition of Pathol. 2007 Jan;60(1):92-3. benzoquinone acetic acid, although ochronotic pigment within nevi of an adult 24. Sutor DJ, Wooley SE, Krízek V. The composition of the benefits of this therapy are still con- man with AKU is reported. This histo- calculi from patients with alcaptonuria. Br J Urol. 1970 Aug;42(4):386-8. troversial.5,74 Studies have shown a lack pathologic finding could be used to help 25. Hollingsworth RP. 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Natural history of alkaptonuria. Porfirio B, Mayatepek E, Aquaron R, Moore MM, Festen cies, may interfere with HGA accumulation, NEJM. 2002 Dec 26;347(26):2111-21. JJ, Sanmartí R, Peñalva MA, de Córdoba SR. Mutation and could possibly neutralize benzoquinone 5. La Du BN. Alkaptonuria. In: Scriver CR, Beaudet AL, and polymorphism analysis of the human homogentisate acetic acid.77 In an in-vitro human ochro- Sly WS, Valle D, Vogelstein B, eds. The Metabolic and 1, 2-dioxygenase gene in alkaptonuria patients. Am J Molecular Bases of Inherited Disease. 8 ed. New York: Hum Genet. 1998 Apr;62(4):776-84. notic-cell model treated with ascorbic acid McGraw-Hill; 2001:2109-23. 32. Gehrig A, Schmidt SR, Müller CR, Srsen S, Srsnova K, and NAC, a significant increase in efficacy 6. Khaled A, Kerkeni N, Hawilo A, Fazaa B, Kamoun Kress W. Molecular defects in alkaptonuria. Cytogenet 77 MR. Endogenous ochronosis: case report and a Cell Genet. 1997;76(1-2):14-6. was seen. However, clinical trials inves- systematic review of the literature. Int J Dermatol. 2011 33. Beltrán-Valero de Bernabé D, Granadino B, Chiarelli I, Mar;50(3):262-7. tigating the use of this agent with ascorbic Porfirio B, Mayatepek E, Aquaron R, Moore MM, Festen acid in combination have not yet been per- 7. Introne WJ, Kayser MA, Gahl WA. Alkaptonuria. In: JJ, Sanmartí R, Peñalva MA, de Córdoba SR. Mutation Pagon RA, Bird TD, Dolan CR, Stephens K, editors. and polymorphism analysis of the human homogentisate formed. GeneReviews [Internet]. Seattle (WA): University of 1, 2-dioxygenase gene in alkaptonuria patients. Am J Washington, Seattle; 1993-. Hum Genet. 1998 Apr;62(4):776-84. Management of ochronotic arthropa- 2003 May 09 [updated 2011 Mar 10]. 34. Ramos SM, Hernández M, Roces A, Larruga JM, thy is based on symptom relief with non- 8. Srsen S, Cisarik F, Paszter L, et al. Alkaptonuria in González P, González AM, Pinto FM, Cabrera VM. specific supportive treatment.78 Joint pain Trencin district of Czechoslovakia. Am 3 Med Genet Molecular diagnosis of alkaptonuria mutation by analysis 1978; 2: 159-166. of homogentisate 1,2 dioxygenase mRNA from urine in AKU is chronic and progressive, and and blood. Am J Med Genet. 1998 Jun 30;78(2):192-4. 9. Albers SE, Brozena SJ, Glass LF, Fenske NA. often requires pain management. Physical Alkaptonuria and ochronosis: case report and review. J 35. Higashino K, Liu W, Ohkawa T, Yamamoto T, Fukui K, Am Acad Dermatol. 1992;27:609-614. Ohno M, Imanishi H, Iwasaki A, Amuro Y, Hada. A novel and occupational therapy help to increase point mutation associated with alkaptonuria. Clin Genet. 10. de Jorge EG, Lorda I, Gallardo ME, et al. Alkaptonuria 1998 Mar;53(3):228-9. range of motion and flexibility. Nonste- in the Dominican Republic: identification of the founder roidals (NSAIDS) and intralesional ste- AKU mutation and further evidence of mutation 36. Beltrán-Valero de Bernabé D, Peterson P, Luopajärvi hot spots in the HGO gene. J Med Genet 2002;39: K, Matintalo P, Alho A, Konttinen Y, Krohn K, Rodríguez roids are sometimes used for symptom Suppl:E40. de Córdoba S, Ranki A. Mutational analysis of the HGO relief.79,80 Joint replacement is often even- gene in Finnish alkaptonuria patients. J Med Genet. 11. Zatkova A, de Bernabe DB, Polakova H, et al. High 1999 Dec;36(12):922-3. tually required for pain relief rather than frequency of alkaptonuria in Slovakia: evidence for the appearance of multiple mutations in HGO involving 37. Beltrán-Valero de Bernabé D, Jimenez FJ, Aquaron 7 increased range of motion. different mutational hot spots. Am J Hum Genet 2000; R, Rodríguez de Córdoba S. Analysis of alkaptonuria 67:1333-9. [Erratum, Am J Hum Genet 2000;68:1313.] (AKU) mutations and polymorphisms reveals that the Restriction of protein, phenylala- CCC sequence motif is a mutational hot spot in the 12. Dogra A, Bajwa GS, Bajwa N, Khurana S. Alkaptonuria. homogentisate 1,2 dioxygenase gene (HGO). Am J Hum nine, and tyrosine are thought to reduce Indian J Dermatol Venereol Leprol 2001;67:271-2. Genet. 1999 May;64(5):1316-22. the production of HGA, but severe 13. Bunim JJ, McGuire JS Jr, Hilbish TF, et al. Alcaptonuria, 38. Müller CR, Fregin A, Srsen S, Srsnova K, Halliger- clinical staff conference at the National Institutes of restriction of these essential amino Keller B, Felbor U, Seemanova E, Kress W. Allelic Health. Ann Intern Med 1957;47:1210. heterogeneity of alkaptonuria in Central Europe. Eur J acids is not practical in the long term 14. Cooper PA. Alkaptonuria with ochronosis. Proc R Soc Hum Genet. 1999 Sep;7(6):645-51. 7,81 and does not seem to be beneficial. Med 1951;44:917. 39. Walter K, Gaa A, Schaefer HE. Sequence analysis Cardiovascular manifestations of AKU 15. Minno AM, Rogers JA. Ochronosis: report of a of the homogentisate 1,2 dioxygenase gene in a case. Ann Intern Med 1957;46:179. family affected by alkaptonuria. J Med Genet. 1999 should be monitored after the age of Aug;36(8):645-6. 16. Iten PH, Goldsmith LA. Cutaneous changes in errors of 40. Echocardiography to rule out valvu- amino acid metabolism. In: Wolff K, Goldsmith L, Katz 40. Felbor U, Mutsch Y, Grehn F, Müller CR, Kress W. S, Gilchrest B, Paller A, Lefell D, editors. Fitzpatrick’s Ocular ochronosis in alkaptonuria patients carrying lopathy (typically aortic stenosis and less Dermatology in General Medicine. 7th ed. New York: mutations in the homogentisate 1,2-dioxygenase gene. Grelck, Sharma, Rosen, Kartsonis 19 Br J Ophthalmol. 1999 Jun;83(6):680-3. 69. Rynes RI, Sosman JL, Holdworth DE. Pseudogout in ochronosis. Arthritis Rheum 1975;18:21-5. 41. Porfirio B, Chiarelli I, Graziano C, Mannoni A, Morrone A, Zammarchi E, De Bernabé DB, De Córdoba 70. Eisenberg H. Alkaptonuria, ochronosis, arthritis and SR. Alkaptonuria in Italy: polymorphic haplotype ruptured intervertebral disc complicated by homologous background, mutational profile, and description of four serum reaction. Arch Intern Med 1950;86:79-86. novel mutations in the homogentisate 1,2-dioxygenase 71. Tanner KE, Warren NP, Coombs RR. Ochronosis of the gene. J Med Genet. 2000 Apr;37(4):309-12. hip joint. Scand J Rheumatol 1991;20:63-4. 42. Zatková A, Polaková H, Micutková L, Zvarík M, Bosák 72. Anikster Y, Nyhan WL, Gahl WA. NTBC and V, Feráková E, Matusek J, Ferák V, Kádasi L. Novel alkaptonuria. Am J Hum Genet.1998;63:920–1. mutations in the homogentisate-1,2-dioxygenase gene identified in Slovak patients with alkaptonuria. J Med 73. Lorenzini S, Mannoni A, Selvi E. Alkaptonuria. N Engl J Genet. 2000 Jul;37(7):539-42. Med. 2003 Apr 3;348(14):1408; author reply 1408. 43. 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Homogentisic acid autoxidation 45. Touart DM, Sau P. Cutaneous deposition diseases. Part and oxygen radical generation: implications for the II. J Am Acad Dermatol 1998;39:197. etiology of alkaptonuric arthritis. Free Radic Biol Med. 1987;3(4):241-50. 46. Zannoni VG, Malawista SE, La Du BN. Studies on ochronosis: II. Studies on benzoquinone-acetic 77. Tinti L, Spreafico A, Braconi D, Millucci L, Bernardini G, acid, a probable intermediate in the connective Chellini F, Cavallo G, Selvi E, Galeazzi M, Marcolongo tissue pigmentation of alcaptonuria. Arthritis Rheum R, Gallagher J, Santucci A. Evaluation of antioxidant 1962;5:547. drugs for the treatment of ochronotic alkaptonuria in an in vitro human cell model. Journal of Cellular Physiology. 47. La Dur BN. Alkaptonuria and ochronotic arthritis. Mol 2010:225:1, 84-91. Biol Med 1991;8:31-38. 78. Maathuis PG, Driessen AP. Painted black. Ann Rheum 48. Aliberti G, Pulignano I, Pisani D, Rocchietti March Dis. 2002 Feb;61(2):100-1. M, Del Porto F, Proietta M (2007) Bisphosphonate treatment in ochronotic osteoporotic patients. Clin 79. Khadagawat R, Teckchandani R, Garg P, Arya A, Rheumatol.26(5):729–735. Choudhary B. Alkaptonuria: early detection. Indian J Pediatr 1994;31:593-5. 49. Findlay GH: Ochronosis. Clin Dermatol 7:28, 1989. 80. Konttinen YT, Hoikka V, Landtman M, Saari H, 50. Ludwig GD, Toole JF, Wood JC. Ochronosis from Santavirta S, Metsarinne K, et al. Ochronosis: a report quinacrine (atabrine). Ann Intern Med. 1963;59:378–84. of a case and a review of literature. Clin Exp Rheumatol 51. Laymon CW. Ochronosis. Arch Dermatol 1953;67:553. 1989;7:435-44. 52. Attwood HD, Clifton S, Mitchell RE: A histological, 81. Morava E, Kosztolanyi G, Engelke UF, Wevers RA. histochemical and ultrastructural study of dermal Reversal of clinical symptoms and radiographic ochronosis. Pathology 3:115, 1971. abnormalities with protein restriction and ascorbic acid in alkaptonuria. Ann Clin Biochem 2003; 40: 108–111. 53. 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Levin CY, Haibach H. Exogenous ochronosis. An update on clinical features, causative agents and treatment options.AM J Clin Dermatol 2001;2:213. 60. Penneys NS. Ochronosislike pigmentation from hydroquinone bleaching creams. Arch Dermatol 1985;121:1239. 61. Geria AN, Tajirian AL, Kihiczak G, Schwartz RA. Minocycline-induced skin pigmentation: an update. Acta Dermatovenerol Croat. 2009;17(2):123-6. 62. Skinsnes OK. Generalized ochronosis; report of an instance in which it was misdiagnosed as melanosarcoma, with resultant enucleation of an eye. Arch Pathol (Chic). 1948;45:552–8. 63. Granstein RD, Sober AJ. Drug- and heavy metal induced hyperpigmentation. J Am Acad Dermatol 1981;5:1-18. 64. Seregard S. Conjunctival melanoma. Surv Ophthalmol 1998; 42:32l-350. 65. Cheskes J, et al. Ocular manifestations of alkaptonuric ochronosis. Arch Ophthalmol 2000; 118:724-727. 66. Fraunfelder FT, Fraunfelder FW. Drug-induced ocular side effects. Woburn, MA: Butterworth-Heinemann, 2001. 67. Roy FH. Ocular syndromes and systemic diseases. 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2002. 68. Siekert RG, Gibilisco JA. Discoloration of the teeth in alkaptonuria (ochronosis) and parkinsonism. Oral Surg 1970;29:197-9. 20 Endogenous ochronosis within melanocytic nevi.t Desmoplastic Melanoma: An Update on Diagnostic and Management Considerations

Sadaf “Sabrina” Waqar, DO, MPH,* Layne Nissenbaum, DO, FAOCD**

*3rd year resident, Columbia Hospital-Dermatology Residency Program, West Palm Beach, FL **Program Director, Columbia Hospital-Dermatology Residency Program, West Palm Beach, FL

ABSTRACT Desmoplastic melanoma is rare and classically presents as a dermal tumor that is highly infiltrative, with minimal epidermal change, comprising of spindled melanocytes and prominent fibroplasia. Here we discuss clinical/histologic features, diagnostic modalities, as well as management considerations of desmoplastic melanoma. Background of spindled melanocytes and prominent scar-like histologic picture, Barnhill fibroplasia.3 et al. list the following warning signs as Accurate and early clinical diagnosis of reminders to carefully consider DM: atypical melanocytic lesions is based upon conspicuous cellularity, solar elastosis, a complex interplay between the patient- Clinical Features lymphoid aggregates, retained adnexal derived “anamnestic data,” analytical Clinically, the lesion presents as a structures, a lack of horizontal fibrosis, reasoning, comparative recognition, nodule or plaque, sometimes depressed and vertically oriented vessels and erythrocyte differential recognition, and pattern 3 often amelanotic.4 A pink papule or scar- extravasation. analysis.1,2 The goal is early and accurate like appearance is also reported, as well as a detection of the atypical or neoplastic Busam et al. have described the level of lentigo-maligna-like discoloration adjacent melanocytic lesion. Practically speaking, the fibroplasia as “pure” or “mixed,” with pure to the lesion.3,5 decision becomes whether to undertake a DM having >90% fibroplasia and mixed skin biopsy or digital mole monitoring with There is a high incidence of having <90% fibroplasia and presence of close follow-up. neurotropism in these tumors. Up to other more typical histologic features of 78% of DM showed neurotropism in melanoma.4 The significance of this study Various logarithms, including the a review conducted by Lens et al. The lies in the finding that the incidence of ABCDE rule (now utilized by physicians same review also showed that the mean neurotropism and lymph node involvement as well as patients) and the “ugly duckling Breslow depth was 2.0 to 6.5 mm, and is different between pure DM and mixed sign” are well-established analytical most cases presented at Clark level DM. The pure DM is more likely to have approaches to evaluating clinically IV or V. Often, the diagnosis is delayed neurotopism (41%) vs. mixed DM (25%). suspicious lesions. More specific criteria and made at an advanced stage, given a In contrast, the incidence of lymph are established for dermoscopic evaluation, nondescript initial presentation. However, node involvement was zero in pure DM including the Menzies method and the lymph node involvement is rare in this and 12% in mixed DM. Thus, histologic- seven-step checklist. These criteria and type of melanoma. The most common criteria subclassification of pure and mixed rules must of course be applied in light of complications are local recurrence and DM appears to have clinical utility in the each patient’s individual presentation of systemic metastasis. management of patients with DM. normal pigmented lesions. Dermatologists have undertaken a great challenge over the The most common associations Busam et al. were also able to last decade to recognize clinical variability are advancing age, male gender, and distinguish DM from conventional types of “normal” pigmented lesions among areas of sun exposure, particularly of melanoma by hierarchical clustering 4 individuals yet successfully develop a the head and neck.5 Clinical differential of certain genes. Their work showed common language, a consistent, systematic diagnosis includes basal cell carcinoma, that in DM, the genes that are commonly approach to physical examination and dermatofibroma, sarcoma, or simply scar. expressed are not those that encode for clinical evaluation of pigmented lesions. pigment synthesis, but rather those for neurotropic factors (such as nerve growth Similar advances have been made in Histologic Features factor receptor) and proteins involved in the area of reflective confocal microscopy There is significant variability in production and homeostasis of fibrous (RCM), an imaging tool that is applied in matrix (such as tissue metalloproteinase conjunction with dermoscopy to evaluate histologic hallmarks of DM consisting of atypical spindled cells amidst fibroplasia.3,4 inhibitor). These findings are consistent suspicious yet otherwise nonspecific with the staining pattern of DM, being lesions. When dermoscopy and RCM The spindled cells can be either single or arranged in fascicles reminiscent of a nerve- S100 positive, P-75 positive, and vimentin were used together, sensitivity (to detect positive but melan-A and HMB-45 negative. atypical melanocytic lesions is) highest.1 derived neoplasm. The dermal-epidermal Both modalities utilize study of en face junction should be examined carefully Histologic differential diagnosis cutaneous structures to ensure recognition to evaluate a possible overlying atypical includes scar, desmoplastic nevus, of seemingly benign aggressive tumors. endogenous melanocytic proliferation. The desmoplastic spitz nevus, sclerosing dermal spindled cells should be scrutinized blue nevus, dermatofibroma, One such aggressive tumor is based on cytomorphology with nuclear dermatofibrosarcoma protuberans, neural desmoplastic melanoma (DM). This variant atypia and enhanced mitotic rate, although tumors, sarcomas, spidles cell squamous cell of melanoma is rare and classically presents tumor mitotic rate is often negligible. carcinoma, and atypical fibroxanthoma. as a dermal tumor that is highly infiltrative, with minimal epidermal change, comprised Regarding an inconspicuous,

W AQAR, NISSENBAUM 21 Dermoscopy and 3. Pigment dots = single large pagetoid based on tumor thickness. cells The use of adjuvant therapy is not well Reflectance Confocal 4. Streaks = radial streaming studied. Some authors recommend post- 1,5 Microscopy (RCM) 5. Light brown pigment = regular operative adjuvant radiation treatment The dermoscopic features are not honeycombed pattern for better local control, given the high consistent with those of typical pigmented frequency of neurotropism and incidence of 6. Dark diffuse pigment = bright local recurrence.11 lesions and are highly variable among cobblestone pattern individual lesions of DM, primarily because References 7. Blue-whitish veil = disarranged pattern they are often dermal tumors with varying 1. Marghoob A, Scope A. (2009) The complexity of degrees of fibroplasia, vascular hyperplasia, and presence of pagetoid infiltration Diagnosing Melanoma. Journal of Investigative and amelanosis. in superficial layers, nonedged papillae Dermatology 129: 11-13 and cytological atypia in basal layer, 2. Gashon J, Beaulieu P, Sei JF, Gouvernet J, Claudel The seven-point checklist defines JP, Lemaitre M, et al. (2005) First prospective study of cerebriform nests, plump cells in the recognition process of melanoma in dermatology well-established, consistently reproducible dermal papillae practice. Archived Dermatology 141:434-8 criteria for evaluation of atypical 3. Barnhill RL, Gupta K. (2009). Unusual variants of melanocytic lesions. These criteria are: 8. Regression = thin epidermis and coarse malignant melanoma. Clinics in Dermatology, 27(6), network of ill-defined grainy bundles 564-587. grey-blue areas, atypical vascular pattern, 4. Busam KJ, Mujumdar U, Hummer AJ, Nobrega atypical pigment network, irregular diffuse or fibers in the dermis, sometimes J, Hawkins WG, Coit DG, Brady MS. Cutaneous intermingled with small, bright desmoplastic melanoma reappraisal of morphologic pigmentation, regression, radial streaming heterogeneity and prognostic factors. Am J Surg Pathol or streaks, and irregular dots and globules.1,5 reflecting spots and plump bright cells 2004;28:1518. Unfortunately, given a highly variable However, DM is lacking in most 5. Lens MB, Newton-Bishop JA, Boon AP. Desmoplastic Melanoma: a systematic review. British Journal fibroplasia, lack of epidermal involvement, of the typical features of a melanocytic Dermatology. (2005) 152: 673-8 Pellacani G, Longo C, Malvehy J, Puig S, Carrera C, Segura S, Bassoli S, and amelanosis, these criteria have limited neoplasm. As discussed earlier, the scar- Seidenari S. (2008) In vivo confocal microscopic and utility in detection of DM. like, structureless area is found to be one histologic correlations of dermoscopic features on 202 melanocytic lesions. Archives Dermatology 144(12): Debarbieux et al. described case of the most common features in DM. 1597-1608 reports of six DM patients focusing This finding could possibly correlate with 6. Gyorki DE, Busam K, Panageas K, Brady MS, Coit DG. findings similar to those in regression, (2003) Sentinel lymph node biopsy for patients with specifically on the dermoscopic cutaneous desmoplastic melanoma. Annals of Surgical presentation of these tumors. Their cases including ill-defined grainy bundles or Oncology 10: 403-7 showed the following trends: fibers in the dermis. In addition, those DM 7. Pawlik TM, Ross MI, Prieto VG, et al. (2006) lesions that have any degree of pigment Assessment of the role of sentinel lymph node biopsy 1. The detection of a pigment network, for primary cutaneous desmoplastic melanoma. Cancer variation or blue-whitish veil should have 106:900-6 aggregated globules or strikes was detectable changes if examined through 8. Thelmo MC, Sagebiel RW, Treseler PA, Morita ET, possible only 50% of the time (3/6 Nguyen LH, Kashani-Sabet M, Leong SP. Evaluation of RCM. Again, RCM is only an adjunctive sentinel lymph node status in spindle cell melanomas. J patients). tool for clinical assessment. Its utility Am Acad Dermatol 2001;44:451. 2. The detection of variability in colors becomes most sensitive in light of all the 9. Quinn MJ, Crotty KA, Thompson JF, Coates AS, O’Brien CJ, McCarthy WH. Desmoplastic and desmoplastic within the suspected lesion was more other components of clinical evaluation. neurotropic melanoma: experience with 280 patients. likely, with 4/6 DM lesions showing Cancer 1998;83:1128. 10. Jaroszewski DE, Pockaj BA, DiCaudo DJ, Bite U. The four colors. clinical behavior of desmoplastic melanoma. Am J Surg Management 2001;182:590. 3. The most consistent feature was 11. Vongtama R, Safa A, Gallado D. (2003) Efficacy of detection of a white, scar-like, Wide excision is standard of care. radiation therapy in the local control of desmoplastic structureless area (6/6). Several studies have shown that patients malignant melanoma. Head and Neck 25: 423-8 with melanomas of desmoplastic type 12. Hoffmann-Wellenhof R, Wurm EMT, Ahlgrimm-Siess 4. A blue-white veil, a classic feature of have a lower frequency of sentinel- V, et al. (2009) Seminars in Cutaneous Medicine and other melanomas, was present in only Surgery. 28:172-179 node positivity than patients with 2/6 lesions. 13. Huttenbach Y, Prieto VG, Reed JA. Desmoplastic nondesmoplastic melanomas.6,7 Some and spindle cell melanomas express protein markers of the neural crest but not of later committed stages 5. Another reliable feature consistent with authors are not recommending sentinel of Schwann cell differentiation. J Cutan Pathol detection of the tumors was presence lymph-node biopsy (SLNB) for pure DM, 2002;29:562. of linear atypical vessels. 14. Skelton HG, Smith KJ, Laskin WB, McCarthy WF, since the incidence of lymphatic spread is Gagnier JM, Graham JH, Lupton GP. Desmoplastic 8 Dermoscopic differential diagnosis extremely rare in these lesions. DM on the malignant melanoma. J Am Acad Dermatol 1995;32:717. includes scar, atypical dermatofibroma, and trunk or lower extremity doubled the risk 15. Longacre T, Egbert B, Rouse R. Desmoplastic and spindle-cell malignant melanoma: an amelanotic melanoma. of SLN positivity compared with location immunohistochemical study. Am J Surg Pathol on the head/neck or upper extremity.9 1996;20:1489. The variability in RCM parallels that of In addition, SLN positivity decreases 16. Tsao H, Sober AJ, Barnhill RL. Desmoplastic neurotropic dermoscopic evaluation in DM. Pellacani et melanoma. Semin Cutan Med Surg 1997;16:131. with age.10 In sum, a good candidate for al. recently described confocal microscopic 17. McCarthy SW, Scoyler RA, Palmer AA. Desmoplastic sentinel lymph-node biopsy in addition to melanoma: a diagnostic trap for the unwary. Pathology and histopathologic correlation of wide surgical excision would be a young 2004;36:445. dermoscopic features in typical melanocytic patient with DM of the trunk or lower 18. Anstey A, McKee P, Jones EW. Desmoplastic malignant lesions. These correlations include: melanoma: a clinicopathological study of 25 cases. Br J extremity. Otherwise, the utility of this Dermatol 1993;129:359. 1. Atypical pigment network = non-edged procedure appears very low for prognostic 19. Bernaba BN, Vogiatzis PI, Binder SW, Cassarino DS. Potentially useful markers for desmoplastic melanoma: papillae measures. The data for mixed DM shows a an analysis of KBA.62, p-AKT, and Ezrin. Am J 2. Irregular pigment globules = irregular different trend, and the lymphatic spread Dermatopathol 2011;33:333. shaped clusters is comparable to conventional melanoma,

22 Desmoplastic Melanoma – An Update on Diagnostic and Management Considerations Erosive Papulonodular Dermatosis: A Case Report and Review of the Literature

Jessica Newburger, DO,* David B. Kessler, DO, FAOCD**

*Intern, Nassau University Medical Center, East Meadow, NY **Attending Dermatology Physician, Massapequa, NY

ABSTRACT Erosive papulonodular dermatosis was a term created to encompass three forms of irritant dermatitis that affect the genital, inguinal, and perineal regions, which may be difficult to distinguish due to overlapping clinical appearance: granuloma gluteale adultorum, pseudoverrucous papules and nodules (PPPN), and Jacquet's erosive diaper dermatitis. We present a case of an 81-year-old Caucasian male with a painful and pruritic inguinal rash for over a year. Pathology revealed erosive papulonodular dermatosis, though no direct causative factor was determined. A review of the literature is presented to elucidate this spectrum of disease. Case Report perineum. The patient was treated with var- Figure 3 ious topical antibacterials and antiprurit- An 81-year-old Caucasian male pre- ics with mild improvement but continued sented to the dermatology office complain- to complain of irritation and discomfort ing of a pruritic and painful rash in his as well as “peeling” of the skin and new groin for three months. During this time, involvement of the scrotum. the patient had used topical antifungals, topical steroids and topical antibiotics with- Patch testing was performed (North out improvement of his symptoms. He American Series 85 Comprehensive Series began using mupirocin cream a few days Chemotechnique Patch Test Allergens) and prior to presentation, which provided mild was negative to all allergens tested. It is to relief. be noted that at this time the patient had a relapse of bladder cancer, for which he Figure 4 His past medical history included underwent transurethral resection (TUR) hypertension, hyperlipidemia, GERD, and with fulguration and received intra-arterial recently diagnosed carcinoma of the blad- chemotherapy to the bladder. The patient der, for which he was being treated and fol- had occasional episodes of incontinence lowed by urology. The patient’s history was following these surgical procedures, but also significant for a below-the-knee ampu- never required the use of a diaper. He still tation of his left leg as a child. His medica- had mild erythema and lichenification of tions included simvastatin, atenolol, aspirin, the inguinal folds and was prescribed a topi- chlordiazepoxide/clidinium, escitalopram cal antifungal as well as calcipotriene/beta- and rabeprazole. He had no known aller- methasone ointment without relief. gies to medication. The patient also denied any prior topical benzocaine use. Following the patch test results, a 4mm punch biopsy of the left groin was per- On physical exam, there was mild formed, which revealed slight spongiotic zinc oxide ointment, which resulted in mild erythema of the inguinal creases bilater- dermatitis with marked hyperkeratosis (Fig- improvement. Due to the lack of signifi- ally (Figures 1 & 2). There were no dis- ures 3 & 4). There were changes suggestive cant response to prior topical treatment tinct papules or nodules noted, nor was of a chronic irritant dermatitis synonymous and based on the results of Frambach, et there any scaling of the skin. There was with erosive papulonodular dermatosis and al., the patient was started on an oral anti- 15 no involvement of the perianal region granuloma gluteale adultorum. These were fungal once a week for 10 weeks. At the or buttocks. The presumptive diagno- not changes of lichen sclerosis et atrophi- patient’s most recent visit, he stated mild to sis at that time was an irritant dermatitis. cus, and there was no evidence of psori- moderate improvement and was advised to The patient was prescribed a compound of asis. Furthermore, a PAS stain failed to continue mycostatin/zinc oxide ointment hydrocortisone-iodoquinol cream with zinc reveal fungal elements. in the morning and was started on topical oxide paste. He complained of increased tacrolimus ointment to use at night. He stinging and burning of the left groin and The patient was prescribed mycostatin/ continues to be monitored. Figure 1 Figure 2 Discussion Erosive papulonodular dermatosis is a term proposed by Robson et al. to encom- pass all variants of genitocrural irritant dermatitis, including granuloma gluteale infantum/adultorum, pseudoverrucous pap- ules and nodules (PPPN), and Jacquet’s ero- sive diaper dermatitis. They had reported two patients with papulonodular and ero-

Newburger, Kessler 23 sive lesions on the diaper area associated parts of the gluteal region and the pres- diaper dermatitis. Pathology revealed epi- with topical benzocaine. Both patients had ence of a dense, mixed dermal inflamma- dermal hyperplasia and a diffuse, dermal lesions that were clinically similar to gran- tory infiltrate. Unlike PPPN and Jacquet's mixed inflammatory infiltrate composed uloma gluteale, PPPN, and Jacquet's ero- erosive diaper dermatitis, granuloma glu- of lymphocytes, plasma cells and sparse sive diaper dermatitis. The multiple biopsy teale infantum/adultorum is not limited to neutrophils. The patient was instructed to specimens taken from these patients over- patients with incontinence.3,9,10 discontinue the use of talcum powder, and lapped histologically with all the aforemen- PPPN is a rare condition that was a colostomy was created. Once the irrita- tioned conditions. Therefore, the authors first reported in association with urostomy tion caused by the stool was removed, the proposed the term "erosive papulonodular sites. It may also occur in the perianal lesions began to resolve, leading to marked 3 dermatosis" for their patients. area secondary to urinary incontinence or improvement in the patient’s pain and dis- 11 Granuloma gluteale infantum is a encopresis, and is also believed to be an comfort. benign skin disorder of controversial eti- irritant dermatitis. Lesions are described Treatment options for patients with ology manifested clinically by oval, red- as shiny, smooth, red, moist, flat-topped erosive papulonodular dermatosis have not dish-purple, granulomatous nodules on and round.1,3,12 The clinical appearance of been thoroughly studied. Patients with the gluteal surfaces and groin areas of PPPN is similar to that of granuloma glu- granuloma gluteale generally do not require infants, classically seen between 2 and 9 teale; however, it consists predominantly treatment, as lesions tend to resolve spon- months of age. Similar lesions have also of wart-like papules. In one case series, taneously over a few months. Lesions per- been described in adults and the elderly one-fifth of patients with urostomies dis- sist for 3-6 weeks, followed by spontaneous who are incontinent, and are referred to played pseudoverrucous skin lesions in a regression over 2-4 weeks.4 Furthermore, as granuloma gluteale adultorum and dia- peristomal location. These lesions were patients with a history of granuloma glu- per area granuloma of the aged, respec- described as wart-like papules, or small, teale associated with topical benzocaine tively. Lesions are similar to those seen in white-gray or reddish-to-brown erosive use tend to have complete resolution once infants, typically being firm, reddish-pur- papules about 2 to 3 mm in size. Many use of the offending agent is discontin- ple, oval, or elongated nodules and plaques of these patients also had erythematous- ued. Regardless of the final classification, in the pubic area, scrotum, buttocks, and erosive skin lesions.3,13 On histology, PPPN management of incontinence most effec- medial aspects of the thighs.3,7-9 demonstrates spongiotic psoriasiform der- tively brings about resolution of Jacquet’s Occlusion from diapers, paper napkins, matitis or acanthosis yet lacks significant erosive diaper dermatitis. Barrier agents 3,11,12 plastic pants, detergents, starch, powder, dermal inflammation. such as zinc oxide ointment, white petro- halogenated steroids, Candida infection, In Jacquet’s erosive diaper dermatitis, latum, and sucralfate are useful adjuncts to and urine and feces are postulated as pos- lesions are localized to the genital and/or protect the skin from irritants and mois- 10 sible etiologies.3-6 Furthermore, benzocaine perianal skin, appearing as non-conflu- ture. is a potent sensitizer and is a common cause ent, small, well-demarcated papules and Moreover, it is important to consider of allergic contact dermatitis of the genital nodules measuring 2 to 8 mm in diameter other differentials in the diagnosis of an region. Topical benzocaine use has previ- with central umbilication and superficial inguinal eruption. Necrolytic migratory ously been reported to be associated with erosions or ulcers, often with heaped-up erythema is a rare syndrome that is usually granuloma gluteale adultorum.3,4 There borders.10,14 The predominant lesions are associated with an islet cell tumor of the is no known systemic association with the erosions. Although typically seen in pancreas. The eruption occurs in periorifi- granuloma gluteale infantum. However, in infancy, Jacquet’s erosive diaper dermatitis cial, flexural, intertriginous, and acral areas, contrast to granuloma gluteale infantum, has been reported in adults with urinary and closely resembles the lesions associated granuloma gluteale adultorum and diaper incontinence.3,10,11,14 Prolonged contact with with zinc or other micronutrient deficien- area granuloma of the aged are observed urine under occlusion compromises skin cies. Annular and arcuate erythematous only in the genitocrural regions and not in integrity and renders it more permeable to lesions coalesce to form large plaques with the intertriginous areas. In addition, the irritants, the most potent being pancreatic necrosis and sloughs of the superficial epi- nodules of granuloma gluteale adultorum proteases and lipases present in feces.2,10 dermis, followed by erosion or crusting. and diaper area granuloma of the aged are Histopathology shows acanthosis, hyper- The condition is poorly responsive to topi- often eroded and do not show an arrange- keratosis, spongiosis, superficial ulceration, cal therapy with corticosteroid and anti- ment parallel to skin lines.4,7,8 and a mixed dermal inflammatory infiltrate fungal medications. Histologically, there Granuloma gluteale has a somewhat consisting of neutrophils, lymphocytes, and is irregular acanthosis with parakeratosis nonspecific histology. It demonstrates plasma cells. However, because the histo- and crust. The upper third of the epider- epidermal hyperplasia accompanied by a pathologic characteristics lack specificity, mis demonstrates pallor and ballooning 10,14 densely mixed, dermal, inflammatory infil- diagnosis remains largely clinical. degeneration of keratinocytes. Laboratory trate of neutrophils, lymphocytes, plasma Askin et al. presented an adolescent findings may include a low serum zinc level, cells and eosinophils, with variable dila- who had prolonged contact with feces hypoaminoacidemia, and elevated gluca- tion and proliferation of blood vessels. The due to encopresis, which was believed to gon levels. The cause of the syndrome is lesions of granuloma gluteale are granu- be a potential causative factor. Long-term unknown, since some cases are not asso- lomatous in clinical appearance but histo- use of talcum powder also was thought to ciated with glucagon-secreting tumors. logically do not demonstrate multinucleated exacerbate the condition. Although non- Amino acid, zinc, and essential fatty acid giant cells or other features of well-devel- specific, the histopathological findings of supplementation have improved the erup- oped granulomas.3,9-11 the biopsy specimen taken from a super- tion without lowering glucagon levels, sug- gesting these secondary consequences of Granuloma gluteale infantum/adul- ficial, eroded, flat-topped nodule were consistent with an irritant contact derma- hyperglucagonemia are the actual cause of torum is distinguished from PPPN and the eruption.16 Jacquet’s erosive diaper dermatitis by the titis, revealing overlapping features with distribution pattern that overlies the convex granuloma gluteale and Jacquet's erosive In conclusion, granuloma gluteale 24 Erosive Papulonodular Dermatosis: A Case Report and Review of the Literature infantum/adultorum, PPPN, and Jac- quet's erosive diaper dermatitis are all forms of irritant dermatitis affecting the genital, inguinal, and perineal regions that may be difficult to distinguish from one another due to overlapping clinical appear- ance.10,12 The term "erosive dermatitis" was created in order to categorize these three dermatological conditions into one disease spectrum. Although these entities are dif- ficult to treat, it is imperative to consider a variety of treatment options, as well as diverse vehicle delivery of topical medica- tions. Barrier repair creams and emulsions, such as Eletone, EpiCeram and Cerave, should be considered given their ability to normalize skin barrier function due to high lipid content, specifically with regard to ceramides. Acitretin, although predomi- nantly prescribed for the treatment of pso- riasis, has also been used to treat Darier's disease, lichen sclerosus et atrophicus of the vulva, and lichen planus. References 1. James WD, Berger TG, Elston DM. Andrews’ diseases of the skin: clinical dermatology. Philadelphia: WB Saunders Co; 2006. p. 42. 2. James WD, Berger TG, Elston DM. Andrews’ diseases of the skin: clinical dermatology. Philadelphia: WB Saunders Co; 2006. p. 80. 3. Robson KJ, Maughan JA, Purcell SD, et al. Erosive papulonodular dermatosis associated with topical benzocaine: a report of two cases and evidence that granuloma gluteale, pseudoverrucous papules, and Jacquet’s erosive diaper dermatitis are a disease spectrum. J Am Acad Dermatol. 2006; 55:S74-80. 4. Dytoc MT, Fiorillo L, Liao J, Krol AL. Granuloma gluteale adultorum associated with use of topical benzocaine preparations: case report and literature review. J Cutan Med Surg 2002;6:221-225. 5. Bluestein J, Furner BB, Phillips D. Granuloma gluteale infantum: case report and review of the literature. Pediatr Dermatol 1990; 7:196-198. 6. Konya J, Gow E, et al. Granuloma gluteale infantum. Australas J Dermatol 1996; 37:57-58. 7. Fujita M, Ohno S, Danno K. Two cases of diaper area granuloma of the adult. J Dermatol 1991; 18:671-675. 8. Maekawa Y, Sakazaki Y, Hayashibara T. Diaper area granuloma of the aged. Arch Dermatol 1978; 114:382- 385. 9. De Zeeuw R, Van Praag MC, Oranje AP. Granuloma gluteale infantum: a case report. Pediatr Dermatol 2000;17:141-143. 10. Van L, Harting M, Rosen T. Jacquet erosive diaper dermatitis: a complication of adult urinary incontinence. Cutis 2008;82:72-74. 11. Aşkin Ü, Ada S, Bilezikçi B, Arda S. Erosive papulonodular dermatosis in an adolescent with encopresis. Br J Dermatol 2008;158:413-415. 12. Goldberg NS, Esterly NB, Rothman KF, Fallon JD, Cropley TG, Szaniawski W, et al. Perianal pseudoverrucous papules and nodules in children. Arch Dermatol 1992;128:240-242. 13. Bergman B, Knutson F, Lincoln K, Lowhagen GB, Mobacken H, Wahlen P. Chronic papillomatous dermatitis as a peristomal complication in conduit urinary diversion. Scand J Urol Nephrol 1979;13:201- 204. 14. Virgili A, Corazza M, Califano A. Diaper dermatitis in an adult: a case of erythema papuloerosive of Sevestre and Jacquet. J Reprod Med. 1998;43:949-951. 15. Frambach G, Hoffman C, Kassardjian M. Granuloma gluteale adultorum. JAAD. 2011;64:AB44. 16. James WD, Berger TG, Elston DM. Andrews’ diseases of the skin: clinical dermatology. Philadelphia: WB Saunders Co; 2006. p. 143-144.

Newburger, Kessle r 25 Regression of Cutaneous Melanocytic Lesions: A Diagnostic and Management Dilemma

Brooke Blumetti, DO,* Stephen Olsen, M.D.,** Howard Lipkin, DO,*** Annette LaCasse, DO, FAOCD****

*Dermatology Resident, Third Year, Pontiac Osteopathic Hospital, Pontiac MI **Dermatopathologist, Pinkus Dermatopathology Laboratory, Monroe, MI ***Brighton Dermatology and Regenesis, Brighton, MI ****Program Director, Dermatology Residency, Botsford/Pontiac Osteopathic Hospitals, Pontiac, MI; Commerce Skin Institute, Commerce, MI

ABSTRACT Regression of malignant melanoma is theorized to be an immunologic response to tumor cells. Partial regression is frequently seen, however, only around 40 cases of complete regression have been reported. This phenomenon presents a host of dilemmas because much is still unknown about the etiology, the prognostic significance, and the treatment of these lesions. Case Report identified. The regressive fibrotic changes extended to a deeper level of the dermis A 71-year-old Caucasian male pre- than these nests, at a Breslow depth of 0.50 sented with a one-year history of an mm. expanding pigmented lesion on his left upper arm. He was a non-smoker with no Slides of the lesion were reviewed by known drug allergies and a past medical two board-certified dermatopathologists, history of well-controlled hypertension, including one at a regional melanoma refer- atrial fibrillation, kidney stones, and COPD. ral center. Each concluded that the lesion He reported a history of several sunburns. represented a regressed melanocytic lesion, His medications were pertinent to his above in the least, a regressed or halo-type dermal reported past medical history. There was no nevus. However, due to the breadth of the family history of melanoma, pancreatic can- lesion, density of melanosis and cytologic cer, or breast cancer. He denied any other Figure 1: Atypical pigmented lesion dem- atypia, regressed melanoma could not be new, changing, bleeding or otherwise symp- onstrating large size, irregular borders excluded. A complete excision was recom- tomatic skin lesions. All other reviewed and pigmentation. mended. body systems, including constitutional, neu- The patient was referred to a univer- rological, lymphatic and respiratory, were sity-based melanoma clinic, where his clini- asymptomatic relating to possible metastatic cal and histopathologic data, including a melanoma. comprehensive melanoma profile, were On physical examination, there was a presented to a multidisciplinary melanoma 1.1 cm black and brown pigmented lesion tumor board. A final recommendation was with an irregular border on his left upper made to treat the lesion as a possible thin arm that was highly clinically suspicious for melanoma, to be excised with a 1 cm mar- malignant melanoma (Figure 1). Complete gin. examination of the rest of his skin revealed The patient was educated on the no other lesions suspicious for melanoma importance of follow-up with his derma- or dysplastic nevi. Lymph node exam of tologist every six months for one to three the head and neck, supraclavicular, axillary, years, and annually there after. The and inguinal basins revealed no lymphade- importance of and instruction in monthly nopathy. Liver and spleen were normal to Figures 2 & 3: A nest of melanocytes self-administered skin and lymph node palpation. An excisional biopsy with a 2 present within brisk inflammation, with examinations were described, and he was mm margin was performed. melanophages and cytoid bodies. (H&E, educated on the early signs and symptoms A = 100x; B = 400x) Pathology revealed a broad, variegated, of melanoma and the risk of additional skin plaque-like lesion of the upper dermis. This cancer and lymphatic and distant recur- was composed of diffuse loose regressive rences. No further radiographic or hemato- fibrosis and variable but focally dense and logical tests were indicated. banded lymphocytic inflammation, accom- panied by foci of dense collections of mel- anophages or melanosis. The epidermis Discussion displayed a flattened rete ridge pattern, and Although regression can be seen in scattered cytoid bodies were noted. Within various benign cutaneous lesions, it is an the inflammation were rare, small compact unusual phenomenon in malignant neo- nests of melanocytes exhibiting low-grade plasms, seen only in three types of tumors, cytologic atypia (Figures 2 & 3). These were including melanoma, neuroblastoma, and confirmed as melanocytic in nature by a hypernephroma.1 It is common for mela- melan-A immunostain. Mitoses were not noma to demonstrate partial regression;

26 Regression of Cutaneous Melanocytic Lesions: A Diagnostic and Management Dilemma however, only around 40 cases of complete tological diagnosis of a completely regressed tion of abnormal antigens expressed by the regression have been reported.2 This may be melanoma is fraught with pitfalls. Changes melanoma.3 Melanoma cells are known to due to the difficulty in retrograde diagnosis characteristic of regression can also be seen have both cytoplasmic and cell-membrane of such lesions and the discrepancies in in benign regressing melanocytic nevi (halo tumor specific antigens that have the abil- the definition. This phenomenon presents nevi) and in inflammatory lichenoid con- ity to stimulate both humoral antibodies a host of dilemmas because much is still ditions.8 When the findings of regression and cytotoxic lymphocytes.1,9 This is sup- unknown about the etiology, the prognostic occur in the background of some residual ported by the finding of lymphocytes and significance, and the treatment of regressed identifiable melanoma, the diagnosis is not plasma cells in the inflammatory infiltrate. lesions. difficult; it becomes more challenging when It is likely that cell-mediated immunity no identifiable tumor is present. plays the largest role in regression, with In most reports of metastatic mela- the apoptotic destruction of tumor cells noma, about 2.5% have an occult primary A halo nevus is one of the histologic mediated by cytotoxic lymphocytes. Cases origin. These usually present with periph- differential diagnoses that should be consid- of severe regression in primary malignant eral lymphadenopathy. It is possible that ered in the diagnosis of a regressed lesion. melanoma with nodal metastases has led to complete regression could explain the ori- A completely regressed halo nevus clini- speculation that the presence of metastasis gins of some of these cases.4,5,6 Another cally shows a more symmetrical annular within a regional lymph node may be the possibility is that these cases arise from ring, whereas a hypopigmented regressed 9 initiating factor in stimulating the immune capsular nevi within lymph nodes. Clini- melanoma tends to be more asymmetric. response, resulting in regression of the pri- cally, regression can be demonstrated when Also, halo nevi are common and considered mary lesion.3 a preexisting nevus or other pigmented benign in children, but are seen less fre- lesion begins to show a decrease in pig- quently in the adult population.6 There tend The prognostic significance of regres- mentation, variation in color, fragmenta- to be more plasma cells and linear scarring sion in primary melanoma is highly con- tion into smaller parts, and eventual scar in regressed melanoma than in halo nevi. troversial. Reported survival among the formation.1,8 In cases of metastatic mela- Other histologic mimickers include benign cases of patients with completely regressed noma, these findings are sometimes, but not lichenoid dermatoses, including lichen pla- melanoma is variable, ranging from 6 weeks always, found in the areas of skin drained nus-like keratosis and verrucae. Usually, to 11 years.3 Some authors indicate that by the node that metastasis was detected in. the clinical presentation differs, and a lesser regression does not increase the risk of degree of melanosis, with a more symmetric metastasis,7 while others have suggested A set of criteria has been established lichenoid infiltrate, is seen.5 Clinical corre- that regression is associated with a rela- to aid in the diagnosis of a completely lation and step sectioning the block, looking tively worse prognosis than non-regressed regressed melanoma:3 for residual melanoma cells, may aid in this lesions. Inconsistencies in the definition of 1. A history or clinical evidence of a differentiation.9 regression and variations in the thickness of pigmented lesion situated in an area Finally, complete regression can lesions probably contribute to the conflict- drained by tumor-involved lymph be challenging to diagnose in cases with ing opinions. It would be intuitive that if nodes. This implies that in order for residual benign nevoid components, as in regression were the result of a successful a lesion to be diagnosed as a regressed the case possibly seen in our patient. It response from the host, that the prognosis melanoma, metastasis must have al- is commonly accepted that many melano- of such lesions would be better than for ready occurred. The diagnosis, there- mas arise within preexisting nevi. When lesions that escaped the body’s innate abil- fore, must be made in retrospect. This immune-mediated regression occurs, it may ity to protect itself, but this does not always criterion does not address the possibil- be directed toward the melanoma cells and appear to be the case. ity that a melanoma could completely not toward the benign nevi cells. This can Without a consensus on the prognos- regress without ever metastasizing. give the appearance of an inflamed dysplas- tic significance of regression, there have 2. There must be an absence of any other tic or traumatized nevi. Careful evaluation been no specific recommendations as to primary lesion identifiable by history of the specimen aids in the diagnosis, with the management of these lesions. It could or physical examination that could rep- the fibrosis in the benign lesions being con- be argued that erring on the side of cau- resent the original lesion of malignant centric or lamellar, the inflammation being tion and treating these lesions as if they melanoma. perivascular and not band-like, and plasma were melanomas would be the best solu- 9 3. The must be the clinical presence of cells being a rarity. tion. The sentinel lymph node (SLN) status atypical pigment or depigmentation In cases of other histologically ambigu- represents an important prognostic factor in at the site of the untreated presumed ous primary cutaneous melanocytic tumors many patients with melanoma. Some have primary lesion, with the typical histo- that do not display clear-cut features of questioned the use of SLN biopsy to search logic features associated with regression malignancy, molecular testing such as com- for occult nodal metastasis in these cases found on biopsy. These findings include parative genomic hybridization, fluores- of complete regression. To date, there is no an attenuated epidermis, dermal mela- cence in situ hybridization, and polymerase evidence to support any benefit in doing nophages, lymphocytic or chronic in- chain reaction (PCR) are being increasingly an SLN in regressed melanocytic lesions, flammatory infiltrate, reactive vascular used.10 At present, molecular testing is not especially when considering the potential 6,10 proliferation, and fibrosis. always definitive or cost effective, but it is morbidity associated with this procedure. As of now, a lesion that is highly suspi- 4. There must be an absence of malignant possible it may someday be of value in these 10 cious for a completely regressed melanoma melanoma cells found within the bi- cases. should probably be excised as if it were a opsy. The etiology of regression is thought melanoma. Physical examination of the Pathologic diagnosis of melanocytic by most to be associated with an immune lymph nodes, liver, and spleen are indi- tumors can be one of the most difficult phenomenon. Most data suggests a T-cell cated, with some suggesting baseline blood areas of diagnostic histopathology. The his- mediated cell death occurs after recogni- work including a complete blood count,

Bm lu etti, Olsen, Lipkin, lacasse 27 liver function testing, and lactate dehy- 7. Kaur C, Thomas RJ, Desai N, et al. The correlation of 6 regression in primary melanoma with sentinel lymph drogenase. Regular self- and physician- node status. J Clin Pathol 2008 61: 297-300. administered skin and lymph node exams 8. Grafton W. Regressing Malignant Melanoma. J La State are recommended every six months. Med Soc. 1994; 146(12):535-9. 9. Barr RJ. The many faces of completely regressed malignant melanoma. Pathology (Phila). 1994;2(2):359- 70. Conclusion 10. Scolyer RA, Murali R, McCarthy S, Thompson J. Histologically ambiguous primary cutaneous melanocytic Our patient presented a diagnostic tumors. Arch Pathol Lab Med. 2010;134:1770-6. and management dilemma. Clinically, the patient presented with a melanocytic lesion that was highly suggestive for melanoma. It was asymmetrical, with an irregular border and multiple and changing colors, and had a diameter of 1.1 cm. The excisional biopsy, however, was not diagnostic for a malignant melanoma. It was interpreted by two sepa- rate dermatopathologists at different labo- ratories and stained with melan-A staining. Neither pathologist could definitively iden- tify the lesion as melanoma, although the size of the regressed lesion and density of the melanosis were more than is typical of halo nevi. The depth of the regressed lesion extended to 0.50 mm. Clinically, the patient did not have palpable lymph nodes. If this had been a definitive melanoma, a re-exci- sion with a margin of 1 cm would have been recommended. It was decided in this case to treat this lesion as such, because a defini- tive diagnosis could not be reached. This case demonstrates the ability of the immune system to remove a rapidly enlarging pigmented lesion. The signifi- cance of this is unknown, especially in light of this lesion not showing metastasis so far. The possibility is raised, however, that a melanoma could indeed completely regress without metastasizing as a successful immune phenomenon. Because of the still unknown significance of this, at this time it is probably best to follow such cases with vigilant observation for future metastasis. In these cases, clinicians must use their best clinical judgment as to the management of these patients. References 1. Bottger D, Dowden RV, Kay PP. Complete spontaneous regression of cutaneous primary malignant melanoma. Plast Reconstr Surg.1992;89(3):548-53. 2. High WA, Stewart D, Wilbers CR, Cockerell CJ, Hoang MP, Fitzpatrick JE. Completely regressed primary cutaneous malignant melanoma with nodal and/or visceral metastases: a report of 5 cases and assessment of the literature and diagnostic criteria. J Am Acad Dermatol. 2005;53(1):89-100. 3. Avril MF, Charpentier P, Margulis A, Guillaume JC. Regression of primary melanoma with metastases. Cancer. 1992;69(6):1377-81. 4. Shai A, Avinoach I, Sagi A. Metastatic malignant melanoma with spontaneous and complete regression of the primary lesion. Case report and review of the literature. J Dermatol Surg Oncol. 1994;20(5):342-5. 5. Emanuel PO, Mannion M, Phelps RG. Complete regression of primary malignant melanoma. Am J Dermatopathol. 2008;30(2):178-81. 6. Berger AC, McClay EF, Toporcer M, Wolchok JD, Morris GJ. Completely regressed cutaneous melanocytic lesion: was it benign or was it malignant? Semin Oncol. 2009;36(5):375-9.

28 Regression of Cutaneous Melanocytic Lesions: A Diagnostic and Management Dilemma

Case Study: Psoriasis Clearing Post Stroke

Jonathan S. Crane, DO, FAOCD,* David G. Jackson, BS,** Ronald P. Benjamin, M.D.,*** Charlene Snyder, PA-C,**** Christine M. Cook, BS, CCRC*****

*Atlantic Dermatology Associates, P.A., Wilmington, NC **University of North Carolina, Wilmington, NC ***Atlantic Dermatology Associates, P.A., Wilmington, NC ****Atlantic Dermatology Associates, P.A., Wilmington, NC *****Atlantic Dermatology Associates, P.A., Wilmington, NC

ABSTRACT Psoriasis occurs in approximately 2 % of the population. The patients who have psoriasis tend to be genetically predisposed. Internal and external factors can result in exacerbation and remission. It is well known that streptococcus pharyngitis can trigger an episode of psoriasis. Stressful events can also precipitate psoriasis, therefore, lack of stress may help psoriasis .Many factors can exacerbate psoriasis, but what conditions can help psoriasis? Ischemic occlusion is of question. It has been reported in the past that psoriasis can clear after a stroke.1 Case Report This patient had been on atenolol, Lipitor, Diovan, A 64-year-old, Caucasian male pre- and amlodipine prior to the sented with a history of moderate pso- stroke as well as after the riasis for nine years. During these nine stroke. He was started on years, he'd had psoriasis involving the nails, Plavix after the stroke. He elbows, knees and back, with thick scales. did not continue the adali- He had used numerous topical steroids mumab after the stroke. He including clobetasol propionate 0.1% spray. regained full neurological When the psoriasis became severe, he was function without any sign of started on adalimumab. At the time he skin psoriasis (Figure 2). His began adalimumab, he had moderate to psoriasis is still clear three severe psoriasis affecting 20% body surface months after his stroke. This area. The Humira significantly improved patient inquired if we had his psoriasis. Within a month after begin- heard of psoriasis clearance ning Humira (adalimumab), he was about after a stroke. He was told 80% better. The once-thickened hyper- that we would review the trophic plaques were now left as thin, ery- literature, and upon review thematous plaques with a mild scale. By we were able to find cases four months into adalimumab, the lesions of spontaneous clearing of were extremely thin, and he felt he was 95% psoriasis after such an event. better as well as being very happy with his improvement. He continued with the bio- Figure 1: Mild psoriasis post injections injectable for the next several years and had Discussion mild psoriasis during that time (Figure 1). Psoriasis has had long- At one point, he tried just one adali- standing evidence of a link mumab injection per month, but the pso- between the plaques formed riasis began to return significantly. He by the disease and the ner- then returned to twice-a-month dosing vous system.1 The primary and improved dramatically. Once doing elements of the neural com- well and having stable psoriasis for sev- ponent of psoriasis are likely eral months, he had a stroke. He reported peripheral nerves and neu- that on the day of his stroke he became ropeptides; however, the dizzy and had numbness in his right arm central nervous system is along with nausea and vomiting. A CT scan probably a uniting portion revealed an acute stroke involving the cer- of the nervous system’s role ebellum and medulla. At that time he was in psoriasis. One patient admitted to the hospital and the adalim- who had recalcitrant psoria- umab was discontinued. He had left-sided sis for upwards of 40 years weakness and diminished sensory responses suffered “diffuse cerebral for several days. He was then discharged. atherosclerosis and brain The MRI showed acute ischemia in the atrophy” secondary to a right parietal lobe and right cerebella hemi- cerebral vascular accident sphere, as well as the medulla. It was felt and consequently lost some that this scenario represented a complete of her neural function.1 At occlusion in the left vertebral artery. This this time, she was confused, Figure 2: Clear skin post stroke was classified as a “Wallenberg-type” stroke. Crane, jackson, benjamin, snyder, cook 31 and her psoriasis lesions entirely disap- Conclusion peared within months. After this patient partially regained her cerebral function, We now know that the nervous system her psoriasis reappeared on some parts of contributes to psoriasis, and there are many her body only (knees, elbows, buttocks, and factors that can exacerbate or improve pso- lumbar region). This case displays some riasis. It appears that stroke may improve evidence of the central nervous system hav- psoriasis in some patients. In addition ing a role in psoriasis, that inhibition of to the immune system, the nervous sys- some functions of the central nervous sys- tem may also significantly affect psoriasis. tem can potentially impede psoriasis, and Future studies in this area may be warranted that subsequent restoration of these func- to bring recognition of this link, and per- tions may lead to the return of some psori- haps develop improved treatments. atic lesions.1 References Nerve growth factor (NGF) may also 1. Stratigos AJ, Katoulis AK, Stavrianeas NG. play a role in psoriasis.2 NGF aids innerva- “Spontaneous clearing of psoriasis after stroke.” Journal of the American Academy of Dermatology. Vol. tion of tissue and regulates some neuro- 38, Issue 5, Pages 768-770. May 1998. peptides including SP (substance P) and 2. Raychaudhuri SP, Jiang WY, Raychaudhuri SK. “Revisiting the Koebner phenomenon: role of NGF and calcitonin gene-related peptide (CGRP). its receptor system in the pathogenesis of psoriasis.” Neurogenic inflammation plays a role in American Journal of Pathology. Vol. 172, Issue 4, psoriasis through paths that include an Pages 961-971. April 2008. 3. Ionov ID. “Self-sustaining pathological processes in skin increase in terminal cutaneous nerves and psoriasis.” Medical Hypotheses. Vol.72, Issue 2, Pages higher levels of substance P and calcitonin 171-173. February 2009. gene-related peptide in psoriatic plaques.2 When psoriatic lesions form, two of the first changes are an increase in nerve growth factor and formation of more keratinocytes. These new keratinocytes in turn produce more active NGF, and NGF in turn aids innervation of tissue. This cycle strongly supports a connection between further innervation of tissue augmented by NGF and the formation of psoriatic plaques.2 There also exists evidence supporting that removal of nerves from tissue, possibly by means of a stroke, leads to some clearing of psoriatic lesions, since some surgeries that have accomplished “resection of superficial cutaneous nerves” have locally eliminated psoriatic lesions.1 A third substance may also contribute to psoriasis by acting alongside substance P and calcitonin gene-related peptide: another neurotransmitter, vasoactive intestinal pep- tide or VIP.3 VIP levels have been shown to increase when psoriasis spreads and decrease when the disease enters remission. This peptide causes many of the associated symptoms of psoriasis and releases hista- mine from the skin’s mast cells. Histamine then causes “events characteristic of pso- riatic plaque,” including the generation of massive amounts of keratinocytes, one of the most noticeable symptoms, along with stimulating angiogenesis and vasodilation, two more characteristics of psoriasis. The release of VIP stimulates further release of itself along with interleukin-6, which up-regulates itself and VIP, thus making a psoriatic “vicious circle.”3 Since this process is highly dependent on neurotransmitters, a stroke has the potential to impair this pro- cess through the nerves and stop the cycle of VIP.1

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Dermatology Foundation To join now, contact the DF at 847.328.2256 or SHAPI NG THE FUT URE O F D ERMAT OLOGY www.dermatologyfoundation.org. Autoimmune Progesterone Dermatitis

Leah Schammel, DO,* Steven K. Grekin, DO, AOBD**

*PGY4, Oakwood Southshore Dermatology Residency, Trenton, MI **Program Director, Dermatology Residency Program, Oakwood Southshore Hospital, Trenton, MI

ABSTRACT Autoimmune progesterone dermatits is a cyclical dermatitis that occurs in women during the luteal phase of their menstrual cycle. The cutaneous eruption can vary in morphology making diagnosis a challenge. Treatment consists of suppression of ovulation through oral hormonal therapy. History A 47-year-old Caucasian female pre- sented with a pruritic cutaneous eruption that started after discontinuing oral con- traceptives in March 2004. The patient stated that the eruption recurred with each menstrual cycle. She stated her menstrual cycles were irregular and extremely painful. The cutaneous eruption consisted of “red bumps” on the forearms, upper thighs, and abdomen (Figures 1 & 2). The patient was otherwise healthy except for a history of tobacco use in the form of cigarettes.

Examination Physical examination revealed a well- appearing, middle-aged adult female with excoriated red papules coalescing into a few plaques on the dorsal forearms, upper thighs, and abdomen. No lymphadenopathy or mucosal lesions were found. At initial presentation in March 2004, the cutaneous eruption consisted of red papules coalescing into plaques along with Figure 1 Figure 2 pustules. The extent of the eruption was neutrophils and an underlying superficial- not a candidate for oral hormonal therapy much more severe. to-mid perivascular and interstitial infiltrate due to her age and use of cigarettes. She also of lymphocytes, histiocytes, and neutro- applies topical mometasone cream 0.1% as Laboratory phils. needed. A complete blood count with differen- 4/16/07 - (Possible lymphomatoid pap- tial, complete metabolic panel, lipid panel, ulosis with mixed cell infiltrate) A vertically Discussion and hepatitis panel revealed a slight eleva- oriented infiltrate of lymphocytes, neutro- Autoimmune progesterone dermatitis tion in cholesterol. phils, and eosinophils with associated pso- riasiform epidermal hyperplasia, spongiosis, (APD) is classically described as a cyclical In April 2007, a bone marrow biopsy and parakeratosis. Many lymphocytes were cutaneous eruption, occurring or worsen- was performed that was negative. A CT of enlarged with hyperchromatic nuclei. ing during the luteal phase of the menstrual the chest, abdomen, and pelvis were also cycle when progesterone levels are elevated. 3/28/08 - (Prurigo nodularis) A performed that revealed cysts on her ova- APD typically occurs in women between dome-shaped lesion with hyperkeratosis, ries. the ages of 12 and 44.1 Patients with APD hypergranulosis, psoriasiform hyperplasia, often present with non-specific symptoms and coarse bundles of collagen in vertical for 5-6 years before diagnosis. Histopathology streaks. 3/24/04 - (CD30 negative lymphoid The cutaneous eruption can vary in infiltrate) A superficial pustule contain- Course and Therapy morphology. The lesions may be urticarial, ing neutrophils, erythrocytes, and fibrinous papular, papulovesicular, eczematous, or debris along with a perivascular lympho- Currently the patient is controlled on erythema multiforme-like. Mucosal surfaces cytic infiltrate, dermal fibrosis, and psoria- a Medrol dose pack. She takes 1-2 tablets may also be involved. The eruption has no 2 siform epidermal hyperplasia. as needed during the luteal phase of her predilection for any specific body site. 6/18/05 - (Intra-epidermal pustular cycle. She has irregular cycles, and so the Symptoms generally appear or worsen dermatitis) An intraepidermal pustule with cutaneous eruption is not consistent. She is within 10 days prior to menses, and resolve

34 Autoimmune Progesterone Dermatitis or begin to improve with the onset of men- ses. Pruritus is typically reported, but the eruption may also be asymptomatic. The diagnosis of APD is typically made on the clinical presentation and history of a cyclical eruption around menses. Improve- ment after ovulation-suppression therapy or worsening after removal of suppression supports the diagnosis. A positive intra-dermal progesterone test performed with a small amount of pro- gesterone suspension 50mg/ml can also support the diagnosis.3 The reaction can take anywhere from 30 minutes to 96 hours to become positive. Histological features of suspected APD vary widely, and there are no clear-cut uni- fying features for the APD cases reviewed. Biopsy may be needed to distinguish APD from other dermatoses. The exact pathogenesis of APD is poorly understood. It is generally agreed to represent an autoimmune condition in which the body forms a response to endog- enous progesterone, manifesting itself clini- cally when progesterone levels are elevated. The highest levels of progesterone are typi- cally during the luteal, or secretory, phase of the menstrual cycle. The treatment for APD is primarily suppression of ovulation through oral con- jugated estrogen therapy (oral contracep- tives). Antihistamines, systemic steroids, and topical steroids are options in patients unable to take oral conjugated estrogen therapy or as adjuvant therapy along with the conjugated estrogens. The prognosis is generally favorable, as the treatment is typically successful. References 1. Chawla SV, Quirk C, Sondheimer SJ, James WD. Autoimmune progesterone dermatitis. Arch Dermatol. 2009 Mar;145(3):341-2. 2. Herzberg AJ, Strohmeyer CR, Cirillo-Hyland VA. Autoimmune progesterone dermatitis. J Am Acad Dermatol. 1995 Feb;32(2):333-8. 3. Stranahan D, Rausch D, Deng A, Gaspari A. The role of intradermal skin testing and patch testing in the diagnosis of autoimmune progesterone dermatitis. Dermatitis 2006 Mar;17(1):39-4

Schammel, Grekin 35 Cutaneous Diffuse Large B-cell Lymphoma: A Case Report and Review of Literature

Helen G. Kaporis, DO,* Michael Kassardjian, DO,** Donna D. Tran, MSIV,*** Bill V. Way, DO, FAOCD****

*3rd year Dermatology Resident, Dermatology Institute, Texas Division of A.T. Still University, Kirksville College of Osteopathic Medicine, Duncanville, TX **1st year Dermatology Resident, Western University/Pacific Hospital of Long Beach, Long Beach, CA ***4th year Medical Student, University of North Texas Health Science Center, Fort Worth, TX ****Dermatology Residency Program Director, Dermatology Institute, Texas Division of A.T. Still University, Kirksville College of Osteopathic Medicine, Duncanville, TX

ABSTRACT Primary cutaneous diffuse large B-cell lymphomas (PCDLBCL) are defined as malignant atypical B-cell proliferations presenting with cutaneous involvement alone and no evidence of extracutaneous manifestations at time of diagnosis. It most commonly presents in elderly women and are often located on the lower legs. We present a case of an 80-year-old Caucasian female who noticed a nodular lesion on her left arm and in subsequent years left lower leg and left arm that rapidly enlarged in a few months. Histological and immunophenotypical features were compatible with PCDLBCL. We also highlight the new classification system of primary cutaneous B-cell lymphomas as well as give a brief overview on prognosis and management.

Introduction onstrated diffuse nodular proliferation of markedly enlarged, atypical lymphocytes Cutaneous lymphomas are an uncom- involving dermis and subcutaneous adi- mon subset of lymphomas, but they repre- pose tissue (Figure 2). The monomor- sent the second most frequent extranodal 1 phic population showed large nuclei and form of lymphoma. Cutaneous lympho- prominent nucleoli with scant cytoplasm. mas may have different lineages of skin Abundant mitotic figures and pleomor- infiltrates. T-cell infiltrates are the most phism were also noted. Epidermotropism common, representing 65% of cutaneous was not observed. Immunohistochemical lymphomas, while 20-25% originate from 2,3 stains were positive for CD20 (Figure 3), B-cells, primary diffuse large B-cell type. PAX5 (Figure 4), and diffusely with BCL-2, In 2005, the World Health Organization- as well as BCL-6, CD-79a, and slightly for European Organization for Research and CD10. Ki-67 immunostain highlighted Treatment of Cancer (WHO-EORTC) pro- a large percentage of the tumor cells. A posed a new classification of cutaneous 1 final diagnosis of diffuse large B-cell lym- lymphomas, which was widely accepted. phoma was made. In this classification, primary cutaneous B-cell lymphomas are divided into three The tumor was surgically removed by groups: primary cutaneous marginal zone surgical oncology and received external B-cell lymphoma, primary cutaneous fol- beam radiation and chemotherapy. The licle center cell lymphoma, and primary patient was worked up by oncology for evaluation of any internal malignancy as cutaneous diffuse large B-cell lymphoma, Figure 1: 30x25mm erythematous to viola- leg type (PCLBCL LT).4 well, which was found to be negative. In ceous nodule on the left arm the subsequent years, she further devel- Primary cutaneous diffuse large oped diffuse large B-cell lymphoma of B-cell lymphomas (PCDLBCL) occur the left lower leg (Figures 5 & 6) and left more commonly in elderly women and are 5 arm, demonstrating a long history of left usually confined to the lower legs. The upper extremity B-cell lymphoma, which five-year overall survival for most cases of required multiple courses of external cutaneous B-cell lymphoma is greater than beam radiation and chemotherapy. Histo- 90%; however, diffuse large B-cell lympho- logically, the findings were consistent with mas are more aggressive, with an average the aforementioned. five-year survival rate of 41%, and location on the leg along with multiple cutaneous Discussion lesions lead to a less favorable prognosis.6,7 Primary cutaneous diffuse large In this article, we describe a case of B-cell lymphoma is an uncommon form primary cutaneous diffuse large B-cell of cutaneous lymphoma, representing lymphoma and present a brief review of Figure 2: Diffuse large B-cell lymphoma 400x: 20-25% of these lymphomas, and gener- the literature. Tumor cells have large, irregular vesicular ally having a poor prognosis.8,9 PCDLBCL nuclei with prominent nucleoli with mitosis are characterized by a neoplastic prolif- present eration of large, atypical B-lymphocytes, Case Report which clinically are most commonly pres- An 80-year-old Caucasian female pre- (Figure 1). The patient had a past medical ent on the lower legs and are described as sented with a 30x25 mm elevated erythema- history of hypertension. A punch biopsy rapidly growing red-brown plaques.10 Typi- tous to violaceous nodule on the left arm was performed. Histologic sections dem- cally, at the time of diagnosis, PCDLBCL 36 Cutaneous Diffuse Large B-cell Lymphoma: A Case Report and Review of Literature has no extracutaneous involvement.11 Nev- ertheless, PCDLBCL has a propensity to spread to lymph nodes and extracutaneous sites.12 Cutaneous diffuse large B-cell lym- phoma has the histological characterization of a diffuse infiltrate throughout the entire dermis and extending into subcutaneous tissue, usually sparing a thin subepidermal grenz zone, and consisting of large B-cells.12 Immunohistochemical stains of the neo- plastic cells in PCDLBCL are typically posi- tive for CD19, CD20, CD79a, Bcl-2, and Figure 3: Diffuse large B-cell lymphoma: The 13 MUM-1. There is an excellent correla- lymphocytes express CD20 tion between CD20 and PAX-5 expression. PAX-5 is a B-cell-specific activator protein (BSAP). PAX-5 is expressed primarily in pro-, pre-, and mature B-cells, but not in plasma cells. Anti-PAX-5 has the ability Figure 5: Violaceous nodule on left leg to detect all committed B-cells. It is very specific to B-cell lineage and does not stain T-cells. The characteristic predominance of the large tumor cells leads to the aggressiveness of this subtype. A histologic predominance of large cells with round nuclei, as opposed to large cells with cleaved nuclei, has a less favorable prognosis.14 Additionally, the Figure 4: Diffuse large B-cell lymphoma: expression of Bcl-2 protein also has been PAX5 is positive identified as an adverse prognostic factor.15 Figure 6: Violaceous nodule on left leg More recently, one study showed that the References five-year survival rate was decreased to a 1. Newton R, Ferlay J, Beral V, Devessa SS. The classification, and prognostic factors in a large series of predicted 27% with the deletion of chro- epidemiology of non-Hodgkin’s lymphoma: comparison patients. Blood. 2005; 106(7):2491-7. of nodal and extra-nodal sties. Int J Cancer. mosome region 9p21, compared to 100% 13. Paulli M, Viglio A, Vivenza D, et al. Primary cutaneous 1997;72(6):923-30. in cases without deletion.16 However, the large B-cell lymphoma of the leg: histogenetic analysis 2. Garbea A, Dippel E, Hildenbrand R, et al. Cutaneous of a controversial clinicopathologic entity. Hum Pathol. location on the leg of PCDLBCL is the large B-cell lymphoma of the leg masquerading as chronic 2002; 33(9):937-43. venous ulcer. Br J Dermatol. 2002; 146: 144-7. main negative prognostic factor for cutane- 14. Grange F, Bekkenk MW, Wechsler J, et al. Prognostic 3. Hembury TA, Lee B, Gascoyne RD, et al. Primary factors in primary cutaneous large B-cell lymphomas: ous lymphomas, representing a three-year cutaneous diffuse large B-cell lymphoma: A a European Multicenter Study. J Clin Oncol. 2001; survival rate of 43% compared to 77% in clinicopathologic study of 15 cases. Am J Clin Pathol. 19(16):3602-3610. 2002; 117:574-80. nonleg anatomic locations.4 Furthermore, 15. Grange F, Petrella T, Beylot-Berry M, et al. Bcl-2 protein 4. Grange F, Beylot-Barry M, Courville P, et al. Primary expression is the strongest independent prognostic nonleg PCDLBCL carries a less favorable cutaneous diffuse large B-cell lymphoma, leg type. Arch factor of survival in primary cutaneous large B-cell prognosis than primary cutaneous marginal Dermatol. 2007;143(9):1144-1150. lymphomas. Blood. 2004; 103(10):3662-3668. zone B-cell lymphoma and primary cutane- 5. Golling P, Cozzio A, Dummer R, et al. Primary cutaneous 16. Senff NJ, Zoutman WH, Vermeer MH, et al. Fine B-cell lymphomas-clinicopathological, prognostic and mapping chromosomal loss at 9p21: correlation with ous follicle center lymphomas, and should therapeutic characterization of 54 cases according to the prognosis in primary cutaneous large B-cell lymphoma WHO-EORTC classification and the ISCL/EORTC TNM leg type. J Invest Dermatol. 2007; 127:S92. therefore be grouped in classification with classification system for primary cutaneous lymphomas 17. Grange F, Maubec E, Bagot M, et al. Treatment of other than mycosis fungoides and Sezary syndrome. Leuk primary cutaneous large B-cell lymphoma cutaneous B cell lymphoma, leg type with age-adapted Lymphoma. 2008;49(6):1094-103. leg type, as proposed by the WHO-EORTC combinations of chemotherapies and rituximab. Arch 4,11 6. Connors JM, Hsi ED, Foss FM. Lymphoma of the skin. Dermatol. 2009; 145(3):329-30. classification. Hematology. 2002; 263-82. 18. Garcia CP, Florez A, Pardavilla R, et al. Primary Radiotherapy is considered the treat- 7. Moore MM, Kovich, OI, Brown LH. Primary cutaneous B cutaneous large B-cell lymphoma, leg type, successfully cell lymphoma (low grade, non large cell), Dermatol Online treated with rituximab plus chemotherapy. Eur J ment of choice in the management of pri- J. 2007; 13:8. Dermatol. 2009; 19(4):394-5. mary cutaneous lymphomas, with 2 cm 8. Senff, NJ, Noordijik EM, Kim YH, et al. European 19. Coiffier B, Lepage E, Briere J, et al. CHOP margins.2 There has also been reported Organization for Research and Treatment of Cancer and chemotherapy plus rituximab compared with CHOP International Society for Cutaneous Lymphoma consensus alone in elderly patients with diffuse large B-cell success with the use of anthracycline-con- recommendations for the management of cutaneous B-cell lymphoma. N Engl J Med. 2002; 346(4):235-42. lymphomas. Blood. 2008.112(5):1600-9. taining chemotherapies and rituximab, a 20. Mounier N, Briere J, Gisselbrecht C, et al. 9. Zinzani PL, Quaglino P, Pimpenelli N, et al. Prognostic Rituximab plus CHOP (R-CHOP) overcomes bcl-2 chimeric monoclonal IgG1 antibody that factors in primary cutaneous B cell lymphoma: the Italian associated resistance to chemotherapy in elderly is directed against the CD20 antigen of B study group for cutaneous lymphomas. J Clin Oncol. patients with diffuse large B-cell lymphoma. Blood. 2006; 2-:1376-82. 2003;101(11):4279-4284. cells.17,18 Additionally, rituximab has been 10. Cerroni L, Gatter H, Kerl H. Large B-cell lymphoma, leg shown to be effective in overcoming Bcl- type. In: Cerroni L, Gatter K, Kerl H (eds). An illustrated 2-associated resistance to chemotherapy, guide to skin lymphoma. Oxford: Blackwell Publishing; 2005. 112-6. which is a poor prognostic factor when 11. Willemze R, Jaffe E, Burg G, et al. WHO-EORTC 19,20 expressed. classification of cutaneous lymphomas. Blood. 2005; 106(7):2491-7. 12. Kodama K, Massone C, Chott A, et al. Primary cutaneous large B-cell lymphomas: clinicopathologic features, K aporis, Kassardjian, TRan, Way 37 Keratoacanthoma-Like Dermatofibroma

Zhi Zhong Wang, MD, MSc,* Andrew Simone, MD**

*Dr. Andrew Simone Dermatology Clinic, Toronto, Ontario, Canada **Board-certified Dermatologist, Dr. Andrew Simone Dermatology Clinic, Toronto, Ontario, Canada

ABSTRACT A solitary pretibial protuberance looked like a keratoacanthoma. Pathological report shows dermatofibroma.

Figure 2 & 3: Underlying dermis shows lesion with proliferation of cells with cyto- plasm admixed with elongated, spindle-shaped cells.

Figure 1: A solitary red, keratoacanthoma-like protuberance on the left leg for four years. Case inflammation. The mor- A Polish female, 42 years old, com- phology of this lesion plained of a solitary red protuberance on was compatible with a the left leg for four years. She injured her fibrohistiocytic tumour. left leg when she shaved it four years ago. The features were rather After the injury healed, an itchy papule suggestive of the epi- occurred and grew slowly into a crater-like thelioid-cell variant of protuberance (Figure 1). She had gestational dermatofibroma. Some of the epithelioid- Treatment appearing cells had an admixture of eosino- diabetes mellitus five years ago and was The patient declined Mohs surgical philic cytoplasm, and foamy cytoplasm was treated with insulin. She has been on dia- excision. betic diet since then. also noted, so a xanthomatous variant of dermatofibroma was also considered in the differential diagnosis. Discussion Physical Exam In order to confirm the epithelioid ori- Dermatofibroma is a common cutane- There was a solitary, round, erythema- gin of the tumour cells, we did cell-marker ous condition of unknown etiology.1 It has tous nodule on the lower one-third of the tests. Immunohistochemical studies showed a predilection for the lower legs of women. left lower extremity, one cm in diameter, a cellular spindle and epithelioid prolifera- Characteristically, it is a solitary firm, well demarcated, with a crater-like surface tion of cells in the dermis, sparing the epi- brown, well-defined nodule with central with yellowish crust. dermis (Figures 4, 5 & 6). The tumour cells dimpling. It is usually asymptomatic, but were positive for vimentin and for CD68 pain and itching may be noted. and factor XIIIA. However, there were large Pathology epithelioid histiocytes present that were Some unusual clinical variants of der- actually only focally positive for CD68 and matofibroma have been reported. Puig et Pathologic report showed parakera- al. reported two cases of atypical polypoid tosis. The epidermis was acanthotic with focally positive for synaptophysin. They were negative for GFAP, neurofilament and dermatofibroma on the lower extremities elongation of the rete ridges. The underly- 1 S100 protein. The features were those of in 1991. The tumors were ten cm and six ing dermis showed a fairly cellular lesion cm in maximal diameters, respectively, with with proliferation of somewhat plump- an epithelioid variant of dermatofibroma. However, while the morphology of the large short pedicles joining to the skin. Patho- appearing histiocytic cells with abundant logical examination showed striking atypia cytoplasm admixed with more elongated, cells was unusual, there was no evidence of atypia or malignancy. and scattered mitotic figures. Requena et spindle-shaped cells (Figures 2 & 3). The al. reported eight cases of giant dermatofi- surrounding stroma showed scattered mild

38 Keratoacanthoma-Like Dermatofibroma Figures 4-6: Immunohistochemical studies confirmed the epithelioid origin of the tumour cells.

dermatofibroma, while anti- levels and the differential expression of transforming growth factor-beta receptors in dermatofibroma and bodies to MAC387, which label dermatofibrosarcoma protuberans. Br J Dermatol. May monocyte-derived macro- 2006;154(5):919-25. phages (histiocytes), show less consistent results. In one study evaluating 28 cases of derma- tofibroma, most of the spindle- shaped cells stained positively with HSP47, indicating that skin fibroblasts are a major con- stituent of dermatofibroma; on the other hand, the presence of CD68-positive histiocytes was inconsistent in these cases.6 broma (greater than five cm in diameter) The cell-surface proteoglycan syn- 2 in 1994. The authors concluded that giant decan-1,7 fibroblast growth factor receptor dermatofibromas usually manifest with a 2,8 and transforming growth factor-beta9 pedunculated appearance below the knee. may each play a role in the growth of der- They are often misdiagnosed as malignancy matofibromas. The patient in this case had due to their large size. Requena et al. also Type 2 diabetes for five years at the time of reported two cases of atrophic dermato- presentation and used insulin for a certain 3 fibroma in 1995. They found out that the time period. Possibly, her condition was thinning of the lesions resulted from the related to her diabetic diathesis and insulin depression rather than from any authentic use. atrophy. Hence, they suggested that delled dermatofibroma would be a more appro- References priate appellation than atrophic dermato- 1. Puig L, Esquius J, Fernández-Figueras MT, Moreno A, de Moragas JM. Atypical polypoid dermatofibroma: fibroma. Sehgal et al. reported an unusual report of two cases. J Am Acad Dermatol. giant combined dermatofibroma on the 1991;24(4):561-5. 4 2. Requena L, Fariña MC, Fuente C, Piqué E, Olivares M, scapula in 2004. The lesion was 25-30 cm Martín L, Sánchez Yus E. Giant dermatofibroma. A little- in diameter and was surrounded by several known clinical variant of dermatofibroma. J Am Acad similar, smaller ones (satellites). Pathologi- Dermatol. 1994;30(5 Pt 1):714-8. 3. Requena L, Reichel M. The atrophic dermatofibroma: a cal studies showed architectural features delled dermatofibroma. J Dermatol. 1995;22(5):334-9. of a deep, penetrating type of dermatofi- 4. Sehgal VN, Sardana K, Khandpur S, Sharma broma with xanthomatous aggregates, myx- S, Majumdar S, Aggarwal AK. Giant combined dermatofibroma with satellitosis. Clin Exp Dermatol. oid changes and probable myofibroblastic 2004;29(2):147-9. differentiation. This case of dermatofibroma 5. Prieto VG, Reed JA, Shea CR. Immunohistochemistry of dermatofibromas and benign fibrous histiocytomas. J occurred on the leg and looked like a kera- Cutan Pathol. 1995;22(4):336-41. toacanthoma. 6. Kuroda K, Tajima S. Proliferation of HSP47-positive skin fibroblasts in dermatofibroma. J Cutan Pathol. The histologic appearance of derma- 2008;35(1):21-6. tofibroma can show different areas with 7. Sellheyer K, Smoller BR. Dermatofibroma: upregulation varying degrees of myofibroblastic and of syndecan-1 expression in mesenchymal tissue. Am J Dermatopathol. Oct 2003;25(5):392-8. histiocytic differentiation.5 Results from 8. Skroza N, Rotolo S, Ceccarelli S, et al. Modulation immunohistochemical testing with anti- of the expression of the FGFR2-IIIb and FGFR2-IIIc molecules in dermatofibroma. J Dermatol Sci. Jul bodies to factor XIIIa, which label dermal 2008;51(1):53-7. dendritic cells, are frequently positive in 9. Kubo M, Ihn H, Yamane K, Tamaki K. The expression

Wang, Simone 39 Elastolytic Granuloma: A Case Report and Discussion

Mounir Wassef, DO,* Layne Nisenbaum, DO, FAOCD**

*Dermatology Resident, 2nd year, Columbia Hospital, West Palm Beach, FL **Program Director, Columbia Hospital Dermatology Residency Program, West Palm Beach, FL

ABSTRACT Annular elastolytic giant cell granuloma is a rare granulomatous dermatosis of controversial origin characterized by loss of elastic fibers and elastophagocytosis by multinucleated giant cells.1 Lesions of AEGCG are usually located on sun-exposed areas.2 We present a case of elastolytic granuloma involving the face.

Case Report vated borders and central depression are typically located on sun-exposed A 74-year-old woman pre- skin. There have been reports of sented with a slightly pruritic skin lesions located on sun-protected eruption evolving for three months. sites.5 There have also been general- There was no family history of skin ized forms reported with red, asymp- disorders. Physical examination tomatic papules.6 revealed an erythematous plaque with annular configuration on the The histopathologic features right jaw line, with central atro- are best demonstrated by a biopsy phy and raised erythematous mar- of the elevated edge of the plaque.7 gins (Figures 1 & 2). There was no They are characterized by granulo- mucous membrane or nail involve- matous infiltrates with multinucle- ment. We performed a skin biopsy. ated giant cells in the upper and mid Histopathologic findings showed dermis, loss and fragmentation of granulomatous infiltrates in the dermis Figures 1 & 2: Erythematous plaque, with annular elastic fibers, and elastophagocyto- consisting primarily of multinucleated configuration, with central atrophy and raised sis by giant cells, without necrobiosis giant cells, some of which contained erythematous margins on the right jaw line. and mucin deposition.2,7,8 These features fragments of elastic tissue (elastophago- help to distinguish AEGCG from granu- cytosis), and loss of elastic fibers in the loma annulare and necrobiosis lipoidica, center of the lesion (Figures 3, 4 & 5). which are the main disorders in the Special stains (PAS, AFB, Fite, GMS, histological differential diagnosis.7 It is Giemsa) were negative for microorgan- speculated that solar radiation, heat or isms. Laboratory tests including com- other unknown factors transform the plete blood cell count, chemistry panel, antigenicity of the elastic fibers and antinuclear antibody, urinalysis, and induce the cellular immunological reac- chest X-ray were within normal lim- tion.1,2,9 Immunohistochemical studies showing that CD4+ cells predominated its. The patient was treated with topical Figures 3-5: Diffuse upper dermal granulomatous over CD8+ cells in the inflammatory betamethasone dipropionate cream for dermatitis consisting predominantly of multinu- infiltrate also support this theory.1,2 It three weeks with complete regression of cleated foreign body giant cell type, eosinophils, the lesion. elastophagocytosis, and focal absence of elastic has also been proposed that diabetes fibers in superficial dermis. mellitus could be implicated in the etiol- Discussion ogy by producing structural damage of 2 In 1975, O’Brien described a new the elastic tissue. There have been reported type of annular skin lesion with elastolysis cases of AEGCG associated with systemic and elastophagocytosis, localized on light- sarcoidosis, cutaneous amyloidosis, mol- exposed body areas. He called this entity luscum contagiosum, squamous cell car- "actinic granuloma."2,3 The term AEGCG cinoma of the lung, and cutaneous T-cell 2 was proposed by Hanke et al. in 1979 and lymphoma. includes the lesions previously called actinic The treatment for AEGCG remains granuloma, atypical necrobiosis lipoidica, a challenge. Variable results have been and Miescher’s granuloma.2,3,4 They defend reported with therapies such as topical or the observation that solar elastosis is not intralesional steroids, cryotherapy, clo- always present; although less common, the fazimine, antimalarials (chloroquine and lesions could be present in covered areas. hydroxychloroquine), dapsone, PUVA, and 1,9 Annular elastolytic giant cell granu- cyclosporine. Some cases resolve spon- 8,9 loma is an uncommon disease that pre- taneously. Our patient was treated with dominantly affects older adults, with no sex topical betamethasone dipropionate cream predilection.2 Clinically, red papules and for three weeks with complete regression of hypochromic or atrophic plaques with ele- the lesion. 40 Elastolytic Granuloma: A Case Report and Discussion References 1. Lee HW, Lee MW, Choi JH, Moon KC, Koh JK. Annular elastolytic giant cell granuloma in an infant: improvement after treatment with oral tranilast and topical pimecrolimus. J Am Acad Dermatol. 2005; 53:S244-246. 2. Doulaveri G, Tsagroni E, Giannadaki M, Bosemberg E, Limas C, Potouridou I, Zakopoulou N. Annular elastolytic giant cell granuloma in a 70-year-old woman. Int J Dermatol. 2003; 42:290-291. 3. Pock L, Blazková J, Caloudová H, Varjassyová I, Konkolová R, Hercogová J. Annular elastolytic giant cell granuloma causes an irreversible disappearance of the elastic fibres. J Eur Acad Dermatol Venereol. 2004; 18: 365-368. 4. Campos-Muñoz L, Díaz-Díaz RM, Quesada-Cortés A, Hernández-Cano N, Martín-Díaz MA, Regojo-Zapata RM, Casado-Jiménez M. Annular elastolytic giant cell granuloma: a case report located in non-sun exposed areas. Actas Dermosífilogr. 2006; 97(8):533-535. 5. Maramatsu T, Shirai T, Yamashina Y. AEGCG: an unusual case with lesions arising in non sun-exposed areas. J Dermatol. 1987; 14:54-58. 6. Sina B, Wood C, Rudo K. Generalized elastophagocytic granuloma. Cutis. 1992; 49(5):355-357. 7. Meadows KP, O’Reilly MA, Harris RM, Petersen MJ. Erythematous annular plaques in a necklace distribution. Arch Dermatol. 2001; 137:1647-1652. 8. Misago N, Ohtsuka Y, Ishii K, Narisawa Y. Papular and reticular elastolytic giant cell granuloma: rapid spontaneous regression. Acta Derm Venereol. 2007; 87(1);89-90. 9. Kelly BJ, Mrstik ME, Ramos-Caro FA, Iczkowski KA. Papular elastolytic giant cell granuloma responding to hydroxychloroquine and quinacrine. Int J Dermatol. 2004; 43:964-966.

Wassef, nisenbaum 41 A Case of a Cutaneous Sinus Tract of Dental Origin

Garrett R. Bohrnstedt, DO,* Daniel S. Hurd, DO, FAOCD**

*1st-year Dermatology Resident, LewisGale Hospital-Montgomery, Edward Via College of Osteopathic Medicine, Blacksburg, VA **Program Director, Dermatology Residency Program, LewisGale Hospital-Montgomery, Edward Via College of Osteopathic Medicine, Blacksburg, VA

ABSTRACT Cutaneous sinus tracts of dental origin can be a challenging diagnosis for dermatologists. The cutaneous manifestations can mimic more common facial lesions and the patient may deny any dental or intraoral complaints. Inappropriate or delayed treatment is frequently encountered. We present a case of a young female presenting with a "cyst like" area on her right cheek. The patient had sought medical attention through primary care multiple times without resolution. Physical examination revealed a palpable cord and she was referred to a periodontist. The patient's history was consistent with a chronic abscess involving her right first maxillary molar. Sinus tract formation was discovered extending from her right first maxillary molar to the ipsilateral nasolabial fold. This case should serve as a reminder to consider adding a dental origin to the differential diagnosis of any persistent nodular facial lesion. We will review the typical presentation and management of this condition.

Figure 2

Figure 1 Case Report lary molar. The patient had just finished another course of oral antibiotics prior A 19-year-old Caucasian female pre- to her initial visit to us. She denied any Figure 3 sented to our office with a 12-month history other symptoms at presentation and had right mid nasolabial fold. The periodon- of a right mid nasolabial-fold nodule. She no other major medical problems. described the nodule as a “cyst like” area tist incised and drained the dental abscess Examination of her right mid nasola- that would get red and irritated at times. and the surrounding area was dissected, bial fold revealed a nontender, fluctuant, She denied any pain or drainage from the explored, and curetted (Figure 3). There partially movable dermal-based cystic nod- site. She wanted the area removed for cos- was no purulent discharge, and no other ule (Figure 1). Slight dimpling of the sur- metic reasons. The patient had been treated dental disease was identified. The patient’s rounding skin was noted. A firm, palpable by her primary care doctor with oral anti- condition is being followed by the perio- cord extended downward from the region biotics multiple times for these “cyst like” dontist until her dental disease and sinus of the previous dental abscess along the flares. She reported reduction in size of the tract have resolved. Upon complete resolu- right lateral maxillary buccal mucosa to nodule but never a complete resolution. tion, she will follow up with us for reeval- the external cystic nodule. No drainage uation and treatment of any remaining Her history also revealed a recent was noted on palpation. The patient was cutaneous findings on her right cheek. evaluation by an endodonist and an oral tentatively diagnosed with a dental sinus surgeon for the treatment of an abscessed and therefore was immediately referred to tooth. Both physicians denied a dental ori- a periodontist. Dental periapical radio- gin for the facial nodule. The patient stated graphs (Figure 2) were obtained, and she Discussion that a few weeks before presenting to our was definitively diagnosed and treated for Dental infection causing a cutaneous office, an oral surgeon had performed a a chronic organized fistula of dental origin sinus tract can be a diagnostic challenge, root canal to her infected right first maxil- associated with the nodular lesion at her as many patients do not present with active

42 A Case of a Cutaneous Sinus Tract of Dental Origin primary dental disease. Often, patients seek root canal.2,5 Sometimes further dissection and treatment of mandibular extraoral sinus of periodontal origin in a 9-year-old boy: A case report. J medical attention from their primary care and soft tissue exploration are needed, as in Indian Soc Pedod Prev Dent 2008;26:76-78. physician or dermatologist for evaluation our case. 8. Johnson BR, Remeikis NA, Van Cura JE. Case and treatment of an associated cutaneous Reports: Diagnosis and treatment of cutaneous facial If antibiotics are used, penicillin or sinus tracts of dental origin. JADA June 1999;130:832- 8 lesion. Typically, cutaneous sinus tracts of amoxicillin are the drugs of choice.2 Eryth- 836. dental origin occur in the setting of chronic romycin, clindamycin, or doxycycline may 9. Sheehan DJ, Potter BJ, Davis LS. Cutaneous 1 draining sinus tract of odontogenic origin: unusual infection or trauma. The most common be effective for patients allergic to peni- presentation of a challenging diagnosis. South Med J. 2005:98(2):250-252. site of primary dental disease occurs at the cillin.2 Antibiotics should not be used as 10. Barrowman RA, Rahimi M, Evans MD, Chandu A, periapical region of the tooth, which subse- primary monotherapy, as disease often 2,6,11 Parashos P. Cutaneous sinus tracts of dental origin. quently drains to the face. Eighty per- recurs after cessation of treatment.9 It has MJA March 5, 2007;186(5):264-265. cent are found in the mandibular region, also been postulated that antibiotics do not 11. Bolognia JL, Jorizzo JL, Rapini RP, editors. Sequelae and 20% arise in the maxillary region.1,5,6,9,10 of dental caries. Dermatology. Edinburgh: Mosby, Inc; “cure” the infection due to the lack of circu- 2003. p. 1042. Cutaneous lesions often manifest in close lation to the necrotic pulp and sinus tract.9 proximity to the dental disease, most nota- bly the chin, jawline, or submental area.1,9 Potential severe complications, if dis- There have been rare case reports where the ease is left undiagnosed or untreated, may tracts have been found at remote locations include a cavernous sinus thrombosis or such as the neck and chest.1 Ludwig’s angina (a life-threatening cellulitis that can lead to airway compromise).2,11 Many patients do not report den- Once the dental infection is treated, careful tal complaints as the sinus tract permits follow-up is necessary until full resolution.2 continuous drainage from the involved Sometimes, cutaneous scarring, retraction, 1,5,6,10,11 tooth. This drainage does not allow or umbilication can remain even after reso- for pressure to build enough to cause pain lution of the dental disease and sinus tract.9 5,6,10,11 or irritation. Patients frequently pres- Some patients may need surgical revision if ent with cutaneous lesions described as ery- they are concerned with cosmetic appear- thematous, nontender, nodulocystic papules ance of the residual cutaneous changes.9 1,5,7 ranging from 1mm-20mm in diameter. This reiterates the importance of early rec- Sometimes crusting, drainage, or ulcer- ognition and treatment, as these cosmetic 1,5,7 ation is present. Drainage is not typically complications occur more commonly with a observed except with palpation of the cuta- chronic relapsing course. neous nodule or manipulation of the sinus tract, which allows expression of the con- In conclusion, a high index of sus- tents.1,5,7 Perinodular dimpling or retraction picion, proper cutaneous and intraoral of the skin may be evident and can indicate inspection, palpation, pertinent dental an associated healing fibrous tract.1 exam, and referral for radiographic studies are imperative for early recognition of cuta- Along with pertinent history, the main neous sinus tracts of dental origin. Many components involved in diagnosing a cuta- patients first seek attention from a derma- neous sinus tract of a dental origin include tologist because they have no associated a palpable cutaneous nodule with or with- dental complaints. This case serves as a out drainage and an attached palpable cord reminder to include a dental etiology in the that extends to periapical disease found on differential diagnosis of persistent nodu- 1,5,7,10 dental radiographs. The differential lar facial lesions. Early recognition of this diagnosis includes an infected or nonin- disease entity will lead to prompt referral fected epidermal inclusion cyst, pilar cyst, and definitive treatment, and additional pyogenic granuloma, foreign body reac- complications, unnecessary surgical proce- tion, mycobacterial infection, squamous cell dures, and distress for the patient may be carcinoma, furuncle, or deep fungal infec- prevented. tion.1,3,4,5,6,8,10 Other entities to consider include osteomyelitis, salivary gland fis- References tula, suppurative lymphadenitis, periauricu- 1. Palacio JE, Altemus DA, Christensen ED, Sorenson GW. Unusual recurrent facial lesion. Arch Dermatol. lar fistula or sinus, tuberculosis, syphilitic 1999;135:593-598. gumma, thryoglossal duct cyst and bran- 2. Cade J. Oral cutaneous fistulas. http://emedicine. chial cleft cyst.1,3,4,5,6,8,10 medscape.com. Updated May19, 2009. 3. Slutzky-Goldberg I, Tsesis I, Slutzky H, Heling I. Management consists of prompt rec- Odontogenic sinus tracts: a cohort study. Quintessence ognition, evaluation, and treatment of the Int 2009;40:13-18. dental disease.2,5 Typically, once the dental 4. Sadeghi S, Dibaei M. Prevalence of odontogenic sinus tracts in 728 endodontically treated teeth. Med Oral disease is treated, the sinus tract and cuta- Patol Oral Cir Bucal. March 1, 2011;16(2)e296-9. 3,8,9 neous lesion will resolve spontaneously. 5. Sleiman P. Cutaneous sinus tracts: an endodontic approach. Diagnosis and treatment for a successful Resolution of the sinus tract should be outcome. Dental Tribune May 12, 2009:6-7. Originally expected to occur within 5-14 days status published in Roots 2009;5(2). post definitive dental treatment.6,8,9 Dental 6. Tavee W, Blair, M. Graham B. An unusual presentation of a cutaneous odontogenic sinus. Arch Dermatol. infection may be treated with antibiotics, 2003;139:1659-1660. incision and drainage, tooth extraction, or 7. Ozdemir A, Guven G, Dilsiz A, Sencimen M. Diagnosis

BOHRNSTEDT, HURD 43 A Rubbery Pink-Blue Nodule on the Scalp of a 93-Year-Old Woman

Michael Centilli, DO,* Peter Saitta, DO,** Michael Whitworth, DO, FAOCD,*** Christopher Schwimer, DO, FAOCD,**** Jean Holland, MD, FAAD*****

*PGY-1, Pontiac Osteopathic Hospital, Pontiac, MI **PGY-4 Resident, Oakwood Southshore Department of Dermatology, Trenton, MI ***Oakwood Southshore Department of Dermatology, Trenton, MI ****Oakwood Southshore Department of Dermatology, Trenton, MI *****Oakwood Southshore Department of Dermatology, Trenton, MI

ABSTRACT Hidradenocarcinomas (HAC) are rare malignant adnexal tumors that develop from eccrine or apocrine sweat glands. There have been less than 100 cases documented in the English-language literature. Clinically HACs may present as firm, subcutaneous, pink to grey nodules or plaques. The skin overlying the tumor can show signs of thickening, atrophy, or appear normal; ulceration, fissuring, and crusting from hemorrhagic or serosanguinous drainage has also been present in some cases. Herein, we present a case of HAC mimicking cylindroma in a 93-year-old Caucasian female with a comorbid diagnosis of Brooke-Spiegler Syndrome. Case Report A 93-year-old Caucasian female pre- sented with a long-standing history of mul- tiple lesions on her face and scalp (Figures 1 and 2). She reported that the lesions devel- oped during adolescence, and subsequently had increased in size and number. However, the patient was presently concerned with the largest scalp lesion, which had recently become tender. She did not report increased growth or bleeding from that particular lesion. Family history was negative for any member or child with similar lesions. A review of systems was negative for preced- ing illness, recent weight loss, or constitu- tional symptoms. Physical examination of the patient revealed a well-appearing elderly female with multiple round, smooth, flesh-colored Figure 1 papules on the mid-face, ranging in size from 0.5 cm to 1.5 cm. The majority of the lesions were located on the glabella and the eyebrows bilaterally. The papules were firm and were non-tender to palpation. Numerous firm nodules and plaques were dispersed throughout the scalp, some pink in color and others grey. They ranged in size from 1 cm to 2.8 cm. The lesion of concern was on the right vertex of the scalp; it was a 2.8 x 1.2cm firm, tender, rubbery, pink- blue nodule (Figure 2). At this time, a shave biopsy was taken of this nodule, along with Figure 2 Figure 3 shave biopsies of three other random lesions ferentiation (Figure 5). The tumor extended enomas, in conjunction with the clinical on the face. deeply and, though more circumscribed findings of cylindromas and trichoepithe- superficially, it demonstrated loss of cir- liomas, confirmed a diagnosis of Brooke- Microscopic Findings and cumscription in its deeper components Spiegler syndrome. (Figure 6). This reading was consistent with The patient received one stage of Mohs Clinical Course hidradenocarcinoma. The surrounding micrographic surgery with clear margins for dermis showed nodules of benign spirad- The lesion on the right vertex scalp the hidradenocarcinoma on the scalp and enoma, which suggested malignant degen- is being monitored routinely for any lesion demonstrated a nodular and cystic col- eration within one of these tumors. lection of atypical cells with sweat gland that may be suspicious for malignancy. differentiation (Figures 3 and 4). Areas of The remaining three biopsies dem- After the case was reviewed with oncol- apoptosis and broader tumor necrosis were onstrated evidence of spiradenoma. The ogy, the patient declined further workup for noted among basaloid cells with ductal dif- presence of multiple biopsy-proven spirad- metastases. The patient has had no evidence 44 A Rubbery Pink-Blue Nodule on the Scalp of a 93-Year-Old Woman Histopathologically, HACs display two main cell types, which are also features of its benign form, hidradenoma (HA). The first type is the clear cell, containing abun- dant glycogen, which has distinctly visible cell membranes and clear cytoplasm.2,3,4 These cells may have an oval or polyhedral appearance, and they contain dark, margin- ated nuclei.2,3,4 The second cell morphology is arranged at the periphery of the clear-cell line and consists of multifaceted squamoid cells with a granular cytoplasm and small, round-to-oval nuclei.2,3,4 These cells have been described as eosinophillic,2,4 but they have also been known to appear dark and take on a basophilic appearance.2,3 Differ- entiating an HAC from its benign counter- part is a difficult task, but several histologic criteria have been recommended in mak- ing the distinction. These criteria include Figure 4 increased mitotic activity, mitoses in clear cells, perineural invasion, angiolymphatic invasion, loss of circumscription, dispersed growth pattern, and deep extension.1,2,4 In addition, Ko et al. advocates further criteria to include necrosis, clefts between tumor and stoma, and p53 and Ki67 positivity with immunohistochemical staining.1 Brooke-Spiegler Syndrome (BSS) is an autosomal-dominantly inherited genoder- matosis caused by mutations affecting the CYLD gene on chromosome 16q12-q13.5,6,7 BSS is characterized by the finding of mul- Figure 5 Figure 6 tiple adnexal cutaneous neoplasms includ- of recurrence or lymphadenopathy for more may be easily mistaken for benign growths. ing trichoepitheliomas, cylindromas, and than six months following treatment. The sites of predilection for HACs include spiradenomas.5,7 Spiradenocylindroma, a the head and neck and less frequently the hybrid neoplasm consisting of features of trunk and extremities.2 There is an equal both spiradenoma and cylindroma, may distribution between both sexes, and there also arise in BSS.8 It is important to note Discussion does not appear to be a preference for age as that these lesions most commonly present Hidradenocarcinomas (HAC) are rare, they have been reported in every decade of sporadically as solitary neoplasms, and less malignant adnexal tumors that develop life.2,3 They range in size from 1.5 to 4.0 cm frequently occur together in the setting of from eccrine or apocrine sweat glands.1 in diameter and have been shown to grow BSS.8 They are often benign, but occasion- There have been less than 100 cases docu- both rapidly and at an indolent rate.2 These ally, de novo malignancies or malignant mented in the English-language literature, tumors are invasive, and once diagnosed transformations occur.5,7 Approximately and in a study reviewing 450,000 consecu- it is imperative that screening for metas- 100 cases of malignant spiradenoma, cylin- tive biopsies over 20 years in a dermatopa- tasis is performed. HACs most commonly droma, and spiradenocylindroma exist in thology laboratory, only two were proven metastasize to regional lymph nodes, with the medical literature.8 The vast majority to be HACs.2 Many of the case reports have distant sites of bone, lung, skin, pleura, and occurred sporadically, but malignant vari- been published using different nomencla- other visceral organs also reported.2 Failure ants were reported in cases of BSS as well.8 ture in addition to HAC, such as malignant to biopsy and diagnose these lesions can Kazakov et al. studied 24 cases of malignant acrospiroma, malignant hidradenoma, and lead to fatal outcomes for patients as HACs neoplasms occurring in pre-existing spirad- malignant clear-cell hidradenoma, in addi- have been associated with a metastatic rate enoma, cylindroma, and spiradenocylin- tion to others.1,2 of 60%, with 40% of patients eventually droma.8 Of the 24 cases studied, five of the Clinically, HACs may present as firm, succumbing to the burden of metastatic patients possessed clinical features consis- 2 8 subcutaneous, pink to grey nodules or disease. If metastatic disease has been ruled tent with BSS. Spiradenomas were found plaques. The skin overlying the tumor can out, the accepted standard of treatment is to progress to malignancy most commonly show signs of thickening, atrophy, or appear surgical excision, with local recurrence rates (22), followed by cylindromas (2) and spi- 2 8 normal; ulceration, fissuring, and crusting between 10 to 50%. Wide local excision is radenocylindromas (2). Due to the rarity from hemorrhagic or serosanguinous drain- then recommended for recurrent lesions. of the lesions and lack of uniform criteria age have also been present in some cases.2 Yavel et al. advocates the use of Mohs sur- and terminology, it is difficult to determine It must be stressed that these lesions do gery to treat HACs as they reported zero a rate of malignant transformation. While not have a distinct clinical appearance and recurrences in five cases of HAC treated no definitive portions undergo malignant with the Mohs procedure.2 Centilli, Saitta, Whitworth, Schwimer, Holland 45 transformation, most malignant neoplasms have been found to arise in a pre-existing benign neoplasm.8 Consequently, these lesions should be biopsied and appropriately monitored for signs of evolution.

Conclusion Hidradenocarcinomas are rare, malig- nant adnexal tumors which possess an indistinct clinical appearance. Unless signs of thickening, atrophy, ulceration, fissuring, or crusting are present, these tumors may be easily mistaken for benign growths. Upon diagnosis, these patients should be screened for metastasis, and the appropriate treat- ment options should be conveyed. Without detection and proper treatment, they are associated with high rates of metastasis and significant mortality. To the best of our knowledge, there has never been a reported case of HAC arising de novo or from malignant transformation of a previously benign lesion in conjunc- tion with BSS. Due to the rarity of HAC, it is unknown if there is any correlation or increased risk of developing an HAC from one of the characteristic lesions of BSS. Regardless of the connection between HAC and BSS, it is critically important to under- stand the potential for malignant transfor- mation of the lesions associated with BSS. Repeat biopsies of lesions may be necessary if clinical suspicion exists for malignancy or complete excision is not performed. References 1. Ko CJ, Cochran AJ, Eng W, Binder SW. Hidradenocarcinoma: a histological and immunohistochemical study. J Cutan Pathol. 2006 Nov;33(11):726-30. 2. Yavel R, Hinshaw M, Rao V, Hartig GK, Harari PM, Stewart D, Snow SN. Hidradenomas and a hidradenocarcinoma of the scalp managed using Mohs micrographic surgery and a multidisciplinary approach: case reports and review of the literature. Dermatol Surg. 2009 Feb;35(2):273-81. 3. Liapakis IE, Korkolis DP, Koutsoumbi A, Fida A, Kokkalis G, Vassilopoulos PP. Malignant hidradenoma: a report of two cases and review of the literature. Anticancer Res. 2006 May-Jun;26(3B):2217-20. 4. Wong TY, Suster S, Nogita T, Duncan LM, Dickersin RG, Mihm MC Jr. Clear cell eccrine carcinomas of the skin. A clinicopathologic study of nine patients. Cancer. 1994 Mar 15;73(6):1631-43. 5. Kazakov DV, Schaller J, Vanecek T, Kacerovska D, Michal M. Brooke-Spiegler syndrome: report of a case with a novel mutation in the CYLD gene and different types of somatic mutations in benign and malignant tumors. J Cutan Pathol. 2010 Aug;37(8):886-90. 6. Young AL, Kellermayer R, Szigeti R, Tészás A, Azmi S, Celebi JT. CYLD mutations underlie Brooke- Spiegler, familial cylindromatosis, and multiple familial trichoepithelioma syndromes. Clin Genet. 2006 Sep;70(3):246-9. 7. Kim C, Kovich OI, Dosik J. Brooke-Spiegler syndrome. Dermatol Online J. 2007 Jan 27;13(1):10. 8. Kazakov DV, Zelger B, Rütten A, Vazmitel M, Spagnolo DV, Kacerovska D, Vanecek T, Grossmann P, Sima R, Grayson W, Calonje E, Koren J, Mukensnabl P, Danis D, Michal M. Morphologic diversity of malignant neoplasms arising in preexisting spiradenoma, cylindroma, and spiradenocylindroma based on the study of 24 cases, sporadic or occurring in the setting of Brooke-Spiegler syndrome. Am J Surg Pathol. 2009 May;33(5):705-19.

46 A Rubbery Pink-Blue Nodule on the Scalp of a 93-Year-Old Woman Essential Alopecia Syphilitica: A Case Report and Review of Literature

Stacy Rosenblum, DO,* Mariel Bird, DO,** Amanda Beehler, DO,*** Steven Alder, MD,**** Stephen Kessler, DO*****

*Dermatology Resident, 1st year, Alta Dermatology/LECOM, Mesa, AZ; Scottsdale Healthcare System, Scottsdale, AZ **Intern, Largo Medical Center, Largo, FL ***Dermatology Resident, 2nd year, Alta Dermatology/LECOM, Mesa, AZ; Scottsdale Healthcare System, Scottsdale, AZ ****Dermatopathologist, Director of Dermatopathology, Clin-Path Associates, PLC, Tempe, AZ *****Program Director, Alta Dermatology/LECOM, Mesa, AZ; Scottsdale Healthcare System, Scottsdale, AZ

ABSTRACT Alopecia syphilitica, a rare manifestation of secondary syphilis, presents as hair loss that occurs in either a diffuse or a more common “moth-eaten” pattern and may be mimicked by other alopecias both clinically and histologically. When a patient presents with non-inflammatory, non-scarring alopecia, syphilis should be included in the differential diagnosis. A case of syphilis with alopecia as the only presenting manifestation is hereby reported and discussed. Case Report A 32-year-old Hispanic male presented to the dermatology office with a progres- sive, one-month history of patchy hair loss on his scalp. He denied loss of hair any- where else on his body or any other skin lesions. Previously, he was seen by his pri- mary care physician and had been using nystatin once a day for approximately five days with no improvement. The patient was otherwise healthy and had no significant past medical history or history of major medical illness in his family. He had no known allergies to medications and was only taking an over-the-counter energy sup- plement and Tylenol as needed. His review of systems was positive for daily headaches for a couple of weeks, but negative for fever, malaise, sore throat, muscle aches, rashes and weight loss. Figure 1: Patchy, moth-eaten alopecia Physical examination showed bilateral parietal, temporal, and occipital scalp with disseminated patches of hair loss in a moth- eaten pattern (Figure 1). The areas of alo- pecia were free from erythema or scale. On complete skin examination, no other cuta- neous lesions were identified. Standard hematoxylin and eosin (H&E) stained vertical sections of two 6.0 mm scalp punch biopsies were prepared. The biopsies demonstrated approximately Figure 2: Low Power, 4X, H&E stain dem- Figure 3: Medium power, 10x, H&E stain. 12 hair follicles in primarily telogen and onstrating miniaturaization of follicles. A “swarm of bees” pattern noted in the catagen phase, and with significant min- peribulbar region. iaturization (Figure 2). Brisk lymphocytic infiltrates were identified in the peribulbar plasma reagin (RPR) with a titer of 1:32 high-risk sexual behavior, but denied any regions of each of these retracting hairs in and a reactive fluorescent treponemal anti- history of sexually transmitted disease or a “swarm of bees” pattern (Figure 3). In body absorption (FTA-ABS). A revised genital lesions. The patient elected to go to addition to lymphocytes, scattered mast diagnosis of syphilis-induced alopecia was the state county health department for his cells and only very rare plasma cells were made. Retrospective histopathological anal- treatment. Further testing for HIV was rec- identified as demonstrated with CD68 and ysis showed only rare plasma cells and an ommended. CD138 stains respectively (Figure 4 and 5). absence of eosinophils within the peribulbar infiltrates. Immunohistochemical staining In the absence of other clinically for Treponema failed to demonstrate iden- Discussion detected signs and symptoms for syphilis, tifiable organisms in either of these biopsies. the diagnosis of alopecia areata was ini- Syphilis is caused by the spirochete tially suspected histologically. Subsequent The patient returned to the office and Treponema pallidum. If left untreated, it laboratory testing revealed a positive rapid was notified of the results. He admitted to becomes a chronic, systemic infection. Rosenblum, Bird, Beehler, Adler, Kessler 47 Figure 4: High power, 40X, CD138 stain depicting a plasma cell Figure 5: High power, 40X, CD68 stain demonstrating multiple mast amidst the inflammatory infiltrate of a retracting hair bulb. cells within the inflammatory infiltrate of a retracting hair bulb.

After penicillin was validated as an effective mous eruption on the trunk, face, extremi- in a limited number of biopsies available cure for syphilis in 1947, the rate of infec- ties and palmoplantar region.2,6 Additional in the literature.12, 14, 19-21 The ESA cases tions decreased dramatically in developed manifestations include condyloma lata, reported share the common characteristics nations.1 Since 2000, there has been a ris- mucous patches, and non-scarring alope- of a perifollicular lymphocytic infiltrate and ing influx of the disease in the United States cia. Reported estimates of the prevalence frequent telogen and catagen hairs.12, 14, 19-21 amongst black and Hispanic individuals of alopecia in secondary syphilis have been Jordaan and Louw documented a number as well as men who have sex with men.1,2 remarkably disparate, ranging from 5 to 50 of histopathological features found in 12 These groups have a 5- to 25-fold higher percent.10 Hair loss as the predominant or patients with moth-eaten alopecia.19 Their incidence rate than the general population.2 only clinical manifestation of secondary main findings included a normal epider- In some developing countries, infection syphilis, however, is generally reported as mis, follicular plugging, vasodilation, endo- rates are as high as 10% of the population.3 occurring in about 3 percent of patients.10 thelial prominence, an increased number There are approximately 12 million new There are two types of alopecia in sec- of telogen and catagen hair follicles, and cases per year worldwide, with the vast ondary syphilis, which were first described follicle-orientated melanin clumping. The majority of these cases occurring in the by McCarthy in 1940. The first type occurs only universal feature present in all their 3-5 developing world. in association with clinically apparent cases was a perifollicular and perivascular Syphilis progresses through four over- syphilitic lesions of the scalp and is termed dermal infiltrate consisting of lymphocytes lapping stages: primary, secondary, latent, “symptomatic syphilitic alopecia.” The sec- and macrophages. Other cells noted in and tertiary syphilis.1-8 Each stage is char- ond occurs in the absence of scalp lesions their cases included mast cells, plasma cells, acterized by unique symptoms, clinical and is termed “essential syphilitic alope- melanophages, and eosinophils. Warthin- manifestations, and levels of infectivity. cia (ESA).”11-13 ESA can be further divided Starry stain failed to confirm the presence On average, the primary manifestation of into three subtypes: as a patchy “moth- of T. pallidum in all cases. syphilis first appears three weeks after expo- eaten” appearance, as a diffuse pattern of In the absence of stereotypical clinical sure.6,8 Typically, it presents at the inocula- generalized thinning, or as a combination features of syphilis, the histology of ESA tion site as a solitary, painless, indurated, of both.11-13 The patchy, moth-eaten sub- may be confused with alopecia areata.12,20 non-purulent ulcer with a clean base, classi- type occurs most frequently.11-15 While ESA Lee and Hsu reported the histopathology cally referred to as a chancre.1,6 Most chan- most commonly involves the scalp, it may of nine patients with syphilitic alopecia.20 cres are found on the penis in men and the affect other places of hair growth, such as They noted a normal dermoepidermal junc- labia or cervix of women. The chancre is the eyebrows, eyelashes, chest, legs, axilla, tion, a decreased number of hair follicles, mostly accompanied by edematous swell- or pubis.11-13, 15-17 The diffuse pattern of ESA and increased catagenization and telo- ing and regional lymphadenopathy. Only may clinically mimic telogen effluvium or genization. In addition, a key finding 30-40% of patients with syphilis are diag- androgenic alopecia. The moth-eaten form included a lymphocytic infiltration around nosed during the primary stage.6 may clinically resemble other localized, the hair bulbs and the fibrous tracts. There Secondary syphilis develops after non-scarring alopecias including alopecia was a notable absence of eosinophils in all hematogeneous and lymphatic dissemina- areata, alopecia neoplastica, tinea capitis, biopsies, and plasma cells were noted in 11 tion of the microorganism, typically six to trichotillomania, and traction alopecia. four specimens. This lack of eosinophils eight weeks after the appearance of the pri- A thorough patient history as well as his- was surmised in their study to be a crite- mary chancre.6 Secondary syphilis is char- topathology can help exclude these other rion to differentiate alopecia areata from acterized by mucocutaneous and systemic diagnoses. syphilitic alopecia. Other studies, however, manifestations. Frequently observed con- The histopathological findings of the have refuted the specificity of eosinophils by stitutional symptoms include fever, mal- papulosquamous lesions of symptomatic reporting several cases of syphilitic alopecia aise, sore-throat, headaches, myalgias and syphilitic alopecia are similar to the find- with eosinophils present in the peribulbar 19,21 generalized lymphadenopathy.5-9 The most ings typically associated with secondary infiltrate. commonly observed cutaneous presentation syphilis.18 However, the histopathologic fea- The histologic detection of T. pallidum is a generalized, non-pruritic papulosqua- tures of ESA differ, and have been described has historically been challenging. The usual 48 Essential Alopecia Syphilitica: A Case Report and Review of Literature

method for detecting spirochetes in tissue the presence of neurosyphilis, and the Cen- report of two cases in Geneva. Dermatology 2001; 202: 376-377 sections is with silver stains, using either ters for Disease Control should be contacted 16. Pareek SS. Unusual location of syphilitic alopecia: a 2,11 the Warthin-Starry technique or the Steiner for support. Alopecia usually resolves case report. Sex Transm Dis 1982; 9: 43-44. 11 15,-17 modification of the Dieterle technique; within three months of treatment. 17. Abdul Gaffoor PM. Syphilitic alopecia. Indian J Sex however, organisms are often difficult to Paradoxically, the treatment of syphilis has Transm Dis 1990; 11: 66-67. 22 18. Sperling L. An atlas of hair pathology with clinical detect with these methods. Nam-Cha et also been shown as a cause of alopecia and correlations. New York: The Parthenon Publishing al. were one of the first to report finding has been described in association with the Group. 2003. T. pallidum in hair follicles by immunohis- Jarisch-Herxheimer reaction.23 19. Jordaan HF, Louw M. The moth-eaten alopecia of 14 secondary syphilis. A histopathological study of 12 tochemistry. This technique yields more patients. Am J Dermatopathol 1995; 17: 158. sensitive results than the standard silver Conclusion 20. Lee JY, Hsu ML. Alopecia syphilitica, a simulator of stains and may become the gold standard alopecia areata: histopathology and differential Syphilitic alopecia usually presents diagnosis. J Cutan Pathol 1991; 10: 87-92. for the histologic detection of occult organ- with other classical findings of secondary 21. Elston DM, McCollough ML, Bergfeld WF, et al. isms. Molecular detection by polymerase syphilis. Only rarely is it the only present- Eosinophils in fibrous tracts and near hair bulbs: a helpful diagnostic feature of alopecia areata. J Am Acad chain reaction is an additional sensitive ing feature of syphilis. Syphilis is known to Dermatol. 1997; 37: 101-106. technique available for the diagnosis of T. be a great imitator of other diseases and can 22. Hoang, MP, High WA, Molberg KH. Secondary syphilis: pallidum in lesional scalp tissue.10 be quite challenging for both clinicians and a histologic and immunohistochemical evaluation. J Cutan Pathol 2004; 31:595-599. The laboratory diagnosis of syphilis is pathologists. The histologic detection of 23. Pareek SS. Syphilitic alopecia and Jarisch-Herxheimer based on either direct detection of trepo- essential syphilitic alopecia is difficult and reaction. Br J Vener Dis 1977; 53: 389-390. nemes or serologic tests that assess antibody may be confused with alopecia areata, espe- response to cardiolipin or treponemal anti- cially in the absence of stereotypical clinical gens. Primary lesions can be present one features of syphilis. New adjunctive tech- to three weeks before the serologic tests niques, including immunohistochemistry become positive.3,5,8 In this phase, it is cru- and PCR, provide more sensitive methods cial to make the correct diagnosis by direct of detection. Ultimately, a combination visualization of T. pallidum via dark field of histologic, serologic, and clinical find- microscopy.3,6,8 Non-treponemal tests, such ings are all important in order to make the as the rapid plasma reagin (RPR) and Vene- proper diagnosis of syphilitic alopecia. real Disease Research Laboratory (VDRL), References are used qualitatively for screening pur- 1. Kent ME, Romanelli F. Reexamining syphilis: an poses and quantitatively as a measurement update on epidemiology, clinical manifestations, and management. Annals of Pharmacotherapy 2008; 42: to monitor antibody titers after antibiotic 226-236. therapy. Although these tests are widely 2. Bolognia J, Jorizzo J, Rapini, R. Dermatology. 2nd available and relatively inexpensive, they are edition. Mosby Elsevier, 2008. limited by their lack of sensitivity in early 3. Buffet M, Grange PA, Gerhardt P, Carlotti A, Calvez A, Bianchi A, Dupin N. Diagnosing Treponema pallidum in and late syphilis and by false-positive reac- secondary syphilis by PCR and immunohistochemistry. tions.2,5-9 J Invest Dermatol 2007; 127: 2345-2350. 4. Gerbase AC, Rowley JT, Heymann DH, Berkley SF, Treponemal tests, due to their higher Piot P. Global prevalence and incidence estimates of specificity, are used as confirmatory tests selected curable STDs. Sex Transm Infect 1998; 74: S12-6. 2,5,6,8 after a reactive non-treponemal test. 5. Singh AE, Romanowski B. Syphilis: review with Specific treponemal tests are based upon emphasis on clinical, epidemiologic, and some biologic features. Clinical Microbiology Reviews 1999; 12: 187- the detection of antibodies against specific 209. treponemal antigens and include: fluo- 6. Lautenschlager S. Cutaneous manifestations of rescent treponemal antibody absorption syphilis, recognition and management. Am J Clin Dermatol 2006; 7: 291-304. (FTA-ABS), microhemagglutination test for 7. Lafond RE, Lukehart SA. Biological basis for syphilis. antibodies to Treponema pallidum (MHA- Clin Microbiol Rev 2006; 19: 29-49. TP), Treponema pallidum particle agglu- 8. Hook EW, Marra CM. Acquired syphilis in adults. N tination assay (TP-PA), and Treponema Engl J Med 1992; 326: 1060-1069. 9. Baughn RE, Musher DM. Secondary syphilitic lesions. pallidum enzyme immunoassay (TP-EIA). Clin Microbiol Rev 2005; 18:205-216 DNA PCR has been used to identify T. palli- 10. Schlüpen E, Meurer M, Schirren CG, Baumann L, dum in clinical specimens, but is not readily Volkenandt. Alopecia specifica in secondary syphilis. 5 Molecular detection of Treponema pallidum in lesional available for routine use. skin. Eur J Dermatol 1996; 6:19-22. The primary treatment for syphilis is 11. Bi MY, Cohen PR, Robinson FW, Gray JM. Alopecia syphilitica-report of a patient with secondary syphilis a single intramuscular dose of penicillin G presenting as moth-eaten alopecia and a review of its benzathine.1-2,5-6,8,9,11 For patients who are common mimickers. Dermatology Online Journal 15 (10): 6. allergic to penicillin, alternative therapy 12. Cuozzo DW, Benson PM, Sperling LC, Skelton HG. 7,8 includes doxycycline or tetracycline. For Essential syphilitic alopecia revisited. J Am Acad patients with latent syphilis longer than one Dermatol 1995; 32: 840-844. 13. Vafaie J, Weinberg JM, Smith B, Mizuguchi RS. year in duration, of unknown duration, or Alopecia in association with sexually transmitted with cardiac involvement, or for patients disease: a review. Cutis 2005; 76: 361-366. with tertiary syphilis, more frequent doses 14. Nam-Cha SH, Guhl G, Fernandez-Pena P, Fraga J. Alopecia syphilitica with detection of Treponema of intramuscular benzathine penicillin pallidum in the hair follicle. J Cutan Pathol 2007; 34:37- should be given.1,5,6,8 Treatment may vary 40. with a patient's positive HIV status or with 15. Friedli A, Chavaz P, Harms M. Alopecia syphilitica:

Rosenblum, Bird, Beehler, Adler, Kessle r 51 Syringofibroadenoma: A Case Report and Discussion

Steffany B. Steinmetz, DO,* Ryan L. Owen, DO,** Robert M. Law, M.D.,*** Bill V. Way, DO, FAOCD****

*2nd-year Dermatology Resident, Northeast Regional Medical Center, Kirksville College of Osteopathic Medicine, Department of Dermatology, Texas Division, Duncanville, Texas **Traditional Intern, LewisGale Hospital-Montgomery, Blacksburg, Virginia ***Clinical Assistant Professor, Departments of Dermatology and Pathology, University of Texas Southwestern School of Medicine, Dallas, Texas; Pro- path Associates, Dallas, Texas ****Program Director, Northeast Regional Medical Center/Kirksville College of Osteopathic Medicine, Department of Dermatology, Texas Division, Duncanville, Texas

ABSTRACT Syringofibroadenoma is an uncommon, benign tumor of eccrine-gland origin. This is a case presentation of a 67-year-old male with a history of multiple sclerosis who developed multiple syringofibroadenomas on his buttocks, which reoccurred after shave excision. Subsequently, full-thickness surgical excision was performed. A brief review of the literature will be presented including tumor classifications, gross as well as histopathological characteristics, and differential diagnoses.

Introduction Eccrine syringofibroadenoma (ESFA) is a rare adnexal neoplasm of eccrine gland differentiation. First described by Mascaro in 1963, it is now considered to originate from the excretory portion of the eccrine sweat gland.1,3 Generally, the tumor is a solitary large nodule but can also manifest as multiple papules and nodules in a sym- metrical or linear nevoid pattern. Figure 1 Figure 2

Case Presentation A 67-year-old, wheelchair-bound Afri- can American male presented with asymp- tomatic, growing pedunculated nodules on the buttocks. The patient had a history of primary progressive multiple sclerosis, diag- nosed in 1999. He had been non-ambu- latory since 2003 and was unable to assist with transfers or perform his activities of daily living. Figure 3 Figure 4 The lesions on the buttocks had been nor is mucin deposition present. On the cutaneous findings. removed five years earlier by shave exci- basis of these findings, a diagnosis of syrin- sion. Physical examination revealed multi- gofibroadenoma was made. 4. Nonfamilial unilateral linear ESFA. ple large (average 20 mm) polypoid nodules 5. Reactive syringofibroadenomatous on the buttocks near the intergluteal cleft hyperplasia (RESFAH). (Figures 1 and 2). Full-thickness surgical Discussion excision was performed. The diagnosis of 6. RESFAH associated with squa- syringofibroadenomas was confirmed by A variety of presentations and mor- mous cell carcinoma, melanocytic and 1,4 histopathology (Figures 3 and 4). phologies have been reported on syringo- vascular neoplasms. fibroadenoma. Starink in 1997 devised a RESFAH is viewed as an epithelial classification for EFSA dividing it into four reactive process of hyperplasia secondary Histopathology clinical subtypes. Since then, the classifica- to numerous inflammatory or neoplastic tion has developed into six subtypes: dermatoses including chronic ulceration Histopathological examination 1. Solitary ESFA. and trauma in diabetes mellitus, neuropa- revealed a polypoid nodule with exten- thy of leprosy, burn scars, venous stasis, sion of thin basaloid cords from the base of 2. Multiple ESFA associated with bullous pemphigoid, sebaceous nevus and the epidermis. Ductular differentiation is Schöpf syndrome (hidrotic ectodermal erosive palmoplantar lichen planus.1 The observed, with a surrounding fibrovascular dysplasia). reactive syringofibroadenomatous hyper- stroma. Peritumoral clefting is not noted, 3. Multiple ESFA without associated plasia variant may likely be the result of 52 Syringofibroadenoma: A Case Report and Discussion repeated tissue damage and repair, as seen in the aforementioned case report regard- ing a wheelchair-bound, non-ambulatory patient secondary to primary progressive multiple sclerosis. On histopathology, ESFA shows an anastomosis of cords and strands of epi- thelial cuboidal cells within a fibrovascu- lar stroma mimicking fibroepithelioma of Pinkus.4 The difference, however, is that ESFA displays ductal differentiation and lacks palisaded dark-staining cells. His- tologically and immunophenotypically, ESFA and RESFAH appear strikingly similar except that RESFAH displays MNF116-positive cytokeratins due to the hyperproliferation and underlying inflam- mation.2 Additionally, RESFAH exhibits an increased number of mast cells. In general, ESFA stains positive for epithelial mem- brane antigen 34βE12 cytokeratins, CK-19 and CEA.4 The differential diagnosis for ESFA includes fibroepithelioma of Pinkus, clear- cell acanthoma, poroma and porocarci- noma.5 Recently, Cota et al. reported a case of ESFA with concomitant clear-cell acan- thoma in a patient with lower-extremity stasis dermatitis; however, the relationship between the two distinct entities remains unclear.4 Due to the potential association between ESFA and malignancy, full-thick- ness excision remains the definitive treat- ment.5 References 1. Tey HL. Characterizing the nature of eccrine syringofibroadenoma: illustration with a case showing spontaneous involution. Journal of Clinical and Experimental Dermatology. 2008; 34, e66-e68.Bjarke T, et al. Carcinoma and eccrine syringofibroadenoma: a report of five cases. Journal of Cutaneous Pathology. 2003; 30: 382-392. 2. Kim YJ, Kim CY, Lee ES. Solitary eccrine syringofibroadenoma with prominent plasma cell infiltration. Journal of Dermatology. 2007; 34: 138-141 3. Cota C, Ferrara, G, Amantea A, Donati P. Eccrine syringofibroadenoma and clear cell acanthoma: an association by chance? American Journal of Dermatopathology. 2011; 33: 195-198. 4. Schadt C, Boyd A. Eccrine syringofibroadenoma with co-existent squamous cell carcinoma. Journal of Cutaneous Pathology. 2007; 34 (suppl. 1): 71-74.

Steinmetz, Owen, Law, Wa y 53 A Case of Migrating Necrotic Ulcers

Kristin L. Regan, DO,* Martin Diamond, DO**

*PGY-1, Nassau University Medical Center, East Meadow, NY **Director of Osteopathic Medical Education, Dermatology Residency, Nassau University Medical Center, East Meadow, NY

ABSTRACT Calciphylaxis is a life-threatening, disabling disease that involves calcium deposition within the walls of small and medium sized arteries leading to ischemia and necrosis of the supplying tissue {1}. Although this condition has been seen in other nonuremic conditions, the primary finding was first described in dialysis patients and has since been the most prevalent population {2}. The development of these lesions is a slow, indolent course, most commonly seen on the lower extremities, and portends a grim prognosis {1, 2}. As most of these lesions progress, the condition is complicated by severe and often fatal complications {1, 2}. In addition, the pathogenesis of this disease is poorly understood and although several strategies have been aimed to treat this condition, the outcome has still been poor. Several risk factors have been identified and in this case, we evaluate the possible risks involved for the development of calciphylaxis. Presentation of the Case Examination A 46-year-old Caucasian female pre- On complete examination of this sented to the emergency department com- patient, she was a largely immobile, alert, plaining of “painful ulcers that have been neurologically intact, cachectic-looking spreading throughout her body” for the past female with distant heart sounds and bilat- few months. She handled the pain up until a eral decreased breath sounds with crackles few days prior to admission, when the pain at the base of the lungs. The most remark- had become “too intense.” This patient had able finding was the tender, extensive an extensive past medical history, including necrotic ulcers and eschars with circum- end stage renal disease secondary to trans- ferential erythema, largely concentrated to plant rejection six months prior for which her back, sacrum and lower extremities (see she received dialysis daily. After her initial Figures 1-5). In addition, there were mul- transplant rejection, she developed diabetes tiple smaller, purple, painful subcutaneous Figure 3: The patient's left shin secondary to pancreatic transplant failure nodules and reticulated plaques as well as as well as hyperparathyroidism. During areas with dry gangrene on her bilateral legs her renal transplant, she had been diag- and arms. The larger ulcerations ranged nosed with a deep vein thrombosis in her from the smallest at 2cm by 2 cm to 110cm right lower extremity and started on war- by 75cm on her left flank. The patient had farin therapy. The patient was admitted exquisite pain during examination of the for dialysis three times per week as well as multiple ulcerations and eschars, making it pain management and wound care. After a difficult task to examine every lesion in examination of the patient on admission, great detail. intravenous morphine and antibiotics were started to aid with her pain, as prophylaxis for wound infection, and for proper healing Further Complications and of her multiple opened ulcerations. Course in Hospital

Figure 4: Left medial malleolus.

Figure 1: The largest surface area, encom- Figure 2: Right dorsal foot, revealing a passing the patient's back, revealing one large eschar with ulceration. Note the of the most impressive lesions on her left great toe is largely necrotic secondary to Figure 5: Right plantar surface, revealing lateral flank. calciphylaxis. multiple eschars with desquamation as well as areas of ulceration.

54 A Case of Migrating Necrotic Ulcers During her two-month hospital stay, to a particular sensitizing agent, there was receiving dialysis. With careful use, it not laboratory work revealed elevated calcium greater risk of developing calciphylaxis, and only reduces the pain in the areas where levels and glucose levels, which remained in fact more rats did develop the condition. new lesions are spreading but also decreases uncontrolled despite medication optimiza- 2,3 Some of these agents included vitamin D, the level of parathyroid hormone signifi- tion. Her left shin and right dorsal foot parathyroid hormone, and tachysterol. In cantly.5 Since the side effects of this par- were cultured multiple times, revealing Pro- humans, the “agent” would be equivalent ticular treatment are minimal, it may also teus mirabilis infection; this was treated to large doses of parathyroid hormone, cal- prove to be an adequate adjuvant treatment with intravenous vancomycin, piperacillin cium or phosphate. However, this is only for calciphylaxis. However, many other tri- and tazobactam. one of the many theories that have been als must be done to adequately gauge its Both dermatology and plastic surgery proposed. efficacy. consulted on the eschars and ulcerations Although calciphylaxis has been seen By far the most successful yet contro- to confirm the clinical suspicion and histo- in other, non-uremic conditions, the pri- versial surgical option has been parathy- logic diagnosis of calciphylaxis via biopsy. mary finding was first described in dialysis roidectomy, which diminishes most of the Additionally, warfarin was discontinued as patients, which has since been the most external disease manifestations. It has been it posed a potential threat to her condition; prevalent population. 2 The development of shown to be the best option for those with- she was subsequently placed on sodium these lesions is a slow, indolent course, most out a known etiology of calciphylaxis but thiosulfate infusion with dialysis three times commonly seen on the lower extremities, with associated hyperparathyroidism. How- per week to treat the calciphylaxis. Plastic and portends a grim prognosis.1,2 As seen ever, this is still a controversial treatment, surgery recommended whirlpool therapy with our patient, as most of these lesions and not every patient is a candidate for every day as well as surgical debridement of progress the condition is complicated by it.6 We describe a patient who was anuric, the larger lesions to aid with wound healing severe and often fatal complications. 1,2 on dialysis, and post pancreatic transplant and potentiate the healing process. Some of these fatal complications include rejection with adrenal insufficiency who Throughout her hospital stay, the rapid sepsis, gangrene, and electrolyte imbalances developed extensive calciphylaxis covering response team was called multiple times leading to arrhythmias. greater than 70% of her body. The treat- due to altered mental status as well as respi- The pathogenesis of this disease is ment of choice for this patient was sodium ratory arrest, leading to multiple studies poorly understood, and although several thiosulfate three times per week for two to rule out other pathologies. Her wounds strategies have been used to treat this condi- weeks during dialysis and piperacillin and continued to expand, and despite whirl- tion, the outcome has still been poor. Dis- tazobactam 2.25 mg intravenous piggy-back pool therapy and multiple wound debride- orders such as chronic renal failure, diabetes for new onset Proteus sepsis. Although the ments with surgery, her condition rapidly mellitus, hyperparathyroidism, medication patient may have been a candidate for a cal- declined. Unfortunately, due to the severity usage, hypercalcemia and hyperphospha- cimimetic, she did not qualify for a parathy- of her condition, our patient had a pro- temia are just a few of the conditions roidectomy because she was not medically tracted hospital course during which she associated with this disease. Though the stable. In addition, the patient’s condition developed poorly managed sepsis in the dysregulation of the calcium-phosphate lev- proved to be refractory to conventional intensive care unit secondary to wound els in end-stage renal disease is a major treatment, and alternative therapy could not infections, leading to her mortality. factor in developing calciphylaxis, it has be implemented as she refused subsequent also been seen in the setting of metastatic dialysis and further treatment, leading to breast cancer. 3 There have been several risk her mortality. Pathology factors identified, including hyperparathy- References roidism, elevated serum calcium levels and A biopsy was taken of the right upper 1. Brucculeri M, Cheigh J, Bauer G. Long-Term elevated phosphate levels, diabetes mellitus, Intravenous Sodium Thiosulfate in the Treatment of a extremity at the lateral edge of the lesion, Patient with Calciphylaxis. 18[5], 431-34. 2005. Dialysis coagulopathies, warfarin and iron dextran including some of the erythematous rim of Rounds. treatment; however, not one has been iden- the lesion. The pathology report described 2. Hanvesakul R, Silva MA, Hejmadi R. Calciphylaxis tified as a major cause. 1,2 following kidney transplantation: case report. Journal of calcification within the media of the small- Medical Case Reports 3, 1-3. 1-22-0009. and medium-sized arterioles with extensive There have been reported cases of cal- 3. Ledbetter L, Khoshnevis M. Calciphylaxis. Cutis: 49-51. June 2000. intimal hyperplasia and fibrosis consistent ciphylaxis that present after kidney trans- 4. Ackerman F, Levy A. Sodium Thiosulfate as First-Line with the calciphylaxis. There was some plantation and treatment with sodium Treatment for Calciphylaxis Archives of Dermatology lymphohistiocytic infiltrate in affected adi- thiosulfate.1,2 Sodium thiosulfate has been, 2007. 143(Oct). pose lobules as well as evidence of pannicu- by and large, the first-line treatment for 5. Robinson M, Augustine J. Cinacalcet for the Treatment of Calciphylaxis. Archives of Dermatology 2007. litis and subcutaneous fat necrosis of some calciphylaxis, as the major aim of this treat- 143(Feb): p. 3. 1,2 of the biopsy site. ment is to restore endothelial function 6. Hafner J, et al. Uremic small-artery disease with through its antioxidant effect. When there medial calcification and intimal hyperplasia (so-called calciphylaxis): A complication of chronic renal failure and is an absence of hyperparathyroidism, this benefit from parathyroidectomy. Journal of the American Discussion of the Case can be a very successful adjunct to ther- Academy of Dermatology, 1995. 33(6): p. 954-962 apy. It has been shown in a small subset of Calciphylaxis is a life-threatening, patients to reduce the appearance of livedo disabling disease that involves calcium as well as normalize the calcium-phosphate deposition within the walls of small- and ratio. 3,4 medium-sized arteries, leading to ischemia and necrosis of the supplying tissue. 1 The Another way to tackle the calcium- etiology of the disease is largely unclear. The phosphate disturbance would be to use first condition was described in rat models cinacalcet, a calcimimetic that lowers the by Selye et al. in 1962.3 By exposing the rat levels of parathyroid hormone in patients

Regan, Diamond 55 Erosive Pustular Dermatosis of the Scalp Resembling Basal cell Carcinoma in an Elderly Woman

Christine Moussa, MSIV,* John Ebner, DO, FAAD,** Keliegh Culpepper, MD***

*4th-year Medical Student, A.T. Still University-School of Osteopathic Medicine in Arizona, Mesa, AZ **Attending Physician, Arizona Dermatology, Phoenix, AZ ***Director of Pathology Services, Dermpath Diagnostics, Tucson, AZ

ABSTRACT Erosive pustular dermatosis of the scalp (EPDS) is a rare skin disorder of unknown etiology that most commonly affects older patients. This case describes an elderly woman who presented with an asymptomatic, hyperkeratotic,ulcerated plaque on the crown of her scalp of two years duration. Basal cell carcinoma was the favored diagnosis, but histopathologic evaluation on three separate occasions showed nonspecific inflammatory infiltrate and scarring. Direct immunoflourescence showed no significant findings. During the third visit, a wound culture grew P. aeruginosa sensitive to ciprofloxacin, yet antibiotics showed no improvement. As the diagnoses of malignancy, infection, neutrophilic dermatoses, and autoimmune diseases had been excluded, a diagnosis of EPDS was suspected. A treatment course with oral prednisone was initiated showing marked improvement within weeks and resolution over 5 months. We report this case to underscore the importance of including EPD in the differential diagnosis as to avoid delay of treatment. Introduction Erosive pustular dermatosis of the scalp (EPDS) was first described in 1979, with no U.S. cases reported until 2006.2,12 It is a rare inflammatory disorder of unknown etiology, although it is often seen in skin traumatized by actinic damage, chemother- apy, cryotherapy, radiation, and grafting, among other traumas.2 It is characterized by sterile pustular lesions with erosion and crusting, resulting in scarring alopecia in the affected areas, most commonly the scalp.3 Erosive pustular dermatosis of the Figure 1: Lesion prior to treatment. Figure 3: The patient two months after extremities is even rarer, most often seen in treatment. the setting of venous insufficiency.2 Infan- tile EPDS may be found in association with Klippel-Feil syndrome or necrotic caput succedaneum.6,12 EPDS is a diagnosis of exclusion, once malignancy, infection, neu- trophilic dermatoses and autoimmune blis- tering disorders have been investigated.2 These lesions have responded to topical corticosteroids, retinoids, tacrolimus, cal- cipotriol, zinc sulphate and photodynamic therapy with methyl 5-aminolaevulinic acid.2,3,4,5,7

Figure 2: The patient two weeks after Figure 4: The patient five months after Case presentation treatment with 20 mg oral prednisone qd. treatment. A 79-year-old Caucasian female pre- ure 1). Three 4-mm punch biopsies were sented with an asymptomatic, enlarg- tigines on the face. To rule out malignancy, taken with concern for the possibility of an ing, hyperkeratotic, ulcerated plaque on the most likely diagnosis, 4-mm punch autoimmune blistering disease. A wound the scalp of two years duration. Her past biopsies were taken from the plaque. No culture grew Pseudomonas aeruginosa, but medical history included colon cancer, signs of malignancy were identified, results a course of ciprofloxacin (500mg BID for diabetes mellitus with chronic kidney dis- showing only an ulcer with superficial frag- 10 days) had no effect in healing the ulcer- ease, glaucoma, hypertension, hyperlipid- ments of neutrophilic crust, hemorrhage, ated plaque. Histopathology showed simi- emia, hypothyroidism and obesity. She had hyperkeratosis and inflamed dermis with lar findings as before, with non-specific no history of skin cancer or other dermato- features of granulation tissue. Clinically, the inflammation and granulation tissue. These logic conditions. The patient’s medications plaque was still suspicious for a malignant inconclusive results led to a decision to per- were reviewed and non-contributory. process, but an additional biopsy rendered form a larger incisional biopsy, revealing similar findings. The patient was lost to On physical exam, the plaque was 3cm essentially the same findings (see Figures 5 follow-up for one year. by 1cm, located on the crown of the scalp, and 6). Direct immunofluorescence showed and appeared erythematous and hyperkera- Upon return, the ulcerated plaque had a negative immunoreactant profile (IgG, totic within a large ulcer. The remaining enlarged and developed more hyperkera- IGa, IgM, C3, C1q, C3d, C4d, C5b-9) and skin exam revealed only a few scattered len- totic crusting with visible purulence (Fig- no features of an autoimmune vesiculobul- 56 Erosive Pustular Dermatosis of the Scalp Resembling Basal-cell Carcinoma in an Elderly Woman lous disorder. Moderately intense dermal Figure 5: (Inci- staining of fibrinogen was identified, a non- sional scalp biopsy, specific finding. The tissue was negative for 4x magnification) S100, no atypical vascular proliferation was Broad ulceration identified with a CD31 marker, and scat- and erosion with tered factor XIIIa positivity was seen in the mild inflammation. areas of dermal scarring. Based on these results, with no findings of malignancy, autoimmune blistering disease, infection, or neutrophilic dermatoses, EPDS was deemed the most likely diagnosis. The patient was started on 20 mg of oral prednisone daily, with close monitor- ing of her blood glucose given her concur- rent diabetes. After two weeks of treatment, the pustular erosion was approximately 50 percent smaller (see Figure 2). One month after starting prednisone, the dose was Figure 6: (Inci- reduced to 10 mg qd, and after two months sional scalp of treatment a dramatic improvement was biopsy, 20x mag- seen (see Figure 3). After the third month, nification) the dose was further reduced to 5 mg qd, Patchy, acute, and followed by two weeks of 5 mg qd, and chronic inflamma- finally two weeks of 5 mg only on Mondays tion in the upper and Thursdays. Complete resolution was dermis. seen five months after the initiation of treat- ment with prednisone, with no recurrence at two months follow-up (see Figure 4).

Discussion Erosive pustular dermatosis of the scalp is an idiopathic disorder that often occurs in elderly patients. It is a diagnosis of exclusion made by negative cultures and histopathologic reports showing nonspe- and leg in association with myasthenia gra- erosive dermatosis of the scalp and extremities: A 8 recharacterization of erosive pustular dermatosis. J Am cific inflammation and scarring. It tends to vis. The development of squamous-cell Acad Dermatol. Sep 2007;57(3):421-7. occur in elderly Caucasian women with a carcinoma has occurred in scars of EPDS, 3. Van Exel CE, English JC 3rd. Erosive pustular which emphasizes the need for close long- dermatosis of the scalp and nonscalp. J Am Acad precipitating history of cutaneous damage, Dermatol. Aug 2007;57(2 Suppl):S11-4 term follow-up in these patients.9 such as actinic keratoses, chemotherapy, 4. Ikeda M, Arata J, Isaka H. Erosive pustular dermatosis of the scalp successfully treated with oral zinc cryotherapy, radiation, and grafting, among Reported treatments include topical sulphate. Br J Dermatol. Jun 1982;106(6):742-3. 2 others. Cases have been reported in the corticosteroids, retinoids, tacrolimus, cal- 5. Peterson BO, Bygum A. Erosive Pustular Dermatosis of pediatric populations in the setting of tissue cipotriol, zinc sulphate and photodynamic the Scalp: A Case Treated Successfully with Isotretinoin. injury and atrophy.2,12 These wounds may therapy with methyl 5-aminolaevulinic Acta Derm Venereol 2008; 88(3):300-301 2-5,7 6. Shimada R, Masu T, Hanamizu H, Aiba S, Okuyama develop years after the cutaneous damage acid. Our patient was treated success- R. Infantile Erosive Pustular Dermatosis of the Scalp occurs. fully with oral prednisone alone. This treat- Associated with Klippel-Feil Syndrome. Acta Derm Venereol. Mar2010;90(2):200-1 ment was chosen in order to quickly reduce EPDS presents with erythema, puru- 7. Meyer T, López-Navarro N, Herrera-Acosta E, Jose A, lence, crusting and erosive changes on the the underlying inflammation and minimize Herrera E. Erosive pustular dermatosis of the scalp: 11 a successful treatment with photodynamic therapy. scalp that progress slowly and result in scar- permanent skin damage. High-potency Photodermatol Photoimmunol Photomed. 2010 ring alopecia.3 Skin cultures are usually topical steroids have been most commonly Feb;26(1):44-5. used, but recurrence has occurred when 8. Sawada Y, Bito T, Kawakami C, Shimauchi T, Nakamura negative for microbes; however, our case M, Tokura Y. Erosive Pustular Dermatosis of the was complicated by bacterial colonization application of topical steroids is decreased Scalp and Leg Associated with Myasthenia Gravis: A or discontinued, with good response with Possible Pathogenetic Role for Neutrophil-stimulating (Pseudomonas aeruginosa) due to chroni- Cytokines and Chemokines. Acta Derm Venereol.2010 2 cally compromised tissue. Biopsies show return to treatment. Nov;90(6):652-3 nonspecific inflammatory changes and scar- 9. Lovell CR, Harman RRM, Bradfield JWB. Cutaneous We hope that this report serves as a carcinoma arising in erosive pustular dermatosis of the ring. EPD is most commonly seen in the reminder to include EPDS in the differential scalp. Br J Dermatol.1980;102:325-8. scalp, although it has been seen with iso- for an ulcerated plaque on the scalp of an 10. Van Exel CE, English JC 3rd. Erosive pustular dermatosis of the scalp and nonscalp. J Am Acad lated involvement of the face and in the elderly person. Dermatol. 2007 Aug;57(2 Suppl):S11-4. extremities in the setting of chronic venous 11. Allevato M, Clerc C, del Sel JM, Donatti L, Cabrera H, 2,10 References insufficiency. Association with auto- Juárez M. Erosive pustular dermatosis of the scalp. Int J Dermatol. 2009 Nov;48(11):1213-6. immune disease has also been described, 1. Pye RJ, Peachey RD, Burton JL. Erosive pustular dermatosis of the scalp. Br J Dermatol. May 12. Siegel DH, Holland K, Phillips RJ, Drolet BA, Esterly although the pathogenesis remains unclear. 1979;100(5):559–566. NB, Frieden IJ. Erosive pustular dermatosis of the scalp One case reported EPD on both the scalp 2. Patton D, Lynch PJ, Fung MA, Fazel N. Chronic atrophic after perinatal scalp injury. Pediatr Dermatol. 2006 Nov- Dec;23(6):533-6. o M ussa, Ebner, Culpepper 57 Sunscreen: Filtering Fact From Fiction

Jessica L. Borowicz, DO,* Cherise Khani, BS,** Richard A. Miller, DO, FAOCD***

*PGY-4 Dermatology Resident, Largo Medical Center, Largo, FL **OMSIV, Nova Southeastern University, Fort Lauderdale-Davie, FL ***Program Director, Dermatology Residency, Largo Medical Center, Largo, FL

ABSTRACT Sunscreens have been a topic of great debate for many decades. The development of an increasing amount of sunscreen products with more advanced sun-protective abilities seems to fuel even greater controversy regarding the safety and efficacy of sunscreen ingredients. By nature of their mechanism of action alone, organic or "chemical" sunscreens have been disputed by many to have risks that potentially outweigh benefits. Many studies have been done on the different UVA and UVB organic sunscreen ingredients to determine if these theoretical risks pose any actual threat. Because of this, it is important to review the UVA and UVB organic sunscreen ingredients, including their UV-attenuating properties, chemical properties, potential limitations to use and studies to support or refute the hypothesized risks of use of specific ingredients. Introduction sure to UVR by absorbing photons. This screens. However, to date, the sunscreen reaction is based on the chemical proper- monograph itself remains to be finalized, As developments have been made ties of the organic molecule and is limited as three documents published by the FDA in uncovering the pathogenesis of skin to specific wavelengths of light. Because of are still under review and call for accepting cancers, it is now known that ultravio- this, organic or “chemical” sunscreen ingre- new data submissions. These documents let radiation (UVR) is one of the primary dients are generally defined as either UVA address the unresolved issues of capping contributing factors to the development blocking or UVB blocking agents (9,10,11). the SPF label at 50+ and dosage formula- of many common skin cancers. Carcino- In 1999, the U.S. Food and Drug tions of various sunscreen product vehicles genesis is only one of several other del- Administration (FDA) issued the Final (such as sprays, wipes, towelettes, powders eterious effects of UVR. Short-term effects Monograph on Sunscreen Drug Products and body washes). While the FDA did not from UVR include tanning of the skin, for Over the Counter Human Use (12). release a timeline of when these remaining sunburn, thickening of the epidermis/der- In this monograph, the FDA defined 16 issues are to be resolved, the results of the mis, increased inflammatory infiltrates, active sunscreen ingredients that it deter- final ruling were scheduled to take effect vasodilation, edema and immunosuppres- mined to be “safe and effective and not and be enforced for all sunscreen manufac- sion. Long-term effects have been shown misbranded” for use in sunscreen, cos- turers beginning June 17, 2012 (a 12-month to include photoaging and photocarcino- metic and toiletry products. The mono- compliance date from release of the final genesis along with further and continued graph outlined the rules and regulations rule) (77). As of May 2012, the FDA again immunosuppression (1,2,3,4). Sunscreens over sunscreen labeling, maximum concen- extended the deadline for compliance with have been proven to reduce the carcino- trations, testing procedures and allowable new labeling to December 2012, giving genic and immunosuppressive effects of combinations of ingredients. Within the larger sunscreen manufacturing companies both short- and long-term UVR (4,5,6,7). testing procedures, the monograph defined six additional months to comply. Despite the trusted beneficial effects, mul- the measurements of sun protection factor Considering that SPF has historically tiple studies on specific sunscreen ingre- (SPF) of a sunscreen as well as determina- remained a measure of protection against dients have fueled controversies over the tion whether a product is water resistant UVB, with no universal measurement or safety and efficacy of sunscreens (8). Sun- or very water resistant. Not discussed in indication of the UVA-protective abilities screen ingredients have been a topic of great this monograph was the subject of UVA of sunscreens, it is important to understand debate ever since the first sunscreens were protection, as the SPF measurement only the attenuation levels of specific sunscreen discovered over 80 years ago. Patients seek indicates protection against the erythemo- ingredients that protect in both UVB and the advice of physicians, especially derma- genic UVB wavelengths of UV light (13,14). UVA wavelengths (Figures 1 & 2). Further- tologists, regarding which sunscreens to On August 27th, 2007, the FDA released more, taking into consideration the new use, which ingredients are safe and how the proposed rule to amend the 1999 FDA FDA ruling, it is important to understand well each ingredient will protect skin from final monograph, addressing the “formula- chemical properties of sunscreen ingre- UVR. Therefore, it is important to be able tion, labeling and testing requirements for dients and potential limitations of use of to define the UV protection levels, outline both UVB and UVA radiation protection” each sunscreen ingredient. By nature of the chemical properties and discuss the cur- (15). On November 28th, 2007, the time their mechanism of action alone, organic rent controversies surrounding specific sun- period for implementation of the amend- or “chemical” sunscreens have been dis- screen ingredients. ment was extended an additional 30 days puted by many to have risks that poten- Sunscreen agents are made from either (16). The proposed changes were to include tially outweigh benefits. Being aware of and inorganic or organic agents with differing a cap in the SPF to 50+, new categories for understanding the risks versus the benefits mechanisms of action. Inorganic or “physi- grading UVB SPF, a 4-star rating system of organic sunscreen ingredients, whether cal” sunscreens work to physically block for UVA protection and various warning potential or proven, is important to main- UVR by reflecting and scattering photons statements and labeling directions for sun- tain the highest degree of safety and efficacy of light. Common ingredients that work by screen products (15). Four years later, on of sunscreens. this method are titanium dioxide and zinc June 17th, 2011, the FDA issued its updated oxide. In comparison, organic sunscreens and comprehensive final ruling regard- are made of chemicals that prevent expo- ing labeling and testing of approved sun- 58S unscreen: Filtering Fact From Fiction Figure 1: UVB chemical sunscreens: UV-attenuation spectrum

Figure 2: UVA chemical sunscreens: UV-attenuation spectrum

Borowicz, Khani, Miller 59 Overview of FDA 2011 W ater Resistance Statement products with an SPF above 50, the FDA has proposed this cap on labeling pending Final Rule “Labeling and The terms “sunblock,” “water proof,” sufficient submission of data to support the and “sweat proof” are no longer permit- Effectiveness Testing; Sun- contrary (80). screen Drug Products for ted on the PDP. Instead, the label can only contain the statements “water resistant (40 Furthermore, the FDA is request- Over-the-Counter Human minutes),” or “water resistant (80 minutes)” ing additional data needed to establish Use” based upon the water resistance test. The specifications for certain dosage forms of The scope of this final rule is to estab- revision of these statements aims to make it sunscreens. Dosage forms such as wipes, lish guidelines and requirements that will easier for consumers to purchase products towelettes, powders, body washes, and ensure that currently marketed sunscreen based upon actual time of water resistance shampoos are currently considered ineli- products are appropriately labeled and (79). gible for inclusion in the sunscreen mono- tested for both UVA and UVB protection. graph. Conversely, eligible dosage forms Drug Facts Labeling: Use Statements anticipated to be included in the mono- This will ultimately improve proper use of and Application Directions these products, as well as increase consumer graph are oils, lotions, creams, gels, butters, protection from the harmful effects of UV For the first time, the FDA has adopted pastes, ointments and sticks. Spray dosage radiation. The following represents new a skin cancer and early skin aging indica- forms are considered potentially eligible yet requirements for Principal Display Panel tor for sunscreen products with an SPF of require additional data to assess their safety (PDP) labeling highlighted in the June 2011 15 or higher, pending also passing the test and efficacy, specifically relating to amount FDA ruling (79): for broad spectrum labeling. These new dispensed, uniform coverage, and possi- benefit claims do not apply to sunscreens bility of inhalation of aerosolized particles S PF Statement that are not broad spectrum, or are broad (81). In the 2007 proposed ruling, it was spectrum but with an SPF below 15. Such There exists a number of new organic suggested to redefine the acronym “SPF” as products must instead include a “skin can- filters awaiting FDA approval; however, the “sunburn protection factor,” recognizing cer/skin aging alert” message in the product limitations on allowable concentrations of that the end-point of SPF testing is ery- label (77). Of important note, the Ameri- active ingredients and certain combina- thema. However, in the final rule, SPF will can Academy of Dermatology still recom- tions pose a formulation challenge. As a remain an abbreviation for “sun protection mends an SPF of at least 30, based upon result, FDA approval of several organic fil- factor,” identical to the 1999 FDA mono- the assumption that in actual daily use, the ters remains pending (77). The following graph, and will continue to appear on the majority of consumers will apply signifi- reviews organic UVB and UVA filters that PDP as it has for several years. This deci- cantly less sunscreen than the FDA-man- have all received FDA approval for use in sion stems from efforts to avoid consumer dated amount used for testing purposes sunscreen manufacturing. confusion and acknowledge the additional (77). harmful effects of sun exposure, such as The final rule also addresses sunscreen Organic UVB filters skin aging and skin cancer, against which application directions, including a required sunscreen protects (77,79). statement that parents of children younger The UVB spectrum ranges from 290- 320nm. While only 5% of UV radiation Broad Spectrum Statement than 6 months old consult a physician prior to using sunscreens (77). The directions for reaching the earth’s surface is comprised The current rule has abandoned the non-water-resistant products state to apply of UVB (9), radiation from this shorter- UVA 4-star rating system, as well as the liberally 15 minutes before sun exposure, wavelength light spectrum has significant requirement of a “no UVA protection” use a water-resistant sunscreen if swim- harmful effects. UVB is primarily absorbed statement proposed in the 2007 rule. This ming or sweating, and reapply at least every in the epidermis with little dermal penetra- decision was again based upon minimizing 2 hours. The only difference in directions tion. UVB radiation primarily causes acute potential consumer confusion regarding for water-resistant products is to reapply erythema, sunburn and cellular DNA dam- choosing between over-the-counter (OTC) after 40 (or 80) minutes of swimming or age such as thymidine dimers, which are sunscreens with various combinations of sweating, and immediately after towel dry- the hallmark of photocarcinogenesis (9,17). SPF values and star ratings (79). The FDA ing (79). Studies have shown that UVB is approxi- has instead adopted a pass/fail test based mately 1,000 times more erythemogenic on an in vitro critical wavelength (CW) to Ongoing FDA Review than UVA (10). Furthermore, both UVA assess UVA protection and ultimately label and UVB radiation can induce immunosup- a product as “broad spectrum.” The CW Despite the 2011 final rule having been pression (9). In the early 1900s it was found is calculated based on UV transmittance issued, there remains ongoing FDA review that skin could be protected from sunburn tested by applying a fixed irradiation dose of products to ensure safety and effective- by specifically filtering out these harmful to plated sunscreen products. The CW rep- ness. One of the pending issues involves UVB wavelengths, and the first sunscreens resents the wavelength below which 90% a maximum allowable SPF label of “50+.” consequently appeared on the market (18). of a sunscreen’s absorption spectra curve Over the years, product manufacturers FDA-approved organic UVB filters are resides. It is thus a measurement of the have continued to increase SPF values, with classified as aminobenzoates (para-ami- breadth of UV absorbance, requiring the some OTC sunscreens exceeding an SPF of nobenzoic acid [PABA] and PABA deriva- amount of UVA protection to increase as 100. The FDA has indicated that although tives), cinnamates, salicylates, octocrylene the product’s SPF is increased (77). While a higher SPF may be beneficial, such prod- or ensulizole (Table 1) (12). The following there has been some recent criticism relat- ucts can also create a false sense of security paragraphs will detail the various organic ing to the exact numerical CW value (78), and result in consumers spending excessive UVB filters currently available in the United the CW at or above which a sunscreen can lengths of time exposed to the sun (77). On States, including the controversial issues be labeled "broad spectrum" has been set at the premise that there is insufficient data linked to certain ingredients. 370nm (77). supporting any increased clinical benefit of 60S unscreen: Filtering Fact From Fiction Table 1

Table 2

Borowicz, Khani, Miller 61 Aminobenzoates PABA and its derivatives. However, photo- protective properties (5). allergic effects remain a deterrent to its use Para-aminobenzoic acid (PABA) is Despite its many desirable physi- (22). one of the most commonly found UVB cal properties, there do exist drawbacks to absorbers in sunscreen products (11). Adverse reactions to PABA led to the the use of cinnamates in sunscreen prod- PABA absorbs UV wavelengths in the 290- creation of PABA ester derivatives via addi- ucts. Because cinnamates are chemically 320nm range (19). It represents one of the tion of hydrocarbon groups to the mol- related to cocoa leaves, balsam of Peru and first organic sunscreens to become widely ecule. These PABA derivatives have peak cinnamon oil, they should be avoided in available, with the formulation patented UV absorption at 311nm (10). Padimate individuals with hypersensitivities to these in 1943 (10,20). PABA is a highly efficient A (amyl-p-demethylaminobenzoate) was products due to the risk of cross-reactiv- UVB filter at 5% concentration in a 50-60% on the market for a few years, but due to ity (30,31). Although octinoxate has been alcohol-based vehicle (21). Any alteration in phototoxic effects grossly resembling a reported to elicit a positive reaction during the alcohol or water content of the formula- sunburn (27), it is no longer listed as an photopatch testing, the incidence is low, tion will decrease its protective effects (18). approved ingredient as per the 1999 FDA with a negligible degree of skin irritation One of the most advantageous properties sunscreen monograph (12,21). Padimate typically seen (22,32,33). of PABA is its chemical composition, con- O (octyl dimethyl-p-aminobenzoate) is Commercially available sunscreens sisting of long-chain aliphatic alcohols that another PABA derivative offering effective must be exposed to both natural and arti- make it nearly insoluble. It therefore has the UVB filtration. Despite a few limited stud- ficial UV radiation in order to study and ability to penetrate the skin by attaching to ies attempting to determine photomuta- determine photostability. While manufac- proteins within keratinocytes via hydro- genicity of padimate-O, in general it has turers commonly market their products’ gen bonding (10). Approximately 30 min- a good safety profile, offering a valuable protection against UVA and UVB radiation, utes after application, the product is able to level of protection against photocarcinogen- labels rarely declare photostability. Gonzalez withstand swimming, perspiration, and the esis (5,21,28). It is the most commonly used et al. performed a study of seven sunscreen trauma of towel abrasion (10,18). PABA derivative and the most potent UVB products available in the U.S. to evaluate absorber according to some texts (17,21). For several years, PABA was the pri- their photostability. Results demonstrated Photoallergy and staining of clothing has marily used organic sunscreen ingredi- that octinoxate is photo-unstable and starts been reported with padimate O, though the ent (20); however, several issues resulted to degrade rapidly following UV expo- frequency is less than that of PABA (18,22). in its limited use over time and the rise sure (34). Octinoxate has been shown by Padimate O binds tightly to the stratum of “PABA-free” products beginning in the nuclear magnetic resonance spectroscopy to corneum, leading to extensive durability. 1980s (10). Disadvantages of PABA include degrade into a configurational isomer fol- It is also cosmetically elegant, being eas- the staining of clothing (18) and subjec- lowing sunlight exposure, thus undergoing ily incorporated into a variety of skin and tive stinging with allergic contact dermatitis a transformational change from the stan- hair products. Despite the advantageous (17). The reported photoallergic reaction to dard E (trans)-configuration to the photo- elements of padimate O, its association PABA likely results in part from its photo- degradation product Z (cis)-configuration, with PABA and manufacturers’ emphasis activation or photodegradation (22). Fur- which has decreased UVB filtering effi- on claiming products to be “PABA-free” thermore, PABA cross-reacts with other ciency (35). Damiani et al. has studied the has resulted in its infrequent use. Padimate molecules such as azo dyes, aniline, pro- ability of octinoxate to induce in vitro lipid O can be found today in conjunction with caine, benzocaine, paraphenylenediamine peroxidation even in the presence of other other UV filters to aid in increasing the and sulfonamides (17,23,24,25). An addi- molecules thought to photostabilize octi- product’s SPF (10). tional historical concern links PABA to noxate, further supporting the photo-unsta- possible carcinogenicity. Multiple in vitro Cinnamates ble properties of octinoxate (36). Despite being considered photounstable, the photoi- studies have demonstrated enhanced cyto- Cinnamates represent the most com- somerization reaction seen with cinnamates toxicity to PABA following UV radiation monly used UV filter globally (22), with is well characterized and highly predictable exposure. Under specific artificial con- nine cinnamate derivatives approved world- (22). Although degradation after brief UV ditions, PABA and its derivatives have wide (18). Only two cinnamate UVB filters exposure decreases product efficacy, factors been shown to interact with DNA and are available in the United States: octinoxate such as base formulation, use of preserva- cause genotoxic damage in the presence (2-ethylhexyl-p-methoxycinnamate, for- tives and nanoencapsulation can serve to of UV (20). Osgood et al. studied mouse merly octyl methoxycinnamate), and improve photostability (5,34,37). lymphoma cells sensitized to PABA. The the rarely used cinoxate (2-ethoxyethyl- results showed that these cells demonstrated p-methoxycinnamate or dietholamine New product formulations of cin- increased inactivation by near-UV radiation methoxycinnamate). Cinnamates absorb namates that aim to decrease allergic or when in the presence of PABA (26). In in UV in the 290-345nm range with peak irritant reactions, decrease percutaneous vitro studies demonstrating sensitization absorption at 300-320nm (17). This class of absorption and increase photostability, lead- by PABA, increased dimer formation and organic sunscreens is the next-most-potent ing to improved efficacy by micro-encap- photomutations led to the hypothesis that UVB absorber after PABA and PABA deriv- sulation, are becoming available. The first PABA enhances UV-induced skin tumor atives (29). Since octinoxate is a less-potent product to use this technique, Eusolex® UV- formation (20). Nonetheless, in vivo studies absorber than padimate O, it requires for- pearls, contains roughly 37% octinoxate with hairless mice contradicted the out- mulation with additional UVB filters to (38). Micro-encapsulation involves entrap- come of prior in vitro experiments (22), achieve a desirable SPF (21). The physical ment of the organic sunscreen ingredient convincingly demonstrating that this sun- form of this ingredient is a thin liquid, com- within a silica glass shell. These extremely screen product instead protects against UV monly used to impart UV protection in stable spheres have a diameter one-hun- radiation-induced tumorigenesis (20). Col- color cosmetics (10,22). Cinnamates have dredth the width of human hair and form lectively, these studies serve to eliminate a high water solubility, leading to potential a protective film on the skin. Because concerns over photocarcinogenecity among skin penetration and thus decreasing its sun the active UV filter is entirely contained 62S unscreen: Filtering Fact From Fiction within the spheres, there is no direct con- Octocrylene or photoallergy (10,22). Despite its cosmetic tact with skin, and the sunscreen ingredi- elegance, ensulizole has disadvantages due Octocrylene (2-ethylhexyl-2-cyano-3, ent remains in the outermost layers of the to its highly selective UVB-attenuating 3 diphenylacrylate) is an organic sunscreen skin. Thus, there is a significantly reduced properties, allowing near-complete UVA with a relatively broad UVB absorption risk for dermatitis and systemic absorption transmission, as opposed to most other UV spectrum, rendering it less effective at UV and improved sun-protective efficacy of the blockers, which have a broader absorption filtration (10). It has both UVB and short- encapsulated sunscreen ingredient (37,38). spectrum (17). Furthermore, studies have wave UVA coverage from 290-370nm, with This encapsulation technique can also be shown that a small amount of ensulizole peak absorbance at 300-320nm. It can be used to solve the problem of incompatibility does penetrate the skin to enter systemic used in combination with other UV absorb- between ingredients (such as avobenzone circulation (22). Nonetheless, the available ers to achieve higher SPF formulas (17). It and octinoxate) by physical segregation information regarding human safety of acts as a photostabilizer and can be com- (38). ensulizole is not nearly as extensive as that bined with other sunscreen ingredients to of other sunscreen products, and it remains S alicylates improve photostability profiles of photo- favorable on the market. Salicylates are a group of aromatic labile products such as avobenzone (21). compounds, with three agents commercially The number of products containing octo- available in the U.S. Octisalate (formerly crylene has thus logically increased over Organic UVA filters octyl salicylate) and homosalate, both water the years since the approval of avobenzone The UVA radiation spectrum ranges insoluble, are the two most commonly used (22). Octocrylene is easily incorporated into from 320-400nm, and is further subdi- salicylate sunscreens. Trolamine salicylate gel sunscreens and is popular in products vided into UVA I (340-400nm) and UVA is the only water soluble of the compounds, labeled as noncomedogenic (10). It has also II (320-340nm). The amount of UVA radia- frequently used in hair photoprotective been shown to have a favorable toxicity pro- tion remains nearly constant throughout agents (10). Salicylates are well tolerated, file, with studies showing no evidence of the day and year, with little temporal flux with rare reports of skin irritation or pho- maternal or developmental toxicity after (30). UVA rays are not filtered by standard tosensitization (22). They are often used in subchronic repeat exposure in mice (40). window glass, whereas UVB rays are fil- combination with other sunscreen products, Despite the various benefits of octo- tered out. Furthermore, UVA rays are rela- such as oxybenzone and avobenzone, to crylene, it is costly and difficult to manufac- tively unaffected by atmospheric conditions minimize photodegradation (21). Salicy- ture, resulting in limitations to widespread and changes in altitude, while UVB inten- lates absorb 290-335nm UV light, with peak use (10). Of additional concern is emerging sity decreases at lower altitudes as the light absorbance at 310-320nm (17). Because data of octocrylene as a photoallergen. It moving toward Earth is scattered, reflected, of their weak UVB absorption, salicylates had initially been considered a non-aller- or absorbed (13,82,83). The longer UVA must be used in higher concentrations than genic, non-irritant molecule(41). In 2003, wavelengths penetrate deeply into the der- most organic sunscreens and are often used the first cases of patch-test-confirmed pho- mis, affecting skin elasticity and produc- in combination with other UVB absorb- toallergy to octocrylene were reported (42). ing prolonged pigmentation, and they have ers. Nonetheless, they all have a favorable It was not until three years later that four been shown to inhibit enzymes necessary safety profile (17,21). The high lipophilicity more cases were reported, with expecta- for repairing the cells damaged by UVB rays of salicylates make them capable of accu- tions for further occurrences of photoal- (10,30). UVA causes immunosuppression by mulating in the lipid phase of the stratum lergy due to the progressively increased use decreasing Langerhans cells and increasing corneum while being unable to significantly of octocrylene in sunscreens and cosmet- the expression of the tumor suppressor gene permeate the hydrophilic epidermis below ics (41,43). Currently, octocrylene is well p53, thus promoting UVB carcinogenicity and therefore having little systemic penetra- described in the literature as a photoaller- and oxidative stress (4,10). These unique tion. Walters et al. studied the in vitro skin gen, with over 50 documented cases of con- characteristics of UVA radiation contribute permeation of octisalate from two differ- tact dermatitis and/or positive photopatch to its predominant role in photoaging and ent vehicles, an oil-in-water emulsion and tests. It has been reported to be a strong immunosuppression, as well as a secondary hydroalcoholic formulation. Results dem- allergen, leading to contact dermatitis in role in photocarcinogenesis. UVA radia- onstrated less than 1% of the applied dose children and in adults with a history of pho- tion also significantly contributes to most of octisalate penetrated the epidermis of the toallergy from ketoprofen (44). It is impor- drug-induced photosensitivity reactions, as skin in 24 hours, regardless of the vehicle tant for clinicians to be aware of this risk well as the exacerbation of photodermatoses (39). These results suggest that the human- and recommend avoidance of octocrylene- such as polymorphous light eruption, lupus skin penetration of salicylate sunscreens containing products in susceptible patients. erythematosus, solar urticaria and actinic is relatively low. Another mechanism for Ensulizole prurigo (4,30,45). the prevention of systemic absorption of the salicylates is their metabolism. Salicy- Ensulizole (2-phenylbenzimidazole- Prior to changes set to be implemented late sunscreens' breakdown in the stratum 5-sulfonic acid or PBSA) is a water-solu- by December 2012, the SPF indicated on corneum results in cleavage of the ester ble and aesthetically pleasing sunscreen. current product labeling is primarily rep- bond, forming salicylic acid and octyl or It absorbs UVB light in the range of 290- resentative of UVB protection, making it trimethylcyclohexyl moieties. Any poten- 335nm almost exclusively, with peak difficult for consumers and physicians to tial systemic toxic effects of the sunscreen absorption at 310-320nm. It became avail- compare the UVA protection afforded by would be limited to the almost negligible able on the U.S. market in 2003, comprising various sunscreens (46). Regardless of such amount of salicylic acid able to be absorbed less than 10% of all sunscreens (10). Ensu- labeling shortcomings, which are soon to and present within the body (21). Overall, lizole is used in products formulated to feel change, there are an increasing number salicylates represent a commonly used sun- lighter and less oily, such as daily cosmetic of organic UVA filters on the market that screen ingredient with several advantageous moisturizers (17). It is a photostable ingre- serve to broaden the absorption spectra attributes. dient with rare occurrence of skin irritation of commercially available products and

Borowicz, Khani, Miller 63 afford protection from damaging UVA benzone was shown to be the most common debate of whether environmental accumu- rays. The present FDA-approved organic UV-filter photoallergen among those tested. lation of oxybenzone leads to effects on UVA filters on the market are benzophe- In this study, a photoallergic reaction was reproduction, there have been several stud- nones, avobenzone, meradimate and ecam- diagnosed if irradiated patch-tested sites ies examining estrogenic activity of oxy- sule. With the 2011 FDA final ruling, these were positive, while non-irradiated sites benzone metabolites (47). Nakagawa and organic UVA filters will represent part of remained negative. An allergic contact der- Suzuki showed that hydroxylated interme- the active ingredients in sunscreens labeled matitis was diagnosed when both irradiated diates of oxybenzone act as a xenoestrogen “broad spectrum.” Drometrizole trisiloxane, and non-irradiated sites were positive. Fur- via biotransformation in human breast- bemotrizinol and bisoctrizole, all available thermore, Darvey et al. found that patients cancer cells (57). In a study performed by in other countries, are currently at various exhibiting an underlying photodermatoses, Coronado et al., it was indicated that oxy- stages of the FDA approval process (Table such as polymorphous light eruption or benzone alters endocrine or reproductive 2). chronic actinic damage, represent a popu- endpoints in two fish species. However, this lation at increased risk of photosensitivity conclusion was reached with concentrations Benzophenones to such products. The exact mechanism of the sunscreen ingredient significantly The benzophenones comprise a class behind this association is unclear; however, higher than those observed in typical waste- of aromatic ketones that provide broad- it is hypothesized that repeated applica- water (58). Ultimately, oxybenzone most spectrum UV coverage (10). Benzophe- tion of high concentrations of UV filters is likely poses no significant risk to fish repro- nones absorb wavelengths predominantly more likely in such individuals, leading to duction, presenting a limited contribution in the UVB and UVA II range from 270- an increased risk of sensitization (33). to estrogenic activity. Schlumpf et al. evalu- 350nm, with peaks at 288 and 350nm (47). In 2010, Chretien et al. reported a ated the estrogenic effect of oxybenzone The benzophenone class consists of oxy- novel strategy that aims to reduce some on uterine weight in rats exposed to the benzone (benzophenone-3), sulisobenzone of the adverse effects of oxybenzone via ingredient. Although the findings indicated (benzophenone-4) and dioxybenzone (ben- a synthetic preparation known as zeolite an increase in uterine weight of oxyben- zophenone-8), with oxybenzone being the encapsulation. Use of zeolites for sunscreen zone-exposed rats, the administered supra- most popular of the substituted derivatives encapsulation creates a supramolecular physiologic oral dosage that was required (22). Oxybenzone is presumably photolabile sunscreen product that retains the protec- to show a statistically significant outcome and rapidly oxidized upon irradiation (21). tive benefits intrinsic to UV filters while was exceedingly high (59). Considering the Schallreuter et al. demonstrated that oxida- eliminating the associated risk of derma- minuscule concentrations of oxybenzone tion of oxybenzone itself inactivates impor- titis. Supramolecular sunscreens maintain applied topically in sunscreen products, tant antioxidant enzymes on the living skin the scattering and absorbing properties of this study did not support the hypothesis surface. Upon photo-oxidation, oxybenzone a UV filter while concomitantly eliminat- that oxybenzone has significant estrogenic is converted to free-radical intermediates ing the interaction between multiple sun- activity. In studies done in 2004 and 2007, with the capacity to inhibit the antioxi- screen ingredients. This phenomenon is Janjua et al. demonstrated that oxyben- dant defense system of enzyme thioredoxin attributable to restricted diffusion of the zone was absorbed through the skin and reductase and substrate glutathione (48,49). zeolite-encapsulated particles. Chretien et excreted in urine; however, it did not accu- This process is hypothesized to disrupt the al. demonstrated with absorption spectros- mulate in plasma and therefore posed no homeostasis of the epidermis and poten- copy that zeolite-encapsulated oxybenzone risk to endocrine function (60,61). Reports tiate photodamage of the skin. However, provides in vitro SPFs that are similar to of potential endocrinologic and metabolic Rapp et al. contends that the methods used unencapsulated formulations. The research- effects of other sunscreen ingredients will to determine photostability of oxybenzone ers further showed that encapsulation sig- be reviewed further in this discussion. were inadequate (50). Thus, the extent of nificantly decreases the degradation of Researchers in India reported a project the potential reactive oxidation effect of oxybenzone in the presence of the inorganic whereby solid lipid nanoparticles (SLNs) oxybenzone remains inconclusive. sunscreen-agent titanium dioxide, which containing oxybenzone were formulated to Ultraviolet filters are frequently added normally occurs when the combination improve the effectiveness of the sunscreen to cosmetic products such as lipstick, mois- product is irradiated. Zeolite encapsulation (62). The product was intended to show turizer, foundation and concealer. Addi- can theoretically eliminate photoallergic slowed drug release and improved SPF. The tion of the organic sunscreens to cosmetics reactions by prevention of direct contact study showed this cream formulation to protects the skin from photoaging, as well between the skin and active organic sun- exhibit good skin retention and enhanced as increases the products’ longevity by screen ingredients (56). The concept of UV protection. Though the use of SLNs did preventing photodegradation (31). The supramolecular sunscreens that serve to not address hormonal alterations due to increase in consumer exposure to UV filters decrease photoallergic dermatitis as well oxybenzone, this innovative drug-delivery has led to numerous reports of photoal- as product degradation, while maintaining system may represent a solution to the issue lergy and allergic contact dermatitis (33). intrinsic UV protective properties, repre- of systemic toxicity of oxybenzone due to Oxybenzone is the most common sunscreen sents a promising strategy for future formu- the intrinsic benefit of displaying superior agent in widespread use to cause photoal- lations. skin retention. If such a formulation can lergic dermatitis (51). Several studies have Since oxybenzone has enhanced bio- maintain the product at the layer of the stra- reported cases of photopatch-test-proven availability following topical application tum corneum, oxybenzone theoretically will photallergic and contact dermatitis to ben- in comparison to other UV filters, it has not enter systemic circulation, thus reduc- zophenone sunscreen agents (52-55). In gained attention in recent years regarding ing the risk of suggested endocrine disrup- 2001, Darvay et al. conducted a retrospec- systemic effects and toxicity (22). One of tion (62). Although systemic absorption of tive analysis of 2,715 patients who under- the major controversies surrounding oxy- oxybenzone has gained significant attention went photopatch testing at their institution. benzone is its potential to disrupt the endo- from both animal and human studies, sig- The results showed an overall low yield of crine system. In an attempt to solve the positive photopatch tests. Nonetheless, oxy- 64S unscreen: Filtering Fact From Fiction

Borowicz, Khani, Miller 66 nificant alterations of endocrine function in product. Stabilization of avobenzone can Ecamsule (terephthalylidene dicam- humans have yet to be indisputably demon- be achieved by addition of diethylhexyl 2,6 phor sulphonic acid; Mexoryl SX) was strated. The lack of conclusive evidence of naphthalate (DEHN). DEHN is a non-UV introduced in the U.S. in 2006 after more a biologically substantial hormonal disrup- filter that accepts excess energy absorbed than 10 years of being available in other tion establishes the need for future studies by avobenzone, thus stabilizing it during regions of the world. In July of that year, in this area. UVA exposure. Combination of DEHN, ecamsule was approved as an active ingredi- avobenzone and oxybenzone is commer- ent in combination products rather than as Avobenzone cially known as Helioplex® (10). Tinosorb S an individual UV sunscreen drug (14). It Avobenzone (trade name Parsol 1789), (bemotrizinol) and enzacamene have both is marketed by LaRoche-Posay™ as Anthe- or butyl methoxydibenzoylmethane, rep- been shown to photostabilize avobenzone, lios SX® and is used in combination with resents a class of substituted diketones. although they are not yet approved in the avobenzone and octocrylene. Ecamsule is Avobenzone provides superior protection U.S. (14,46). Other agents that photosta- a photostable, broad-spectrum ultraviolet- throughout the UVA spectrum, with peak bilize avobenzone, as well as provide the light absorber (51). It is water resistant and coverage within the UVA I range (10). This added benefit of broadening the absorption has minimal systemic absorption owing to ingredient revolutionized UVA protection spectra, are the UVB filters homosalate, its inability to penetrate the stratum cor- and provided great benefit to consumers octisalate, and octocrylene. The UVA filter neum (10). This new agent has been shown by allowing manufacturers to broaden the oxybenzone and inorganic filters titanium to reduce photoaging characteristics such as spectrum of UV coverage in available sun- dioxide and zinc oxide can be incorporated pigmentation, epidermal hyperplasia, and screen products. Systemic bioavailability of into formulations to stabilize avobenzone as decreased skin hydration and elasticity (21). avobenzone is considered to be low, attrib- well (14). It has also been reported to prevent pyrimi- utable to the lipophilicity of the molecule. Avobenzone also has the potential to dine dimer formation, p53 protein accu- Extensive evaluation via toxicity studies has degrade other sunscreen ingredients when mulation and alterations in Langerhans cell shown avobenzone to have a favorable pro- used in combination products. It has spe- density (65). Ecamsule is additionally effec- file (22). It is an uncommon photoallergen; cifically been reported to strongly enhance tive in treating photodermatoses, owing however, Collaris et al. reported a case of a the degradation of octinoxate (63,64). Fol- to its superior UVA-absorption capacity delayed-type hypersensitivity reaction after lowing rapid photodegradation, avobenzone (10,45). use of sunscreen products containing avo- can react with octinoxate via formation of Drometrizole trisiloxane (Mexoryl XL) benzone (32). cycloaddition products. This product has is a photostabile organic sunscreen with Photodermatoses represent a group of the ability to destabilize the otherwise pho- mid-range UVA protection. The addition conditions characterized by a heightened tostable cinnamate molecule (63). Sayre et of Mexoryl XL to Mexoryl SX is shown to sensitivity and reaction to UV radiation, al. demonstrated that the resulting pho- have a synergistic effect on increasing UVA particularly the longer-wavelength ranges. tolysis products exhibit drastically dimin- protection and prevention of pigmentation The management of a photosensitive patient ished UV protection (64). An encapsulation induction (51). Drometrizole trisiloxane always includes use of sunscreen. Of the technique whereby organic sunscreen active was introduced in Canada in 2006 and is currently FDA-approved organic sun- ingredients are entrapped within a silica available around the world. However, this screens, avobenzone is the only active ingre- glass shell can be employed to address the active ingredient is not yet approved in the dient for which the absorption spectrum problem of product incompatibility. The U.S. (46). As of June 2010, drometrizole extends well into the UVA I range. Avoben- microsized silica spheres are extremely trisiloxane, in concentrations of up to 15 zone has thus been shown highly effective stable and form a protective film over the percent, became eligible to be considered in treatment of the photodermatoses such skin. Encapsulation of the organic sun- for potential inclusion in the OTC sun- as lupus syndromes, polymorphous light screen ingredient prevents direct contact screen drug monograph. It is being consid- eruption and actinic prurigo (45). of the molecule with skin, thus decreasing ered as both a single active ingredient and A major disadvantage of avobenzone is the risk for allergic contact dermatitis; this in combination with other sunscreen active its photoinstability. Gonzalez et al. demon- technique was first commercially available ingredients generally recognized as safe and strated that in three out of six combination in a sunscreen product containing octinox- effective (66). ate (38). In addition to diminished contact sunscreen products studied, avobenzone T inosorb S and Tinosorb M was degraded following UV irradiation dermatitis, physical segregation of avoben- (34). In formulations where avobenzone zone and octinoxate eliminates the chemical Tinosorb S (bemotrizinol; ani- is not photostable, UV radiation trans- interaction between these two UV filters. zotriazine; bis-ethylhexyloxyphenol forms the molecule into one that no longer This encapsulation technique stabilizes avo- methoxyphenol triazine) and Tinosorb M absorbs UVA wavelengths. Photoprotection benzone/octinoxate formulations by pre- (bisoctrizole; methylene-bis-benzotriazoyl therefore decreases with increased duration venting any chemical interaction and thus tetramethylbutylphenol) were submitted of sun exposure, and can occur rather rap- prevents product degradation (38). to the FDA in April 2005 by Ciba Specialty Chemicals Corporation (67,68). They are idly (46). The photoprotective capacity of M eradimate avobenzone is shown to decrease by 50-60% currently undergoing FDA approval via the after only 1 hour of UV exposure (21). In Meradimate (formerly known as Time and Extent Application (TEA) process such photounstable products, continuous methyl anthranilate) is a weak UVA filter for inclusion in the OTC sunscreen mono- reapplication becomes necessary in order to that absorbs primarily in the UVA II range graph (14). Both products have been avail- provide adequate sun protection. (21). It has been available for over 70 years able in Europe since 2000, with Tinosorb but is rarely used due to its inferior UVA- S currently sold in 31 countries worldwide Due to its photoinstability, avoben- absorption capacity compared to the benzo- (67), while Tinosorb M is available in 39 zone is frequently combined with other phenones and avobenzone (10). countries (68). Tinosorb S is a photostable, sunscreens or stabilizing agents in order to broad spectrum filter, absorbing UVB as Ecamsule reduce UV-induced degradation of the final well as UVA rays (14). It is an oil-soluble Borowicz, Khani, Miller 67 filter, intended for oil-phase sunscreen for- Considering the data stating that epi- mice. They sought to determine the physi- mulations as well as for use in photostabiliz- dermal penetration is required for ROS for- ologic impact of these chemicals on pitu- ing avobenzone and octinoxate. Tinosorb M mation (49), it is reasonable to assume that itary, thyroid and uterine function, as these is intended for use in aqueous formulations, a vehicle or product formulation that limits organs possess estrogen and estrogen-like as it consists of microfine organic particles penetration would also decrease systemic receptors. The results suggested that BP2 easily dispersed in the aqueous phase of a absorption and potential oxidative damage. exerts estrogenic effects similar to those of sunscreen emulsion (51). It is marketed as Thus, new strategies are being developed to estradiol on all three organs, but that BP3 the first of a new class of sunscreens that minimize penetration of UV filters. Encap- lacked any effect (72). These results appar- combines the benefits of both an organic sulation of octinoxate with poly-D,L-lactic ently contradict those of Schlumpf et al., and inorganic filter in that in can reflect, acid nanoparticles has shown that the prod- making the physiologic relevance of these scatter, and absorb UV radiation (65). The uct remains at the skin surface and within studies uncertain and yet-to-be established significant photostability profiles of both the stratum corneum at significantly higher (59,72). Tinosorb S and Tinosorb M are due to a concentrations than nonencapsulated octi- Seidlova-Wuttke et al. tested the estro- unique molecular structure that facilitates noxate. Nanoparticles coat the skin surface genicity of orally administered octinoxate the dissipation of energy by intramolecu- and are impeded by the stratum corneum, and 4-MBC by comparing it to the effects lar heat transfer and vibrational relaxation. representing an ideal technique for reducing of chronic estradiol treatment in ovari- Consequently, there are no reactive inter- transdermal penetration of UV filters and ectomized female mice. The data showed mediate species or photolytic decomposi- increasing the efficacy of photoprotection that octinoxate slightly stimulated uter- tion products generated in the skin (21). (37). ine weight only at the higher dose, while Considering these unique qualities, both S ystemic Endocrinologic and Meta- 4-MBC did so equally at both doses tested. Tinosorb M and Tinosorb S possess great bolic Effects Histologic examination of both uterine and potential in the future of sunscreen ingre- vaginal tissue, as well as quantitative com- dients. In 2001, Schlumpf et al. studied in puter tomography of the tibial metaphysis, vitro and in vivo estrogenic effects of six revealed a very weak estrogenic effect of organic sunscreens: padimate O, octinox- octinoxate and 4-MBC in the uterus and Other controversies of ate, homosalate, oxybenzone, avobenzone, vagina, and no estrogenicity in bone (73). organic sunscreen agents and the non-US FDA approved 3-(4-meth- Considering systemic absorption of topi- ylbenzylidene) camphor (4-MBC). In vitro cally applied sunscreen ingredients has been Phototoxicity, Skin Absorption and estrogenicity was evaluated by exposure Encapsulation shown to be negligible, and this study was of the UV filters to MCF-7 breast-cancer done with high doses of orally-administered Hayden et al. studied the penetration cells, and five out of the six ingredients dis- octinoxate and 4-MBC, it is unlikely that and retention of five organic sunscreen played dose-dependent estrogenic activ- these results would support or prove any agents (padimate O, octinoxate, octo- ity. Oxybenzone demonstrated the most risk of metabolic effects from topical sun- crylene, avobenzone and oxybenzone) in active cell proliferation, while avobenzone screen exposure (60,61,73). human skin. Results showed that after 24 remained inactive. However, the authors Because in vivo estradiol has other hours, detectable amounts were present in state that it cannot be determined whether metabolic effects besides reproductive, the the stratum corneum and viable epider- the observed estrogenic effects are attribut- same team of investigators additionally mis. Cell culture studies further showed able to the actual sunscreen ingredients or studied octinoxate and 4-MBC on fat and these levels to be too low to cause toxicity instead to possible metabolites. Further- lipid homeostasis along with thyroid hor- in keratinocytes after topical application to more, the data did not entirely correlate mone production. Results showed effects intact skin, with octinoxate demonstrating with in vivo studies, in which only three that differed from those of estradiol in the the least cytotoxic effect in vitro (69). Taken out of the six UV filters displayed estroge- measures of weight gain, size of fat depos- into consideration with additional studies nicity. These three sunscreens, octinoxate, its, serum leptin, lipid profiles, LH, T4 and of epidermal penetration of UV filters, con- oxybenzone, and 4-MBC, were found to TSH levels. Thus, researchers concluded cern was fueled regarding photodegradation elicit dose-dependent increases in uterine that octinoxate and 4-MBC may affect the leading to incomplete photoprotection as weight among immature hairless rats (59). endocrine system in ways differing from well as the possibility of photogeneration Investigation of the same three sunscreen that of in vivo estrogen, and further studies of reactive oxygen species (ROS) among ingredients was later undertaken by Jan- are warranted (74). sunscreen molecules (35,49,69,70). Direct jua et al., who examined the plasma and imaging of various epidermal depths by flu- urine of 32 subjects after topical applica- Coronado et al. sought to evaluate oxy- orescence microscopy allowed for the study tion of each formulation. The aim of the benzone’s impact on the estrogenic effects of ROS levels after application of octinoxate, studies was to investigate systemic uptake and reproduction of juvenile rainbow trout octocrylene and oxybenzone. Results of the and effects on endogenous reproductive after several studies came out concerning data showed that if the aforementioned UV hormones. The researchers concluded that the levels of oxybenzone in wastewater out- filters are able to penetrate the stratum cor- despite systemic presence of the three sun- falls along the New York and California neum, they can in fact generate ROS within screens, there was no apparent influence on coasts. The theory was that benzophenones keratinocytes of the epidermis (49). Dami- the levels of endogenous hormones in men potentially affect estrogen receptors, either ani et al. have done several studies in sup- and women (60,61). by impacting gene expression or by acting port of avobenzone’s ability to inflict DNA Oxybenzone was further studied by as a direct ligand (58,72). This interaction strand breaks and cause oxidative modifica- Schlecht et al. in 2004. Their study com- could lead to developmental and reproduc- tion of in vitro proteins (71). The mecha- pared the effects of estradiol to benzophe- tive effects in fish and other aquatic organ- nism of oxygen free-radical formation and none-2 (BP2) and benzophenone-3 (BP3) isms living in waters affected by wastewater the extent of damage caused by ROS war- on estrogen and estrogen-like receptors in outfall. Results showed that oxybenzone did rants further exploration. induce vitellogenin, a plasma marker of 68S unscreen: Filtering Fact From Fiction estrogenic activity, but the measured con- tial risks will continue to concern patients, sunscreen/insect repellent products. J Am Acad Dermatol. 2008 Aug;59(2):316-23. centration of oxybenzone in wastewater is physicians, researchers and the FDA. The 15. Food & Drug Administration, Health and Human much lower than the concentrations neces- vast majority of current sunscreen ingredi- Services. Sunscreen drug products for over-the-counter human use; proposed amendment of final monograph sary to affect estrogenic activity or repro- ent controversies have not been proven, proposed rule. Fed Regist 2007 Aug 27;72(165):49070- duction. The researchers concluded that and further research is necessary to deter- 122. oxybenzone most likely is not a significant mine specific risks. In spite of concern over 16. Food & Drug Administration, Health and Human Services. Sunscreen drug products for over-the-counter risk to fish and other aquatic wildlife (58). safety and efficacy, the American Academy human use; proposed amendment of final monograph; of Dermatology (AAD) and most physi- extension of comment period. Fed Regist 2007 Nov While several experimental models 28;72(228):67264-5. cians support the use of “broad-spectrum have evaluated systemic absorption and 17. Levy SB. Chapter 38: Sunscreens. In: Wolverton SE ed. hormonal effects, the precise estrogenic and sunscreen with SPF 30 or higher” as defined Comprehensive Dermatologic Drug Therapy, 2nd Ed. Philadelphia, PA: Elsevier Incorporated, 2007: 703-718. other metabolic activity of these various UV in the AAD position statement (76). The 2011 FDA final rule on labeling and testing 18. Roelandts R. Shedding light on sunscreens. Clin Exp absorbers is still controversial and unclear Dermatol. 1998 Jul;23(4):147-57. of sunscreen marks a major advancement in (14). Future studies on the possible endo- 19. Wu, Corinna. Melanoma Madness The scientific flap crine effects of organic sunscreens, particu- the regulation of OTC sunscreen products. over sunscreens and skin cancer -- Chemical studies. The inclusion of UVA protection in label- Science News Online. 1998 June 6. larly among human subjects and at actual 20. Gasparro, F. P.; Mitchnick, M.; Nash, J. F. A Review of concentrations in commercially available ing products as "broad spectrum" as well as Sunscreen Safety and Efficacy. Photochem Photobiol. 1998 Sep;68(3):243-56. products, are warranted. modifications in product claims and state- ments represents a large step in the right 21. Kullavanijaya P, Lim HW. Photoprotection. J Am Acad Dermatol. 2005 Jun;52(6):937-58; quiz 959-62. direction toward improvement in consumer 22. Nash JF. Human safety and efficacy of ultraviolet Conclusion safety and increased protection from harm- filters and sunscreen products. Dermatol Clin. 2006 ful effects of UV irradiation. While there Jan;24(1):35-51. Safe sun practices involve a combina- remain pending issues to be addressed prior 23. Bergfeld W, Belsito D, Marks J Jr, Andersen F. Safety tion of sunscreen, sun-protective clothing of ingredients used in cosmetics. J Am Acad Dermatol. to a release of the final sunscreen mono- 2005;52:125-32. and sun-avoidance behaviors such as shade- graph, such comprehensive guidance set 24. Fisher AA. Esoteric contact dermatitis. Part 1: The seeking and abstaining from strong mid- to be enforced by December 2012 aids in paraben paradox. Cutis. 1996 Feb;57(2):65-6. day sun (75). When choosing a sunscreen, validation of the crucial protective role of 25. Lorenzetti OJ, Wernet TC. Topical parabens: benefits there are numerous options in brand, SPF, and risks. Dermatologica. 1977;154(4):244-50. sunscreen in halting both skin cancer and 26. Osgood PJ, Moss, SH, Davies, DJ. The sensitization of properties, and ingredients. Studies on the photoaging. near-ultraviolet radiation killing of mammalian cells by risks versus benefits of organic (chemical) the sunscreen agent para-aminobenzoic acid. J Invest Dermatol. 1982 Dec;79(6):354-7. sunscreen ingredients will continue to be References 27. Kaidbey KH, Klingman AM. Phototoxicity to a carried out, further fueling the debate, and 1. Gil EM, Kim TH. UV-induced immune suppression and sunscreen ingredient. Padimate A. Arch Dermatol. 1978 sunscreen. Photodermatol Photoimmunol Photomed. Apr;114(4):547-9. patients will turn to their physicians and 2000;16:101-10. 28. Knowland J, McKenzie EA, McHugh PJ, Cridland NA. skin-care specialists for advice on sunscreen 2. Guarrera M. 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Leah K. Shama, DO,* Vienna Lowenbraun, DO,** Kimball Silverton, DO, FAOCD***

*PGY-2 Family Medicine Resident, NSUCOM/Largo Medical Center, Largo, FL **2nd-year Dermatology Resident, Genesys Regional Medical Center, Grand Blanc, MI ***Program Director, Department of Dermatology, Genesys Regional Medical Center, Grand Blanc, MI

ABSTRACT Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, and potentially fatal adverse cutaneous reactions that must be recognized rapidly in order to minimize morbidity and mortality. Medications are implicated in the majority of cases and initial lesions can vary in morphology. The progression to bullae formation, erythroderma, and desquamation leave the patient acutely vulnerable. Mucosal involvement is reported in greater than 90% of patients and, in conjunction with suspicious skin lesions, should alert the clinician for risk of rapid progression to SJS/TEN. Mortality for SJS is estimated to be 1-5% and 25-35% for TEN. Management currently includes immediate withdrawal of the offending drug, and aggressive supportive care in a multidisciplinary approach, ideally in a burn unit. The case described is of a patient that developed SJS, and rapidly progressed to TEN. The goal of this paper is to emphasize the importance of early recognition, biopsy and empiric treatment. Case Report month later, approximately 10 days prior to cal exam, his blood pressure was 86/48, his hospitalization, was unremarkable. with a pulse of 79, respiratory rate of 23, A 44-year-old Caucasian male with an Review of systems was positive for and an oxygen saturation of 99% on BiPAP, extensive past medical history presented to lumbar back pain, occasional mild head- and his temperature had been down as low the emergency department with complaints aches, nausea, fatigue, and near syncope as 94.8 degrees F. He was noted to have of excessive bleeding from insulin injection that was made worse with standing. decreased breath sounds with crackles in sites, oozing from his legs, nausea, and near the left lower lobe of his lung, non-pitting syncope. His past medical history included His home medications included insu- edema of the upper extremities, and mild B-cell type acute lymphoblastic leukemia lin glargine, methocarbamol, allopuri- pitting edema of the lower extremities. (ALL), insulin dependent diabetes type II, nol, omeprazole, metoprolol, nifedipine, Exam of HEENT was normal, and no skin obesity, gout, benign prostatic hypertrophy, indomethacin, nortriptyline, lorazepam, manifestations were present at this time. migraine headaches, gastritis, hypertension, isometheptene/dichloralphenazone/acet- Laboratory value abnormalities other than obstructive sleep apnea, and hyperlipid- aminophen (midrib) as needed for head- mentioned previously were a lactate dehy- emia. He had no known drug allergies but aches, and butalbital/acetaminophen/ drogenase (LDH) elevated at 1689. He was did admit to an upset stomach with eryth- caffeine (Fioricet) as needed for headaches. given fluid resuscitation with normal saline, romycin ingestion. Family history included He also required the use of a BiPAP for and electrolytes were corrected. Allopuri- breast cancer, hypertension, and fibromy- sleep apnea. All home medications were nol was discontinued in light of his ARF. algia. His social history was negative for continued, and the patient was started on Blood cultures were obtained and empiric tobacco, alcohol, or illicit drug abuse. He hyper-CVAD, phase 2 chemotherapy for antibiotics were started, including cipro- was married with three children. treatment of his B-cell type ALL. floxacin, ceftazidime and vancomycin. On Magnetic resonance imaging (MRI) On physical exam, this 5ft, 10in male day seven, posaconazole oral suspension of the brain performed in the emer- weighed 295lbs with a BMI of 42. His heart was added for prophylactic prevention of gency department was negative for acute was regular and rhythmic at 100 beats per invasive fungal infection, and filgrastim abnormality. When compared to a study minute, and he had petechiae on the lower was added to his daily medications for his approximately two months prior showing extremities, as well as several ecchymotic pancytopenia. On day eight, the patient chemotherapy-induced CNS arachnoiditis, lesions at abdominal injection sites. His became diffusely erythrodermic, and van- there was no change. He was admitted for baseline labs showed thrombocytopenia at comycin was discontinued by primary care ALL with acute anemia, acute renal failure, 10,000/mL, and electrocardiogram (ECG) secondary to the possibility of red man syn- and thrombocytopenia. All other labora- demonstrated normal sinus rhythm at 87 drome. The patient developed atrial fibril- tory data were within normal limits. Hema- beats per minute. lation with rapid ventricular rate at 121-211 tology-oncology was consulted, and a blood During the first four days of the beats per minute with prolonged QT inter- transfusion was administered. patient's hospital stay, he was given a blood vals. The patient was transferred to the intensive care unit and diltiazem titration Of note, the patient was treated transfusion, chemotherapy (hyper-CVAD was initiated. Total parenteral nutrition approximately four months prior with phase 2) was initiated, and supportive care was started on the tenth day of admission cyclophosphamide, vincristine, doxorubi- was provided. On the fifth day of admission, as the patient had intractable nausea, vom- cin, dexamethasone, cytarabine, and metho- the patient was evaluated by nephrology iting, mucositis and odynophagia. On trexate (induction hyper-CVAD) for B-cell for hyponatremia and an elevated creat- physical examination, his temperature was type ALL. He was also on imatinib for a inine, and by pulmonology/critical care. found to be 101.7 degrees F, blood pressure short time, but it had to be discontinued The patient had become hypotensive, had 172/84, heart rate 147 beats/min, respira- secondary to protracted nausea and vomit- developed acute renal failure (ARF) with tory rate 22 and pulse ox 98% on 50% Ven- ing. He achieved remission approximately an anion gapped metabolic acidosis, and timask. Electrocardiogram again showed 40 days prior to this hospitalization, and electrolyte abnormalities, including hypo- atrial fibrillation with a variable ventricu- chemotherapy was discontinued. Patient calcemia and hypophosphatemia. The lar rate range of 129-185 beats/min. His deferred any further treatment at that time. patient remained pancytopenic. Review of HEENT exam was notable for congested Follow-up with hematology/oncology one systems was positive for nausea. On physi- conjunctivae and dry oral mucosa. Skin Shama, Lowenbraun, Silverton 71 exam was again notable for eryth- Figure 1: Abdominal bullae Perirectal skin had erythema without roderma, as well as petechiae on the denudement. Bilateral conjunctivae lower extremities present since admis- were erythematous, and yellow crust sion and a single bulla on the abdomen. was adherent to the periorbital skin An unspecified intertriginous rash was (Figure 3). His ears were erythematous also noted. Blood cultures were still with yellow exudate emerging from the pending, and stool culture and stool auditory canals. There were bullae on for Clostridium difficile were negative. bilateral upper extremities, but there Laboratory values showed pancytope- were no bullae on the palms, soles, or nia, blood urea nitrogen of 34, blood dorsal feet at that time. However, pete- glucose of 300, and serum bicarbonate chiae were present on the dorsal aspect of 17. SCORTEN was 6 (calculated ret- of the patient’s feet. Approximate total rospectively from hospital records). He body surface area (TBSA) with bul- was diagnosed with neutropenic fever lae was 15%. Diagnosis of SJS/TEN and systemic inflammatory response overlap was made, and STAT ophthal- syndrome (SIRS), with possible sepsis mology and wound care consults were (blood cultures pending). It was felt Figure 2: Erosions and crusting of the oral mucosa ordered. Initial dermatology recom- that the skin findings of erythroderma and labia mendation was for the patient to be and the single abdominal bulla were transferred to a burn unit once stable. more likely the result of an allergy to Two perilesional 3mm punch biopsies, vancomycin rather than red man syn- one for hematoxylin and eosin (H&E) drome. It was noted that they doubted staining and the other for direct immu- Stevens-Johnson syndrome. Linezolid nofluorescence (DIF), were obtained was added along with intravenous from the patient’s abdomen. His oral metoprolol 5mg every 6 hours, as well cavity was cultured for aerobic, anaero- IV metronidazole, lorazepam, pan- bic, and fungal organisms. A regimen toprazole, diphenhydramine, hydro- of kanamycin topical, mupirocin, and morphone, methylprednisolone, and mineral oil were applied to the body ondansetron. Miconazole powder was twice daily. SCORTEN was calculated prescribed to be applied three times to be 7. Ophthalmology evaluated the daily, presumably for the unspecified patient and agreed he had early ocular intertriginous rash noted the previous involvement secondary to SJS. Con- day. junctiva had +1 chemosis, subconjunc- tival hemorrhage, and +1-2 injection. Dermatology was consulted to Figure 3: Erythematous conjunctiva rule out SJS on the eleventh day of An inferior corneal staining defect was admission. Physical exam revealed present on second exposure. He was diffuse erythroderma of the patient’s started on AKWA ophthalmic oint- face, abdomen and extremities and ment (petroleum jelly, mineral oil, and the majority of his back. Petechiae lanolin), ¼” applied to each eye every were present on the upper extremi- 2 hours for aggressive lubrication, and ties. Approximately 10% of his back ciprofloxacin ophthalmic 0.3% solu- had flaccid bullae, and there were areas tion, one drop to each lid margin of denudation. Multiple tense bullae twice daily for antimicrobial coverage. on erythematous bases, along with When reevaluated by dermatology later ruptured bullae, were located in his that morning, bullae were present on intergluteal fold, axilla, antecubital fos- approximately half of the patient's back sae, abdomen (Figure 1), groin, and (Figure 4). The rectum was boggy with thigh. The oral mucous membranes yellow crusts and erythema. The scalp had black, eroded crusts (Figure 2). also had crusting and denuded areas.

Figure 4: Back and flank with epidermal Figure 5: Left upper extremity with epider- Figure 6: Massive desquamation of the back detachment mal detachment

72 The Importance of Rapid Recognition and Management of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis In Adult Patients There were also large areas of epidermal ity of cases. Several theories describing has been associated with larger percentage sloughing on bilateral upper extremities molecular and immunological mechanisms of total body surface area (TBSA) of epider- with palm involvement (Figure 5). TBSA of this apoptotic process exist, but despite mal detachment.1 A study from Germany epidermal detachment was estimated to considerable research to identify the pre- found individuals of more advanced age be 40% (Figure 6). His conjunctiva now cise pathophysiologic mechanism(s) of SJS/ (average 63 years) and women to be more showed swelling and injection in addition to TEN, this has yet to be fully elucidated.1,4 at risk for TEN.18 A small retrospective previously noted erythema. A severity-of-illness score, or score-TEN study also found women to be more com- The patient subsequently became unre- (SCORTEN), based on seven independent monly affected by TEN, but average mean sponsive and required cardiopulmonary prognostic factors of death is used to pre- age for development of TEN was younger 5 19 resuscitation and intubation. At that time, dict clinical outcome. Immediate with- (22.3 years). Mortality rates vary, but it was obvious that there was sloughing of drawal of the offending drug(s), providing an estimated average mortality for TEN the esophagus and oral cavity evidenced supportive care, ideally in a burn unit, and is 25-35%, and for SJS is estimated to be 6,7,18 by the exsanguination during intubation. use of a multidisciplinary approach are the 1-5%. Complications and factors lend- 6-8 Transfer to a burn unit would require a mainstays of management. Additional ing to high mortality include sepsis, massive greater than one-hour ambulance ride to treatment of SJS/TEN has largely been anec- transdermal fluid loss, electrolyte imbal- the facility. Due to a constant need for dial- dotal based on case reports in the literature, ances, impaired temperature regulation, and ysis for renal failure treatment and unstable clinicians’ prior treatment experience, and interstitial pneumonitis, which may prog- 7 atrial fibrillation, transfer to a burn unit was current understanding of disease mecha- ress to adult respiratory distress syndrome. not possible at that time. nisms. Experimental treatments showing Medication use strongly correlates with variable success are being explored. Some On the 13th day of admission, the the development of SJS/TEN, and over 200 of these experimental therapies may aug- drugs have been identified.6 Medications patient was deemed stable enough for trans- ment supportive care, and a few are aimed fer to a burn unit in critical condition. Burn are implicated in 72.6% of cases of SJS, an at thwarting the proposed disease mecha- infectious etiology in 10.4% and unknown unit hospital records for days 13 and 14 nisms.9-12 state that the patient required multiple vaso- cause in 17%, according to a review of the pressors to maintain perfusion and that he Stevens-Johnson syndrome (SJS) was literature from 1975 to 2003. This same was started on continuous hemodialysis. originally described in 1922 as a pediat- review established drugs as the causative He remained severely acidotic and poorly ric mucocutaneous affliction thought to agents in 76.2% of TEN cases, whereas 1 perfused, despite aggressive volume resusci- be of infectious etiology. SJS later became infection and etiology unknown accounted 1 tation. He continued to deteriorate, and the known as erythema multiforme major for 3.2% and 20.6% of cases, respectively. family and physicians agreed to withdraw (EMM), and the terms were used synony- Medications observed to have high relative care. The patient expired on day 14. mously from approximately 1983 until more risk based on data from the SCAR study recently.1 Bastuji et al. presented a pro- and more recent EuroSCAR study include: spective case-control study on causative sulfonamide antibiotics (especially trime- Histopathology factors for severe bullous erythema multi- thoprim/sulfamethoxazole), anticonvulsants forme (EM), SJS, and TEN, and developed (carbamazepine, phenobarbital, phenytoin, The two perilesional 3mm punch criteria to classify the diseases into five cat- lamotrigine), non-steroidal anti-inflamma- biopsies of the abdomen were evaluated egories. The authors suggested that SJS tory drugs (NSAIDS) of the oxicam class, by pathology. They showed full-thickness should be distinguished from EM, but that allopurinol, and nevirapine.21 Antibiotics epidermal necrolysis with subepidermal further investigation was necessary.2 Lyell are the most commonly blamed medica- clefting consistent with toxic epidermal published a paper in 1956 describing four tions in the development of both SJS and necrolysis. DIF was negative for any immu- patient cases characterized by eruptions TEN.1 However, in Europe and Israel, allo- noglobulin or other protein deposition. resembling scalding of the skin and pro- purinol was found to be the most common posing the term toxic epidermal necroly- cause of SJS/TEN. This risk was higher for sis.14 But it wasn’t until more cases were dosages of at least 200 mg daily. Higher Discussion described with similar clinical character- risk was also associated with the start of Steven-Johnsons syndrome (SJS) and istics to those cases presented by Lyell that allopurinol in the two months preceding toxic epidermal necrolysis (TEN) are rare medications were identified as the primary development of SJS/TEN.22 The co-morbid and potentially fatal adverse cutaneous etiologic agents.1,15 It is now well accepted conditions for which our patient was taking reactions that must be recognized rapidly that SJS and TEN are separate entities and an offending medication were diabetes mel- in order to minimize morbidity and mor- should be distinguished from EM based on litus, gout, migraine headaches, chemother- tality.1 SJS and TEN are currently believed different clinical characteristics and etiol- apy-related nausea and vomiting and ALL. to be diseases in a continuum, based on ogy, as SJS and TEN are largely associated The patient’s medications were analyzed for total body surface area (TBSA) of epider- with medication use and EM is more com- incidence of SJS/TEN (see Table I20). The mal detachment.1-3 Clinical symptoms may monly post-infections.1,16 importance of rapid recognition of SJS and include a prodromal fever and skin pain, The incidence of SJS and TEN are esti- TEN and identification of possible causes is with primary lesions varying in appear- mated to be 1.1 to 7.1 and 0.4 to 1.3 cases clear based on the high morbidity and mor- 14 ance. Distribution of epidermal detach- per million, per year, respectively.1 The tality mentioned previously (1-5% of SJS 4,14 8,10,14 ment may be diffuse or localized in addition incidence can regionally vary, based on and 25-35% of TEN cases). Typically, to mucosal and possibly systemic involve- genetics, comorbidities such as immuno- SJS and TEN begin four to 28 days after the ment. Keratinocyte apoptosis leading to compromised states (malignancy and HIV), start of the offending medication, or within epidermal exfoliation is the hallmark of SJS and regional differences in medication pre- the first 2 months for aromatic anticonvu- 21 and TEN, and idiosyncratic reactions to scription.3,17 SJS and TEN can occur in lants, and SJS/TEN occurs more rapidly medications are implicated in the major- patients of any age, and higher average age on re-challenge of offending medication.

Shama, Lowenbraun, Silverto n 73 3

74 The Importance of Rapid Recognition and Management of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis In Adult Patients It is recommended that all medications be 10% TBSA epidermal detachment, TEN HLA-B*1502 and carbamazepine in this considered suspect regardless of duration of with greater than 30% TBSA detachment, same population; however, it should be therapy.7 and SJS-TEN overlap with 10%-30% TBSA noted that this allele is not an independent In this case report, the medication affected (see Table II). When measuring population marker for SJS/TEN in patients causing SJS/TEN in our patient was not TBSA, both detached and detachable epi- exposed to carbamazepine, as it has since 1-3,7 clear. Of note, our patient had a past medi- dermis should be included. been associated with exposure to phenytoin 3 cal history of gout, for which allopurinol Despite considerable research to iden- and lamotrigine. Other HLA alleles shown was used as treatment. This medication tify the precise pathophysiologic mecha- to be associated with increased suscepti- was being taken prior to hospital admission nism of keratinocyte apoptosis leading to bility for the development of SJS/TEN are 23 for several years. As mentioned previously, necrosis in SJS/TEN, it has yet to be fully HLA-B12 and HLA-DQB1*0601. the cause of SJS and TEN may not be iden- elucidated. It is currently proposed to be Clinically, a prodrome that may tifiable in a significant number of patients.1 an immune-mediated mechanism since, as include a fever with malaise, cough, sting- Individuals may be on several medications mentioned previously, re-challenging an ing eyes, and headache precedes the when they develop cutaneous signs worri- individual with a drug can lead to rapid onset of cutaneous lesions by a few days some for the development of a drug reac- recurrence of SJS/TEN.3 Several theo- to two weeks.6,2 Tender cutaneous lesions, tion, and they may be on more than one ries describing the molecular mechanism described as irregularly shaped, dusky-red medication associated with the develop- of apoptosis in SJS/TEN exist, including or purpuric macules, generally first appear ment of SJS/TEN. Although medications the involvement of the death receptor Fas on the trunk, and then spread symmetri- are the most frequent agents to cause SJS/ and its ligand, FasL, tumor necrosis factor cally to the neck, face, and upper extremi- TEN, it is important to keep in mind other (TNF)- α, cytotoxic T lymphocytes (CTLs), ties. The palms and soles are sometimes an

5

less commonly associated causes. Infec- perforin, and granulysin.1,3,17,32 Cell death early site of involvement.3 Distal upper and tion, vaccination, systemic disease, physical via apoptosis is an organized process pos- lower extremities are infrequently affected, agents, and foods are associated with the sible through several mechanisms including and the scalp is typically spared.1 Progres- development of SJS. In addition to medica- ligation of cell surface death receptors such sion to a vesiculobullous eruption with vari- tions, food additives, fumigants and contact as tumor necrosis factor (TNF)- α, Fas, or able levels of lesion confluence follows, and with chemicals have also been reported to through receptor-independent mechanisms, full-thickness epidermal necrosis, as a result cause TEN.1,7 primarily though the release of perforin and of keratinocyte apoptosis, can occur rapidly. SJS and TEN are considered to rep- granzyme B from cytotoxic T cells. The The bullae are typically flaccid and are the resent two ends of a clinical spectrum of most well accepted theories point to the result of fluid filling the spaces where the cutaneous disease, differing in severity. Fas-FasL interaction or to cytotoxic T cells epidermis has detached. When involved 4 Histological findings are indistinguishable as the mediators of apoptosis in SJS/TEN. epidermis is subject to any slight trauma, between SJS/TEN, and the causative drugs Genetic susceptibility has been shown it tends to tear and has been described as 23 are similar. They are differentiated based to play a role in the development of SJS/ resembling “wet cigarette paper.” Clini- on extent of TBSA (total body surface area) TEN. HLA-B*5801 has been shown to be cally appearing involved tissue where epi- of detached epithelium, appearance and dis- present in almost 100% of Han Chinese dermal detachment has not occurred can tribution of primary skin lesions, mucous patients who develop severe adverse drug be lightly stroked with a finger to induce membrane, and systemic involvement.3 The reactions as a result of allopurinol use.3,17 A epidermal separation, a positive Nikolsky accepted criteria defines SJS with less than strong association was also found between sign. It should be noted, however, that

Shama, Lowenbraun, Silverton 75 although used in the diagnosis of SJS/TEN, addition to these seven prognostic factors, and avoidance of debridement (commonly the Nikolsky sign is not specific.3 This acute neutropenia, lymphopenia, and throm- performed in burn units). Ophthalmol- epidermal sloughing phase of TEN lasts for bocytopenia in TEN are associated with ogy involvement is essential in the care of eight to 12 days. Systemically, mucositis poor outcome.7 Factors contributing to patients with SJS and TEN. A significant can occur on conjunctiva, respiratory tract, higher mortality in general for SJS/TEN are number of patients (60-85%6,7,24) have ocu- gastrointestinal tract, and vaginal and peri- patient age, number of medications, neu- lar involvement, with chronic problems neal mucosae.1 Mucous membrane involve- tropenia, lymphopenia, thrombocytopenia, remaining in 35%, a prevalence of ocular ment is present in 90-100% of cases,1,3 and and extent of exfoliation.6,7 As described morbidity that has remained unchanged for ocular complications, usually involving the in the present case, our patient was not the past 35 years.1,24 Additionally, according cornea, conjunctiva, and eyelids, has been only on multiple medications but also had to a recent retrospective observational case reported in 60-84% of cases.6,24 This muco- B-cell type ALL and remained pancytopenic series by Morales et al., SCORTEN is not sal involvement helps to distinguish SJS/ throughout his hospitalization. useful to predict ophthalmic complications, TEN from TSS, SSSS, and some immuno- The differential diagnoses for SJS/ further necessitating ophthalmology partic- 24 bullous disorders. Visceral involvement TEN include: staphylococcal scalded skin ipation in the care of these patients. Topi- may be overlooked, which contributes to syndrome (SSSS), drug hypersensitivity/ cal antibiotics and corticosteroids, along 7 high morbidity and mortality in SJS/TEN. DRESS syndrome, linear IgA bullous dis- with frequent lubrication are commonly The frequency of visceral involvement (gas- ease, toxic shock syndrome (TSS), and ery- provided. Amniotic membrane trans- trointestinal mucosa, tracheal or bronchial thema multiforme (EM).3,26 SSSS affects plantation has been successfully used for 6 erosions, glomerulonephritis, and hepati- children more commonly than adults, has treatment of severe corneal involvement. 1 tis) is from 8.1% to 61.5%. Depending on no mucosal involvement, and histologically Therapy used in the treatment of SJS/TEN how widespread the epidermal necrosis, the detachment is in the stratum granulo- is largely anecdotal based on case reports re-epithelialization may begin within one to sum; in SJS/TEN, mucositis is prominent, describing successful modalities and on our three weeks, but could take as long as three and histologically, epidermal separation is current understanding of molecular mecha- to six months to fully heal. The skin gener- at the basement membrane.6,9 Erythema- nisms to date. Corticosteroid treatment of ally heals without scarring when no infec- tous drug eruptions usually lack mucosal SJS/TEN is not universally accepted. Some tion is present, but pigmentary changes are involvement and the skin pain common in authors state that steroids do not alter the 1,7 reported in 88% of patients. SJS/TEN. Linear IgA bullous disease less course of disease and actually increase risks Diagnosis relies not only on the ini- frequently presents with mucous membrane for complications such as prolonged wound tial high index of suspicion, progressive involvement, and it can be further excluded healing and increased risk of infection, and skin lesions, TBSA, and presence of two or on immunofluorescent study. TSS presents place patients at risk for gastrointestinal 7,9 more regions of mucosal involvement as with more prominent involvement of mul- bleeding. However, others believe that described previously, but also on histologi- tiple organ systems and is caused by toxin- short-term high-dose steroids, such as pred- cal features. Two to three 4mm skin punch releasing strains of group A streptococci nisone at 2mg/kg/day for a short course of biopsy specimens should be taken. One and Staphylococcus aureus.28 EM and SJS 7-10 days, very early on in the disease may biopsy is sent for immediate frozen section have primary lesions that appear similar, improve survival, and there have been a few for emergent diagnosis, if available; another although rarely, and EM primary lesions are cases of TEN treated with dexamethasone 10,11 for formalin-fixed hematoxylin and eosin described as “targetoid.” Although red man pulse therapy early. Our patient was staining; and a third biopsy for immuno- syndrome is associated with erythroderma, treated with dexamethasone as part of his fluorescent studies to exclude immunobul- it usually presents on the back of neck, hyper-CVAD induction chemotherapy for lous diseases. Histologically, in early lesions occasionally spreading to upper trunk, face treatment of his ALL. (prior to dermal-epidermal separation) of and arms. It is not a diffuse erythroderma Although the use of intravenous SJS and TEN, there are scattered apoptotic and does not continue to form bullae.23 immunoglobulin (IVIG) and cyclospo- keratinocytes in basal and suprabasal layers Immediate withdrawal of the offending rine for SJS and TEN have not been fully of the epidermis, which can be a warning drug (when implicated), aggressive support- researched, reports of their benefits in gen- sign that epidermal necrolysis and detach- ive care, ideally in an intensive care or burn eral suggest they should be considered. ment are impending. Later lesions (after unit, and a multidisciplinary approach are Serum Fas ligand (FasL), a transmembrane epidermal detachment) show full-thickness the mainstays of management. Acute man- protein responsible for apoptosis, has been epidermal detachment with splitting above agement of SJS/TEN should also include found to be increased in patients with SJS/ the basement membrane, minimal inflam- determination of the severity and prognosis TEN. Human pooled IVIG contains anti- matory infiltrate, and normal immunofluo- of the disease (Table III) so that further Fas antibodies, and therefore the basis for 3,6 rescence. management can be directed.5 Interest- IVIG therapy is blockade of Fas and the Bastuji et al. in 2000 developed a now ingly, it was found that rapid withdrawal of FasL interaction. Case reports show ben- widely used severity-of-illness score for the offending drug only affected outcome efits when using a total of 3 g/kg infused TEN (SCORTEN), based on seven indepen- when the drug had a short half-life (T1/2), slowly over several days, and increased sur- dent prognostic factors of death. It is useful and there was no difference when drugs vival is seen with higher doses (increased for predicting clinical outcomes, where a with long half-lives were removed early on survival with each 1g/kg per day) of 10,30 SCORTEN of 0-1 confers 3.2% mortality, or late in management.6 Supportive care IVIG. The side effects of IVIG include and a score of 5 or greater predicts 90% includes wound care, fluid and electro- anaphylaxis and acute renal failure; how- mortality (Table III). It is recommended lyte management, temperature regulation, ever, these risks can be avoided with slow 9 that SCORTEN be calculated within the nutritional support, ocular care, pain con- infusion. first 24 hours of admission, and then again trol, and monitoring for infection. Wound A small case series of four patients on day three.5,25 Our patient’s initial score care should be treated conservatively with with SJS/TEN demonstrated rapid clinical was 6. Calculation on day three was 7. In non-adhesive, loosely draped dressings improvement using cyclosporine A (CsA)

76 The Importance of Rapid Recognition and Management of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis In Adult Patients 5mg/kg daily.31 Interleukin (IL)-2 has been 2. Bastuji-Garin S, Rzany B, Stern R, et al. Clinical epidermal necrolysis. J Invest Dermatol. 2006;126:272. Classification of Cases of Toxic Epidermal Necrolysis, 26. Pereire FA, Mudgil AV, Rosmarin DM. Toxic epidermal demonstrated in blood samples of patients Stevens-Johnson Syndrome, and Erythema Multiforme. necrolysis. J Am Acad Dermatol. 2007 Feb;56(2):181- Arch Dermatol. 1993;129(1):92-92. with TEN and has been found to promote 200 3. Harr and French. Toxic epidermal necrolysis and 27. Dobson CM, King CM. Adult staphylococcal scalded inflammation through its receptor CD25 Stevens-Johnson syndrome. Orphanet J Rare Diseases skin syndrome: histological pitfalls and new diagnostic 2010; 5: 39. and the activation and proliferation of lym- perspectives. Br J Dermatol. 2003;148:1068. 4. Khalili B, Bahna SL. Pathogenesis and recent phocytes in skin lesions. CsA inhibits IL-2, 28. Chuang YY, Huang YC, Lin TY. Toxic shock syndrome in therapeutic trends in Steven-Johnson syndrome and children: epidemiology, pathogenesis, and management. therefore preventing its pro-inflammatory toxic epidermal necrolysis. Ann Allergy Asthma Immunol. Paediatr Drugs. 2005;7(1):11-25. action. CsA was demonstrated to shorten 2006;97:272-281. 29. Arca E, Kose O, Eerbil AH, et al. A 2-year-old girl with 5. Bastiju-Garin S, Fouchard N, Bertocchi M, et al. the duration of active disease and time to Stevens-Johnson syndrome/toxic epidermal necrolysis SCORTEN: a severity-of-illness score for toxic 9,31 treated with intravenous immunoglobulin. Ped Dermatol complete re-epithelialization. Treatment epidermal necrolysis. J Invest Dermatol. 2000: 115: 2005; 22:317-320. using plasmapheresis and cyclophospha- 149-153. 30. Ricotti C. Toxic epidermal necrolysis supportive care 6. Knowles S, Shear NH. Clinical risk management of saves lives. MD Consult News: AAD. 10 Feb. 2011. mide have more conflicting levels of effec- Stevens-Johnson syndrome/toxic epidermal necrolysis tiveness, and thalidomide was shown to spectrum. Dermatologic Therapy 2009; 22:441-51. 31. Reese D, Henning S, Rockers K, et al. Cyclosporine for SJS/TEN: A case Series and Review of the Literature. 9 7. Roujeau JC, Stern RS. Severe adverse cutaneous increase mortality in patients with TEN. Cutis 2011; 87:24-29. reactions to drugs. N Engl J Med. 1994;331:1272. 32. Chung WH, Hung SI, Yang IY, et al. Granulysin is a Although the mainstay of treatment 8. Dalli RL, Kumar R, Kennedy P, et al. Toxic epidermal key mediator for disseminated keratinocyte death necrolysis/Stevens-Johnson syndrome: Current trends for SJS/TEN at this time is early recognition in Stevens-Johnson syndrome and toxic epidermal in management. ANZ J Surg 2007; 77:671-76. and supportive treatment, it is difficult to necrolysis. Nature Medicine. 2008; 14:1311-13. 9. Teo L, Tay YK, Liu TT, Kwok C. Steven-Johnson 33. Ferrell BP Jr, McLeod HL. Carbamazepine, HLA-B1502 determine the most effective management syndrome and toxic epidermal necrolysis: efficacy of and risk of Stevens-Johnson syndrome and toxic intravenous immunoglobulin and a review of treatment of SJS/TEN for several reasons. As SJS/TEN options. Singapore Med J. 2009;50(1):29. epidermal necrolysis: US FDA recommendations. are likely immune-mediated processes, drug 10. Rijal A, Agrawal S. Outcome of Stevens Johnson re-challenge with a suspected medication is syndrome and toxic epidermal necrolysis treated with corticosteroids. Indian J Dermatol Venerol Leprol 2009; not an option. In addition, our knowledge 75:613-14. of treatment options to date is based on ret- 11. Kardaun SH, Jonkman MF. Dexamethasome Pulse rospective case studies, and these are gen- Therapy for Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis. Acta Dermao-Venereol 2007; erally limited by small sample size. Once 87:144-48. a therapy is found to be effective, a larger, 12. Study of a Potential New Treatment for Patients with Toxic Epidermal Necrolysis (TEN). http://clinicaltrials. randomized controlled clinical study will gov/ct2/show/NCT00372723. need to be conducted to confirm its effec- 13. Stevens AM, Johnson FC. A new eruptive fever tiveness.3,9 Survivors must be educated of associated with stomatitis and ophthalmia: a report of the importance of avoiding offending medi- two cases in children. Am J Dis Child.1922; 24:526. 14. Roujeau JC, Chosidow O, Saiag P, Guillaume JC. Toxic cations if found to be the cause of their SJS/ epidermal necrolysis (Lyell syndrome). J Am Acad TEN and should be counseled to advise Dermatol. 1990 Dec;23(6 Pt 1):1039-58. their medical caretakers of their history 15. Lyell A. Toxic epidermal necrolysis: an eruption resembling scalding of the skin. B J Dermatol. 1956, of SJS/TEN. The US FDA currently rec- 68:335-361 ommends screening Asian patients for the 16. Assier H, et al. Erythema multiforme with mucous membrane involvement and Stevens-Johnson syndrome HLA-B*1502 allele prior to the initiation of are clinically different disorders with distinct causes. carbamazepine due to the casual association Arch Dermatol. 1995 May;131(5):539-43 found between carbamazepine use and SJS/ 17. Zhang Y, Wang J, Zhao LM, et al. Strong association 33 between HLA-B*1502 and carbamazepine induced TEN in this population. Stevens-Johnson syndrome and toxic epidermal necrolysis in mainland Han Chinese patients. Eur J Clin Pharmacol. 2011 Mar 19 [Epub ahead of print]. 18. Schopf E, Stuhmer A, Rzany B, Victor N, Zentgraf R, Literature search and data Kapp JF. Toxic epidermal necrolysis and Stevens- Johnson syndrome. An epidemiologic study from West sources Germany. Arch Dermatol. 1991 Jun;127(6):839-42. Medline searches for Stevens-Johnson 19. Sharma VK, Sethuraman G, Minz A. Stevens Johnson (SJS), toxic epidermal necrolysis (TEN) and SJS-TEN syndrome, toxic epidermal necrolysis, and overlap: A retrospective study of causative drugs and clinical outcome. Indian J Dermatol Venerol Leprol 2008; Stevens-Johnson syndrome and toxic epi- 74:238-40. dermal necrolysis were performed. Sev- 20. Litt JZ, ed. Litt’s Pocketbook of Drug Eruptions and eral clinical case reports and reviews of Interactions, Third Ed. Publisher: Informa HealthCare, the current literature were provided. Also 2003-09-24, ISBN: 184214296; 716 pages. 21. Mockenhaupt M, Vibound C, Dunant A, et al. Stevens- searched for the previously mentioned top- Johnson syndrome and toxic epidermal necrolysis: ics were Cochrane Database of Systematic assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR study. J Invest Reviews, which produced a single article, Dermatol 2008; 128:35-44. and UpToDate. A search of evidence-based 22. Halevy S, Ghislain PD, Mockenhaupt M, Fagot JP, Bouwes Bavinck JN, Sidoroff A, Naldi L, Dunant A, guidelines from the National Guidelines Viboud C, Roujeau JC. Allopurinol is the most common Clearinghouse and the United States Pre- cause of Stevens-Johnson syndrome and toxic epidermal necrolysis in Europe and Israel. J Am Acad ventive Services Task Force did not provide Dermatol. 2007. any results. Search date range: March 2011- 23. Bolognia J, Jorizzo J. Dermatology. www.expertconsult. May 2011. com. 24. Morales EM, Purdue GF, Verity SM, et al. Ophthalmic References Manifestations of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis and Relation to SCORTEN. Am J 1. Letko E, Papaliodis DN, Papaliodis GN, Daoud YJ, Ophthalmol. 2010 Apr: 505-510. Ahmed R, Foster SF. Stevens-Johnson syndrome and toxic epidermal necrolysis: a review of the literature. Ann 25. Guégan S, Bastuji-Garin S, Poszepczynska-Guigné Allergy Asthma Immunol. 2005;94:419-436. E, et al. Performance of the SCORTEN during the first five days of hospitalization to predict the prognosis of

Shama, Lowenbraun, Silverton 77 Micronodular Juvenile Xanthogranuloma Versus Benign Cephalic Histiocytosis

Mari M. Batta, DO,* Yoon Cohen, OMS IV,** Stephen Kessler, DO,*** Ronald Hansen, MD****

* Dermatology Resident, 1st year, Alta Dermatology / LECOMT, Mesa, AZ; Scottsdale Healthcare System – Osbourn Campus, Scottsdale, AZ ** Medical Student, 4th year, University of New England College of Osteopathic Medicine, Biddeford, ME *** Program Director, Alta Dermatology / LECOMT, Mesa, AZ; Scottsdale Healthcare System – Osbourn Campus, Scottsdale, AZ **** Pediatric Dermatologist, Phoenix Children’s Hospital, Phoenix AZ

ABSTRACT We report a case of an 11-month old Caucasian male who presented with a persistent reddish-orange macular discoloration of the central face that bridged multiple papules on bilateral cheeks as well as red, orange and tan papules diffusely scattered over the torso. The clinical features were not typical of either classic juvenile xanthogranuloma or benign cephalic histiocytosis. These non-Langerhans cell histiocytoses have been described as separate pathologic entities. However, based on the history, physical examination, and skin biopsies, we support the theory that these disorders may be a continuous spectrum of disease, as our patient had overlapping features of both juvenile xanthogranuloma and benign cephalic histiocytosis. Case Report An 11-month-old boy presented for evaluation of a six-month history of a persistent, reddish-orange macular discoloration of the cheeks. Soon after this eruption appeared, the patient developed a solitary papule on his forehead, with subsequent development and expansion of numerous papules over his arms, legs and torso. The child was the prod- uct of artificial insemination from a sperm donor and a mother on levothyroxine for hypothyroidism. His birth history was significant for being large for gestational age (birth weight 5.3 kg / Figure 1: Red-yellow macular confluence on cheeks Figure 3: Few orange-tan papules noted on back; note 11.7 lbs). He had no known and bridging the nose. scarcity compared to upper extremity and cheek. drug allergies and took no medications. There was no personal or family history of celiac disease, thyroid cancer, neurofibromatosis or optic pathway gliomas. Physical examination revealed a well- appearing Caucasian male. Bridging mul- tiple 1-3mm papules on bilateral cheeks was a yellowish-orange macular confluent discoloration of the central face (Figure 1). Diffusely scattered 1-3mm red, orange and tan papules were concentrated over both upper and lower extremities and were scarce on the abdomen, lumbosacral and gluteal regions (Figures 2, 3). The remain- der of the physical examination was appro- priate for age. A biopsy of the right cheek, performed by another dermatologist several months earlier, was consistent with juvenile xan- thogranuloma, displaying Touton giant Figure 2: Right upper extremity with diffusely scattered red-orange and tan papules.

78 MicroNODular Juvenile Xanthogranuloma Versus Benign Cephalic Histiocytosis cells and mixed inflammatory infiltrate Juvenile xanthogranuloma (JXG) is the Distinction between multinodular JXG with lymphocytes and eosinophils. Punch most common histiocytosis of childhood.7 and BCH is dependent upon the correla- biopsies of the distal and proximal forearm There is a slight male predominance, and tion of clinical and histopathologic findings. of both macular and papular areas were almost 75% appear during the first year Overlap of these two entities has also been performed. The histopathology revealed of life, although it may be present at birth reported, suggesting that benign cephalic a dermal histiocytic infiltrate, containing or appear in adulthood.3 The micronodu- histiocytosis may in fact be an early variant xanthomatous histiocytes with a few lym- lar variant presents with widely scattered, or aborted phase of juvenile xanthogranu- phocytes and eosinophils, and an absence asymptomatic, pink-to-red-brown, 2-5mm loma. Our patient’s findings were most of Touton giant cells. CD68 immunoper- dome-shaped papules that rapidly turn yel- consistent with this overlap of long-stand- oxidase stains were positive, whereas CD1a low-orange in color.6 JXG lesions are most ing multinodular JXG and BCH. was negative for both lesions. These find- commonly seen on the head and neck, and References ings were consistent with benign cephalic may extend to the upper torso as well as 1. Zelger BG, Zelger B, Steiner H, Mikuz G. Solitary giant histiocytosis. upper and lower extremities. Extracutane- xanthogranuloma and benign cephalic histiocytosis: ous sites of involvement may include ocular, variants of juvenile xanthogranuloma. Br J Dermatol Biopsies of the upper gastrointestinal 1995;133:598-604. tract revealed mild esophagitis and mild pulmonary, hepatosplenic, musculoskeletal 3,8,9 2. Rodriguez-Jurado R, Disran-McKinster C, Ruiz- chronic gastritis; duodenal biopsy was and central nervous systems. Unilateral Maldonado R. Benign cephalic histiocytosis progressing lesions of the iris are rare but may present into juvenile xanthogranuloma. Am J Dermatopathol negative for Langerhans cell histiocytosis. 2000;22:70-4. prior to 2 years of age with potential com- Laboratory tests, including complete blood 3. Bolognia J, Jorrizo J, Rapini R. Dermatology. 2nd count, metabolic and lipid profiles, sedi- plications such as heterochromia, hyphema, edition. Spain: Mosby; 2008. glaucoma, and rarely blindness. Classic his- 4. Satter EK, Gendernalik SB, Galeckas KJ, et al. mentation rate and serum protein electro- Diffuse xanthogranulomatous dermatitis and systemic phoresis, were all within the normal range. tologic findings are foamy “xanthomatous” Langerhans cell histiocytosis: A novel case that histiocytes and Touton giant cells within the demonstrates bridging between non-Langerhans cells Ophthalmology and oncology were also histiocytosis and Langerhans cell histiocytosis. J Am consulted; their findings revealed no abnor- papillary dermis. These lesions also stain Acad Dermatol. 2009; 60: 841-8. malities. positively with HAM56, CD68 and factor 5. Tomaszewski M-M, Lupton GP. Unusual expression of XIIIa and are generally negative for CD1a S-100 protein in histiocytic neoplasms. J Cutan Pathol 1998;25:129-35. Because of the intense redness associ- and S100.3,11 Spontaneous involution with 6. Sidwell RU, Francis N, Slater DN, Mayou SC, et al. Is ated with his cheek and extremity lesions, a resultant atrophic scars occurs over 3 to 6 Disseminated Juvenile Xanthogranulomatosis Benign single treatment with pulsed dye laser (Can- years. Although JXG is usually benign and Cephalic Histiocytosis? Pediatr Dermatol. 2005; 22(1): dela Perfecta, 8.75J/cm2) was given to all of 40-3. limited to the skin, due to the potential for 7. Caputo R. Juvenile xanthogranuloma. In: Text Atlas of the areas. It was not beneficial. extracutaneous involvement it is prudent Histiocytic Syndromes: A Dermatological Perspective. London: Martin Dunitz, 1998:39-58. The clinical features of diffusely scat- to monitor these patients and refer for oph- 3,4,10 8. Freyer DR, Kennedy R, Bostrom BV, Kohut GK, Dehner tered red-orange and tan papules with thalmologic evaluation. LP. Juvenile xanthogranuloma: forms of systemic unusual reddish-yellow macules and disease and their clinical implications. J Pediatr Benign cephalic histiocytosis is a rare 1996;129:227-37. patches bridging the papules are not typi- histiocytic proliferative disorder, affecting 9. Haughton A, Horii K, Shao L, Daniel K, Nopper cal of either classic juvenile xanthogranu- A. Disseminated juvenile xanthogranulomatosis in a generally healthy young children within newborn resulting in liver transplantation. J Am Acad loma (JXG) or benign cephalic histiocytosis the first 3 years of life without gender pre- Dermatol 2008;58:S12-5. (BCH). It has recently been theorized that dilection. Multiple asymptomatic, 2-5mm 10. Gianotti F, Caputo R. Histiocytic syndromes: A review. J JXG and BCH may be part of the same red-brown macules and papules initially Am Acad Dermatol 1985;13:383-404. clinical spectrum.1,2 Based on our patient’s 11. Marrogi AJ, Dehner LP, Coffin CM. Benign cutaneous present on the cheeks, progressing toward histiocytic tumors in childhood and adolescence, findings, we support this theory, as our the ears and rest of the face.3,10,12 Lesions excluding Langerhans’ cell proliferations. A patient had overlapping features of both clinicopathologic and immunohistochemical analysis. may then appear on the trunk and extremi- Am J Dermatopathol 1992;14:8-18. JXG and BCH. ties, but are infrequently found on the but- 12. Jih D, Salcedo S, Jaworsky C. Benign cephalic histiocytosis: A case report and review. J Am Acad tocks or thighs. The mucous membranes, Dermatol 2002;47:908-13. Discussion 3,10,12 acral surfaces and viscera are spared. 13. Arnold Ml, Anton-Lamprecht I. Multiple eruptive A benign proliferation of histiocytic Histologic and ultrastructural studies reveal cephalic histiocytomas in a case of T-cell lymphoma. A xanthomatous stage of benign cephalic histiocytosis cells, non-Langerhans cell histiocytoses a well-circumscribed dermal histiocytic in an adult patient? Am J Dermatopath 1993;15:581-6. (non-LCH) arise from a monocyte/mac- infiltrate with cytoplasmic worm-like bod- 14. Weston WL, Travers SH, Mierau GW, Heasley D, rophage or dermal dendritic cell lineage, ies and desmosome-like junctions between Fitzpatrick J. Benign cephalic histiocytosis with diabetes insipidus. Pediatr Dermatol 2000;17(4):296-8. recognized immunohistochemically by the histiocytes.10 Touton cells are absent; foamy expression of factor XIIIa, CD68, CD14, cells and multinucleate giant cells are rarely CD11b, lysozyme and vimentin.3,4 The observed in early lesions, but xanthomati- absence of Birbeck granules ultrastructur- zation can occur with time.13 Histiocytes ally and lack of CD1a surface antigen and express CD11b, CD14, CD68, HAM56 and S100 protein expression distinguish non- factor XIIIa but are negative for CD1a and LCH from Langerhans cell histiocytoses.4,5 S100.4,11,12 Most children have a self-limited The main types of non-LCH include benign course without internal organ involvement. cephalic histiocytosis, juvenile xanthogran- Resolution with flattening and hyperpig- uloma, xanthoma disseminatum, and gen- mentation of the papules occurs after a eralized eruptive histiocytomas. Although mean of 26 months from onset.3,10 An asso- they have been described as separate patho- ciation with diabetes insipidus has been logic entities, recent reports indicate that reported, thus clinical monitoring is recom- these disorders may rather be a continuous mended.14 spectrum of disease categorized as non- Langerhans cell histiocytoses.6 Conclusion Batta, Cohen, Kessler, Hansen 79 Bullous Tinea Corporis Secondary to Trichophyton Tonsurans

Leah Kohler, DO, LT, MC/FS, USN,* Tony Clinton, MD, CDR, MC/FS, USN**

*Flight Surgeon, Marine Aerial Refueler Transport Squadron 152, Okinawa, Japan **Board-Certified Dermatologist, United States Naval Hospital, Okinawa, Japan

ABSTRACT Tinea corporis is a common fungal infection of the glabrous skin that classically presents as an erythematous annular plaque with central clearing and an advancing, raised border. We present a case of a highly atypical manifestation of tinea corporis: bullous tinea corporis secondary to Trichophyton tonsurans. Case Presentation A 31-year-old African American female presented with an 8-month history of disseminated papules and plaques that would turn into vesicles and fragile bul- lae within days of their appearance. The lesions were focused mainly over her extremities and upper chest, and tended to follow a 3-week progression. Flat-topped reddish papules and plaques of variable shapes and sizes progressed into fragile vesicles and bullae ranging from nickel- to quarter-size that would rapidly break and drain clear fluid. Scales and crust for- mation soon developed after that. Post- inflammatory hyperpigmentation patches marked areas of resolution. The patient was asymptomatic with the exception of pruritus during the papular phase of lesion development.

The patient recalled that her symptoms Figure 1: Resolving bulla with slight vesiculation at the border. began when she was staying in multiple hotels on a family vacation. Of note, the patient’s husband and two male children The initial differential diagnosis biopsy of a new plaque was performed. began exhibiting similar symptoms during included bullous impetigo, eczematoid der- the same period. Past medical histories Histologic examination showed com- matitis, papular urticaria (attributed to pos- pact keratosis with focal areas of parakera- were unremarkable for all members of the sible arthropod bites from hotel infestation family. They did not own any pets. All tosis. The epidermis was mildly spongiotic. at time of symptom onset), and pityriasis Marked papillary dermal edema was noted. family members experienced temporary lichenoides. The patient was prescribed improvement but not complete clearance The mid-dermis displayed perivascular a 2-week course of trimethoprim-sulfa- lymphohistiocytic infiltrates, characterized following a 10-day course of trimethoprim- methoxazole and a decolonization regi- sulfamethoxazole (prescribed by their pri- by rare neutrophils and eosinophils (Fig. men for her family. She demonstrated no 2, 3). Both periodic Acid-Schiff (Fig. 4) mary care provider after aerobic cultures improvement and even developed new revealed a few Staphylococcus warneri, and Grocott methenamine silver stains (Fig. lesions while on the medication. Additional 5) revealed multiple hyphae in the stra- which were later determined to be contami- bacteriologic cultures of the affected areas nants). tum corneum. Fungal culture confirmed and nares were negative. Trichophyton tonsurans from the patient, Examinations revealed few-to-spo- Fungal cultures were performed on as well. radic, mildly crusted or significantly scaly the patient’s children, whose inflamma- flat-topped eczematous papules and small Treatment of the patient and her family tory papules were isolated to their hairline, with oral terbinafine 250mg daily for four plaques asymmetrically distributed on the occiput, and posterior neck. Trichophyton patient’s neck, shoulders, upper extremi- weeks resulted in rapid improvement and tonsurans (the leading cause of tinea capitis complete resolution of all skin lesions. ties, and back. No bullae were visualized, in the United States) was isolated from both but two lesions had slight vesiculation at children.1 Further questioning of the family borders and a few crusted lesions appeared revealed that the patient would frequently Discussion to be sequelae from preceding small bullae use the same clippers to cut her children’s (Fig. 1). Patches of hyperpigmentation were and husband’s hair at home. Despite the Tinea corporis is a fungal infection of evident at sites of resolved lesions. No scar- highly atypical appearance, the patient’s bul- the face, trunk, or limbs caused by dermato- ring was noted. lae were cultured for fungus, and a punch phytes of the Microsporum, Trichophyton, 80 tBullous Tinea Corporis Secondary to Trichophyton Tonsurans Figure 2. Subepidermal edema on H&E stain (4x). Figure 3. Subepidermal edema on H&E stain (10x).

Figure 4. Branching hyphae on PAS stain. Figure 5. Multiple hyphae in stratum corneum on GMS stain or Epidermophyton genera. Following an Bullous dermatomycoses can be eas- 2. Terragni L, Marelli MA, Oriani A, Cecca E. Tinea corporis bullosa. Mycoses. 1993; 36:135-137. incubation period of 1-3 weeks, the der- ily misdiagnosed as allergic bullous impe- 3. Habif T. Clinical Dermatology: A Color Guide to matophytes invade, attacking the top layer tigo, contact dermatitis, herpes simplex, and Diagnosis and Therapy 4th ed. Mosby. 2004. PP. 409, (stratum corneum) of the skin, hair, and dishydrotic eczema. In all reported cases 420-421. nails, surviving only on dead keratin.2,3 (including ours), the correct diagnosis was 4. 5. Ziemer M, Seyfarth F, Elsner P, Hipler UC. Atypical Invasion typically occurs in a centrifugal established only after biopsy and culture of manifestations of tinea corporis. Mycoses. 2007; pattern, creating the classic presentation of the lesions. Delay of these simple tests can 50(2):31-35. an erythematous annular plaque with cen- result in a missed diagnosis and prolonged 6. Veraldi S, Scarabelli G, Oriani A, Vigo GP. Tinea corporis bullosa anularis. Dermatology. 1996; 192:349– tral clearing and an advancing, scaly raised treatment course. A high index of suspicion 350. 4 border. Although vesicles and pustules is necessary to prompt the examining physi- 7. Azfar RS, Ogunleye T, Treat J. Annular blisters on the may be seen in inflammatory cases, frank cian to search for fungi in atypical bullous arm. Arch Dermatol. 2009; 145(4):497. bullae are exceedingly rare. Less than 15 lesions. As demonstrated in all cases of 8. Cullen S, Ionnides G. Bullous Dermatophyte Infections. Cutis. 1970; 6(6):661-668. cases of bullous tinea corporis have been bullous tinea corporis, the value of a fun- 9. Bennion S. Annular Vesiculation. Arch Dermatol. 1989; reported in the literature. Trichophyton gal culture and biopsy cannot be under- 125(11):1569-1570. rubrum and Microsporum canis were iso- estimated when investigating the cause of lated in all but one.2,4,5,6,7,8 Our patient rep- refractory bullous eruptions. resents the second ever reported case of References bullous tinea corporis caused by Trichophy- 1. Abdel-Rahman SM, Farrand N, Schuenemann E, et ton tonsurans (the first case was reported by al. The prevalence of infections with Trichophyton Azfar et al. in 2009).6 tonsurans in schoolchildren: the CAPITUS study. Pediatrics. 2010; 125(5):966-973.

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