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Volume 41 November 2018 JAOCD Journal Of The American Osteopathic College Of Dermatology The Final Issue

AsCultural dermatologists seeDermatoses: a shift toward a minority patientA Review base, recognizing dermatoses linked to non-U.S. cultural practices will be invaluable.

Also in this Issue: A New Trigger of Morbilliform Eruption -like Hypopigmentation with Topical Imiquimod An Unusual Presentation of Pachydermodactyly

Journal of the American Osteopathic College of Dermatology

2018-2019 AOCD OFFICERS

PRESIDENT Daniel Ladd, DO, FAOCD

PRESIDENT-ELECT John P. Minni, DO, FAOCD

FIRST VICE-PRESIDENT Reagan Anderson, DO, FAOCD

SECOND VICE-PRESIDENT David Cleaver, DO, FAOCD

Editor-in-Chief THIRD VICE-PRESIDENT Amy Spizuoco, DO, FAOCD Karthik Krishnamurthy, DO SECRETARY-TREASURER Steven Grekin, DO, FAOCD Assistant Editor Julia Layton, MFA TRUSTEES Danica Alexander, DO, FAOCD (2016-2019) Peter Saitta, DO, FAOCD (2016-2019) Jonathan Crane, DO, FAOCD (2017-2020) Michael Whitworth, DO, FAOCD (2017-2020) Steven Brooks, DO, FAOCD (2018-2021) Jerome Obed, DO, FAOCD (2018-2021)

IMMEDIATE PAST-PRESIDENT Karthik Krishnamurthy, DO, FAOCD

EXECUTIVE DIRECTOR Marsha A. Wise, BS

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

JOURNAL OF THE AMERICAN OSTEOPATHIC COLLEGE OF DERMATOLOGY Page 2 Journal of the American Osteopathic College of Dermatology Volume 41 Table of Contents November 2018 Review Board...... 4 Letter from the JAOCD Founders, 2003...... 5 Letter from the Executive Director ...... 6

FEATURE ARTICLES Cultural Dermatoses: A Review...... 9 John C. Howard, DO, Sergey Arutyunyan, DO, MS, Jere Mammino, DO, FAAD, FAOCD, Stanley Skopit, DO, MSE, FAAD, FAOCD A New Trigger of Morbilliform Eruption in the Setting of Atypical Infectious Mononucleosis...... 13 Roxanne Rajaii, DO, Megan Furniss, DO, John Pui, MD, Brett Bender, DO Induction of Vitiligo-like Hypopigmentation with Use of Topical Imiquimod for Superficial and Nodular Basal Cell Carcinomas...... 16 Roxanne Rajaii, DO, Elizabeth Young, DO, Sean Stephenson, DO, Michelle Legacy, DO, Lynn Sikorski, DO An Unusual Presentation of Pachydermodactyly: A Case Presentation and Discussion...... 19 Abby Russell, BSN, Albert E. Rivera, DO, Nathan E. Lee, MD

Aleukemic Leukemia Cutis - A Preview of Systemic Malignancy: A Case Report and Literature Review...... 21 Ryan Jones, DO, Mark Kuriata, DO Autoinoculation in a Patient with Longstanding Chromoblastomycosis: A Case Presentation and Discussion...... 23 Cuong Le, DO, Michael Noparstak, DO, William Bethea, DO A Case of Arsenical Keratoses After Chronic Consumption of Water from Tube Wells...... 25 Sealtiel Adrian Tinajero, DO, Camille Howard, DO, Suzanne Rozenberg, DO A Case of Cutaneous ALCL in a Patient with ...... 28 Taraneh Matin, DO, Richard Rubenstein, MD Cutaneous Metastatic Melanoma Masquerading as a Pigmented Rash: A Case Presentation and Discussion...... 31 Jonathan Bellew, DO, Soham P. Chaudhari, DO, Shiva Kheradmand, BA, Vernon T. Mackey, DO Excimer Laser for the Treatment of Inflammatory Linear Verrucous Epidermal (ILVEN): A Novel Therapy...... 35 Jessica Kim, DO, Christina Steinmetz-Rodriguez, DO, Anna Krishtul, MD, Shakira Payne-Blackman, MD Incidence and Time to Diagnosis of Pemphigus Foliaceus in a Private Dermatology Practice Over 10 Years...... 38 Joseph Michael Dyer, DO, Patrick Hardigan, PhD, Richard Alan Miller, DO Late-Onset Focal Dermal Elastosis: A Case Report and Review of the Literature...... 40 Jessica Newburger, DO, Michelle Foley, DO, FAOCD Madelung’s Disease: A Report of a Rare Case with an Atypical Presentation...... 42 Tam H. Nguyen, BS, Blake Sanders, DO, Franciso A. Kerdel, MD Patterns and Treatment of Post-Herpetic Neuralgia: A Case Study...... 44 Kaylie Pierce, Kathryn Wanat, Stephanie Egwuatu, Carolyn Withee, Nathaniel Allen-Slaba, Manon Begert, Megumi Sugita, James Keene, DO, Michael Scott, DO, Holly Novion, Dan Selski, DO, Michele McCarroll, DO Primary Cutaneous Apocrine Carcinoma of the Scalp: A Case Presentation and Discussion...... 46 Derek Hirschman, DO, Cassandra Beard, DO, Howard D. Lipkin, DO Treatment of Minocycline-Induced Dermal Pigmentation Deposition with the Q-Switched Alexandrite Laser...... 48 John Feigner Linabury, DO, Lisa Ann Zaleski-Larsen, DO, FAAD, Mitchel P. Goldman, MD, FAAD Understanding Livedo Reticularis: A Unique Case of Cutis Marmorata Telangiectatica Congenita and Discussion of Differential Diagnoses and Work-Up...... 50 Rachel M. White, DO, Sonya Zarkhin, DO, Brad Glick, DO, MPH, FAOCD Utilization of Ovine Collagen Extracellular Matrix in Surgical Excision of Recurrent Keloids...... 53 Christopher Mancuso, MHS, Megan Hemmrich, Joseph K Francis, MD

Page 3 JOURNAL OF THE AMERICAN OSTEOPATHIC COLLEGE OF DERMATOLOGY Editor-In-Chief Founding Editor Assistant Editor Karthik Krishnamurthy, DO Jay Gottlieb, DO Julia Layton, MFA Editorial Review Board Sami Abbasi, DO Merrick Elias, DO Mark Lebwohl, MD Amara Sayed, DO Brownstown, MI Pembroke Pines/Davie, FL New York, NY San Marcos, TX

Ali Banki, DO Marcus Goodman, DO Angela Leo, DO Joseph Brant Schneider, DO Glastonbury, CT Roswell, GA New York, NY Shawnee Mission, KS

Brett Bender, DO Melinda Greenfield, DO Scott Lim, DO Michael Scott, DO Farmington Hills, MI Albany, GA Erie, PA Seattle, WA

Ryan Carlson, DO Andrew Hanly, MD Jere Mammino, DO Sean Stephenson, DO Hilliard, OH Miami, FL Winter Springs, FL Troy, MI

Michael P. Conroy, MD Joel Harris, DO John Minni, DO Jacqueline Thomas, DO Columbus, OH Madison Heights, MI Port St. Lucie, FL Fort Lauderdale, FL

John Coppola, DO David Horowitz, DO Navid Nami, DO Ormond Beach, FL Torrence, CA Newport Beach, CA

Jonathan Crane, DO Francisca Kartono, DO Dimitria Papadopoulos, DO Wilmington, NC Canton, MI Bellmore, NY

Matthew Elias, DO Jon Keeling, DO Richard Rudnicki, DO Lighthouse Point, FL Lexington, KY Mesquite, TX

EDITORIAL REVIEW BOARD Page 4 Letter from the JAOCD Founders, 2003

Page 5 LETTER FROM THE JAOCD FOUNDERS, 2003 Letter from the Executive Director

Marsha Wise Executive Director, AOCD

Hello, Everyone, The end of an era is upon us. This issue of the JAOCD will be the last issue published. We’ve enjoyed 15 years of articles written by our membership. The JAOCD was founded by Dr.’s Jay Gottlieb, Stanley Skopit, and James Del Rosso, and Dr. Karthik Krishnamurthy took over the helm in 2012. Throughout much of the JAOCD’s existence, we were fortunate to have the very talented Julia Layton as the Assistant Editor. Of course, we cannot forget the many volunteers who have served on the editorial board. To all of you, the AOCD is grateful for your service. We are also grateful to the pharmaceutical support received in the early years of the Journal. To Dr. Gottlieb, thank you for having the foresight to create our publication. To Dr. Krishnamurthy, thank you for picking up the baton passed on, and to Julia Layton, thank you for sticking with the AOCD all of these years and putting the polish on the journal. While the journal may be ending, we hope to offer new educational opportunities in the new year. You can still read the JAOCD; all of the issues are on our website. You can also earn CME credit by reading recent issues and taking a quiz. Sincerely, Marsha Wise

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*Resident, Department of Dermatology, Larkin Community Hospital, South Miami, FL ** Traditional Rotating Intern, Larkin Community Hospital, South Miami, FL ***Medical Director, Orlando Dermatology Residency, Orlando, FL ****Program Director, Dermatology Residency Training Program, Larkin Community Hospital, South Miami, FL

Disclosures: None Correspondence: John C. Howard, DO; Department of Dermatology, Larkin Community Hospital, 7031 SW 62nd Ave., South Miami, FL 33143; ph: 305-284-7500

Abstract Minorities are expected to make up more than half of the U.S. population by 2044 and of the U.S. child population much sooner. Meanwhile, between 2012 and 2016, the number of insured individuals among minority groups such as Blacks, Hispanics, and non-white non-Hispanics increased significantly.As demographics continue to change, and as more minority individuals gain access to healthcare, dermatology practices will see a shift toward a minority patient base. Recognizing and understanding dermatoses linked to non-U.S. cultural practices will be invaluable for maintaining thriving patient-physician relationships and achieving successful clinical outcomes. In this review, we describe various cultural dermatoses -- conditions caused by culture-specific therapeutic, cosmetic, and/or religious practices -- of ethnic and racial groups found in the United States.

Introduction such as fever, congestion, pneumonia, asthma, , The population of the United States is becoming abdominal discomfort, acute myelitis, lower back pain, headaches, and nephritis.4,7,8 It has also been increasingly diverse as the growth of the minority 6 population outpaces the growth of the non- used to eliminate toxins from the body. The areas used for cupping most commonly include the back, Hispanic White population. Recent projections 4 estimate more than half of the U.S. populace will chest, abdomen, and buttocks. The mechanism of belong to a minority group (any group other than cupping is based on creating a vacuum effect. This is non-Hispanic White) by 2044. When the minority achieved by lighting an alcohol-soaked cotton ball population accounts for more than 50% of the total or piece of paper and placing it in a cup. The cup is U.S. population, the U.S. will be what some have inverted onto the skin, the flame gets terminated described as a “majority-minority” nation.1 The due to lack of oxygen, and air begins to cool, creating child population in the United States is even more a vacuum. This leads to the suction of the skin into diverse and is expected to experience the “majority- the cup and subsequent damage of superficial Figure 1 1 blood vessels in the papillary dermis, resulting in minority” crossover much sooner. Additionally, 4,6 the U.S. Census Bureau estimates that in 2015, circular erythema or ecchymosis (Figure 1). leads to parallel ecchymotic streaks12 or petechiae12 the foreign-born segment of the U.S. population These circular burns in a child who was treated with on the skin of the affected patients and may even cupping therapy might be easily mistaken for child was the highest since 1910, comprising 13.5% of 9 lead to burns, as the oiled skin has been reported the populace. That number is projected to increase abuse. Although circular, ecchymotic lesions are to catch fire.13 to approximately 20% by 2060.1 In 2015, the U.S. the most common presentation of cupping, linear purpuric streaks can also be seen if a lubricant is foreign-born population was born in Africa (~5%), 7 Possible causes of allergic contact the Americas (~53%), Asia (~30.6%) and Europe used to move the cup around to cover a larger area. Capsaicin treatment (~11.1%).2 Capsaicin is an active component of the chili Moxibustion peppers commonly used as condiments in Latin- Moxibustion is commonly practiced in Asian 10,14 The Patient Protection and Affordable Care Act 5,6 American food preparations. Topical capsaicin (PPACA), commonly known as Obamacare, was cultures. This therapy is used for treating fever, preparations have been safely and successfully enacted in 2010. A U.S. Department of Health asthma, , and abdominal pain and used in various fields of medicine. For instance, consists of burning moxa herb (Artemisia vulgaris) and Human Services report indicates that between 5,6,8 the agent has been used by dermatologists for 2012 and 2016, reduction in the uninsured rate either on the skin or very close to the skin. a wide range of conditions, such as neurogenic was greatest among Black non-Hispanics, with 3 Indirect moxibustion, the more commonly used pain or pruritus, , pruritus million people gaining health-insurance coverage.3 variant, involves burning of the moxa stick near the of hemodialysis, aquagenic pruritus, , The second highest reduction was seen among skin until it becomes erythematous. A less-common apocrine , , Hispanic adults, with 4 million gaining health- variant of this technique, direct moxibustion, , and .15,16 3 entails burning cones of the wood directly on the insurance coverage. 10 However, peeling the peppers with bare hands while skin, leading to second-degree burns. Although cooking may lead to erythema, edema, burning pain, most lesions caused by moxibustion are transient, 14 As the population makeup of the United States 10 and irritation. It is important to keep capsaicin continues to change, and as more people gain access permanent scarring has been reported. Similarly to dermatitis on the differential because patients may those produced by cupping, these lesions might be to healthcare, it is likely that dermatology practices 5 not recall the exposure, as handling the peppers is across the nation will see a shift in their patient base. mistaken for signs of abuse in adults and children. part of their routine. In this review, we attempt to raise awareness about both therapeutic and cosmetic cultural practices Coining To alleviate the symptoms of capsaicin dermatitis, of various ethnic and religious groups and review Coining (cao gio in Vietnamese) or spooning (gua patients are advised to wash their hands with soap associated dermatological manifestations associated sa in Chinese) is a widely used technique in Asian and water and apply vegetable oil. The use of high- cultures in Vietnam, China, Thailand, Malaysia with those practices. 4,10,11 potency corticosteroids and topical anesthetics has and Indonesia. This therapy is used to treat also been reported.14 Furthermore, to prevent this fever, flu, headaches, and myalgia and is believed to condition, patients are advised to wear gloves when Cultural Practices improve these symptoms by improving circulation peeling the peppers. in soft tissues.11 Coining is performed by applying and Associated Conditions water or aromatic oils onto the skin of the chest and Toothpaste Cupping back and subsequently rubbing the skin with a coin Cupping is a technique used widely in the Asian, 11 Toothpaste-induced allergic in a downward motion until the skin is reddened. usually affects the index finger of individuals Latin American, Middle Eastern , and Eastern While a coin is widely used in this remedy, the European cultures.4-6 In the United States, cupping from Southeast Asia who use their index finger 5 literature also reports use of several other tools, such to rub toothpaste over their teeth. In one report, is practiced primarily by Russian immigrants. It as combs and porcelain spoons. Coining usually has been used for treating a wide range of ailments toothpaste-induced allergic contact dermatitis

Page 9 CULTURAL DERMATOSES: A REVIEW of the index finger presented concurrently with darker pigment but also shortens drying time, is important as it can be reversed if hairstyle dermatitis of the lip.17 reducing the time required for henna sessions modifications are made. Sikh individuals should be from 12 hours (when red henna is used) to less advised to tie loosely during the day and leave Colored string than two hours.29 PPD-enhanced black henna it untied during the night.40 Colored-string-induced allergic contact dermatitis has been associated with not only allergic contact results from wearing colored strings around the dermatitis but also papulovesicular eruptions, Prayer nodules neck, arms, or waist and is common in South bullae formation, and erythema multiforme-like Prayer nodules are painless calluses that occur in Asian individuals. These strings may cause skin reactions.26,28,30,31 Emerging evidence of long- response to repeated pressure to the skin while friction, leading to allergic reactions. Furthermore, term or even permanent adverse effects associated praying. These nodules have been reported in depigmentation may develop at the sites of skin with the use of PPD-enhanced black henna individuals of Christian, Buddhist, and Muslim contact due to the chemicals in the string, leading are particularly concerning. Leukoderma, post- faiths and are most common in elderly Latin- 18 6,41,42 to linear leukoderma. inflammatory hyperpigmentation, keloids, and type American women and Muslim men. These I hypersensitivity reaction leading to angioedema lesions have most commonly been reported on Drawstring and acute renal failure have been described in the knees, ankles, and dorsum of the feet in these 41,43 Drawstring dermatitis results from wearing the the published literature.32-34 Since the practice of populations. Among Muslims, the forehead traditional clothes favored by many South Asians. henna is an integral part of spiritual and traditional is also a common location. Position modification Clothes like the sari, a traditional dress worn by rituals in many cultures, it is important to educate while praying can prevent these nodules, and women in India, Pakistan, Bangladesh, and Sri patients about potential side effects of black-henna topical use of 40% urea ointment can be used to 44 Lanka, and salwaar, the baggy trousers worn by preparations and advise them to choose red henna treat them. men and women from the same cultures, are tightly as their decorative agent of choice. tied with a drawstring at the waist. This results in Scarification friction and may cause irritation as well as lead to Acne Scarification is practiced in many parts of Africa lichenification, post-inflammatory leukoderma, for aesthetic and cultural purposes, with scars hyperpigmentation, and koebnerization of existing Pomade acne is a caused by pomades, indicating rank in society, family, clan, and tribe 19,20 45 dermatoses like vitiligo and . substances used to straighten hair and lubricate the and also serving as decoration. Sometimes A case of squamous cell carcinoma at the scalp. Pomade contains high-melting hydrocarbons scarring is performed on youth for medical reasons. 19 drawstring-friction site has also been reported. that allow the substance to stay in the hair longer For example, in Ethiopia, placing superficial scars Loose drawstrings have been recommended to than gels and sprays.35 Pomade acne primarily around the eye is believed to prevent eye disease prevent this condition. Weight reduction is also affects individuals from African American and and improve vision (Figure 3). Some governments recommended in these patients since fatty tissue Latin American cultures.10,35 Clinically, these are now banning this practice, considering it child is proinflammatory and a major source of tumor lesions manifest as perifollicular , pustules, abuse and a contributor to the spread of HIV. necrosis factor-alpha, which may lead to significant and closed comedones and occur on the forehead, 21 inflammatory response. temples, and cheeks.10,35,36 Pearling Pearling, also known as penile beading, is the Bindi Steroidal acne practice of permanently implanting small objects Bindi, also known as kumkum or tilak, is a disc- Steroidal acne is caused by excessive use of potent shaped ornament worn by Indian women for topical corticosteroids on the face. These lesions 4 socio-religious purposes. It is applied to the usually present in individuals from Asian cultures forehead, between the eyebrows, to indicate with darker skin types who use topical steroids to marital status, but can also be worn as a fashion lighten their skin.35 accessory.4,22 Historically, the bindi has been made from turmeric pastes with addition of various Acquired dyes to complement the color of the dress. Also, Acquired trichorrhexis nodosa is a hair disorder that bindi discs have been made of nickel or polyvinyl results from external physical or chemical insults chloride with a resinous adhesive material.23,24 that damage the hair shaft. The proximal variant Several adverse reactions to bindi materials have of trichorrhexis nodosa affects proximal hair and been reported, including allergic dermatitis, contact is most common among African Americans.10 This leukoderma, hyperpigmentation, and foreign-body condition is caused by excessive hair straightening 4,22,25 granuloma. Reports in the published literature with hot combs and ceramic flat irons, permanent Figure 2 describe contact dermatitis to nickel dyes, such weaves, brushing and combing, or use of chemicals as Brilliant Lake Red R, Disperse Blue 124, and and hair dyes.10,37 The examination of hair will Disperse Blue 106, as well as chemical additives, reveal one or more nodes presenting as white specks such as thimerosal and gallate mix and para- on the affected hair shaft. Since breakage of the tertiary-butylphenol.4,22-24 hair occurs close to the skin surface, patients may present with areas of alopecia.10,38 The distal variant Henna of trichorrhexis nodosa is more common in White Henna, also known as hina, is a natural dye or Asian individuals. This variant is characterized by derived from the leaves of the Lawsonia inermis nodes and breakage that occur several inches from plant. This product is frequently used to dye skin, the scalp, producing hair that appears uneven. This 26 hair, fingernails, leather, silk, and fur. Although condition is caused by excessive hair styling and is widely used in South Asian, Middle Eastern, and commonly associated with longitudinal splitting, North African cultures, many reported cases of commonly known as split ends.38 adverse dermatologic reactions to henna involve patients who were not part of these cultures and received a henna tattoo or were otherwise exposed Traction alopecia is a hair-loss disorder that to henna products.27 Pure henna, known as “red commonly presents in the African American henna,” is hypoallergenic and has rarely been population and in men practicing the Sikh religion associated with adverse reactions, with only two (Figure 2).10,39 Like acquired trichorrhexis nodosa, reported cases of red-henna contact dermatitis traction alopecia results from physical insults to the in the literature.4,28 However, there are multiple hair. Various styling techniques, such as braiding, reports of contact dermatitis associated with “black cornrowing, and tightly rolling the hair, have been henna,” a preparation consisting of red henna associated with this condition.10 Sikh men tie their and pigment enhancers such as coffee, black tea, hair into a tight knot on the vertex area of the head 4,27 39 animal urine, and paraphenylenediamine (PPD). and twist facial hair into a knot under the chin. Figure 3 PPD is a coal-tar hair dye that not only enhances Early recognition and diagnosis of traction alopecia

HOWARD, ARUTYUNYAN, MAMMINO, SKOPIT Page 10 beneath penile skin, most commonly that of the 46 Conclusion References dorsal surface of the shaft (Figure 4). Typically, As the United States becomes ever more diverse, 1. Colby S, Ortman J. Projections of the size and the implanted objects are beads made from a wide dermatoses caused by therapeutic, cosmetic and composition of the US population: 2014 to 2060. range of materials, including metal, glass, and silicon. religious practices will be more commonly seen by [Internet]. US Department of Commerce: US The custom of implanting foreign materials under dermatologists across the country. Practices such as Census Bureau; 2015 Mar 1 [cited 2017 Jan 8]. the penile skin has been practiced in Asia and the 47 cupping, moxibustion, and coining cause erythema Available from: https://www.census.gov/content/ Pacific region for hundreds of years. These implants and may lead to burns. Using condiments containing dam/Census/library/publications/2015/demo/p25- have served as “charms” in Asian cultures, believed to capsaicin while cooking, rubbing toothpaste with 1143.pdf. prevent the shrinking of the penis, a fear attributed to the index finger to brush teeth, wearing colored koro syndrome, which involves the delusional belief strings or drawstrings, and applying a bindi may 2. Regions of birth for immigrants in the United that the genitalia are retracting and disappearing, 46 cause allergic contact dermatitis. PPD-enhanced States, 1960-2015. [Internet]. Migration Policy possibly causing death. In the 18th century, pearling black henna may lead to both cutaneous and Institute Data Hub; [cited 2017 Jan 8]. Available was widely practiced among Japanese Yakuza systemic complications, while use of pomades and from: http://www.migrationpolicy.org/programs/ gangsters, who implanted pearls under penile skin to steroids may cause acne. Hairstyling techniques and data-hub/us-immigration-trends?gclid=CLTF0YS pledge loyalty to the clan, with pearls indicating the 47,48 chemicals are associated with acquired trichorrhexis LtNECFdC3wAodGVYI3w. number of years spent in prison. More recently, nodosa and traction alopecia in certain populations. pearling has become more popular in the U.S. inmate Long and frequent prayers lead to calluses 3. Health insurance coverage and the Affordable population. A review of the published literature known as prayer nodules. Penile beading may Care Act, 2010-2016. [Internet]. U.S. Department describing pearling in prisoners indicates implanted lead to significant genitourinary complications. of Health and Human Services; 2016 Mar 3 [cited beads have been made from materials such as spoons, Understanding these cultural dermatoses will 2017 Jan 8]. Available from: https://aspe.hhs. dominoes, buttons, toothbrushes, rubber erasers, 48-50 promote a better physician-patient relationship, gov/pdf-report/health-insurance-coverage-and- dice, and even deodorant roller balls. Pearling decrease misdiagnoses, encourage patients to adhere affordable-care-act-2010-2016. has been associated with a range of complications to treatment plans, and possibly result in patents such as edema, subcutaneous hematoma, infection, refraining from certain problematic practices. 4. Lilly E, Kundu RV. Dermatoses secondary abscess, and erectile dysfunction and may also lead to to Asian cultural practices. Int J Dermatol. increases in transmission of HIV and other sexually 2012;51(4):372-9. transmitted infections.47,51,52 5. Swerdlin A, Berkowitz C, Craft N. Cutaneous Gingival Tattooing signs of child abuse. J Am Acad Dermatol. Gingival tattooing is practiced in Ethiopia and some 2007;57(3):371-92. other populations in the African sub-Saharan region known as the Sahel (Figure 5). Today it is primarily 6. Albares MP, Belinchon I. Cultural Practices performed for cosmetic purposes; however, some in Immigrant Populations and Their Relevance still believe it helps with dental disease and pain to Dermatology. Actas Dermosifiliogr. management.53 The tattoo process uses a needle 2012;103(10):849-52. dipped in a paste made primarily of ash. The needle repeatedly punctures the gingiva, working the paste 7. Yoo SS, Tausk F. Cupping: East meets West. Int into the tissue. Medical practitioners not familiar J Dermatol. 2004;43(9):664-5. with this practice might confuse the presentation with drug-induced hyperpigmentation (e.g., from 8. Chen D, Jiang N, Cong X. 47 cases of acne minocycline), heavy-metal ingestion (e.g., lead treated by prick-bloodletting plus cupping. J Tradit toxic effect), amalgam tattoo, smoker’s melanosis, Chin Med. 1993;13(3):185-6. or Addison’s disease.54 9. Stewart GM, Rosenberg NM. Conditions mistaken for child abuse: part II. Pediatr Emerg Care. 1996;12(3):217-21.

10. Halder RM, Nootheti PK, Richards GM. Dermatological disorders and cultural practices. The Dermatologist [Internet]. 2008 Sep 4 [cited 2017 Jan 8]; 2002;10(8). Available from: http:// www.the-dermatologist.com/article/704.

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12. Hansen KK. Folk remedies and child abuse: a review with emphasis on caida de mollera and its Figure 4 relationship to shaken baby syndrome. Child Abuse Negl. 1998;22(2):117-27.

13. Amshel CE, Caruso DM. Vietnamese “coining”: a burn case report and literature review. J Burn Care Rehabil. 2000;21(2):112-4.

14. Halder R, Nootheti P. Ethnic skin disorders overview. J Am Acad Dermatol. 2003;48(6 Suppl):S143-8.

15. Sommer C, Cruccu G. Topical Treatment of Peripheral Neuropathic Pain: Applying the Evidence. J Pain Symptom Manage. 2017;53(3):614-29. Figure 5

Page 11 CULTURAL DERMATOSES: A REVIEW 16. Boyd K, Shea SM, Patterson JW. The role 34. Ernst E. Adverse effects of herbal drugs in 53. Brooks J, Reynolds M, Ethnobotanical of capsaicin in dermatology. Prog Drug Res. dermatology. Br J Dermatol. 2000;143(5):923-9. Tattooing of the Gingiva, J Am Dental Assoc. 2014;68:293-306. 2007;138:1097-101. 35. Bhate K, Williams HC. Epidemiology of acne 17. Ghosh SK, Bandyopadhyay D. Concurrent vulgaris. Br J Dermatol. 2013;168(3):474-85. 54. Tinklepaugh A, Norton S, Traditional Gingival allergic contact dermatitis of the index fingers and Tattooing of Maxillary Denture, Arch Dermatol. lips from toothpaste: report of three cases. J Cutan 36. Laude TA. Approach to dermatologic disorders in 2011;147:1334-5. Med Surg. 2011;15(6):356-7. black children. Semin Dermatol. 1995;14(1):15-20.

18. Ghosh SK, Bandyopadhyay D. Chemical 37. Martin AM, Sugathan P. Localised acquired leukoderma induced by colored strings. J Am Acad trichorrhexis nodosa of the scalp hair induced by a Dermatol. 2009;61(5):909-10. specific comb and combing habit - a report of three cases. Int J Trichology. 2011;3(1):34-7. 19. Verma SB. Dermatological signs in South Asian women induced by sari and petticoat drawstrings. 38. Schwartz RA, Seiff DB. Trichorrhexis Nodosa. Clin Exp Dermatol. 2010;35(5):459-61. [Internet]. Medscape; [updated 2017 Jun 6; cited 2017 Jun 8]. Available from: http://emedicine. 20. Verma SB. Striae: stretching the long list of medscape.com/article/1073664-overview. precipitating factors for “true koebnerization” of vitiligo, lichen planus and psoriasis. Clin Exp 39. James J, Saladi RN, Fox JL. Traction alopecia Dermatol. 2009;34(8):880-3. in Sikh male patients. J Am Board Fam Med. 2007;20(5):497-8. 21. Fontana L. Neuroendocrine factors in the regulation of : Excessive adiposity and 40. Karimian-Teherani D, El Shabrawi-Caelen L, calorie restriction. Exp Gerontol. 2009;44:4-5. Tanew A. Traction alopecia in two adolescent Sikh brothers-an underrecognized problem unmasked 22. Kumar AS, Pandhi RK, Bhutani LK. Bindi by migration. Pediatr Dermatol. 2011;28(3):336-8. dermatoses. Int J Dermatol. 1986;25(7):434-5. 41. Ur Rehman H, Asfour NA. Clinical images: 23. Laxmisha C, Nath AK, Thappa .DM Bindi Prayer nodules. Can Med Assoc J. 2010;182(1):E19. dermatitis due to thimerosal and gallate mix. J Eur Acad Dermatol Venereol. 2006;20(10):1370-2. 42. Sanchez MR. Cutaneous diseases in Latinos. Dermatol Clin. 2003;21(4):689-97. 24. Baxter KF, Wilkinson SM. Contact dermatitis from a nickel-containing bindi. Contact Dermatitis. 43. Monk EC, Lowenstein EJ. Thick plaques on the 2002;47(1):55. foot. Cutis. 2014;93(2):E3-4.

25. Ramesh V. Foreign-body granuloma on the 44. English JS, Fenton DA, Wilkinson JD. Prayer forehead: reaction to bindi. Arch Dermatol. nodules. Clin Exp Dermatol. 1984; 9(1):97-8. 1991;127(3):424. 45. Dr. Y. Scarification: An Ancient African Tattoo 26. Redlick F, DeKoven J. Allergic contact Culture. [Internet]. [cited 2018 Feb 19]. Available dermatitis to paraphenylendiamine in hair dye after from: https://afrolegends.com/2015/09/16/ sensitization from black henna tattoos: a report of 6 scarification-an-ancient-african-tattoo-culture. cases. Can Med Assoc J. 2007;176(4):445-6. 46. Fischer N, Hauser S, Brede O, Fisang C, Muller 27. Wang MX, Maranda EL, Cortizo J, Lim S. Implantation of artificial penile nodules–a review V, Jimenez J. Henna-A Temporary Body of Art. of literature. J Sex Med. 2010;7(11):3565-71. JAMA Dermatol. 2016;152(3):290. 47. Yap L, Butler T, Richters J, et al. Penile implants 28. Belhadjali H, Akkari H, Youssef M, Mohamed among prisoners-a cause for concern? PLoS One. M, Zili J. Bullous allergic contact dermatitis to 2013;8(1):e53065. pure henna in a 3-year-old girl. Pediatr Dermatol. 2011;28(5):580-1. 48. Tsunenari S, Idaka T, Kanda M, Koga Y. Self-mutilation. Plastic spherules in penile skin 29. Wolf R, Wolf D, Matz H, Orion E. Cutaneous in yakuza, Japan’s racketeers. Am J Forensic Med reactions to temporary tattoos. Dermatol Online J. Pathol. 1981;2(3):203-7. 2003;9(1):3. 49. Loue S, Loarca LE, Ramirez ER, Ferman 30. Sidwell RU, Francis ND, Basarab T, Morar J. Penile marbles and potential risk of HIV N. Vesicular erythema multiforme-like reaction to transmission. J Immigr Health. 2002;4(2):117-8. paraphenylenediamine in a henna tattoo. Pediatr Dermatol. 2008;25(2):201–4. 50. Hull TH, Budiharsana M. Male circumcision and penis enhancement in Southeast Asia: matters 31. Evans CC, Fleming JD. Images in clinical of pain and pleasure. Reprod Health Matters. medicine. Allergic contact dermatitis from a henna 2001;9(18):60-7. tattoo. N Engl J Med. 2008;359(6):627. 51. Hudak S, McGeady J, Shindel A, Breyer 32. Valsecchi R, Leghissa P, Di Landro A, Bartolozzi B. Subcutaneous penile insertion of domino F, Riva M, Bancone C. Persistent leukoderma after fragments by incarcerated males in Southwest henna tattoo. Contact Dermatitis. 2007;56(2):108-9. United States prisons: a report of three cases. J Sex Med. 2012;9(2):632-4. 33. Gunasti S, Aksungur VL. Severe inflammatory and keloidal, allergic reaction due to para- 52. Marzouk E. Implantation of beads into the phenylenediamine in temporary tattoos. Indian J penile skin and its complications. Scand J Urol Dermatol Venereol Leprol. 2010;76(2):165-7. Nephrol. 1990;24(3):167-9.

HOWARD, ARUTYUNYAN, MAMMINO, SKOPIT Page 12 A New Trigger of Morbilliform Eruption in the Setting of Atypical Infectious Mononucleosis Roxanne Rajaii, DO,* Megan Furniss, DO,** John Pui, MD,*** Brett Bender, DO****

*Dermatology Resident, PGY2, Beaumont Hospital - Farmington Hills, Farmington Hills, MI **Dermatology Resident, PGY4, Beaumont Hospital - Farmington Hills, Farmington Hills, MI ***Dermatopathologist, Beaumont Hospital - Farmington Hills, Farmington Hills, MI ****Dermatologist, Beaumont Hospital - Farmington Hills, Farmington Hills, MI

Disclosures: None Correspondence: Roxanne Rajaii, DO; [email protected]

Abstract Morbilliform eruptions, also commonly referred to as exanthematous or maculopapular drug eruptions, are the most common type of hypersensitivity reaction and can vary in etiology. Antibiotics are a common trigger, most notably amoxicillin or ampicillin in the setting of a concomitant and acute Epstein-Barr virus (EBV) infection. However, other antibiotics have been identified to cause a similar reaction in the setting of EBV. Cephalexin, a commonly used cephalosporin, is the only antibiotic in its class that has been implicated in causing such a phenomenon. We present a unique case of a morbilliform eruption in the setting of EBV secondary to the use of cefepime, further outlining the importance of conservative antibiotic use and awareness of such a reaction in this specific patient population, not only with penicillins but also with a wider spectrum of antibiotics.

Introduction acquired pyelonephritis, as she had been admitted Work-up included the following laboratory tests: Epstein-Barr virus (EBV) infects more than a month prior to that for status asthmaticus. complete blood count, complete metabolic panel, 98% of the world’s adult population and is the Four days later, she presented with an urticarial anti-nuclear antibody, creatinine phosphate kinase, most common cause of infectious mononucleosis morbilliform rash. She was told she was allergic lactic acid, blood cultures, rapid plasma reagent, (IM).1,2 IM is a clinical syndrome characterized by to cefepime, was prescribed diphenhydramine immunoglobulin (Ig) G and immunoglobulin prominent fever, fatigue, malaise, lymphadenopathy, and a weeklong course of ciprofloxacin, and was M titers for rubeola, human immunodeficiency and sore throat.2 It is a self-limiting disease most discharged home the day prior to presenting at virus, cytomegalovirus, EBV, and parvo B19. All commonly seen in older children and young our hospital. labs were within normal limits and demonstrated adults. Symptoms persist over a period of weeks expected adult immunities, with the exception of On examination, the patient had a diffuse to months, typically without sequela; however, a white blood cell count of 12.4 and EBV titers morbilliform and urticarial eruption, with neurologic, hematologic, hepatic, respiratory, positive for IgM and negative for IgG, indicating accentuation on the trunk, neck and upper and psychological complications may occur. In an acute Epstein-Barr virus infection, also known as extremities. The truncal eruption had overlying this patient population, a rash can develop with infectious mononucleosis. A computed tomography marked (Figure 1), while the neck and concomitant use of an antibiotic, most commonly scan of the abdomen and pelvis noted the spleen to extremity eruptions were indurated and urticarial ampicillin or amoxicillin. Clinically, a generalized be at “top normal size,” measuring 13 centimeters. in nature (Figure 2). The patient’s skin was maculopapular, urticarial, or petechial rash develops notably sensitive to touch, and she complained A skin biopsy was taken from each of the within five to 14 days of antibiotic treatment in a 1,2 of generalized itching and stinging. There was an representative areas, one purpuric and the other patient with an acute EBV infection. absence of mucosal involvement, including the urticarial. The biopsy of the left dorsal hand This eruption -- particularly in response to throat, and the face was spared. The exam was showed a focal vacuolar interface dermatitis with amoxicillin or penicillin administration -- is well also positive for left costovertebral angle pain and occasional lymphocytes present at the dermal- known amongst clinicians, especially dermatologists tenderness of the spleen on palpation. The spleen epidermal junction and a sparse underlying and infectious-disease specialists.1,2 Lesser known was palpable 1 cm below the left ribcage. superficial perivascular lymphocytic infiltrate. These is the ability of other classes of antibiotics to trigger this immunologic phenomenon. Although amoxicillin and ampicillin are most commonly the causative agents of this eruption, other penicillin derivatives and other antibiotic classes have also been cited in the literature. These include methicillin, pivampicillin, talampicillin, cephalexin, minocycline, sulfonamides, quinolones, and macrolides including erythromycin and azithromycin. To date, although cephalexin, a commonly used cephalosporin, has been cited to cause this reaction, cefepime, another well-known cephalosporin, has not been implicated in this phenomenon, making this case report novel in adding another antibiotic to the list of potential causes for a morbilliform rash in the setting of infectious mononucleosis.1 Case Report A 29-year-old woman presented to the emergency department with left-sided back and leg pain, leg weakness, fever, rash, nausea, vomiting, and malaise and was admitted for further work-up. Approximately one week prior, she had been admitted to a nearby hospital with similar complaints plus pelvic pain and dysuria, Figure 2. Eruption on the back, diffusely for which she was treated with intravenous (IV) Figure 1. Eruption on the neck and acral sites covered in a tender, morbilliform, markedly cefepime and vancomycin for presumed hospital- with an indurated, urticarial appearance. purpuric rash.

Page 13 A NEW TRIGGER OF MORBILLIFORM ERUPTION IN THE SETTING OF ATYPICAL INFECTIOUS MONONUCLEOSIS findings were consistent with a morbilliform viral antibiotics as the causative agent.4 Although most rarely. Acral sites are often spared in mild cases. exanthem. The biopsy of the left lower abdomen often confined to the skin, severe cases may exhibit However, the face, palms, and soles may be affected. revealed a different histologic pattern consisting involvement of the mucosa and appendages.2,3 Aside from this maculopapular rash, patients often of a superficial to mid perivascular and interstitial experience pruritus, low-grade fever, elevation mixed-cell infiltrate composed of lymphocytes and The pathophysiology of exanthematous drug of acute-phase proteins, and mild eosinophilia.2 neutrophils with extravasated erythrocytes, with eruptions is variable. Many are believed to be a Timing of these eruptions is variable; the consensus, minimal epidermal changes. These findings were result of a delayed-type T-cell mediated (type however, is that the rash commonly develops within 5 consistent with an urticarial . IV) immune reaction. However, the exact five to 14 days of antibiotic initiation.2 In those mechanism by which drugs cause an immune individuals who have been previously sensitized, the Based on the positive acute EBV titers, biopsy response resulting in a maculopapular eruption eruption may appear within only two or three days. results, and clinical presentation, the patient was is poorly understood. The number of drugs that diagnosed with acute infectious mononucleosis have been cited as culprits for such a reaction is If antibiotics are postulated to be the causative complicated by a morbilliform drug eruption vast. The penicillins, cephalosporins, and agents agent, the eruption may even appear up to several elicited by administration of cefepime. The patient with sulfhydryl groups, for instance, are among days after treatment termination. Although the was treated with a two-week steroid taper, beginning the most commonly used drugs that cause a drug eruption in many individuals evolves rapidly, it with IV methylprednisolone and transitioning to eruption.1,2 These specific classes of drugs act reaches its maximum intensity approximately two oral prednisone on discharge. She was also treated as haptens, bind to macromolecules, and then days after discontinuation of the causative agent with topical corticosteroids, antipyretics, and anti- become full antigens.6 Aromatic sulfonamides and resolves within one to two weeks. Many , and fared well. She was discharged (trimethoprim-sulfamethoxazole), anticonvulsant individuals experience desquamation throughout home after a five-day admission. drugs such as carbamazepine and phenytoin, some the process of resolution, and some may suffer from nonsteroidal anti-inflammatory drugs (NSAIDs), post-inflammatory hyperpigmentation. Discussion and paracetamol are other agents that are notorious Exanthematous drug eruption, also known as for causing a drug eruption. However, these specific Diagnosis is often clinical in nature and should morbilliform or maculopapular drug eruption, is the drug classes require biotransformation to form be suspected in an individual who is receiving most common type of hypersensitivity reaction and reactive metabolites.1,6 drug therapy and presents with a new-onset can have a variety of etiologies.5 It often manifests rash.1,2 History of present illness, clinical features, as a diffuse and symmetric eruption of erythematous Although drugs play a crucial role in exanthematous laboratory testing, and sometimes histopathologic macules or small papules that can be triggered within drug eruptions, concomitant diseases, namely viral examination of a skin biopsy are used to confirm approximately one week of drug initiation.3,4 Roughly infections, may predispose an individual to such a suspected diagnosis.15 Treatment involves 2% of individuals exposed to drugs will experience an eruption as well.7-9 Diseases cited in current prompt withdrawal of the offending drug along a cutaneous drug reaction, most commonly with literature that increase an individual’s risk of with symptomatic treatment including topical such an eruption include infection with Epstein- corticosteroids and oral antihistamines for the Barr virus, cytomegalovirus, and human herpes pruritic eruption. Systemic corticosteroids are viruses 6 and 7. In the setting of EBV-caused typically only indicated in severe cases. infectious mononucleosis, a maculopapular rash almost always occurs following the administration This case demonstrates the importance of accurate of ampicillin or amoxicillin.2 In addition, diagnosis and early identification of mononucleosis, immunocompromised patients, namely those particularly in the setting of a new-onset rash after afflicted with human immunodeficiency virus antibiotic initiation. Although not among the (HIV) infection, cystic fibrosis, and autoimmune numerous antibiotics previously reported to cause a disorders, are also at increased risk of developing maculopapular eruption in individuals infected with an exanthematous drug eruption.7,11,12 EBV, this case demonstrates that cefepime can be added to the long list of antibiotics that can cause an While the pathophysiology is not fully understood, immune response in this patient population. While the histopathology of these drug eruptions has been this reaction can be severe, it is important to note better described.13 At the dermoepidermal junction, that it does not imply a true allergy to that specific Figure 3. H&E (200x): Skin biopsy of the left a vacuolar interface dermatitis with scattered antibiotic or even the general drug class, as patients dyskeratotic keratinocytes is often observed. A often tolerate the antibiotic of concern without an dorsal hand showing a focal vacuolar interface 3 superficial perivascular and interstitial infiltrate of adverse reaction in the absence of mononucleosis. dermatitis with occasional lymphocytes lymphocytes, neutrophils, and eosinophils is often In this case, the marked reaction to the antibiotic present at the dermal/epidermal junction and seen under histology as well. Other features that provided a clue to pursuing the correct diagnosis a sparse underlying superficial perivascular may be seen include extravasation of erythrocytes, in a less-than-typical presentation of acute lymphocytic infiltrate. foci of lymphocytes at the dermoepidermal mononucleosis. Ultimately, the severity and sudden junction, and fibrin deposition within the blood onset of the rash after antibiotic administration was vessel walls of the papillary plexus. the key clue to the unifying diagnosis. Epstein-Barr virus is the most common cause of Conclusion infectious mononucleosis, which is characterized by This case report documents a new and previously prominent fever, fatigue, malaise, lymphadenopathy, undocumented trigger of morbilliform eruption, and sore throat.2 However, other viruses, such as cefepime, in the setting of infectious mononucleosis. cytomegalovirus (CMV), HIV, human herpesvirus While antibiotics such as amoxicillin and type 6 (HHV-6), and hepatitis B virus (HBV), can ampicillin have commonly been associated with the also spread through bodily fluids and cause this development of a maculopapular rash in the setting disease.15 Symptoms of infectious mononucleosis of an acute EBV infection, this clinical scenario persist over a period of weeks to months, typically demonstrates the important role other antibiotic without sequela; however, neurologic, hematologic, classes may play in similar drug eruptions. This hepatic, splenic, respiratory, and psychological further supports the importance of conservative complications can arise.2,15 antibiotic use and awareness of such a reaction Figure 4. H&E (200x): Skin biopsy of the left in this patient population with all antibiotics, not lower abdomen showing a superficial to mid- In patients with infectious mononucleosis, a rash just the penicillins. Further reports documenting can develop with concomitant use of an antibiotic, a morbilliform eruption after treatment with perivascular and interstitial mixed-cell infiltrate 14 most commonly ampicillin and amoxicillin. The cefepime in the setting of infectious mononucleosis composed of lymphocytes and neutrophils with rash presents as erythematous macules and papules, are needed for a more definitive association. extravasated erythrocytes; minimal epidermal closely resembling eruptions of viral exanthems. changes are noted. Pustules and bullae may be seen, although very

RAJAII, FURNISS, PUI, BENDER, Page 14 References Acknowledgment 1. Dakdouki GK, Obeid KH, Kanj SS. Azithromycin- Author Contributions: Drs. Rajaii and Furniss had induced rash in infectious mononucleosis. Scand J full access to all of the data in the study and take Infect Dis. 2002; 34(12):939-41. responsibility for the integrity of the data and the accuracy of the data analysis. 2. Jenson HB. Acute complications of Epstein-Barr virus infectious mononucleosis. Curr Opin Pediatr. Study concept and design: Drs. Rajaii, Furniss 2000;12(3):263-8. and Bender

3. Bigby M, Jick S, Jick H, Arndt K. Drug-induced Acquisition, analysis, and interpretation of data: cutaneous reactions: a report from the Boston Drs. Rajaii, Furniss, and Pui Collaborative Drug Surveillance Program on Drafting of the manuscript: Drs. Rajaii, Furniss, 15438 consecutive inpatients, 1975 to 1982. JAMA. and Bender 1986;256(24):3358-63. Critical revision of the manuscript for important 4. Bigby M. Rates of cutaneous reactions to drugs. intellectual content: Drs. Rajaii, Furniss, Bender, Arch Dermatol. 2001;137(6):765-70. and Pui 5. Adam J, Pichler WJ, Yerly D. Delayed drug hypersensitivity: models of T-cell stimulation. Br J Clin Pharmacol. 2011;71:701.

6. Litt JZ. Litt’s Drug Eruptions and Reactions Manual. 16th ed. Informa Healthcare: London, 2010.

7. Stokes SC, Tankersley MS. HIV: practical implications for the practicing-allergist immunologist. Ann Allergy Asthma Immunol. 2011;107:1.

8. Tohyama M, Hashimoto K. New aspects of drug- induced hypersensitivity syndrome. J Dermatol. 2011;38:222.

9. Aota N, Shiohara T. Viral connection between drug rashes and autoimmune diseases: how autoimmune responses are generated after resolution of drug rashes. Autoimmun Rev. 2009;8:488.

10. McCloskey GL, Massa MC. Cephalexin rash in infectious mononucleosis. Cutis. 1997;59:251.

11. Whitaker P, Shaw N, Gooi J, et al. Rapid desensitization for non-immediate reactions in patients with cystic fibrosis. J Fibros. 2011;10:282.

12. Spoerl D, Scherer K, Tyndall A. Aspects of allergy in rheumatology. Clin Exp Rheumatol. 2011;29:560.

13. Justiniano H, Berlingeri-Ramos AC, Sánchez JL. Pattern analysis of drug-induced skin diseases. Am J Dermatopathol. 2008;30:352.

14. Bircher AJ. Uncomplicated drug-induced disseminated exanthemas. 2012;97:79-97.

15. Ebell MH. Epstein-Barr virus infectious mononucleosis. Am Fam Physician. 2004;70:1279.

Abbreviations and acronyms: EBV: Epstein Barr Virus CMV: Cytomegalovirus IM: Infectious mononucleosis CBC: Complete blood count UA: Urinalysis CMP: Complete metabolic panel CT: Computed Tomography ANA: Anti-nuclear anti-body CPK: Creatinine phosphate kinase HIV: Human Immunodeficiency virus RPR: Rapid plasma reagent

Page 15 A NEW TRIGGER OF MORBILLIFORM ERUPTION IN THE SETTING OF ATYPICAL INFECTIOUS MONONUCLEOSIS Induction of Vitiligo-like Hypopigmentation with Use of Topical Imiquimod for Superficial and Nodular Basal Cell Carcinomas Roxanne Rajaii, DO,* Elizabeth Young, DO,** Sean Stephenson, DO,*** Michelle Legacy, DO,**** Lynn Sikorski, DO****

*Dermatology Resident, PGY3, Beaumont Hospital – Farmington Hills, Farmington Hills, MI **Traditional Rotating Intern, Capital Region Medical Center – Jefferson City, MO ***Dermatopathologist, Dermatopathology Laboratory of Central States – Troy, MI ****Dermatologist, Beaumont Hospital – Farmington Hills, Farmington Hills, MI

Disclosures: None Correspondence: Roxanne Rajaii, DO; [email protected]

Abstract This case report presents a 60-year-old Caucasian male who had been treated with imiquimod 5% cream for numerous superficial and nodular basal cell carcinomas, with treatments five times per week for six weeks, resulting in vitiligo-like hypopigmentation that eventually extended beyond the borders of the treatment area. Imiquimod is an immune-response modulator currently FDA-approved for the treatment of external anogenital , actinic keratoses, and superficial basal cell carcinomas. Hypopigmentation is a rare side effect of topical imiquimod use, but it has been noted in previous literature of imiquimod treatment for both condylomata acuminata and superficial and nodular basal cell carcinomas. Previous studies report this phenomenon being attributed to the drug’s Th1-stimulating activity. With this striking patient presentation, we aim to demonstrate the importance of discussing this rare side effect with any patient who is to be treated with imiquimod, particularly in cases involving younger patients or lesions in cosmetically sensitive areas.

Introduction that after a full course of therapy, the macules began to depigmentation. On histopathological examination, Topical imiquimod 5% is an immune-response- coalesce and enlarge to form patches several times the both areas showed evidence of mild post-inflammatory modifying cream that induces cellular immune responses size of the initial lesion and beyond the area of cream hypopigmentation (Figures 4a-d) with some retained like local release of pro-inflammatory cytokines and application. The most striking areas of involvement stimulation of antigen-presenting cells. These effects included the arms and chest (Figures 1-3). 2x make it a treatment modality for condyloma acuminata, The patient denied any other significant irritation and actinic , and basal cell carcinoma, particularly side effects with topical application of imiquimod but the superficial subtype. The side-effect profile of topical did recall having feelings “similar to having the flu” imiquimod is well known, and the more common during each treatment course. He denied use of any potential adverse reactions of erythema, xeroderma, other topical treatments, including over-the-counter crusting, and irritation are regularly discussed. One therapies, to the areas being treated with imiquimod. of the least common side effects, dyspigmentation, In this patient, despite discontinuation of imiquimod particularly hypopigmentation, is dramatic when and over several years of follow-up, repigmentation in it occurs but seldom encountered, so it is often not these areas was not observed. Furthermore, the patient discussed with patients prior to treatment. Our case experienced the same side effect with each application 4x discusses a patient who experienced hypopigmentation of imiquimod. Although topical therapies to help with not only at the treatment site but also beyond the well- repigmentation of these lesions were offered to the circumscribed treatment area. patient, he refused treatment for the hypopigmented Case Report areas and denied being bothered by their appearance. This case presents a 60-year-old Caucasian male at our The patient’s medical history included osteoarthritis clinic with a significant history of numerous, biopsy- and hyperlipidemia. He denied any personal or family proven, superficial and nodular basal cell carcinomas history of autoimmune disorders and depigmenting dated from August 2010 to present. They were located diseases such as vitiligo, thyroid disease, Addison’s on his arms, chest, and back and were treated with disease, and alopecia areata. The patient also denied any 10x topical imiquimod 5% cream five times per week for personal or family history of diabetes with the exception a total treatment course of six weeks to each lesion. On of his father, who suffered from diabetes mellitus type examination, the patient had multiple hypopigmented II. The patient’s surgical history was significant for macules coalescing into large hypopigmented patches bilateral knee surgery. The patient denied any tobacco involving and extending locally far beyond the use. His medications included simvastatin. treatment site. The patient reported that approximately two weeks following every six-week treatment course, Two punch biopsies were taken from affected he observed hypopigmented macules developing at the areas on the left anterior shoulder and left anterior site of application. He stated that these hypopigmented proximal upper arm, respectively, in order to macules were initially the size of the initial lesion but distinguish between hypopigmentation and true Figure 1 Figure 2 Figure 3 20x

Figures 4a-d. (H&E, 2x-20x) Biopsy of a Figures 1-3. Patient with multiple hypopigmented macules coalescing into large hypopigmented hypopigmented patch showing retained patches at the site of topical imiquimod therapy. melanocytes at the dermoepidermal junction.

RAJAII, YOUNG, STEPHENSON, LEGACY, SIKORSKI Page 16 melanocytes at the dermoepidermal junction. 10x References MITF-1 showed positively staining melanocytes at the 1. Mashiah J, Brenner S. Possible mechanisms in dermoepidermal junction (Figures 5a-b). A periodic the induction of vitiligo‐like hypopigmentation acid-Schiff stain showed no fungi. by topical imiquimod. Clin Exp Dermatol. Discussion 2008;33(1):74-6. Vitiligo-like hypopigmentation is a rare side effect 2. Dahl M. Imiquimod: A cytokine inducer. J Am of topical imiquimod application. Of the few cases Acad Dermatol. 2002;47(4):205-8. that have been reported, the majority occurred following treatment of condyloma acuminate, 3. Kim C, Ahn J, Kang S, Hwang H, Lee M, and a small subset followed treatment of basal 5-7,11 20x Pyun J, Kang H. Imiquimod induces apoptosis cell carcinomas. The exact mechanism of the of human melanocytes. Arch Dermatol Res. hypopigmentation, often with concurrent , 2009;302(4):301-6. has been debated, and several theories are currently in favor. 4. Serra M, Menicanti C, Pennacchioli E, Tosti G. Vulvar vitiligo-like depigmentation and multiple Imiquimod’s stimulation of toll-like receptor 7 halos of hypomelanosis at the trunk following with up-regulation of nuclear factor-kappaB and treatment with imiquimod 5% cream for vulvar subsequent induction of multiple pro-inflammatory condylomata: casual or related events? An Bras cytokines, along with stimulation of antigen- Dermatol. 2014;89(5):806-7. presenting cells and other cellular immune-response Figures 5a-b. (10x-20x) Positive mediators, is responsible for the treatment’s efficacy. MITF-1 staining of melanocytes at the 5. Jacob S, Blyumin M. Vitiligo-like The T-helper-1 subset population of lymphocytes dermoepidermal junction. Hypopigmentation with Poliosis following induces further proliferation of T-helper cells and undergoing treatment with imiquimod. Treatment of Superficial Basal Cell cytotoxic T-cells. Pro-inflammatory cytokines Carcinoma with Imiquimod. Dermatol Surg. such as tumor necrosis factor (TNF)-α, interferon 2008;34(6):844-5. (IFN)-α, interleukin (IL)-6, IL-8, IL-10, Conclusion In conclusion, vitiligo-like hypopigmentation and IL-12 are produced. IL-12 stimulates the following topical imiquimod use is a rare side 6. Sriprakash K, Godbolt A. Vitiligo-like existing T-helper-cell subset to produce more effect and one uncommonly discussed with patients depigmentation induced by imiquimod treatment IFN-α and IL-2, further ensuring a cascade before treatment. Even less likely is extension of of superficial basal cell carcinoma. Australas J of pro-inflammatory cytokines and activated Dermatol. 2009;50(3):211-3. 1,2 the hypopigmentation beyond the confines of T-lymphocytes. IFN-α, IL-6, IL-8, and IL-10 the treatment area. Considering the striking and are known mediators in the pathogenesis of vitiligo, 7. Grahovac M, Ehmann LM, Flaig M, often persistent course of the hypopigmentation, and it is logical to believe imiquimod could induce Reibke R, Wollenberg A. Giant Basal Cell 1,2,5 we recommend more practitioners have detailed similar pigmentary changes. Carcinoma. Improvement and Vitiligo-Like discussions of imiquimod’s extensive side-effect Hypopigmentation after Intermittent Treatment profile with patients before recommending its use, With this robust increase of the T-lymphocyte with 5% Imiquimod. Acta Dermatovenerol Croat. particularly in patients concerned with cosmesis. population, a small subset of autoreactive cytotoxic 2012;20(4):272-83. T-cells against melanocytes can be observed. The autoreactive T-cells’ destruction of the local 8. Schöfer H, Van Ophoven A, Henke U, Lenz melanocyte population is believed to cause of some T, Eul A. Randomized, comparative trial on cases of vitiligo-like hypopigmentation following the sustained efficacy of topical imiquimod 5% imiquimod use. This mechanism would also explain cream versus conventional ablative methods the extension of pigmentary change beyond our in external anogenital warts. Eur J Dermatol. patient’s treatment area, as well as reports of halo 2006;16(6):642-8. phenomena occurring around pre-existing nevi with imiquimod treatment of distant sites.1,4,8 9. Stefanaki C, Nicolaidou E, Hadjivassiliou M, Melanocytes have also been shown to activate toll- Antoniou C, Katsambas A. Imiquimod-induced like receptor 7, the target of imiquimod, which vitiligo in a patient with genital warts. J Eur Acad could further explain the apoptosis and depletion of Dermatol Venereol. 2006;20(6):755-6. the local melanocyte population.11,13 10. Long F, Zhao L, Qian Y. Vitiligo or Vitiligo-like Permanent reduction in the local melanocyte Hypopigmentation Associated with Imiquimod population may explain the persistent nature of Treatment of Condyloma Acuminatum: Not a the pigmentary change.1,3,4,9 In a study of patients Casual Event. Chin Med J. 2017;130(4):503. with vitiligo-like hypopigmentation following imiquimod treatment, all but one case was found 11. Wang HW, Miao F, Shi L, Lü T, Huang Z, to be permanent. Stefanaki et al. observed a case Wang XL. Imiquimod-induced localized vitiligo of 2% repigmentation in a patient with vitiligo-like in wife and lichen planus in husband. Chin Med J. hypopigmentation following imiquimod treatment 2013;126(13):2593. for condyloma.9 One proposed non-immunological mechanism of depigmentation following 12. Li W, Xin H, Ge L, Song H, Cao W. imiquimod use is the benzyl alcohol found in the Induction of vitiligo after imiquimod treatment cream vehicle inducing a contact leukoderma.12 of condylomata acuminata. BMC Infect Dis. 2014;14(1):329. Hypopigmentation is an exceedingly uncommon side effect, and the extension beyond the circumscribed 13. Taylor JS, Maibach HI, Fisher AA, Bergfeld treatment area is even rarer; we believe this supports WF. Contact leukoderma associated with the use of an immunologic mechanism for pigmentary change hair colors. Cutis. 1993;52(5):273-80. following imiquimod use.4-7,9,12 There are no case reports of repigmentation in areas of basal cell 14. Kang H, Park T, Jin S. Imiquimod, a Toll-Like carcinomas treated with imiquimod complicated Receptor 7 Agonist, Inhibits Melanogenesis and by vitiligo-like hypopigmentation. This further Proliferation of Human Melanocytes. J Invest necessitates a thorough prescribing discussion so Dermatol. 2009;129(1):243-6. a patient can make an informed decision before

Page 17 INDUCTION OF VITILIGO-LIKE HYPOPIGMENTATION WITH USE OF TOPICAL IMIQUIMOD FOR SUPERFICIAL AND NODULAR BASAL CELL CARCINOMAS Acknowledgment Author contributions: Drs. Rajaii and Young had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Drs. Rajaii, Young, Legacy, and Sikorski

Acquisition, analysis, and interpretation of data: Drs. Rajaii, Stephenson, Legacy, and Sikorksi

Drafting of the manuscript: Drs. Rajaii, Young, Stephenson, Legacy, and Sikorksi

Critical revision of the manuscript for important intellectual content: Drs. Rajaii, Young, Stephenson, Legacy, Sikorksi, and Lacasse

Abbreviations and acronyms IL: Interleukin INF: Interferon TNF: Tumor necrosis factor

RAJAII, YOUNG, STEPHENSON, LEGACY, SIKORSKI Page 18 An Unusual Presentation of Pachydermodactyly: A Case Presentation and Discussion Abby Russell, BSN,* Albert E. Rivera, DO,** Nathan E. Lee, MD***

*Medical Student, 4th year, Edward Via Virginia College of Osteopathic Medicine, Blacksburg, VA **Dermatologist and Mohs Surgeon, Southeastern Skin & Dermatology, Madison, AL ***Dermatopathologist, Pathology Associates, Huntsville, AL

Abstract Pachydermodactyly (PDD) is an infrequently diagnosed, benign joint swelling of the proximal interphalangeal joints. It is most frequently found in males and is associated with a variety of disorders and syndromes, including psychiatric and congenital conditions. The majority of cases are associated with repetitive mechanical trauma to the hands. Many other disorders mimic PPD, leading to extensive testing. We report a case of proximal interphalangeal joint swelling in a young adult male with a history of congenital heart disease.

of normal range included angiotensin-converting extremities or extension into the proximal hand, Introduction enzyme, which was slightly elevated at 87 U/L which is further described as pachydermodactyly Pachydermodactyly (PDD) is a benign condition 6 typified by skin thickening in the joint spaces of the (reference range 14-82 U/L). transgrediens. Originally, this disorder was hands, particularly the proximal interphalangeal described as a variant of knuckle pads; however, A 4-mm punch biopsy of the proximal (PIP) joints. The term comes from the Greek for unlike knuckle pads, PDD is associated with ulnar interphalangeal joint of the right ring finger was “thick-skin-finger.” PDD was first described by Bazex and radial expansion of the soft tissue without obtained. Histopathological sections demonstrated 4,7 et al. in 1973 as “pachidermie digitale des primières dorsal growth. The typical manifestation presents slight epidermal acanthosis with thickening of the most similarly to juvenile idiopathic arthritis, phalanges,” and the term “pachydermodactyly” was 8 1,2 dermis. Within the dermis there were thick collagen coined by Verbov in 1975. It is frequently found psoriatic arthritis, and rheumatoid arthritis. bundles ordered in a haphazard arrangement, in asymptomatic, healthy, adolescent males and has Because of this, many patients, such as the one consistent with pachydermodactyly (Figure 2). some associations with hereditary disorders and in this case, undergo numerous lab and imaging repetitive trauma. On histopathology, the findings studies to evaluate and treat possibly disfiguring Differential Diagnosis disorders. The lack of pain, tenderness, or functional include increased accumulation of irregular bundles Multiple etiologies for this patient’s condition of thickened collagen in the dermis, typically with limitations despite swelling of the joints in PDD 3 were considered. The most benign cause considered helps differentiate this diagnosis from more serious no other distinguishing characteristics. Few cases was knuckle pads (KP), which can be primary have been reported in the literature. We present a possibilities, such as juvenile idiopathic arthritis or (idiopathic) or secondary. The differential diagnosis rheumatoid arthritis. case of PDD in an 18-year-old male with a history also included juvenile idiopathic arthritis, psoriatic of congenital heart disease, as well as a review of arthritis, rheumatoid arthritis, gouty tophus, PDD has been associated with various disorders in this disease. juvenile hyaline fibromatosis, and subcutaneous the past but is frequently idiopathic. Familial PDD granuloma annulare. has been reported, but it is uncommon.9 It has Case Report also been suggested as another cutaneous finding An 18-year-old male presented with continuing Diagnosis and Treatment 10 complaints of progressive, painless swelling of the in and Ehlers-Danlos. PDD The histopathology and clinical history led to is associated with repetitive mechanical friction, proximal interphalangeal joints of both hands. the diagnosis of pachydermodactyly. The patient He was referred by a pediatric rheumatologist including repetitive-motion activities, along with was reassured that this is a benign disorder and manual labor and psychiatric disorders. Tic-like for evaluation of a possible connective-tissue was instructed to avoid excess manipulation of disorder. His mother reported the swelling of his behaviors, obsessive-compulsive disorder, autism, the hands. Because of his congenital medical and playing video games have all been linked to knuckles has worsened since childhood. The patient conditions, genetic testing for possible syndromic 11-13 described his knuckles as slightly pink and swollen, PDD. These associations with PDD are believed presentation of a larger genetic condition was to be a result of trauma, such as knuckle-cracking, with no nodularity. Symptoms did not improve recommended. After referral to a geneticist, our or worsen with activity. He denied any pruritus, frequent interlocking of the fingers, or squeezing of patient elected to postpone further testing due to the joints. fatigue, fever, joint pain, easy bleeding or bruising. logistical constraints. Furthermore, the patient reported no rashes, The diagnosis of PDD is based on clinical picture, arthralgias, fever, or gastrointestinal symptoms. laboratory findings, and imaging. Laboratory The patient denied any recent trauma or repetitive- Discussion Pachydermodactyly is a rare, benign disorder of the findings are consistent with a non-inflammatory or motion activities. Medical history was significant skin characterized by swelling of the soft tissue at non-immunological response. Imaging reveals soft- for asthma, allergic rhinitis, of the proximal interphalangeal joints, particularly tissue swelling with possible increased vascularity unknown etiology, and congenital heart disease. 6,8,14 in young males. Most commonly, the second, but without any injury to or joint spaces. His surgical history included repair for coarctation third and fourth digits are affected, sparing the of the aorta and bicuspid aortic valve, for which thumb.2 Occasionally, the disease may involve other he was followed by a cardiologist. Birth history was significant for his being one of triplets. The patient’s siblings did not have similar complaints, and other family history was noncontributory. He had been treated previously with urea 20% topical cream and clobetasol 0.05% for the swelling with no improvement. Physical exam showed lateral swelling of the PIP joints of the hands (Figure 1). The remainder of the exam was benign.

Testing Radiographs of the hands ordered by the rheumatologist showed no bony changes. Complete blood count, liver function tests, C-reactive protein, erythrocyte sedimentation rate, rheumatoid Figure 2. Histopathological examination shows arthritis panel, antinuclear antibody testing, and thickening of the dermis with collagen bundles serum ferritin were within normal limits. Labs out Figure 1. Increased lateral volume on the fingers. in a haphazard arrangement.

Page 19 AN UNUSUAL PRESENTATION OF PACHYDERMODACTYLY: A CASE PRESENTATION AND DISCUSSION Histologically, PDD is defined by non-specific References changes like epidermal and increased 1. Verbov J. Letter: Pachydermodactyly: a variant collagen deposition in a haphazard arrangement. of the true knuckle pad. Arch Dermatol. 1975 There is typically an increased amount of type III Apr;111(4):524. and V collagen compared to normal skin.8,15 2. Pereira JM, Pereira FC, Pereira VN. Because of its benign nature, treatment is Interphalangeal pads on pachydermodactyly. An symptomatic. For many patients, discontinuing Bras Dermatol. 2004 May;79(3):313-21. repetitive-motion or trauma-inducing activities is first-line treatment. Controlling mechanical trauma 8 3. Seo SH, Sung HW. A case of may resolve or reverse the appearance of swelling. pachydermodactyly. Ann Dermatol. 2011 For those patients with tics or compulsive hand May;23(2):258-61. doi: 10.5021/ad.2011.23.2.258. movements, treatment focuses on the underlying psychiatric disorder. For those wishing to reduce 4. Weiss E, Amini S. A novel treatment for the cosmetic appearance of PDD, options include knuckle pads with intralesional . Arch topical and intralesional steroids or surgical 6,8 Dermatol. 2007;143(11):1447-62. doi:10.1001/ intervention. archderm.143.11.1458. Conclusion 5. Nofal A, Sanad M, Assaf M, et al. Juvenile The case presented herein is an example of hyaline fibromatosis and infantile systemic pachydermodactyly in a patient with a history hyalinosis: a unifying term and a proposed grading of congenital heart disease. Our patient did not system. J Am Acad Dermatol. 2009;61(4):695-700. present with historical findings of repetitive doi:10.1016/j.jaad.2009.01.039. mechanical trauma or any psychiatric disorders, which prompted further testing. This may indicate 6. Beltraminelli H, Itin P. Pachydermodactyly--just that PDD could be part of a larger genetic a sign of emotional distress. Eur J Dermatol. 2009 syndrome in some cases and could lead to a better Jan-Feb;19(1):5-13. doi: 10.1684/ejd.2008.0543. understanding of associations between PDD and other disorders. Because of the presentation of 7. Tolis K, Stavropoulos N, Mavrogenis A, this disorder with other multisystem concerns, this Spyridonos S. Pachydermodactyly: An Unknown patient was encouraged to seek further testing. In Entity. J Hand Surg Am. 2016 Aug;41(8):e239-41. the future, similar reported cases could potentially doi: 10.1016/j.jhsa.2016.05.013. strengthen a syndromic association. 8. Chen CK, Shyur SD, Chu SH, Huang LH, Kao YH, Liu LC. Pachydermodactyly: Three new cases in Taiwan. J Microbiol Immunol Infect. 2015 Jun;48(3):340-4. doi: 10.1016/j.jmii.2012.09.002.

9. Dallos T, Oppl B, Kovács L, Zwerina J. Pachydermodactyly: a review. Curr Rheumatol Rep. 2014;16(9):442. doi: 10.1007/s11926-014- 0442-7.

10. Russo F, Rodriguez-Pichardo A, Camacho F. Familial pachydermodactyly. Acta Derm Venereol. 1994 Sep;74(5):386-7.

11. Lo WL, Wong CK. Localized pachydermodactyly in tuberous sclerosis. Clin Exp Dermatol. 1993 Mar;18(2):146-7.

12. Cabanillas M, Monteagudo B, León- Muíños E, Suárez-Amor O. Pachydermodactyly in a young girl: cutaneous manifestation of a psychiatric disorder? Pediatr Dermatol. 2010 May-Jun;27(3):306-8. doi: 10.1111/j.1525- 1470.2010.01146.x.

13. Sagransky MJ, Pichardo-Geisinger RO, Muñoz-Ali D, Feldman SR, Mora DC, Quandt SA. Pachydermodactyly from repetitive motion in poultry processing workers: a report of 2 cases. Arch Dermatol. 2012 Aug;148(8):925-8. doi: 10.1001/ archdermatol.2012.983.

14. Small S, Murthy V, Sridhar AV. A 12-year- old boy presenting with unilateral proximal interphalangeal joint swelling. BMJ Case Rep. 2011 Apr 13;2011. pii: bcr0120113719. doi: 10.1136/ bcr.01.2011.3719.

15. Reichert CM, Costa J, Barsky SH, Claysmith AP, Liotta LA, Enzinger FM, Triche TJ. Pachydermodactyly. Clin Orthop Relat Res. 1985 Apr;(194):252-7.

RUSSELL, RIVERA, LEE Page 20 Aleukemic Leukemia Cutis - A Preview of Systemic Malignancy: A Case Report and Literature Review Ryan Jones, DO,* Mark Kuriata, DO**

*Dermatology Resident, Lakeland Medical Center, Saint Joseph, MI; Michigan State University, East Lansing, MI **Program Director, Dermatology Residency, Lakeland Medical Center, Saint Joseph, MI; Michigan State University, East Lansing, MI

Disclosures: None Correspondence: Ryan Jones, DO; 1234 Napier Ave., Saint Joseph, MI 49085; Ph: 269-429-7546; Fax: 269-429-0807; [email protected]

Abstract We present the case of an 83-year-old female who presented with red macules of varying sizes, including one area of focal ulceration located on the pretibial region of her lower extremities. The lesions had been present for three weeks. She denied any systemic symptoms or current complaints at the time of presentation. Her past medical and surgical histories were non-significant with the exception of a hospitalization for acute colitis three months prior to presentation (12 weeks prior to rash development). Punch biopsies were obtained, and histology showed an atypical lymphocytic infiltrate consistent with leukemia cutis. The patient was referred to Hematology/Oncology. Initial peripheral blood flow cytometry did not reveal atypical leukocytes, resulting in the diagnosis of aleukemic leukemia cutis. Six weeks later, she underwent a core bone- marrow biopsy and a repeat flow cytometry that revealed atypical leukocytes, leading to a final diagnosis of acute monocytic leukemia.

Case Report replacements, and squamous cell carcinoma of the extravasation (Figures 2, 3). A periodic acid-Schiff An 83-year-old female presented with a chief upper lip. Social history included no alcohol use stain for fungi was negative for both specimens. complaint of multiple skin lesions on her bilateral and no history of smoking. Current medications Immunohistochemistry staining was then applied lower extremities, in particular on the pretibial included low-dose aspirin, bisoprolol fumarate, to the biopsy samples. In both biopsies, the atypical- regions. The lesions first appeared three weeks prior digoxin, lisinopril, and pravastatin. She denied any appearing cells were highlighted by CD68 (Figures to presentation to the office. She stated that she known allergies. 4, 5). CD3 staining was also completed and showed awoke with the lesions present and did not note only focally positive in one biopsy specimen and Upon examination, the patient had non-pruritic, any associated events or activity the night before. negative in the other. Last, a CD20 stain was violaceous, poorly demarcated macules of varying They had not changed in appearance or number sizes on both pretibial areas (Figure 1). On the of lesions since onset. The lesions did not , had patient’s left lower extremity, one of the lesions had no drainage, and were not painful. She denied any focal ulceration with a distinct border; otherwise, other symptoms, including fevers, chills, fatigue, no secondary characteristics were appreciated. A nausea, vision changes, oral lesions, or any other full body examination was performed and revealed rash/cutaneous changes elsewhere. She also denied no other dermatologic involvement. a history of lower extremity edema or trauma. Pertinent recent history included a hospitalization The differential at that time included excoriations, three months prior for atrial fibrillation and an traumatic ecchymosis, vasculopathy, leukocytoclastic acute colitis of unknown etiology. She did not have , Schamberg’s disease, and early stasis any cutaneous manifestations prior to, during, or dermatitis changes. Two 4-mm punch biopsies, one immediately after the hospitalization. The only from each lower extremity (right proximal pretibial Figure 4. (10x) CD68 stain highlighting health change since discharge was an anemia of and left proximal pretibial locations), were obtained monocyte proliferation seen on H&E. uncertain etiology without white blood cell count and sent for histology. On histologic exam, both abnormalities, and she had been following up with specimens showed a superficial dermal infiltrate of her primary care provider periodically with no atypical inflammatory cells that were enlarged and further changes to her health. hyperchromatic with surrounding red blood cell The patient had a past medical/surgical history of anxiety, arthritis, atrial fibrillation, hypertension, hypercholesterolemia, breast cancer with mastectomy (right), cholecystectomy, bilateral hip

Figure 5. (20x) CD68 stain highlighting perivascular proliferation of atypical monocytes.

Figure 2. (10x): H&E stain showing superficial dermal and perivascular inflammatory infiltrate.

Figure 1. Gross presentation of suspicious Figure 6. Needle core bone-marrow biopsy macules and one focal ulceration, prior to Figure 3. (20x): H&E stain showing atypical demonstrating hypercellularity and proliferation biopsy/treatment. perivascular inflammatory infiltrate. of atypical monocytes.

Page 21 ALEUKEMIC LEUKEMIA CUTIS - A PREVIEW OF SYSTEMIC MALIGNANCY: A CASE REPORT AND LITERATURE REVIEW applied and was negative in both specimens. Based positive for lysozyme, CD68, CD15, CD43, and References on these findings, leukemia cutis was the suspected CD45 but can be differentiated from monocytic 1. Cho-Vega JH, Medeiros LJ, Prieto VG, Vega diagnosis, and the slides were sent out to a second types by chloroacetate esterase in some cells and F. Leukemia cutis. Am J Clin Pathol. 2008 lab with expertise in this area for final confirmation. a more distinct grenz zone. Chronic lymphocytic Jan;129(1):130-42. This second opinion confirmed the diagnosis. leukemia cutis can be ruled out with negative CD3 and CD45 staining. Finally, acute T-cell leukemia 2. Desch JK, Smoller BR. The spectrum of The patient was referred to Hematology/ is differentiated by positive staining with CD3, 5,6 cutaneous disease in leukemias. J Cutan Pathol. Oncology after being seen in the office to CD4, CD5, and CD25. 1993 Oct;20(5):407-10. discuss the pathology results. The hematologist obtained new lab testing, which showed Leukemia cutis is most commonly diagnosed in 3. Horlick HP, Silvers DN, Knobler EH, Cole normocytic anemia with a hemoglobin of 10.1 patients with known/active systemic leukemia; J T. Acute myelomonocytic leukemia presenting g/dL and no leukemic cells detected in the however, in rare cases, skin involvement can occur as a benign-appearing cutaneous eruption. Arch blood on flow cytometry. Six weeks later, the before involvement of bone marrow or peripheral Dermatol. 1990 May;126(5):653-6. patient underwent computed tomography- blood, termed “aleukemic leukemia cutis” or 1 guided bone marrow core biopsy, which showed “primary extramedullary leukemia.” Aleukemic 4. Travassos AR, Soares-de-Almeida L, Kutzner increased hypercellularity with 60% immature leukemia cutis is extremely rare, occurring in only 7 H, Guerra L, Alves do Carmo J, Filipe P, Marques monocytes/promonocytes (Figure 6). She had 7% of all leukemia cutis cases. While rare, there MS. Sweet syndrome-like neutrophilic infiltrate a repeat flow cytometry completed on the same have been reports in the literature regarding this as initial presentation of acute myelogenous day, which also found abnormal monocytic cells condition since it was first termed and reported in leukemia. Am J Dermatopathol. 2014 and monocytic precursors. This was interpreted 1948 by Epstein in the Archives of Dermatology Oct;36(10):e167-70. by the hematologist to be compatible with and Syphiology.8 The majority of the articles acute monocytic leukemia (AML). Due to the are either case reports or case series reports. No 5. Jin CC, Martinelli PT, Cohen PR. What are These grave prognosis, the oncologist recommended formal, large-scale epidemiology studies have been Erythematous Skin Lesions? The Dermatologist. palliative treatment versus observation only. The completed to date, but a review in 2016 by Pena- 2012 Mar:20(3). patient elected for palliative chemotherapy and Romero et al. involving 27 patients found that was immediately started on azacytidine daily for 60% of those affected were male, the mean age 6. Su WP. Clinical, histopathologic, and five consecutive days given every four weeks. At of diagnosis was 42 years, and the predominant immunohistochemical correlations in leukemia the time of writing, the patient remains alive and leukemia type was acute myeloid leukemia.9 cutis. Semin Dermatol. 1994 Sep;13(3):223-30. well after six months of this treatment regimen. Another review described the observed clinical presentation as polymorphic, varying from a single 7. Yonal I, Hindilerden F, Coskun R, Dogan OI, Discussion nodule to erythroderma.7 Nalcaci M. Aleukemic Leukemia Cutis Manifesting In the large majority of cases with leukemia- with Disseminated Nodular Eruptions and a associated cutaneous disease, there is no direct Overall, the diagnosis of aleukemic leukemia cutis Plaque Preceding Acute Monocytic Leukemia: A involvement of neoplastic leukocytes in the has an associated poor prognosis with an aggressive Case Report. Case Rep Oncol. 2011;4(3):547-54. manifestations. Cutaneous disease usually seen clinical course after original diagnosis similar to in patients with leukemia includes petechiae, classic leukemia cutis.5,12 The average time between 8. Epstein S. A case for diagnosis; aleukemic purpura, ecchymosis, vasculitides, neutrophilic confirmed diagnosis of aleukemic leukemia cutis leukemia of the skin? lymphosarcoma? Arch Derm dermatoses, thrush, disseminated zoster, and and involvement of blood or bone marrow is Syphilol. 1948 Mar;57(3 Pt. 2):586-8. herpes simplex.1 When neoplastic leukocytes usually several months and typically less than one directly invade the skin, the disease is known year.2,3,10 Another recent review found the mean 9. Peña-Romero AG, Domínguez-Cherit J, as leukemia cutis. Leukemia cutis is a clinical duration between diagnosis and death to be about Méndez-Flores S. Leukemia cutis: clinical manifestation of cutaneous lesions resulting from 10 months.9 However, longer latency periods have features of 27 Mexican patients and a review the infiltration of any type of neoplastic leukocytes been rarely reported, including one case in which of the literature. Gac Med Mex. 2016 Sep- into the , dermis, or subcutaneous the development occurred seven years after original Oct;152(5):439-43. tissue. Resulting cutaneous manifestations are diagnosis.11 Based on the immunologic subtype, variable and most commonly include multiple patients with aleukemic leukemia cutis are managed 10. Benez A, Metzger S, Metzler G, Fierlbeck small erythematous/hemorrhagic papules as the same way as patients with classic leukemia G. Aleukemic leukemia cutis presenting as benign- well as plaques, nodules, ecchymosis, ulceration, cutis and patients with diagnosed blood or bone appearing exanthema. Acta Derm Venereol. 2001 and erythroderma.2,3 Sites of involvement most marrow involvement.2,12 There are reported cases Jan-Feb;81(1):45-7. commonly include the legs, followed by the arms, of successful treatment remission using a variety of back, face, scalp, and face, with a predilection regimens in younger adult patients.13,14 11. Narváez-Moreno B, Pereyra-Rodríguez JJ, for areas of current or previous inflammation.1 Pulpillo-Ruiz A, Cabrera-Pérez R, Espigado- The tendency of leukemia cutis to present in Conclusion Tocino I, Conejo-Mir J. Acute myeloid leukemia areas of inflammation has been exemplified in Aleukemic leukemia cutis is a rare cutaneous 7 years after aleukemic leukemia cutis. Int J cases involving Sweet’s syndrome.2,4 Overall, disease that is an early manifestation of systemic Dermatol. 2015 Apr;54(4):459-61. leukemia cutis is more commonly seen in lymphoproliferative disease. The distinctive feature children with leukemia than adults.5 Of specific is atypical myeloproliferative cells in the skin 12. Vishalakshi V, Torsekar RG, Shinde types of leukemia, monocytic leukemias are more prior to their detection in the peripheral blood, a S. Aleukemic leukemia cutis. Indian J Dermatol commonly associated with direct blast infiltration distinguishing characteristic from classic leukemia Venereol Leprol. 2007 Mar-Apr;73(2):109-11. of the skin, which has been estimated to occur cutis. The cutaneous manifestations can occur 13. Martínez-Poventud G, Fradera J, Pérez S, in 10% to 15% of patients with acute myeloid anywhere in the body but tend to favor areas 1,3 Fernández A, Pacheco E, Acabá L, López-Enriquez leukemia (AML). of preexisting inflammation. Progression from histologic diagnosis on skin biopsy to detection A, Román-Díaz A, Castro-Montalvo J, Vélez- The diagnosis of leukemia cutis requires a full- in blood typically evolves over several months, García E. Aleukemic leukemia cutis preceding thickness skin biopsy with immunohistochemical although latency periods can rarely last years. When acute monocytic leukemia: a case report. P R analysis. Histological findings associated compared to classic leukemia cutis, there is no Health Sci J. 2008 Sep;27(3):256-8. with leukemia cutis include a combination of significant difference in prognosis or progression. 14. Chang H, Shih LY, Kuo TT. Primary aleukemic perivascular, periadenexal, interstitial, nodular Overall, the diagnosis of aleukemic leukemia cutis, myeloid leukemia cutis treated successfully with infiltrates of the dermis and subcutis, with sparing much like classic leukemia cutis, carries a very combination chemotherapy: report of a case of a narrow area of papillary dermis (grenz poor prognosis with rapidly progressive disease. 1,6 and review of the literature. Ann Hematol. 2003 zone), and associated stromal fibrosis. With Typically, these patients have a high mortality rate, Jul;82(7):435-9. IHC staining, myeloid subtypes are typically with progression in less than one year. We present lysozyme- and CD68-positive. Monocytic types this case for clinical interest and to highlight the are positive for lysozyme, CD68, CD15, CD43, importance of early recognition of this disease to and CD45. Myelomonocytic types are also decrease overall mortality.

JONES, KURIATA Page 22 Autoinoculation in a Patient with Longstanding Chromoblastomycosis: A Case Presentation and Discussion Cuong Le, DO,* Michael Noparstak, DO,** William Bethea, DO***

*Transitional Year Intern, Firelands Regional Medical Center, Sandusky, OH **Dermatology Resident, LECOMT/Dermatology Residency of Orlando, Maitland, FL ***Dermatologist, LECOMT/Dermatology Residency of Orlando, Maitland, FL

Disclosures: None Correspondence: Cuong Le, DO; [email protected]

Abstract Chromoblastomycosis (CBM) is a deep fungal infection that affects cutaneous and . It occurs most commonly in tropical regions and is considered an occupational disease affecting outdoor workers. CBM classically has been described as having five clinical presentations: nodular, tumoral, verrucous, plaque, and cicatricial. First-line treatment of CBM is often surgical removal or physical destruction of smaller lesions, often with concomitant use of oral antifungal agents. Surgery on larger lesions is generally not performed as there is concern for dissemination of the underlying organism. Larger lesions are often treated with oral antifungal therapy and/or physical destruction. We present a patient from central Florida with plaque-type CBM of the left knee that autoinoculated to the left forearm, forming nodular CBM. The left forearm completely resolved following shave biopsy/removal and the use of topical ketoconazole 2% cream. The left knee partially responded to topical ketoconazole alone.

Introduction outside. He had no other known risk factors and The biopsy of the left upper knee seven years prior, CBM is a fungal infection of cutaneous and was immunocompetent. The patient last travelled which had been diagnosed as tinea corporis, was subcutaneous tissue that occurs mainly in tropical outside of the United States more than 50 years requested and on second look was also consistent and subtropical areas around the globe. The prior, well before his rash started. A shave biopsy, with CBM. After an in-depth discussion with infection begins following traumatic inoculation of encompassing the whole , was performed the patient, he declined oral therapy, surgery, and one of the causative organisms into the skin. CBM on the left forearm. The biopsy demonstrated physical destruction of his lesions. The patient is often chronic, difficult to treat, and can rarely acanthosis, pseudoepitheliomatous hyperplasia, did agree to use topical ketoconazole 2% cream progress to squamous cell carcinoma of the skin. The and a granulomatous infiltrate with multinucleate to his left forearm and left knee. On follow-up causative organisms are dematiaceous, or - giant cells extending down to the reticular dermis, at six weeks, the patient’s left forearm was 100% producing, fungi. The most common organisms surrounded by neutrophils and a lymphohistiocytic improved. Moreover, the left knee was less scaly include Fonsecaea pedrosoi, Phialophora verrucosa, infiltrate (Figure 2). On higher magnification, in nature (Figure 4), and the patient stated it was and Cladophialophora carrionii. Less commonly it is numerous sclerotic bodies were visualized in the no longer pruritic. The patient again declined caused by Rhinocladiella aquaspersa and Exophiala dermis, consistent with the diagnosis of CBM physical destruction and oral therapy. dermatitidis. There has been confusion in the (Figure 3). A culture of the specimen was obtained literature regarding the nomenclature of these and grew Fonsecaea pedrosoi. organisms, as they have been referred to by multiple different names based on history and locale. Moreover, advances in culturing these organisms have unified prior nomenclature.1,5

The epidemiology of CBM varies based on the region that is studied. The incidence rate in Madagascar is thought to be 1:6,800, compared to 1:8,625,000 in the United States and 1:100,000 in Brazil. The male-to-female ratio ranges from 5:1 to 9:1 depending on the study. Middle-aged men are thought to be at higher risk because they are more likely to work outdoors, increasing their exposure to the fungi. CBM is considered an occupational disease, and risk factors are lack Figure 3. On higher magnification, multiple of protective shoes, gloves, and garments, poor Figure 1. Scaly, erythematous papule on the 2 sclerotic bodies are observed within a hygiene, and poor nutrition. Diabetes might also left forearm. be a risk factor. Patients with diabetes are at an multinucleated giant cell. Surrounding increased risk for mycotic infections, but there the granuloma are neutrophils and a have only been two cases reported of diabetes in lymphohistiocytic infiltrate. association with CBM. It also may be possible for patients to get infected with CBM without traumatic inoculation. Zarei et al. reported on a diabetic patient with CBM that had no history of trauma to the area.3 Case Report A 77-year-old male with a past medical history of hypertension, atrial fibrillation, and hypercholesterolemia presented with a chronic, pruritic, erythematous, scaly rash present for many years on his left upper knee, as well as a newer, 8-mm, scaly red papule on his left forearm, which had been present for weeks to months (Figure 1). Figure 2. Shave biopsy from left forearm The rash on his left upper knee was diagnosed seven demonstrating acanthosis, pseudoepitheliomatous years prior as a dermatophyte infection. Of note, the hyperplasia, and a granulomatous infiltrate Figure 4. Scaly, erythematous plaque on the patient was retired and stated he often did yardwork extending down to the reticular dermis. left knee.

Page 23 AUTOINOCULATION IN A PATIENT WITH LONGSTANDING CHROMOBLASTOMYCOSIS: A CASE PRESENTATION AND DISCUSSION Discussion are often first-line treatment modalities for smaller References CBM classically begins, following traumatic lesions. Oral itraconazole or terbinafine can be given 1. Carrasco-Zuber JE, Navarrete-Dechent C, inoculation, as a smooth macule that grows into three months prior to a wide and deep excision Bonifaz A, Fich F, Vial-Letelier V, and Berroeta- a papule or warty growth. The most common and then continued for another six to nine months. Mauriziano D. Afectacion cutanea en las micosis cause of CBM, accounting for up to 96% of For larger lesions, or if the patient declines surgery, profundas: una revision de la literature. Parte 1: lesions, is Fonsecaea pedrosoi.4 The time to lesion- destructive modalities and/or antifungal therapies micosis subcutaneas. Actas Dermo-Sifiliograficas. onset after inoculation can range from weeks to are often utilized. Destructive methods include 2016;107(10):806-15. months. Patients often experience pruritus and/ cryosurgery, electrocoagulation, heat therapy, laser or pain. The infection can occur anywhere but is therapy, photodynamic therapy, and curettage. First- 2. Queiroz-Telles F. Chromoblastomycosis: A most common on the extremities. The disease can line pharmacologic treatment for CBM is generally Neglected Tropical Disease. Rev Inst Med Trop spread via autoinoculation. itraconazole 200 mg/day to 400 mg/day for six to 12 Sao Paulo. 2015 Sep;57(Suppl. 19):46-50. months or until the lesions have cleared. Itraconazole There are five classic clinical presentations of CBM: is often used by itself but may be combined with 3. Zarei M, Schneider S, Villasante A, et al. nodular, tumoral, verrucous, plaque, and cicatricial. 5-fluorocytosine 30 mg/kg four times a day for six Chromoblastomycosis in a Diabetic Patient Nodular is often the earliest form of the disease, months. Terbinafine 250 mg/day to 500 mg/day for Without a History of Trauma. Am J Dermatopathol. and it can progress to tumors. The nodules are 12 months is also commonly used. For extensive and 2015 Sep;37(9):e112-5. soft, raised, and pink to purple in color and can systemic disease, intravenous amphotericin B at 1 have a smooth, verrucous, or scaly surface. The mg/kg or lipid-complex at 3 mg/kg/day to 5 mg/kg/ 4. Khan K, Mondal K, Dutta R, Mandal PK, Mandal day may be used. Treatment can stop when all lesions R, Gua MMS. Unusual Presentation of Cutaneous tumor lesion is much larger and has a lobulated, 1,9,10 cauliflower-like appearance. The verrucous type have cleared. Chromoblastomycosis. Am J Dermatopathol. 2017 is characterized by hyperkeratosis and looks like Feb; 39(2):159-61. verruca vulgaris; it occurs most commonly on the Conclusion feet. The plaque type is the least common and has CBM is a cutaneous and subcutaneous fungal 5. Krzysciak PM, Pindycka-Piaszczynska M, large areas of infiltration with a red-to-violaceous infection most commonly caused by Fonsecaea Piaszczynski M. Chromoblastomycosis. Postepy color, often with scale. Cicatricial lesions are pedrosoi, Phialophora verrucosa, and Cladophialophora Dermatologii Alergologii. 2014 Oct;31(5):310-21. flat and can involve large areas of the body. They carrionii. It occurs more commonly in tropical and enlarge peripherally and centrifugally, with atrophic subtropical regions. Our patient presented with a 6. Martinez RL, Tovar LJM. Chromoblastomycosis. scarring in the center. persistent rash for years that had been previously Clin Dermatol. 2007 Mar-Apr;25(2):188-94. misdiagnosed as tinea corporis. The rash had spread CBM has traditionally been classified as mild, from the left knee to the left forearm, likely by 7. Mohanty P, Vivekanandh K, Mohapatra L, Dash moderate, or severe. Mild lesions are small, single autoinoculation. The 8-mm left forearm papule G. Squamous cell carcinoma in long-standing nodules that are less than 5 cm in diameter. resolved via shave biopsy/removal followed by chromoblastomycosis. Indian J Dermatol Venereol Moderate lesions consist of single or multiple topical 2% ketoconazole cream twice a day. CBM is Leprol. 2017 May-Jun;83(3):363-5. tumoral-, verrucous-, or plaque-type lesions that are an uncommon fungal infection in the United States adjacent and less than 15 cm in diameter. Severe- that is difficult to treat and can become widespread 8. Jamil A, Lee YY, Thevarajah S. Invasive squamous type involves single or multiple lesions covering and rarely systemic. Early diagnosis and treatment cell carcinoma arising from chromobastomycosis. large areas of skin (adjacent or nonadjacent) that are best for optimal results, as chronic lesions are Med Mycol. 2012 Jan;50(1):99-102. do not respond well to treatment and can easily often more resistant to treatment. 5,6 9. Queiroz-Telles F, de Hoog S, Santos DWCL, become resistant. Modified classification systems Salgado CG, Vicente VA, Bonifaz A, et al. have been proposed that also encompass response Chromoblastomycosis. Clin Microbiol Rev. 2017 to treatment and symptomatology. Jan;30(1):233-76.

Complications associated with CBM include 10. Torres-Guerrero E, Isa-Isa R, Isa M, Arenas R. systemic spread, secondary infections, and 7 Chromoblastomycosis. Clin Dermatol. 2012 July- malignancy. Chronic infection with CBM can Aug;30(4):403-8. lead to squamous cell carcinoma, presumably due to long-standing inflammation and scarring. Onset of malignancy is about 20 to 30 years after inoculation, and it is most commonly seen in males after the age of 60.8

Diagnosis of CBM is made by direct examination, histology, and culture. Lesions often contain pigmented fungal elements on the surface that can be seen with the naked eye, appearing as small black dots. A potassium-hydroxide (KOH) test of scrapings may reveal fungal elements. Muriform cells, also known as sclerotic bodies, Medlar bodies or copper pennies, are needed to diagnose CBM. These cells are darkly pigmented round or polyhedral cells with septa. These cells can germinate filaments. Histology of CBM may show hyperkeratosis, pseudoepitheliomatous hyperplasia, and neutrophilic microabscesses. Treatment can be started upon visualization of the muriform cells, but a culture is often recommended, as the Fonsecaea species may be less sensitive to itraconazole compared to C. carrionii. Serologic studies are not routinely performed.9

CBM is often recalcitrant to therapy. Pharmacologic and nonpharmacologic therapies are available to treat CBM, but the disease is often persistent. Surgery or physical destruction and/or antifungal therapy

LE, NOPARSTAK, BETHEA Page 24 A Case of Arsenical Keratoses After Chronic Consumption of Water from Tube Wells Sealtiel Adrian Tinajero, DO,* Howard Camille, DO,** Suzanne Rozenberg, DO***

*2nd-year Resident, Dermatology Residency Program, St. John’s Episcopal Hospital, Far Rockaway, NY **1st-year Resident, Dermatology Residency Program, St. John’s Episcopal Hospital, Far Rockaway, NY ***Program Director, Dermatology Residency Program, St. John’s Episcopal Hospital, Far Rockaway, NY

Disclosures: None Correspondence: Sealtiel Adrian Tinajero, DO; [email protected]

Abstract has been shown to increase the risk of developing skin , including basal cell carcinoma and squamous cell carcinoma. A 44-year-old male from Bangladesh presented to the clinic for evaluation and treatment of scaly plaques on his palms and soles, and skin biopsy showed arsenical keratosis. The World Health Organization defines the maximum amount of arsenic allowed in drinking water as 0.01 mg/L, but testing of tube wells in Bangladesh found that up to 30% had levels exceeding 0.05 mg/L. This represents approximately 36 million people at risk of drinking water with unsafe levels of arsenic. This case highlights the importance of being aware of this rare presentation, as early treatment and close monitoring is key to preventing cutaneous malignancies.

Case Report in Bangladesh showed that up to 30% of tube A 44-year-old male presented to the clinic for wells had levels exceeding 0.05 mg/L, representing approximately 36 million people drinking water evaluation and treatment of scaly plaques on his 2 palms and soles. On physical exam, there were with unsafe levels of arsenic. Trivalent inorganic diffuse, punctate, hyperkeratotic, yellow-to-brown arsenic is the most toxic form, with a latent plaques on both palms (Figure 1) and large, period of up to 50 years; therefore, symptoms of hyperkeratotic, scaly plaques on the soles of both chronic exposure to arsenic can show up later in feet (Figure 2). The patient had been using multiple life. Furthermore, arsenic is considered a class I emollients, including urea, ammonium lactate, and human carcinogen by the International Agency salicylic acid, with minimal effect. for Research on Cancer, mostly because of the increased risk for cancer in organs such as the lung 1 The patient was a native of Bangladesh until 2009, and bladder. In a recent study, the Health Effects of when he moved to the United States. During most of Arsenic Longitudinal Study (HEALS), there was his life, he drank water from tube wells, which were an increase in overall mortality rate among people the only available sources of water in his town. His exposed to arsenic compared to control cohorts. The Figure 2. Multiple brown-yellow hyperkeratotic lesions started developing approximately 15 years study concluded that in the studied population, an plaques on sole. prior as small, scaly plaques. Initially, the areas were estimated 21.4% of all deaths and 23.5% of deaths itchy, but they had been asymptomatic for several associated with chronic disease could be attributed years. His past medical history was significant for to arsenic exposure. An important finding in this diabetes mellitus and hyperlipidemia. His surgical longitudinal study was the associated increase in history was significant for cholecystectomy. Labs overall mortality in people chronically exposed to arsenic at relatively low concentrations compared were obtained, which showed elevated triglycerides, 15 LDL and VLDL as well as elevated glucose levels. to prior studies. This highlights the risk to our All other labs were within normal limits. A shave patient, since he was exposed to arsenic through skin biopsy was obtained from one of the plaques drinking water over a long period of time. on the patient’s right hand, and histopathology showed papillated and acanthotic epidermis with some hints of keratinocyte atypia and overlying columns of hyperkeratotic alternating with hyperkeratotic orthokeratosis (Figures 3, 4). Figure 3 (4x). Papillated and acanthotic The clinical/pathological correlation was consistent epidermis with overlying columns of with arsenical keratoses. hyperkeratotic parakeratosis alternating with hyperkeratotic orthokeratosis. Our patient did not have any symptoms, and he decided to use topical modalities to reduce the hyperkeratosis and overall appearance. The patient was treated with topical 5-FU under occlusion and daily emollients, which provided significant symptom relief. No cutaneous malignancy was found on initial exam or on follow-up. Although a cutaneous malignancy was not appreciated, periodic check-up was instructed, as chronic exposure to arsenic has been shown to be a risk factor for skin malignancies.6 Discussion The contamination of water with arsenic in Bangladesh has been called the “largest poisoning of a population in history.”2 By the 1990s, up to 95% of Bangladesh’s population was drinking from tube wells. The World Health Organization (WHO) Figure 4 (20x). Hints of keratinocyte atypia defines the maximum amount of arsenic allowed Figure 1. Small, punctate, yellow hyperkeratotic within the superficial portion of the spinous and in drinking water as 0.01 mg/L; however, testing plaque on palm. granular layers.

Page 25 A CASE OF ARSENICAL KERATOSES AFTER CHRONIC CONSUMPTION OF WATER FROM TUBE WELLS Background of IP joints, and weight-bearing plantar surfaces. in improvement of arsenical keratosis lesions.8 Atomic number 33, also known as arsenic, was Although rare, there are reports of arsenical keratoses Although a few reports note vast improvement of discovered by Albertus Magnus in 1250.1 It was on the trunk, proximal extremities, eyelids and both lesions with management via oral acitretin, solo later that German physician and pharmacologist male and female genitalia.8 therapy has been found to be ineffective in other Johann Schroder recognized arsenic as an element. cases. Topical 5-fluorouracil is a mainstay topical Arsenic occurs in the environment and can Systemic effects of arsenic toxicity can be chemotherapeutic agent used in the treatment combine with other elements to create inorganic categorized as either acute or chronic. Acute effects of actinic keratosis and Bowen’s Disease.12 arsenic compounds. Arsenic changes its form in include flushing of skin, erythema, alopecia, Mees’ Intralesional 5-FU has been used as a treatment the environment by reacting with oxygen and other lines, abdominal pain, diarrhea, pancytopenia, modality in some patients with basal cell carcinoma molecules in the air, water or soil. This element cardiac arrhythmias, renal failure, respiratory and squamous cell carcinoma. In the case of has the capacity to attach itself to large- or small- failure, and acute neuropathy that can progress to arsenical keratosis, a combination of acitretin and capacity molecules that can settle in soil.1 Its Guillain-Barre-like ascending paralysis. Chronic intralesional 5-FU has been tried. Combining fluidity enables it to be present in lakes, rivers, and exposure is often summarized by skin abnormalities, keratolytics and acitretin has proven effective in underground water. Around the globe, initiatives hyperpigmentation and keratoses; other systemic limited cases. An alternative therapy is imiquimod, to prevent geographical arsenic contamination effects of chronic arsenic exposure include nasal- an immune-response modifier causing activation of have been undertaken, including testing drinking septum perforation, peripheral neuropathy, bone- immune cells to produce cytokines. Lonergan et al. water, heavily regulating pesticides and industrial marrow hypoplasia, chronic diarrhea, obstructive reported success with imiquimod cream 5% topical compounds, and implementing organic farming. or restrictive lung disease, diabetes mellitus, and daily for six weeks, with no evidence of recurrence 9 Despite 21st century interventions, arsenic hepatomegaly that can lead to hepatic fibrosis. of arsenical cutaneous lesions after more than three continues to contaminate the drinking supply years.13 Clinicians also report success with the use in some developing countries.2 Regions most Malignancies of photodynamic therapy. Herbert et al. reports impacted by pollution from naturally occurring Cutaneous malignancies include basal cell one case of refractory arsenical keratosis managed arsenic in groundwater are Central America, Africa, carcinoma, squamous cell carcinoma and, with photodynamic therapy using visible blue light and South and Southeast Asia.3,4 less often, Merkel cell carcinoma. These non- and topical 20% weight/volume aminolevulinic melanoma skin cancers occur on non-sun- acid (ALA).14 There is still room for investigation Pathogenesis exposed areas and tend to be multiple. Invasive regarding photodynamic therapy as well as the The pathogenesis of arsenic’s toxicity to squamous cell carcinomas arising from keratoses possible synergetic efficacy of various topical humans is thought to be an interference with in arsenic-exposed areas are more likely to chemotherapeutic and keratolytic agents. cellular respiration and uncoupling of oxidative metastasize than those arising from normal skin. phosphorylation. Arsenic can also cause direct Other reported non-cutaneous malignancies effects to DNA in areas of transcription, repair and include genitourinary cancers, especially of the 9 amplification. Furthermore, tumor-suppression bladder, as well as lung and liver cancers. factors such as p53, nuclear factor-kappaB and activating protein-1 have been affected by arsenic Histopathology exposure. A study in the Journal of Cutaneous Arsenical keratosis has prominent hyperkeratosis Pathology also demonstrated that arsenic exposure and without atypia. There is a induces abnormal keratinocyte differentiation via moderate amount of parakeratosis and vacuolation the effects of integrin expression.5 Arsenic causes of keratinocytes. Adnexal structures are spared. oxidative stress through the production of reactive There are variable changes of dermal connective 6 tissue. When malignancy is present, the features are oxygen species and reactive nitrogen species. A 10 recent article in Cancer Letters provides a detailed the same as in cases not related to arsenical toxicity. explanation of the pathway by which arsenic induces oxidative stress. Arsenic increases expression and Differential Diagnosis activity of NADPH oxidase by upregulation of the Arsenical keratosis bears a close resemblance to protein p22hox and by the translocation of Rac1 palmoplantar psoriasis, palmoplantar keratoderma (a low-molecular-weight guanosine triphosphate), and verruca vulgaris. The inherited keratodermas which is responsible for the activation of are differentiated by central keratotic plugs in small NADPHO. Nitric oxide (NO), a molecule involved pits; arsenical keratoses do not have plugs. Psoriasis in multiple protective roles such as vasodilation and has more scale and involvement of other body areas. anti-inflammation, is downregulated by arsenic In the nevoid basal cell carcinoma syndrome, onset through inactivation of NO synthase.6 Exposure to is early, and there are other characteristic features, including odontogenic jaw and typical arsenic has been shown to carry an increased risk 9 for development of skin cancers including basal cell basaloid proliferative histology. carcinoma and squamous cell carcinoma. Treatment Cutaneous and Systemic Disease The pillar in management of arsenical keratosis is Arsenic exposure can lead to a broad spectrum of recognition, as lesions may develop into cutaneous cutaneous findings, including hyperpigmentation, malignancies, and chronic exposure can lead to hyperkeratosis of the palms and soles, Bowen’s visceral malignancies. There are multiple treatment disease, squamous cell carcinoma, and basal cell options, and effectiveness appears to vary case carcinoma. One of the earliest findings of arsenic by case. Choice of treatment modality needs to exposure is changes in pigment, especially on the consider the chronicity of arsenic exposure as palms and soles. These changes are described as well as patient tolerance of therapy options. In macules, leukomelanosis, and mucosal pigmentation. acute arsenic toxicity, the mainstay is chelation Ruiz et al. graded the progression of skin findings therapy with a 3 mg/kg intramuscular injection of on a scale from mild to severe, mostly defined by dimercaprol or British antilewisite (BAL) every four hours for two days, then every six hours for lesion size, from less than 2 mm (mildest) to greater 10 than 5 mm (most severe).7 Severe disease can include one day, and then every 12 hours for 10 days. fissuring and cracking of the skin. More than 40% of For cutaneous lesions, therapy modalities have affected people develop keratosis of the palms and included cryotherapy, topical chemotherapy, soles. The lesions are hyperkeratotic, and they can be photodynamic therapy and retinoids. Retinoids erythrodermic. The keratoses can be very exophytic have long been studied. They have been shown to change the terminal differentiation of cells to non- and cause discomfort when walking or under direct pressure. They favor the thenar and hypothenar keratinizing epithelium. Yerebakam et al. found eminences, distal palms, lateral fingers, dorsal aspect 1 mg/kg of acitretin daily for 10 months resulted

TINAJERO, HOWARD, ROZENBERG Page 26 References 1. Agency for Toxic Substances and Disease Registry [Internet]. [Accessed 24 Jan. 2018]. Available from: http://www.atsdr.cdc.gov.

2. The World Health Organization. Guidelines for Drinking Water Quality. 3rd ed. Geneva; 2008. 668 p.

3. Garelick H, Jones H, Dybowska A, Valsami- Jones E. Arsenic pollution sources. Rev Environ Contam Toxicol. 2008;197:17-60.

4. Kumar A, Kumar P, Rahman S, Iqubal A, Ali M, Niraj PK, Anand G, Abhinav, Ghosh AK. Ground Water Arsenic Contamination: a local survey in India. Int J Prev Med. 2016 Aug 9;7(1):100.

5. Lee CH, Chen JS, Sun YL, Liao WT, Zheng YW, Chai CZ, Chen GS, Yu HS. Defective βı-integrins expression in arsenical keratosis and arsenic-treated cultured human keratinocytes. J Cutan Pathol. 2006 Feb;33(2):129-38.

6. Hunt KM, Srivastava RK, Elmets CA, Athar M. The mechanistic basis of arsenicosis: pathogenesis of skin cancer. Cancer Letters. 2014 Nov 28;354(2):211-9.

7. Ruiz de Luzuriaga AM, Ahsan H, Shea CR. Arsenical Keratoses in Bangladesh-update and prevention strategies. Dermatolic Clin. 2011 Jan;29(1):45-51.

8. Wong SS, Tan KC, Goh CL. Cutaneous Manifestations of Chronic Arsenicism: review of seventeen cases. J Am Acad Dermatol. 1998 Feb;38(2):179-85.

9. Bolognia JL, Lorizzo JL, Schaffer JV. Dermatology. 3rd rev. ed. London: Saunders; 2012. 2776 p.

10. Patterson JW. Weedon’s skin pathology. 4th ed. Hosler GA, contributor. London: Churchill Livingstone; 2016. 1262 p.

11. Hoffman RS, Howland MA, Lewin NA, Nelson LS, Goldfrank LR. Goldfrank’s Toxicological Emergencies. 10th ed, New York: McGraw Hill Education; 2015. 1904 p.

12. Habif TP. Clinical Dermatology: a color guide to diagnosis and therapy. 6th ed. Amsterdam: Elsevier; 2015. 1064 p.

13. Lonergan CL, McNamara EK, Cordoro KM, Greer KE. Imiquimod cream 5% for the treatment of arsenic-induced cutaneous . Cutis. 2010 Apr;85(4):199-202.

14. Adelaide H, Phillips C, Hymes S, Wang W. Photodynamic therapy for arsenical keratoses. J Am Acad of Dermatol. 2010 Mar 1;62(3 Sup 1):AB115-AB115.

15. Ahsan H, Chen Y, Parvez F, Hussain AI, Argos M, Momotaj H, Levy D, van Geen A, Howe G, Graziano J. Health Effects of Arsenic Longitudinal Study (HEALS): description of a multidisciplinary epidemiologic investigation. J Expo Sci Environ Epidemiol. 2006 Mar;16(2):191-205.

Page 27 A CASE OF ARSENICAL KERATOSES AFTER CHRONIC CONSUMPTION OF WATER FROM TUBE WELLS A Case of Cutaneous ALCL in a Patient with Sarcoidosis Taraneh Matin, DO,* Richard Rubenstein, MD**

*Traditional Rotating Intern, Larkin Community Hospital, South Miami, FL **Faculty, Dermatology Residency Program, Larkin Community Hospital - Palm Springs Campus, Hialeah, FL

Disclosures: None Correspondence: Taraneh Matin, DO; [email protected]

Abstract Anaplastic large cell lymphoma (ALCL) is a rare type of non-Hodgkin’s lymphoma (NHL) that can present with difficult-to-diagnose cutaneous symptoms. Here we present a patient with a history of cutaneous sarcoidosis who was complaining of worsening subcutaneous nodules on her lower extremities. What may have easily been misdiagnosed as recurrent sarcoidosis was biopsy-proven to be a rare case of CD30-positive large cell lymphoma. The association between sarcoidosis and malignancy has been a topic of debate for many years. Here we explore the possible correlation between sarcoidosis and lymphoma and whether our patient’s history of sarcoidosis placed her at an increased risk for developing cutaneous ALCL. We also review the two main clinical presentations of ALCL, systemic and primary cutaneous.

Introduction Case Report subcutaneous and cutaneous nodules limited to Anaplastic large cell lymphoma (ALCL) is a A 60-year-old African American women with a the legs and arms, representing primary cutaneous rare type of non-Hodgkin’s lymphoma (NHL) history of cutaneous sarcoidosis presented with anaplastic large cell lymphoma (PC-ALCL). The involving proliferation of neoplastic lymphoid cells painful nodules dispersed over her lower extremities. patient was advised to begin chemotherapy as soon of either T- or null-cell lineage and expressing the The nodules had been present and growing in size for as possible. CD30 antigen.1 ALCL comprises only about 3% the past three months and were beginning to ulcerate Due to our patient’s history of sarcoidosis, her of all lymphomas in adults and 10% to 30% of (Figure 1). The patient admitted to discomfort and 1,2 atypical presentation, and the rare nature of her lymphomas in children. Clinically, there are two increasing pain in her legs, especially at the tumor , a correct clinical diagnosis of PC- main subtypes of ALCL: systemic (S-ALCL) and sites, but denied any systemic symptoms of fever, ALCL was difficult to establish. It was only once a primary cutaneous (PC-ALCL). Both share the chills, joint pain, or weight loss. thorough work-up was performed and a PET scan same histopathologic features, but they differ with 1-4 was completed that the diagnosis of PC-ALCL respect to their clinical and biologic characteristics. On physical examination, there were tender, 3-cm was established, a delay that significantly impacted S-ALCL is an aggressive lymphoma affecting to 5-cm erythematous nodules with induration and the patient’s disease prognosis. internal organs and lymph nodes. Patients typically secondary ulceration diffusely spread over her lower present with painless lymphadenopathy and systemic legs, as well as two to three solitary lesions on her 5 bilateral upper forearms. A biopsy was taken from Discussion B symptoms such as fever, weight loss, and fatigue. This case shows the importance of differentiating an intact nodule on the right lower leg. Histological Additionally, S-ALCL may secondarily involve the cutaneous lesions of ALCL from sarcoidosis and the skin and present with cutaneous lesions, which review showed infiltrates of plump amphophilic cells, 6 distinguishing between PC-ALCL and S-ALCL. with abundant cytoplasm and irregular vesicular affects 10% to 20% of S-ALCL patients. Subcutaneous nodular sarcoidosis lesions are nuclei within the dermis (Figure 2). Immunostaining usually nontender, firm, flesh-colored or violaceous PC-ALCL, on the other hand, is a localized and for CD30, CD3, CD20, CD117, S-100, Melan-A, 11 nodules that are 0.5 cm to 2 cm in diameter. PC- indolent lymphoma primarily affecting the skin. CD1a, pankeratin, CK903, CK20 and CK7 was ALCL typically presents as solitary nodules, most Extracutaneous dissemination occurs in about 10% positive only for CD30, establishing a diagnosis of 12,13 often seen in men, with spontaneous regression, of patients with PC-ALCL and mainly involves CD30-positive anaplastic large cell lymphoma. 7 while S-ALCL typically presents with noted the regional lymph nodes. PC-ALCL lesions are 1 lymphadenopathy as well as B symptoms. typically confined to the upper extremities and The patient’s clinical picture did not correspond with most commonly occur in males. The lesions present either PC-ALCL (typically solitary nodules, most 12,13 It is significant to ask whether sarcoidosis was a risk often seen in men, with spontaneous regression ) as tender, slow-growing, solitary or localized factor for the development of ALCL in our patient. erythematous nodules with superimposed ulcers. or S-ALCL (typically noted lymphadenopathy and B 1 The term “sarcoidosis lymphoma syndrome” was Multifocal lesions are seen in about 20% of symptoms ). Although our patient did not present with 15 8-9 first coined by Brincker in 1986, and the idea has patients. Due to the rarity of PC-ALCL and its either lymphadenopathy or systemic symptoms, her clinical similarity with other cutaneous diseases, multifocal presentation and the severity of her lesions many patients with PC-ALCL go undiagnosed for were initially suggestive of systemic involvement. years before receiving treatment. Furthermore, the location of her nodules, primarily on her lower extremities, was atypical and believed to be Life expectancies and disease prognoses vastly indicators of a poor prognosis.14 differ between the two subtypes. PC-ALCL has a favorable prognosis, with a 10-year disease-related On further work-up, the patient’s HTLV antibodies survival rate exceeding 85 percent.2,10 In contrast, for infectiously acquired lymphoma were negative, S-ALCL is much more aggressive, with a disease- and she had no signs of systemic involvement except related five-year survival rate of 29% to 44%. for leukocytosis. PET scan demonstrated multiple

Figure 1 Figure 2

MATIN, RUBENSTEIN Page 28 since been re-explored in several cases. Sarcoidosis References of a new type of cutaneous lymphoma lymphoma syndrome refers to the theory that there 1. Armitage J, Weisenburger D. New approach to with a favorable prognosis. A European is a linear relationship between the progression of classifying Non-Hodgkin’s lymphomas: clinical multicenter study of 47 patients. Cancer. sarcoidosis and the development of lymphoma. It features of the major histologic subtypes. Non- 1993 Mar;71(6):2097-104. is believed that lymphoma and other malignancies Hodgkin’s Lymphoma Classification Project. J Clin 14. Lee WJ, Moon IJ, Lee SH, Won CH, Chang develop more often than expected in middle- Oncol. 1998 Aug;16(8):2780-95. aged patients with chronic active sarcoidosis SE, Choi JH, Moon KC, Park CS, Huh J, Lee as a consequence of the chronic inflammation 2. Yang S, Pooja K, Wahlgren C, Ho J. Cutaneous MW. Cutaneous anaplastic large-cell lymphoma and immunological abnormalities initiated by (ALCL): A comparative clinical feature and 16 anaplastic large-cell lymphoma should be sarcoidosis. Sarcoidosis reflects a dysregulation evaluated for systemic involvement regardless survival outcome analysis of 52 cases according to of the immune system due to a persistent antigenic of ALK-1 status. Am J Clin Dermatol. 2011 primary tumor site. J Am Acad Dermatol. 2016 stimulus, causing the formation of non-caseation Jun;12(3):203-9. Jun;74(6):1135-43. granulomas. Persistent immune dysregulation and inflammation may lead to unbalanced 3. Kempf W, Pfaltz M, Vermeer MH, Cozzio A, 15. Brincker, H. The sarcoidosis-lymphoma proliferation of immune cells and the development syndrome. Br J Cancer. 1986 Sep;54(3):467-73. 16 Ortiz-Romero PL, Bagot M, Olsen E. EORTC, of lymphoproliferative disease. If sarcoidosis and ISCL, and USCLC consensus recommendations 16. Cohen PR, Kurzrock R. Sarcoidosis lymphoma occur in association, lymphoma almost for the treatment of primary cutaneous and malignancy. Clin Dermatol. 2007 invariably develops subsequent to sarcoidosis after CD30-positive lymphoproliferative disorders: Jun;25(3):326-33. disease-free intervals of a number of years, similar lymphomatoid papulosis and primary cutaneous to the timeline presentation in our patient. anaplastic large-cell lymphoma. Blood. 2011 17. Rømer K, Hommelgaard P, Schou G. Sarcoidosis Oct;118(15):4024-35. Brincker made the first attempt to objectively and cancer revisited: a long-term follow-up study of 555 Danish sarcoidosis patients. Eur Resp quantify the incidence of lymphoma in patients 4. Medeiros L, Elenitoba-Johnson KS. Anaplastic Journal. 1998 Sept;12(4):906-12. with sarcoidosis. In a 10-year study, 48 sarcoidosis Large Cell Lymphoma. Am J Clin Pathol. 2007 patients out of 2,544 developed malignant May;127(5):707-22. neoplasms.15 Romer revisited this issue in a 1998 18. Hulshof M. Ulcerating cutaneous sarcoidosis and non-Hodgkin›s lymphoma. Brit J Dermatol. 1993 study in which 48 of 555 sarcoidosis patients 5. Bekkenk MW, Geelen FA, Voorst Vader PC, 17 Sept;129(3):343-44. developed malignancy. Following those studies, Heule F, Geerts ML, Vloten WA, Meijer CJ, a Swedish risk analysis of cancer in sarcoidosis Willemza R. Primary and secondary cutaneous patients not only showed that sarcoidosis and 19. Gelfand J, Mariusz A, Vittorio C, Rook A, CD30(+) lymphoproliferative disorders: a report Junkins-Hopkins J. Progressive epidermotropic malignancy may be etiologically related in at least from the Dutch Cutaneous Lymphoma Group 25% of patients but also specified a predilection for CD8+/CD4− primary cutaneous CD30+ on the long-term follow-up data of 219 patients lymphoproliferative disorder in a patient lymphoma tumors to affect the same organs affected and guidelines for diagnosis and treatment. Blood. 18,19 with sarcoidosis. J Am Acad Dermatol. 2004 by the sarcoidosis. This is especially interesting 2000 Jun;95(12):3653-61. in the context of our patient, who was diagnosed 51(2):304-8. with cutaneous lymphoma localized to her lower 6. Campo E, Swerdlow S, Harris N, Pilerti S, 20. Le J, Gribbin J, West J, Smith C, Cullinan extremities four years after an initial diagnosis of Stein H, Jaffe E. The 2008 WHO classification P, Hubbard R. The incidence of cancer in cutaneous sarcoidosis. Although the association of lymphoid neoplasms and beyond: evolving patients with idiopathic pulmonary fibrosis between sarcoidosis and malignancy has not yet concepts and practical applications. Blood. 2011 and sarcoidosis in the UK. Respir Med. 2007 been established, medical literature exploring this May;117(19):5019-32. 20-25 Dec;101(12):2534-40. relationship is on the rise. To date, there have been at least five cases of patients with sarcoidosis 7. Bolognia J, Jorizzo J, Schaffer J. Dermatology. 25-29 21. Patompong U, Srivali N, Wijarnpreecha K, and concurrent cutaneous T-cell lymphomas. 3rd rev. ed. Philadelphia: Elsevier Saunders; 2014. Thongprayoon C, Cheungpasitporn W, Knight It is our belief that a causality link between 2776 p. EL. Is the incidence of malignancy increased sarcoidosis and malignancy, especially lymphoma, in patients with sarcoidosis? A systematic 8. Krishnan J, Tomaszewski MM, Kao GF. Primary requires greater consideration. There needs to be review and meta-analysis. Respirology. 2014 cutaneous CD30-positive anaplastic large cell more meticulous care in examining and biopsying Oct;19(7):993-8. cutaneous nodules in sarcoidosis patients in order lymphoma. Report of 27 cases. J Cutan Pathol. to recognize a diagnosis of cutaneous lymphoma. 1993 Jun;20(3):193-202. 22. Patompong U, Crowson CS, Matteson EL. Risk of malignancy among patients with sarcoidosis: a 9. Eimpunth S, Sittinamsuwan P, Pattanaprichakul Conclusion population-based cohort study. Arthritis Care P, Silpa-archa N, Sethabutra P, Chularojanamontri Cutaneous ALCL is extremely rare and infrequently Res. 2017 Jan;69(1):46-50. encountered in a dermatology setting. Due to the L, Hanamornroongruang S, Mahaisavriya P. rarity of this neoplasm and its wide spectrum of Cutaneous anaplastic large cell lymphomas: a 23. Alexandrescu DT, Kauffman C, Ichim T, clinical presentations, a proper diagnosis can be report of 9 cases from Thailand. J Med Assoc Thai. Riordan N, Kabigting F, Dasanu C. Cutaneous difficult to make. Familiarity with potential risk 2012 Mar;95(3):437-43. sarcoidosis and malignancy: An association factors, such as sarcoidosis, and early manifestations between sarcoidosis with skin manifestations and 10. Banerjee SS, Heald J, Harris M. Twelve cases are essential in making an accurate and timely systemic neoplasia. Dermatology Online J. 2011 of Ki-1 positive anaplastic large cell lymphoma of diagnosis. Furthermore, distinguishing between Jan;17(1):2. the two subtypes, S-ALCL and PC-ALCL, is skin. J Clin Pathol. 1991;44(2):119-25. imperative in providing effective management and 24. Kapoor S. Cutaneous and systemic 11. Marcoval J, Moreno A, Mana J, Peyri J. an accurate prognosis. malignancies in patients with sarcoidosis: A close Subcutaneous sarcoidosis. Dermatol Clin. 2008 association. Ann Acad Med Singapore. 2009 Oct;26(4):553-6. May;38(2):179. 12. Benner MF, Willemze R. Applicability 25. Schmuth M, Prior C, Illersperger B, and prognostic value of the new TNM Topar G, Fritsch P, Sepp N. Systemic classification system in 135 patients with primary sarcoidosis and cutaneous lymphoma: is the cutaneous anaplastic large cell lymphoma. Arch association fortuitous? Br J Dermatol. 1991 Dermatol. 2009 Dec;145(12):1399-404. May;140(5):952-5. 13. Beljaards RC, Kaudewitz P, Berti E, 26. McFarland JP, Kauh YC, Luscombe HA. Gianotti R, Neumann C, Rosso R, Paulli Sarcoidosis associated with mycosis fungoides. M, Meijer CJ. Primary cutaneous CD30- Arch Dermatol. 1978 Jun;114(6):912-5. positive large cell lymphoma: definition

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28. Gargallo V, Ramos J, Rodriguez-Peralto J, Postigo C. Sarcoidosis and cutaneous lymphoma: What is the relationship? An Bras Dermatol. 2017 Feb;92(1):158-9.

29. Yoshida S, Fujimura T, Kambayashi Y, Furudate S, Mizuashi M, Aiba S. Sarcoidosis-lymphoma syndrome associated with folliculotropic peripheral T cell lymphoma not otherwise specified. Case Rep Oncol. 2017 Apr;10(1):372-6.

MATIN, RUBENSTEIN Page 30 Cutaneous Metastatic Melanoma Masquerading as a Pigmented Rash: A Case Presentation and Discussion Jonathan Bellew, DO,* Soham P. Chaudhari, DO,** Shiva Kheradmand, BA,*** Vernon T. Mackey, DO****

*Dermatology Resident, 1st year, Advanced Desert Dermatology / Midwestern University, Peoria, AZ **Dermatologist, Dermatology Clinic of McAllen, McAllen, TX ***Medical Student, 4th year, Arizona College of Osteopathic Medicine at Midwestern University, Glendale, AZ ****Program Director, Dermatology Residency Program, Advanced Desert Dermatology / Midwestern University, Peoria, AZ

Disclosures: None Correspondence: Jonathan Bellew, DO; 2928 Lake East Dr., Las Vegas, NV 89117; Ph: 702-254-1588; Fax: 702-243-5012; [email protected]

Abstract Cutaneous melanoma has a high metastatic potential. Spontaneous eruption of darkly pigmented papules is a rare manifestation of cutaneous metastatic melanoma. Herein, we describe a case of a 79-year-old male with a history of superficial spreading malignant melanoma, status post lymphadenectomy, who presented with rapidly progressing, asymptomatic, hyperpigmented papules. Biopsy revealed metastatic melanoma. We report this case to highlight the unique presentation of cutaneous metastatic melanoma to increase detection of this deadly disease. Timely diagnosis is essential for staging, prognosis, and therapeutic options and may maximize disease-free survival.

Introduction melanoma was histologically classified as superficial but no evidence of pigmentation or recurrence of Cutaneous melanoma is an aggressive disease spreading and nodular type with a Breslow’s depth melanocytic features (Figure 3). More than 100 arising from the proliferation of melanocytes. of 1.4 mm and Clark’s level IV, with no ulceration, non-tender, smooth, firm, 3-mm, dark purple- Melanocytes are a type of dendritic cell that lymphovascular invasion, or satellitosis ( January brown-black papules were localized to the provide melanin to keratinocytes and can be found 2016). Sentinel node biopsy showed extension to right shoulder, axilla, chest and upper abdomen in most organ viscera.1 Melanosomes within the right axillary lymph nodes, prompting axillary melanocytes of melanoma have been shown to lymphadenectomy (February 2016). carry microRNA into primary fibroblasts and Past medical history included multiple non- serve to increase proliferation, migration, and 2 melanoma skin cancers, treated with wide pro-inflammatory gene expression. Although excision on the left upper back (2006) and melanoma represents less than 5% of all skin Mohs micrographic surgery on the right upper cancers, it has a high potential for widespread occipital scalp (2010), and lymphoma treated metastasis and is subsequently associated with 3 with chemotherapy and radiation three years high mortality. The incidence of melanoma prior. His family history was significant for is growing faster than any other potentially lung cancer in both parents and brain and breast preventable cancer in the United States, with an cancer in his brother and sister, respectively. approximate 1.9% annual growth rate between 4 The patient denied systemic complaints, pain, 2000 and 2009. Globally, 132,000 new cases of pruritis, and discomfort. melanoma were predicted to arise in 2017, with 48,000 deaths per year.5 On physical examination, the excision scar at the Figure 2. Palpation revealed smooth, firm, and right mid-back had signs of hypertrophic scarring Metastasis involves dissemination of neoplastic cells soft surface texture without sensitivity, pain, or to different anatomic sites and the adaption of these blanching to pressure. cells into a foreign-tissue microenvironment.6,7 The interplay between metastatic tumor cells, host factors, and homeostatic mechanisms determines the process.8,9 The interaction between neoplastic cells and non-neoplastic stromal cells are important in the progression of the invasion-metastasis cascade.6,7 The skin and subcutaneous tissue represent a common site of metastasis in melanoma. The most common presentation of cutaneous metastatic melanoma is of single or multiple papules and nodules that are brown-to-black or skin-colored.10 Various other morphologic patterns of cutaneous metastasis from malignant melanoma have been reported, including erythematous patches and plaques and inflammatory cellulitis- like lesions.11 Presentations such as diffuse sclerodermiform induration of the skin, zosteriform vesiculobullous lesions and even alopecia areata of the scalp have been documented as presentations of malignant melanoma.11-15 Case Report A 79-year-old Caucasian male presented to the outpatient office setting with a six-month history of progressive, asymptomatic, brown-to-black Figure 1. Multiple (> 100) hyperpigmented, pigmented papules, plaques, and nodules of the right shoulder, axilla, chest, upper abdomen and lateral purple/brown/black papules with mild erythema Figure 3. Lesions were in a remote location trunk (Figures 1, 2). Two months prior to this skin and variable size coalescing into plaques and from the excision scar at the right mid-back eruption, the patient underwent primary resection nodules localized to the right shoulder, axilla, representing resection of primary melanoma in of a right mid-back malignant melanoma. The chest, and upper abdomen. January 2016.

Page 31 CUTANEOUS METASTATIC MELANOMA MASQUERADING AS A PIGMENTED RASH: A CASE PRESENTATION AND DISCUSSION (Figures 4, 5). There was no evidence of secondary skin-lesion morphology. No palpable adenopathy was appreciated.

Histopathologic evaluation of two isolated lesions at the right chest wall via two 5-mm punch biopsies revealed extensive involvement of the papillary dermis demonstrating confluence of heavily pigmented pleomorphic melanocytic nests with absence of maturation (Figure 6). Additional microscopic features included: epidermal and adnexal sparing, thinning of the epidermis around melanocytes, flattening of rete ridges, prominent nucleoli with increased mitoses, and increased nuclear-to-cytoplasmic ratio (Figure 7). Figure 4. Two 5-mm punch biopsies were Figure 7. Medium power (100x): Pleomorphic Interestingly, a focal area of intravascular invasion obtained from the right chest wall at the and heavily pigmented, atypical melanocytic was noted in the dermis, representing angioinvasion superior and inferior positions. nests in the papillary dermis. Melanocytes (Figures 8, 9). Immunostaining was positive in this proliferation demonstrated increased for pan-melanoma stain (HMB45/MART-1/ nuclear-to-cytoplasmic ratio, absence of tyrosinase). CD31 positivity was noted as well, maturation, and prominent nucleoli with confirming the intravascular focus of melanoma cells. Genetic testing failed to detect mutations in increased mitoses. BRAF V600, EGFR, or NRAS.

Histopathology, clinical presentation, and recent history of malignant melanoma were diagnostic for metastatic malignant melanoma with cutaneous propensity, representing stage IV disease (T2aN3M1a, AJCC 2009).16 Whole- body positron emission tomography/computed tomography scan revealed no evidence of lymph- node or solid-organ metastasis. Immunotherapy was initiated with the immune checkpoint inhibitor pembrolizumab, which targets the Figure 5. Post punch biopsy close-up view of programmed cell death 1 (PD-1) receptor. right central chest-wall involvement along with extension and involvement of the right axilla Discussion and right shoulder. Cutaneous melanoma has the potential to Figure 8. Angioinvasion of vasculature by metastasize hematogenously, via the lymphatic metastatic malignant melanocytes. system, or both ways.17 The progression of primary cutaneous melanoma has been explained by three models. The stepwise-spread model suggests that melanoma spreads initially toward regional lymph nodes via the lymphatic system, and systemic dissemination occurs subsequently.17,18 This model argues in favor of sentinel lymph node biopsy, as lymphatic spread occurs prior to systemic metastasis.19 The second predominant model is the simultaneous-spread model, which maintains that hematogenous and lymphatic spread of cutaneous 20 Figure 6. Low power (40x): Hematoxylin melanoma can occur simultaneously. In this model, lymph node involvement is a marker of systemic and eosin (H&E) stain illustrating extensive disease.21 The final, differential-spread model involvement of the papillary dermis by atypical proposes multiple independent dissemination melanocytic nests pushing up against the pathways to explain the progression of cutaneous epidermis, causing flattening of the rete ridges Figure 9. High power: Atypical melanocytic melanoma.17,18,22 Some cutaneous melanomas do and epidermal . angioinvasion within the dermis. not have the biological potential to metastasize. present with loco-regional metastases, and one- with distant metastasis and stage IV disease, Others metastasize only to regional lymph nodes, 18,23,25-27 17,22 third presents with distant metastases. compared to 62.5 months for those with local only hematogenously, or in both modes. 28 This is consistent with our patient, who did not recurrence and stage IIIB disease. The short time Cases of skin metastasis can be divided into demonstrate distant metastases. period of six months in our patient is unique for different categories based on distance from the in-transit metastasis and emphasizes the rapidly Meier et al. found that the time course to the primary melanoma: 1) satellite metastasis (within 2 progressive and destructive course. development of metastases in patients with primary cm of the primary tumor); 2) in-transit metastasis cutaneous melanoma differed significantly between Clinically, the differential diagnosis for dark purple- (within the dermal and subdermal lymphatics the different routes of metastasis. The median time black papules coalescing into plaques and nodules in the drainage area before the first regional course to the development of distant metastases as is broad. It may include: cutaneous metastasis, lymph node basin); 3) intralymphatic metastasis first tumor recurrence was 25 months; it was16 angiosarcoma, Kaposi’s sarcoma, leukemia cutis, (both satellite and in-transit metastasis); and 4) months for regional lymph node metastases and 17 cutaneous B-cell lymphoma, lymphangioma distant metastasis (beyond regional lymph nodes, 23 9,23,24 months for satellite or in-transit metastases. The circumscriptum, lymphomatoid papulosis, frequently involving visceral sites). Satellite clinical outcome is reported to be less favorable cutaneous tuberculosis, coccidioidomycosis, metastasis, in-transit metastasis, and lymph node 29 when the site of metastatic skin involvement , and secondary syphilis. metastasis represent loco-regional metastases, is distant to the primary melanoma. One trial Histologically, metastatic melanoma generally which occasionally can occur distal to the primary reported cutaneous-to-visceral progression of invades the dermis and subcutis without invasion tumor in the limbs. Studies have found that two- metastasis at a median of 17.8 months for patients of the epidermis. While at low power, this may thirds of patients who develop metastases initially

BELLEW, CHAUDHARI, KHERADMAND, MACKEY Page 32 resemble a benign intradermal nevus, on high power References 15. Biswas J, Ahuja VK, Shanmugam MP, Kurian one can appreciate the nuclear atypia with mitoses 1. Giannini I, Cutrignelli DA, Resta L, Gentile R, Fernandez T. Malignant melanoma of the and lack of maturation. At times, the metastatic A, Vincenti L. Metastatic melanoma of the choroid presenting as orbital cellulitis: report of two melanoma can invade the epidermis and closely gallbladder: report of two cases and a review of the cases with a review of the literature. Orbit. 1999 mimic a primary melanoma. Rarely, melanoma that literature. Clin Exp Med. 2016 Aug;16(3):295-300. Jun;18(2):123-30. has metastasized to the dermis may closely resemble a blue nevus. Histopathologic evaluation in our 2. Dror S, Sander L, Schwartz H, Sheinboim 16. Balch CM, Gershenwald JE, Soong SJ, patient revealed not only striking pleomorphic D, Barzilai A, Dishon Y, et al. Melanoma Thompson JF, Atkins MB, Byrd DR, et al. melanocytic nests located predominantly within miRNA trafficking controls tumour primary Final version of 2009 AJCC melanoma staging the papillary dermis but also notable angioinvasion. niche formation. Nat Cell Biol. 2016 and classification. J Clin Oncol. 2009 Dec Periendothelial migration of melanoma cells Sep;18(9):1006-17. 20;27(36):6199-206. from angiogenic spread can serve as an additional 30 indicator for metastatic disease. 3. Dong XD, DeMatos P, Prieto VG, Seigler HF. 17. Mervic L. Time course and pattern of metastasis Melanoma of the gallbladder: a review of cases seen of cutaneous melanoma differ between men and Treatment of melanoma skin metastasis is at Duke University Medical Center. Cancer. 1999 women. PLOS One. 2012;7(3):e32955. extremely difficult, with primary focus on Jan 01;85(1):32-9. decreasing disease progression to prolong survival. 18. Tejera-Vaquerizo A, Barrera-Vigo MV, When surgical resection is not reasonable, case 4. Howlader N, Noone AM, Krapcho M, et al., Fernandez-Canedo I, Blazquez-Sanchez N, reports have shown some success with use of editors. SEER Cancer Statistics Review, 1975– Mendiola-Fernandez M, Fernandez-Orland A, topical imiquimod, regional chemotherapy with 2009 (Vintage 2009 Populations). Bethesda, MD, et al. [Longitudinal study of different metastatic drugs such as melphalan through hyperthermic USA: National Cancer Institute; 2012 [cited 2017 patterns in the progression of cutaneous isolated limb perfusion (ILP) or isolated limb March 3]; Available from: http://seer.cancer.gov/ melanoma]. Actas Dermosifiliogr. 2007 infusion (ILI), immunotherapy with systemic csr/1975_2009_pops09/. Oct;98(8):531-8. agents or intralesional immunotherapy, and 28,31-33 electrochemotherapy. However, aggressive 5. Dasgupta T, Brasfield R. Metastatic Melanoma. 19. Morton DL, Thompson JF, Cochran AJ, treatments may lead to unwanted toxicity. With A Clinicopathological Study. Cancer. 1964 Mozzillo N, Elashoff R, Essner R, et al. Sentinel- multiple new targeted therapies on the horizon, Oct;17:1323-39. node biopsy or nodal observation in melanoma. N accurate staging and close surveillance of high-risk Engl J Med. 2006 Sep 28;355(13):1307-17. patients is of utmost importance. 6. Gupta GP, Massague J. Cancer metastasis: building a framework. Cell. 2006 Nov 20. Pizarro A. [Models of melanoma spread Conclusion 17;127(4):679-95. and final results of the Multicenter Selective Melanoma undergoes rapid growth, causes Lymphadenectomy Trial-I]. Actas Dermosifiliogr. extensive damage, and leads to high morbidity and 7. Valastyan S, Weinberg RA. Tumor metastasis: 2015 Mar;106(2):82-5. mortality. The spontaneous eruption of extensive, molecular insights and evolving paradigms. Cell. coalescing, purple-black pigmented papulonodular 2011 Oct 14;147(2):275-92. 21. Mealy N, Ackerman AB. Sentinel node biopsy lesions as a presentation of metastatic melanoma has no benefit for patients whose primary cutaneous is uncommonly reported. We have presented 8. Fidler IJ. The biology of melanoma melanoma has metastasized to a lymph node and this case to address the need for prompt workup metastasis. Journal Dermatol Surg Oncol. 1988 therefore should be abandoned now. Br J Dermatol. with a potential diagnosis of metastasis, especially Aug;14(8):875-81. 2004 Aug;151(2):298-307. in patients with a known history of cutaneous melanoma, and initiation of aggressive treatment to 9. Leiter U, Meier F, Schittek B, Garbe C. The 22. Clark WH. Tumour progression and the nature prolong survival. Physicians must maintain a high natural course of cutaneous melanoma. J Surg of cancer. Br J Cancer. 1991 Oct;64(4):631-44. Oncol. 2004 Jul 01;86(4):172-8. index of suspicion for cutaneous metastasis in rare 23. Meier F, Will S, Ellwanger U, Schlagenhauff B, eruptive presentations in patients with a previous 10. Savoia P, Fava P, Bernengo MG. Cutaneous Schittek B, Rassner G, et al. Metastatic pathways history of malignant melanoma, as it may be the and time courses in the orderly progression result of an underlying life-threatening event. Metastases from Malignant Melanoma: Clinical Features and New Therapeutic Perspectives. of cutaneous melanoma. Br J Dermatol. 2002 Immunotherapy advancements over the past six Jul;147(1):62-70. years have had a profound impact on how clinicians In: Morton R, editor. Treatment of Metastatic Melanoma. InTech. 2011. Available from: https:// approach metastatic melanoma treatment, and we 24. Grotz TE, Mansfield AS, Kottschade LA, hope this case study helps physicians in all specialties www.intechopen.com/books/treatment-of- metastatic-melanoma/cutaneous-metastases-from- Erickson LA, Otley CC, Markovic SN, et al. In- understand the complexity of presentation for this transit melanoma: an individualized approach. deadly disease. malignant-melanoma-clinical-features-and-new- therapeutic-perspectives. Oncology. 2011 Dec;25(14):1340-8. Acknowledgements 25. Cohn-Cedermark G, Mansson-Brahme E, The authors would like to thank Jaldeep Daulat, DO, 11. Hwang SJ, Kong BY, Chou S, Wakade D, Carlino MS, Fernandez-Penas P. Acute Truncal Rutqvist LE, Larsson O, Singnomklao T, Ringborg from the Mohave Centers for Dermatology and U. Metastatic patterns, clinical outcome, and Plastic Surgery, and Prakash Chaudhari, MD, and Secondary to Axillary Metastatic Melanoma Presenting Like Cellulitis. Case Rep malignant phenotype in malignant cutaneous Howard Hoffman, MD, from the dermatopathology melanoma. Acta Oncol. 1999;38(5):549-57. department at Quest Diagnostics in Las Vegas, NV, Med. 2017;2017:5462929. for their invaluable clinical and histopathologic 26. Reintgen DS, Cox C, Slingluff CL Jr, Seigler HF. insight regarding this case. 12. Erstine EM, Elwood HR, Westbrook KC, McCalmont TH, Shalin SC, Gardner JM. Recurrent malignant melanoma: the identification Desmoplastic melanoma presenting as primary of prognostic factors to predict survival. Ann Plast alopecia neoplastica: a report of two cases. J Cutan Surg. 1992 Jan;28(1):45-9. Pathol. 2016 Oct;43(10):872-9. 27. Soong SJ, Harrison RA, McCarthy WH, 13. Varghese A, Singh A, Ambujam S. Carcinoma en Urist MM, Balch CM. Factors affecting survival cuirasse: a cutaneous clue for systemic malignancy. following local, regional, or distant recurrence Int J Prev Med. 2013 Jan;4(1):122-3. from localized melanoma. J Surg Oncol. 1998 Apr;67(4):228-33. 14. Chaudhary S, Bansal C, Husain A. Literature meta-analysis of zosteriform cutaneous metastases 28. Savoia P, Fava P, Nardo T, Osella-Abate S, from melanoma and a clinico-histopathological Quaglino P, Bernengo MG. Skin metastases of report from India. Ecancermedicalscience. malignant melanoma: a clinical and prognostic 2013;7:324. survey. Melanoma Res. 2009 Oct;19(5):321-6.

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30. Gerami P, Shea C, Stone MS. Angiotropism in epidermotropic metastatic melanoma: another clue to the diagnosis. Am J Dermatopathol. 2006 Oct;28(5):429-33.

31. Daryanani D, de Vries EG, Guchelaar HJ, van Weerden TW, Hoekstra HJ. Hyperthermic isolated regional perfusion of the limb with carboplatin. Eur J Surg Oncol. 2000 Dec;26(8):792-7.

32. Kroon HM, Huismans AM, Kam PC, Thompson JF. Isolated limb infusion with melphalan and actinomycin D for melanoma: a systematic review. J Surg Oncol. 2014 Mar;109(4):348-51.

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BELLEW, CHAUDHARI, KHERADMAND, MACKEY Page 34 Excimer Laser for the Treatment of Inflammatory Linear Verrucous Epidermal Nevus (ILVEN): A Novel Therapy Jessica Kim, DO,* Christina Steinmetz-Rodriguez, DO,** Anna Krishtul, MD,*** Shakira Payne-Blackman, MD****

*Dermatology Fellow, 4th Year, Dermatology Residency Program, Palm Beach Consortium for Graduate Medical Education - JFK Medical Center North Campus, West Palm Beach, FL **Dermatology Fellow, 6th Year, Dermatology Residency Program, Palm Beach Consortium for Graduate Medical Education - JFK Medical Center North Campus, West Palm Beach, FL ***Staff Dermatologist, VA Medical Center, West Palm Beach, FL 33410 ****Staff Pathologist/Hematopathologist, VA Medical Center, West Palm Beach, FL

Disclosures: None Correspondence: Jessica Kim, DO; Ph: 561-842-6141; Fax: 561-844-8955, [email protected] Shakira Payne-Blackman, MD; Ph: 561-422-6824; Fax: 561-422-6827, [email protected]

Abstract Patients seek treatment of inflammatory linear verrucous epidermal nevus (ILVEN) for symptomatic relief of pruritus and cosmesis. Most treatment options provide only temporary relief or carry risks of scarring. We present the case of a 56-year-old male who developed a pruritic papular plaque following the lines of Blaschko, consistent with ILVEN clinically and histologically. The patient was refractory to topical treatment, so other options were explored. Due to the excimer 308-nm laser’s anti-inflammatory capabilities and effective treatment of psoriasis, we proposed the possibility of the excimer laser as a new treatment option for ILVEN. Our patient showed significant improvement in pruritus and cosmesis with concurrent use of excimer laser twice a week for 52 weeks and topical therapy. The excimer laser showed promising results without side effects or scarring, making it an encouraging treatment option that should be researched further.

Introduction Inflammatory linear verrucous epidermal nevus (ILVEN) is a rare type of epidermal nevus, accounting for only 5% of all epidermal-nevus cases. It is associated with pruritus, erythema and scaling with papules that follow the lines of Blaschko. ILVEN is usually located unilaterally on a limb and is predominant in females. It normally presents at a young age, though there have been rare reports of adult-onset ILVEN.1,2 Patients seek treatment for cosmetic disfigurement and severe pruritus. There are various treatment options, but most are considered temporary fixes; very few to none have achieved lasting cures. ILVEN is characteristically refractory to treatment.

The excimer 308-nm laser is a narrow-band UVB (NB-UVB) laser developed in 1997 for the treatment of psoriasis.3 The targeted treatment allowed for use of a higher concentration of light without affecting surrounding normal skin, resulting in quicker clearance of psoriasis plaques. It has been particularly effective in difficult-to- treat areas such as the knees, elbows, scalp, palms and soles.4 ILVEN and psoriasis have clinical and histopathologic similarities, which led us to Figure 1a Figure 1b believe that the excimer 308-nm laser could be an effective treatment option for ILVEN. As far as we know, there have been no prior ILVEN treatments attempted with the excimer 308-nm laser. Case Report We present the case of a Fitzpatrick 4, 56-year-old male who presented to the clinic with complaints of a very pruritic rash on his right leg present for about a year. Prior to presenting to the office, the patient had tried various topical treatments, including steroids and calcipotriene, with no improvement. He had no significant past medical, surgical or family history.

Upon physical exam, the right leg showed a grey, papular plaque on the dorsum of the second toe extending up the posterior and lateral aspect of the leg to the buttocks (Figure 1). No similar lesions were present elsewhere. Figure 1c

A 3-mm punch biopsy was obtained, which showed Figure 1. Lesions prior to starting treatment with excimer 308-nm laser: (a) grey, papular plaque on ILVEN’s classic alternating orthokeratosis overlying posterior aspect of right leg; (b) close-up of right leg; (c) close-up of grey plaque on right lateral ankle.

Page 35 EXCIMER LASER FOR THE TREATMENT OF INFLAMMATORY LINEAR VERRUCOUS EPIDERMAL NEVUS (ILVEN): A NOVEL THERAPY hypergranulosis with parakeratosis (Figure 2). Due to the definitive histological findings and the clinical presentation, the patient was diagnosed with a rare case of adult-onset ILVEN.

The patient was initially prescribed halobetasol ointment and calcipotriene cream, which he used for about eight months. The topicals helped with the itch but did not improve the cosmetic appearance of the lesion. The option of trying a course of treatment with the excimer laser was discussed, and it was decided that the patient would be treated twice a week with an increase in energy with every treatment. The patient started seeing dramatic improvement in pruritic Figure 2a Figure 2b symptoms and the appearance of the lesion after 20 weeks (Figure 3). Figure 2. H&E: (a) 40x, showing alternating orthokeratosis with parakeratosis and hypergranulosis under the orthokeratosis; (b) 400x, close-up of hypergranulosis with overlying orthokeratosis. The patient continued to receive excimer laser Additional histological changes were present due to application of topical medications prior to biopsy. treatment twice weekly for a total of 52 weeks. After 52 weeks, he continued only topical therapy and monitored for recurrence. The patient continued to exhibit remission of lesions and pruritus several weeks post-excimer treatment. Discussion ILVEN is notoriously refractory to treatment. Several treatment options have been explored, but very few have produced adequate results without reoccurrence. Many cases have attempted treatment with topical steroids, but most of the time this only achieved temporary relief of pruritus. There are a few reported cases of large ILVEN lesions not responsive to other forms of treatment being treated with full-thickness excision and skin grafting with successful long-term remission.5,6 But with every large surgical procedure comes the risk of disfiguring scarring.

Phototherapy has been around since the time of the ancient Egyptians and is used to treat vitiligo, alopecia, eczema and psoriasis.4 Despite further advancements in treatment, phototherapy continues to be a mainstay treatment for psoriasis. Studies have shown that through a complex mechanism, UV light can promote immunosuppression and alter cytokines to reduce inflammation in psoriasis through various possible pathways.4,7-9

Psoriatic lesions result from abnormal interaction between the innate immune system, T cells and keratinocytes, which leads to the activation of Figure 3a Figure 3b cytokines and the immune axis of T-helper cells types 1 and 17 (Th1/Th17).4 This activation leads to keratinocyte hyper-proliferation and the inflammation seen in psoriasis.4 Phototherapy alters the immune response by suppressing the proinflammatory Th1/Th17 pathway, which decreases the systemic release of IFN-γ, IL-8, IL-12, IL-17, IL-20, IL-22 and IL-23 and causes a switch toward the counter-regulatory Th2 pathway.4,10 Studies have shown a decrease in plasma levels of TNF-a, IL-17 and IL-23 after a six-week treatment period with NB-UVB.4 Furthermore, regulatory T cells (Treg) have an enhanced propensity to convert IL-17A-producing cells in psoriasis.4 This leads to a loss of forkhead box P3 (FOXp3).4 UVB increases FOXp3-positive Treg cells in psoriatic skin, which ultimately causes a local reduction in inflammatory Th1/Th17 cytokines.4

ILVEN and psoriasis have clinical and Figure 3c histopathologic similarities. Clinically, both lesions have psoriasiform and inflammatory changes. Figure 3. After 20 weeks of treatment with excimer 308-nm laser: (a) posterior right leg and (b) lateral Histopathologically, both lesions have psoriasiform right leg showing improvement in appearance of ILVEN lesion; (c) close-up of right ankle and foot.

KIM, STEINMETZ-RODRIGUEZ, KRISHTUL, PAYNE-BLACKMAN Page 36 hyperplasia of the epidermis.11,12 Due to these 16. Conti R, Bruscino N, Campolmi P, Bonan P, similarities, many believe that psoriasis and ILVEN References Cannarozzo G, Moretti S. Inflammatory linear 11 1. Goldman K, Don PC. Adult onset of inflammatory have a common pathogenesis. There is evidence linear verrucous epidermal nevus in a mother and verrucous epidermal nevus: why a combined that ILVEN upregulates TNF-a, IL-1, IL-6 her daughter. Dermatology. 1994;189(2):170-2. laser therapy. J Cosmet Laser Ther. 2013 Aug and intercellular adhesion molecule-1, similar to 15(4):242-5. 11 psoriasis. Previous studies have looked at the 2. Kawaguchi H, Takeuchi M, Ono H, clinical and histological similarities between the Nakajima H. Adult onset of inflammatory linear 17. Alonso-Castro L, et al. Carbon dioxide laser two disease processes and hypothesized that the verrucous epidermal nevus. J Dermatol. 1999 treatment of epidermal nevi: response and long- same treatment used on psoriasis could also work Sep;26(9):599-602. term follow-up. Actas Dermosifiliogr. 2012 on ILVEN.11,13 The proposed theory was that Dec;103(10):910-8. ILVEN might be a phenotypic variant of psoriasis, 3. Mehta D, Lim HW. Ultraviolet B Phototherapy with a postzygotic loss of gene mutation leading for Psoriasis: Review of Practical Guidelines. Am J 18. D’Antuono A, et al. Carbon dioxide laser: to the production of a linear area of skin with Clin Dermatol. 2016;17(2):125-33. first-line therapy in vulvar inflammatory linear the pruritic plaques of ILVEN.11,14,15 The use of verrucous epidermal nevus. Dermatol Ther. 2012 etanercept in ILVEN produced favorable results 4. Nakamura M, Farahnik B and Bhutani T. Jan-Feb;25(1):92-4. in symptoms and appearance, so the use of other Recent advances in phototherapy for psoriasis 13 psoriasis therapies for ILVEN was proposed. The [version 1; referees: 2 approved]. F1000Research. 19. Ulkur E, et al. Carbon dioxide laser therapy for use of lasers as a possible treatment option is a fairly 2016;5(F1000 Faculty Rev):1684 (doi: 10.12688/ an inflammatory linear verrucous epidermal nevus: new concept. There are several reports of using CO2 f1000research.8846.1). a case report. Aesthetic Plast Surg. 2004 Nov- lasers to treat ILVEN, but results are mixed.16-19 Dec;28(6):428-30. The decision to pursue treatment with the excimer 5. Behera B, Devi B, Nayak BB, Sahu B, Singh B, 308-nm laser was due to its anti-inflammatory Puhan MR. Giant inflammatory linear verrucous properties and effectiveness in treating psoriasis.3,5 epidermal nevus: Successfully treated with full Fifty-two weeks of treatment with the excimer thickness excision and skin grafting. Indian J laser produced very promising results achieved with Dermatol. 2013;58:461-3. minimal risk of adverse side effects and no scarring. 6. Lee BJ, Mancini AJ, Renucci J, Paller AS, Conclusion Bauer BS. Full-thickness surgical excision for We report a rare case of adult-onset ILVEN that the treatment of inflammatory linear verrucous was not improving with common topical treatment epidermal nevus. Ann Plast Surg. 2001;47:285-92. options, so alternative treatment options were pursued. After twice-weekly treatment with the 7. Higgins E, et al. A randomized half body excimer laser for 52 weeks and concurrent, twice-daily prospective study of low and medium dose use of halobetasol ointment and calcipotriene cream, regimens using the 308 nm excimer laser in the the patient demonstrated significant improvement treatment of localized psoriasis. J Dermatol Treat. in the appearance and pruritic symptoms of an 2017;28(1):8-13. ILVEN lesion located on his right lower extremity. The excimer laser is a very encouraging treatment 8. El-Ghorr AA, Norval M. Biological effects of option because it is minimally invasive with few to narrow-band (311 nm TL01) UVB irradiation: a no adverse effects. As this is a novel form of therapy review. J Photochem Photobiol B. 1997;38:99. to treat ILVEN, more research should be pursued to confirm our findings. 9. Raj D, Brash DE, Grossman D. Keratinocyte apoptosis in epidermal development and disease. J Invest Dermatol. 2006;126:243.

10. Walters IB, Ozawa M, Cardinale I, et al. Narrowband (312 nm) UV-B suppresses interferon gamma and interleukin (IL) 12 and increases IL-4 transcripts: differential regulation of cytokines at the single-cell level. Arch Dermatol. 2003;139:155.

11. Khachemoune A, Janjua SA, Guidbakke KK. Inflammatory linear verrucous epidermal nevus: a case report and short review of the literature. Cutis. 2006 Oct;78(4):261-7.

12. Renner R, et al. Acitretin Treatment of a Systematized Inflammatory Linear Verrucous Epidermal Naevus. Acta Derm Venereol. 2004;Oct (85):348-50.

13. Bogle MA, Sobell JM, Dover JS. Successful treatment of a widespread inflammatory verrucous epidermal nevus with etanercept. Arch Dermatol. 2006;142:401-2.

14. Menni S, Restano L, Fianotti R, Boccardi D. Inflammatory linear verrucous epidermal nevus (ILVEN) and psoriasis in a child? Int J Dermatol. 2000;39(1):30-2.

15. Happle R. A rule concerning the segmental manifestation of autosomal dominant skin disorders. Arch Dermatol. 1997;133:1505-9.

Page 37 EXCIMER LASER FOR THE TREATMENT OF INFLAMMATORY LINEAR VERRUCOUS EPIDERMAL NEVUS (ILVEN): A NOVEL THERAPY Incidence and Time to Diagnosis of Pemphigus Foliaceus in a Private Dermatology Practice Over 10 Years Joseph Michael Dyer, DO,* Patrick Hardigan, PhD,** Richard Alan Miller, DO***

*Dermatology Resident, Third Year, Largo Medical Center, Largo, FL **Statistician, Nova Southeastern University, Fort Lauderdale, FL ***Dermatology Residency Program Director, Largo Medical Center, Largo, FL

Disclosures: None Correspondence: Joseph Michael Dyer, DO; 20114th St SW, Largo, FL 33770; 727-588-5704; [email protected]

IRB status: Granted exemption per Nova Southeastern University IRB #2017-363.

Abstract Data on the incidence of pemphigus foliaceus in the community setting are sparse. This retrospective chart review analyzed one decade of patient visits to a private dermatology practice in the greater Tampa Bay area of Florida and identified four new diagnoses of pemphigus foliaceus. Time to diagnosis and factors associated with prompt and delayed diagnosis were noted. This study may allow community dermatologists to recognize this infrequent immunobullous condition more rapidly.

Introduction Results office visits were required for cases with disease limited Pemphigus foliaceus (PF) is an uncommon autoimmune Four patients out of 154,230 were newly diagnosed with to the head and neck and a biopsy initially diagnosed blistering disorder propagated by antibodies to PF during the studied time period, with an incidence of as lichen simplex chronicus (Figure 1). The limitations desmoglein 1, an intercellular adhesion protein found one per 38,558 new patient visits. The median TTD of the present study include small sample size and preferentially in the upper epidermis.1,2 Classic cases of was 240 days (range: 60 to 480), or 3.5 office visits retrospective nature and reflect the rarity of PF. PF are characterized by flaccid bullae or crusted erosions (range: 1 to 8). Fewer office visits were associated with in a seborrheic distribution on the face, scalp, and upper widespread clinical distribution. Additional office visits Conclusion This report represents unique data on incidence and trunk. Its presentation, however, may be subtle and were associated with limited disease distribution and TTD of PF in the private practice setting. Increased protean, which can lengthen time to correct diagnosis. misdiagnosis by initial histopathology. awareness of PF may accelerate its TTD and reduce Objective Discussion its morbidity. This study determined the incidence of new While the dermatologic literature is replete with diagnoses of PF, established the time to diagnosis descriptions of PF—its clinical appearance, histology, (TTD), and examined factors associated with management, and prognosis—little has been said prompt diagnosis and delayed diagnosis. about its incidence and TTD in the private practice setting. Cited incidence of PF is often combined Methods with pemphigus vulgaris and stated relative to general This study was designed as a retrospective cross-sectional populations: The incidence of pemphigus ranges from review using data previously gathered for patient care. The 0.76 to 16.1 new cases per million.3 Our data allow patient data utilized were selected using the following a more specific grasp of the incidence of PF: Ina criteria: 1) The patient must have been seen at one of community dermatology clinic, an average of 38,558 eight private practice dermatology clinics in western new patients must be seen before encountering one Florida from March 2007 to March 2017; and 2) the new diagnosis of PF. This infrequency leads to patient must have a new diagnosis of PF as identified by unfamiliarity and, possibly, delayed diagnosis. International Classification of Diseases, version 9, and substantiated by manual chart review. The TTD of PF A retrospective review of seven cases from a tertiary care Figure 1. Patient 4: PF presenting as after symptom onset was recorded in days and number of center reported a mean diagnostic delay of 300 days 4 erythematous, crusted plaques of the left office visits. These and other salient data were gathered in PF. Our data show a median TTD of 240 days jawline. Time to diagnosis was prolonged after using the private practice’s electronic medical record with a sample size of four patients. This demonstrates initial histopathology misdiagnosed lichen system and are summarized in Table 1. This study was PF is uncommonly encountered and not immediately simplex chronicus. granted institutional review board exemption. diagnosed, regardless of practice setting. Increased Table 1. New diagnoses of PF at western Florida private dermatology practice, Mar. 2007 to Mar. 2017 Pt Age Sex Lesion Description Lesion Initial TTD Bx Results TTD- Diagnostic method Comments (y) Distribution Clinical DDx OV (H&E, DIF, +/- Abs) 47 M Erythematous scaly Left parietal scalp Seborrheic 480 OV 4: PF 4 H&E Limited disease patch dermatitis distribution† 72 F Erythematous, crusty, Upper back, central Drug eruption 270 OV 1: PF 1 H&E, DIF More distributed at excoriated patches chest, cheek with impetigo clinical presentation‡ 71 F Erythematous, scaly Upper back, left ACD 60 OV 1: PF 1 H&E, DIF, Abs More distributed at papules and plaques breast, forehead clinical presentation 65 M Erythematous, scaly Bilateral jawline LSC, DLE, 210 OV 4: LSC 8 H&E, DIF, Abs Limited disease distribution plaques sarcoidosis OV 8: PF Initial Bx results may have increased TTD-OV Abs, serum antibodies against desmoglein 1; ACD, allergic contact dermatitis; DIF, direct immunofluorescence of perilesional skin; DLE, discoid erythematosus; H&E, histologic analysis of lesional skin with H&E stain; LSC, lichen simplex chronicus; OV, office visit; PF, pemphigus foliaceus; TTD, time to diagnosis, measured in days from onset of symptoms to PF diagnosis; TTD-OV, time to diagnosis, measured in number of office visits until PF diagnosis †Limited disease distribution: lesions limited to head/neck or trunk ‡More distributed at clinical presentation: lesions on head/neck and trunk

DYER, HARDIGAN, MILLER Page 38 References 1. Stanley JR, Koulu L, Klaus-Kovtun V, Steinberg MS. A monoclonal antibody to the desmosomal glycoprotein desmoglein 1 binds the same polypeptide as human autoantibodies in pemphigus foliaceus. J Immunol. 1986;136(4):1227-30.

2. Ohata C, Ishii N, Furumura M. Locations of in pemphigus vulgaris and pemphigus foliaceus. J Cutan Pathol. 2014;41(11):880-9.

3. Murrell DF, et al. Consensus statement on definitions of disease, end points, and therapeutic response for pemphigus. J Am Acad Dermatol. 2008;58(6):1043-6.

4. Woldegiorgis S, Swerlick RA. Pemphigus in the southeastern United States. Southern Med J. 2001;94(7):694-8.

Page 39 INCIDENCE AND TIME TO DIAGNOSIS OF PEMPHIGUS FOLIACEUS IN A PRIVATE DERMATOLOGY PRACTICE OVER 10 YEARS Late-Onset Focal Dermal Elastosis: A Case Report and Review of the Literature Jessica Newburger, DO,* Michelle Foley, DO, FAOCD**

*Dermatology Resident, 2nd year, OMNEE/Park Avenue Dermatology, Orange Park, FL **Dermatologist, Parks Dermatology Center, Ormond Beach, FL

Disclosures: None Correspondence: Jessica Newburger, DO; Park Avenue Dermatology, 906 Park Ave., Orange Park, FL 32073; Ph: 516-384-4750; Fax: 904-541-0316; [email protected]

Abstract Late-onset focal dermal elastosis is a dermatologic condition that clinically resembles pseudoxanthoma elasticum (PXE); on histology, however, lesions seem to result from an accumulation of elastic fibers in the dermis. Unlike the histologic changes seen in PXE, there is no elastolysis in the papillary dermis and no deposition of calcium. Instead, there is a focal accumulation of normal-appearing elastic fibers in the mid dermis and deep dermis. The most important difference is that in patients with focal dermal elastosis, only cutaneous manifestations are present, without the systemic manifestations that are seen in PXE.

1 Case Report Initial biopsy revealed a sparse superficial perivascular originally described by Tajima et al. in 1995. It A 74-year-old Caucasian female presented to our dermatitis. A repeat punch biopsy was performed clinically resembles pseudoxanthoma elasticum clinic for a rash of her bilateral axillae. The rash had and demonstrated increased dermal elastic fibers with (PXE); based on histology, however, lesions appear been present for one week, and the patient complained occasional fragmentation on hematoxylin and eosin to be primarily the result of an accumulation of of mild itch. She was asymptomatic otherwise and stain (H&E) (Figure 3) and Verhoeff-van Gieson stain elastic fibers in the dermis. On histology, there are denied any systemic symptoms. The patient did state (VVG) (Figure 4). Additionally, a negative Von Kossa no elastolytic changes in the papillary dermis, unlike that she was using a new body wash. She had tried stain demonstrated a lack of calcification. These findings in PXE, and no deposition of calcium. Instead, there triamcinolone cream to the area but stated that the were consistent with late-onset focal dermal elastosis. is a focal accumulation of normal-appearing elastic rash had worsened and become irritated. fibers in the mid dermis and deep dermis. Most We prescribed pimecrolimus 1% cream for the important, patients with focal dermal elastosis have patient, but she stated that it irritated her skin only cutaneous manifestations, whereas systemic The patient’s past medical history was significant for 1 hypothyroidism, for which she was taking levothyroxine. similarly to the triamcinolone. The patient refused manifestations are seen in PXE. Her pertinent dermatologic history was significant for any other treatment, and over the course of a few squamous cell carcinoma, actinic keratoses and xerosis. weeks she stated that she believed there was an The pathogenesis of focal dermal elastosis is There was no family history of similar skin lesions. overall improvement in the irritation and pruritus. unknown, but some theories have been presented. It has been proposed that it represents an intrinsic aging process rather than a condition secondary to On exam, there were flesh-colored to yellowish Discussion 1,2 papules coalescing into plaques in a cobblestone Late-onset focal dermal elastosis is a rare, though sun exposure. This is supported by the clinical pattern on the bilateral axillary vaults (Figures 1, 2). possibly underdiagnosed, dermatologic condition and histopathological absence of solar elastosis and the presentation of lesions in sun-protected Figure 1 areas. Tajima et al. also suggested that there is increased elastin synthesis versus a reduction in elastic tissue degradation.1

Clinically, late-onset focal dermal elastosis occurs in healthy adults after the sixth decade, presenting with firm, yellow papules that coalesce into thickened plaques. Lesions are typically located on the neck or flexural areas of the arms or legs. They may be pruritic or completely asymptomatic.1,3

PXE is a condition caused by an autosomal- recessive defect in the ABCC6 transporter gene. It is similarly characterized by yellowish papules that coalesce into plaques on the sides of the neck and Figure 3. Increased dermal elastic fibers lacking flexural areas; however, patients with PXE have significant inflammation or obvious calcification varying degrees of systemic manifestations that of the (H&E, 100x). include hypertension, accelerated , cerebrovascular accident, intermittent claudication, Figure 2 gastric hemorrhage and ocular angioid streaks.2,3 The association with systemic features in PXE underscores the importance of distinguishing between PXE and focal dermal elastosis.

The principal histological feature of late-onset focal dermal elastosis is focal accumulation of normal-appearing elastic fibers in the mid-to-deep reticular dermis. The papillary dermis is typically unaffected, and the individual elastic fibers show no significant alterations in their morphology at the level of light microscopy. Additionally, there is no extensive solar damage and no evidence of calcification.1 These characteristics contrast those Figures 1, 2. Focal dermal elastosis of the Figure 4. Increased dermal elastic fibers with of PXE, which shows fragmented, curled and bilateral axillae. mild elastolysis (VVG, 100x). frayed elastic fibers and fine, granular-to-bulky

NEWBURGER, FOLEY Page 40 calcium deposits in the mid-to-deep reticular 4-7 References dermis. Although elastosis is the predominant 1. Tajima S, Shimizu K, Izumi T, et al. Late-onset feature, mild elastolysis on histology does not focal dermal elastosis: clinical and histological exclude a diagnosis of focal dermal elastosis. features. Br J Dermatol. 1995;133:303-5.

Even though there are irreversible changes to the 2. Higgins HJ, Whitworth MW. Late-Onset Focal elastic fibers in focal dermal elastosis, treatment Dermal Elastosis: A Case Report and Review of of this benign condition is directed at providing the Literature. Cutis. 2010;85:195-7. symptomatic relief of pruritus. High potency topical corticosteroids are usually an effective 2 3. Wang AR, Fonder MA, Telang GH, et al. treatment modality. Late-onset focal dermal elastosis: an uncommon mimicker of pseudoxanthoma elasticum. J Cutan While the condition is considered rare, it is possible Pathol. 2012;39:957-61. that focal dermal elastosis is underdiagnosed due to its benign nature and asymptomatic clinical course 4. Limas C. Late Onset Focal Dermal Elastosis: and that case reports do not accurately reflect the 4 A Distinct Clinicopathologic Entity? Am J prevalence of this condition. Dermatopathol. 1999;21:381-3.

Conclusion 5. Christen-Zach S, Huber M, Struk B, et The clinical appearance and distribution as well al. Pseudoxanthoma elasticum: evaluation of as the late onset, lack of family history, absence diagnostic criteria based on molecular data. Br J of systemic symptoms, and skin biopsy findings Dermatol. 2006;155:89. differentiate focal dermal elastosis from PXE.8 Late-onset focal dermal elastosis appears to be a 6. Pasquali RI, Volpin D, Baccarani CM, et al. distinct clinical and histopathological entity that Pseudoxanthoma elasticum: biochemical and should be considered in patients presenting with ultrastructural study. Dermatologica. 1981;163:307. PXE-like clinical symptoms. 7. Baccarani CM, Boraldi F, Taparelli F, et al. Matrix proteins with high affinity for calcium ions are associated with mineralization within the elastic fibers of pseudoxanthoma elasticum dermis. Am J Pathol. 1996;148:569.

8. Kossard S. Pseudoxanthoma-like late-onset focal dermal elastosis. Australas J Dermatol. 2005;46:47-50.

Page 41 LATE-ONSET FOCAL DERMAL ELASTOSIS: A CASE REPORT AND REVIEW OF THE LITERATURE Madelung’s Disease: A Report of a Rare Case with an Atypical Presentation Tam H. Nguyen, BS,* Blake Sanders, DO,** Franciso A. Kerdel, MD***

*Medical Student, 3rd year, Nova Southeastern University College of Osteopathic Medicine, Ft. Lauderdale, FL **Dermatology Resident, 1st year, Larkin Community Hospital Dermatology Residency Program, South Miami, FL ***Dermatologist, Florida Academic Dermatology Center, Coral Gables, FL

Disclosures: None Correspondence: Tam H. Nguyen; [email protected]

Abstract Madelung’s disease is a rare condition characterized by the symmetric deposition of non-encapsulated lipomas throughout the body. This article reports an atypical presentation of Madelung’s disease and provides important epidemiologic, diagnostic, and treatment options that contribute to the ever-growing body of medical literature regarding this uncommon disease.

Introduction of (Figure 2). The neck and two years, imaging studies were not preformed. Madelung’s disease, also known as multiple supraclavicular areas were completely spared, The patient was referred to plastic surgery for symmetric lipomatosis, is a rare condition of suggesting an atypical presentation of this disease. liposuction of the upper extremities. metabolism that results in the symmetrical A tissue punch biopsy of the proximal segment of deposition of most commonly around the anterior surface of the patient’s right upper arm Discussion This report describes a highly atypical presentation the mental, cervical, supraclavicular and upper- was reported as a lipoma with focal lipodystrophic of Madelung’s disease. First, while Mediterranean extremity regions. The disease was first reported in changes (Figures 3 and 4), which, combined descent is most characteristic, our patient was native 1846 and has since troubled the medical community with the patient’s presentation, was diagnostic of 1,2 Madelung’s disease. Due to the lack of symptoms to India. Cases of Madelung’s have been reported due to its unknown etiology and pathophysiology. 9,10 only rarely in patients of Asian descent. Second, Literature on this rare disease reports that men from these adipose deposits over the course of 3,4 the patient’s physical presentation of this disease are most commonly affected, at a ratio of 15:1. was not typical of reported cases. Most often, Furthermore, disease manifestation is most often Madelung’s disease presents first and foremost seen in those of Mediterranean descent, suggesting with adipose deposition around the cervical and a possible genetic inheritance pattern. Up to supraclavicular regions. Along with infiltrations in 90% of patients with Madelung’s disease suffer 1,2,4-6 these regions, adipose tissue can be found along the from chronic alcoholism as well. Common upper extremities. The disease is rarely reported to comorbid conditions such as hyperlipidemia, occur with adipose tissue deposits isolated strictly hyperuricemia and diabetes have been reported in 2,7 within the upper extremities, with no involvement cases of Madelung’s disease. As such, the disease of the neck region. Third, the most common process can be associated with both environmental comorbid condition associated with this disease is and genetic predispositions, but a definitive etiology a history of chronic alcohol abuse. Our patient had has not yet been identified. no history of alcohol abuse and described himself as As the disease most commonly presents in the strictly a social drinker. Thus, our case demonstrates cervical and upper-extremity regions, the typical that Madelung’s disease can present in patients even presentation of Madelung’s disease is a male in the absence of common associated risk factors. patient in his fourth or fifth decade complaining Diagnosis of Madelung’s disease is made by a of progressive dysphagia, dyspnea, myopathy and thorough history and physical exam, a clinical paresthesia, which are due to mass effect of the knowledge of the disease, and clinical suspicion, adipose deposition on the vascular and anatomic 2 and it is confirmed by biopsy of the tumors to structures in these respective regions. The prognosis confirm non-encapsulated lipomas. Imaging of Madelung’s disease is based upon infiltration studies like CT and MRI are commonly ordered of adipose tissue into vascular and anatomic Figure 1 structures. The most common cause of mortality in these patients is sudden cardiac death due to mass effect of tumors on autonomic nerve fibers coursing through the superior thoracic aperture.8 Case Presentation The patient was a 59-year-old male of Indian descent who was referred by rheumatology for evaluation of profound adipose deposition in the bilateral arms. The patient reported this first occurred in May 2015, following a three-week hospital stay for Henoch-Schönlein purpura. The Figure 3 patient denied any pain or tenderness in the lesions but did note intermittent swelling localized to the upper extremities. Family history was negative for any similar conditions. Upon further questioning, the patient noted that he was a social alcohol drinker and past smoker.

On physical inspection, symmetrical enlargements of the bilateral upper extremities were observed (Figures 1 and 2). The masses were soft, homogeneous, and non-edematous to palpation, with overlying atrophic epidermis with areas Figure 2 Figure 4

NGUYEN, SANDERS, KERDEL Page 42 to assess tumor infiltration in symptomatic patients, although MRI is preferred because it is References 11 1. Jae Hoon J, Anbok L, Sang-Ah H, Jung-Kyu R, more sensitive in delineating soft-tissue masses. Jeong-Yoon S. Multiple Symmetric Lipomatosis In this case, imaging studies were not ordered due (Madelung’s Disease) Presenting as Bilateral to the chronic, two-year, asymptomatic history of Huge Gynecomastia. J Breast Cancer. 2014 the tumors. In instances where patients present Dec;17(4):397–400. with paresthesias, pain, or other sensory changes, imaging should be considered to evaluate for 2. Mladen M, Danijel P, Emina NI, et al. Multiple potential nerve-root compression. The diagnosis Symmetric Lipomatosis: A Diagnostic Dilemma. of Madelung’s disease is often missed because of Case Rep Med. 2013;836903. lack of awareness of the disease and because it can present similarly to many other common disease 3. Abdurrahman T, Ridvan M, Arif K, Mehmet ET, processes. For example, in patients presenting with Berivan B, Mehmet AO, Seminur Haznedaroğlu symmetric fatty deposits in the neck and upper- BG. An Unusual Case of Madelung’s Disease with extremity region, physicians often attribute the 2,12 Multiple Atypical Fractures. Case Rep Orthop. condition to obesity and Cushing’s syndrome. 2012 Dec;180506. However, the fatty tumors of Madelung’s disease do not decrease in size with exercise and weight loss, 4. Sousa EC, Fernandes FR, Rechtman R. which helps differentiate them from the adipose Multiple symmetric lipomatosis. Braz J Plast. deposits in obesity. Madelung’s tumors often remain 2013;28(2):324-37. even in patients with cachexia.7,11,13 Furthermore, a patient’s history of prescription oral steroid use and 5. Adamo C, Vescio G, Battaglia M. Madelung’s serum cortisol levels on laboratory investigation can Disease: Case Report and Discussion of Treatment help to distinguish it from Cushing’s syndrome. Options. Ann Plast Surg. 2001 Jan;46(1):43–5.

Lack of extensive medical literature regarding 6. Wollina U, Heinig B. Madelung’s Disease – Case Madelung’s disease results in lack of diagnosis Series and Treatment by Tumescent Liposuction or of the condition.2,7 Most commonly, patients Lipectomy. Maced J Med Sci. 2017;5:427-31. are diagnosed based on their clinical history of a slowly growing, symmetric adipose mass and by 7. Adi ML, Meir R, Yoav G. A Typical Presentation tissue biopsy, which is crucial to diagnosis, showing of Madelung Disease. J Gen Pract. 2016;4:240. non-encapsulated lipomas. First-line treatment is surgical excision or liposuction, with liposuction 8. Foseca VR, Freitas C, Palmeira M, Ferreira C, preferred due to its less-invasive approach and Victorino R. Cardiac noradrenergic denervation minimal scarring.10 However, surgical excision is in patient with multiple symmetric lipomatosis. utilized in instances of more-extensive infiltration . 2012;121:160-3. of vascular and anatomic structures.9 Recurrence is common, with tumors often slowly re-growing 9. Hoi-Fong C, Yu S, Cheng-Huai L, Rong-Chi C. after intervention.4,5,11 Alcohol cessation is often Madelung’s disease associated with polyneuropathy recommended in these patients, though there is and symptomatic hypokalemia. J Formos Med no proof this is effective in preventing further Assoc. 2013;112(5):283-6. adipose growths. There has been no reported case of Madelung’s disease following an exacerbation of 10. Wu CS, Wang LF, Tsai KB, Tai CF, Kuo WR. Henoch-Schönlein purpura, such as in our patient, Multiple symmetric lipomatosis (Madelung’s so our case may demonstrate an association not yet disease): report of two cases. Kaohsiung J Med Sci. reported in the literature. 2004;20:133e6. Conclusion 11. Sharma N, Hunter-Smith DJ, Rizzitelli A, This case illustrates the importance of considering Rozen WM. A surgical view on the treatment of Madelung’s disease in any patient presenting Madelung’s disease. Clin Obes. 2015;5:288-90. with a progressive increase in subcutaneous mass in a symmetrical distribution, with or without 12. Ardeleanu V, Chicos S, Georgescu C, Tutunaru D. Multiple benign symmetric lipomatosis -- a associated comorbid conditions. Prognosis is 1 entirely dependent upon the distribution of adipose differential diagnosis of obesity. See comment deposition and penetration of anatomic and vascular in PubMed Commons below Chirurgia (Bucur). structures, resulting in a potentially benign or life- 2013;108(4):580-3. threatening condition. Hopefully, as more cases are 13. Verhelle N, Nizet JL, Van den Hof B, Guelinckx reported in the literature, we can begin to investigate P, Heymans O. Liposuction in Benign Symmetric other possible associations with Madelung’s disease, Lipomatosis: Sense or Senseless? Aesthetic Plast such as Henoch Schönlein purpura (as seen in our Surg. 2013;27:319-21. case), and alternative treatment protocols.

Page 43 MADELUNG’S DISEASE: A REPORT OF A RARE CASE WITH AN ATYPICAL PRESENTATION Patterns and Treatment of Post-Herpetic Neuralgia: A Case Study Kaylie Pierce,* Kathryn Wanat,* Stephanie Egwuatu,* Carolyn Withee,* Nathaniel Allen-Slaba,* Manon Begert,* Megumi Sugita,* James Keene, DO,** Michael Scott, DO,*** Holly Novion,**** Dan Selski, DO,***** Michele McCarroll, DO***

*Osteopathic Medical Student III, College of Osteopathic Medicine, Pacific Northwest University of Health Sciences, Yakima, WA **Interim Chair, Department of Osteopathic Principles and Practice, College of Osteopathic Medicine, Pacific Northwest University of Health Sciences, Yakima, WA **Assistant Professor, Department of Clinical Medicine, College of Osteopathic Medicine, Pacific Northwest University of Health Sciences, Yakima, WA ****Medical Assistant, Seattle Dermatology Center, Seattle, WA *****Assistant Professor, Department of Anatomy, College of Osteopathic Medicine, Pacific Northwest University of Health Sciences, Yakima, WA

Disclosures: None Correspondence: Kaylie Pierce, College of Osteopathic Medicine, Pacific Northwest University of Health Sciences; Butler-Haney Hall; 200 University Parkway, Yakima, WA 98901; Ph: 509-499-1142; [email protected]

Abstract Post-herpetic neuralgia (PHN) results from a herpes zoster complication in the elderly, with variable onset and presentation of nerve pain. Diagnostic criteria of post- herpetic neuralgia include onset of pain persisting for greater than three months with or without the persistence of a maculopapular rash and vesicular eruptions along dermatomes. Understanding PHN is useful for early diagnosis and treatment to minimize the severity of pain. To properly diagnose PHN, clinical symptoms, risk factors, and antibodies for varicella zoster are analyzed. Studies demonstrate that preventative measures, including early varicella-zoster vaccination in children and vaccination in adults over 60 years with live and attenuated shingles, were likely to reduce post-herpetic neuralgia by 66.5%. Osteopathic treatment options, including indirect manipulative techniques, can help alleviate the pain caused by PHN. Thus, by creating an understanding of prompt treatment and prevention, we may reduce the overall risk and severity of PHN.

About 20% of patients infected with herpes zoster affected with PHN and the health care system Introduction 1 Postherpetic neuralgia (PHN) is a common will experience PHN with significant morbidity, as a whole. complication following reactivation infection with with elderly patients (those over 60 years) most 5 Postherpetic neuralgia (PHN) is a painful human herpesvirus 3 (HHV-3) or varicella zoster often affected. Risk factors for developing PHN neuropathic syndrome lasting more than three virus (VZV). This reactivation is referred to as include worsening, acute zoster pain, increased 1,2 age, a more severe eruption at presentation, months caused by reactivation of dormant herpes zoster and presents as a blistering, painful 6 3 varicella zoster virus (VZV) in sensory ganglia of rash in the affected dermatomes Figure( 1). Risk and the presence of a painful prodrome. The cranial or spinal nerves. Those affected by PHN factors for reactivation of the virus, commonly annual incidence of herpes zoster is about 3.4 cases per 1,000 persons; in those over 90 years report severe interference in their daily lives known as shingles, include autoimmune disease, 1,4 2 physically and subsequently psychologically. immunomodulation, and advanced age. In most of age, the incidence rate increases to 11 cases 6 Recognizing the implications of PHN may patients, the painful vesicular rash resolves within per every 1,000 persons. Of note, the rate of benefit early recognition, diagnosis, and a few weeks; however, in some patients the pain reinfection in immunocompetent patients is therapeutic treatment. associated with the rash persists long after the less than 6%. PHN can present as persistent rash has dissipated. If pain continues for greater “burning,” “stabbing,” “electric,” or “shooting” than three months after the rash has resolved, pain along a single affected dermatome. Physical Case Report 4 exam findings include increased or decreased A 95-year-old male was examined seven days after it is termed PHN. The pain is believed to be a vesicular-bullous rash occurred on the right side generated by nerve damage, specifically to the sensation, scarring, allodynia (pain from stimuli that don’t usually cause pain, such as a light of his chest and back (Figures 2, 3). He complained trigeminal nerve and geniculate or dorsal root of severe pain in the involved areas as well as the ganglion, where the virus remains dormant after touch with a cotton swab or clothing touching 2 right aspect of his head. Interestingly, he stated he the initial infection. the affected area), mechanical hyperalgesia (heightened sensitivity to mechanical stimulus had been vaccinated for herpes zoster. or pain) and/or altered autonomic function.7 Diagnosis: Multiple dermatomal herpes zoster PHN treatment options are limited, and many (T₃-T₆) with associated neuralgia. patients express dissatisfaction with treatment outcomes. This presents an issue for the Treatment: Due to extensive involvement and population of patients experiencing decreased severe discomfort, the patient was prescribed oral quality of life, psychological wellbeing, and famciclovir antiviral 500 mg TID and prednisone 5 physical functioning1 due to long-standing pain.8 mg TID for 10 days. PHN may play a role in the loss of independent functioning and lead to an increased need for a Results: Ten days later, follow-up exam showed higher level of care, which results in suffering considerable improvement of the vesicular-bullous and a disproportionate burden on both those

Figure 1. Progression of shingles: A cluster of small bumps (1) turns into blisters (2) that resemble chickenpox lesions, fill with pus, break open (3), over (4), and finally disappear. The process takes four to five weeks, after which postherpetic neuralgia may occur, thought to be Figure 2. Herpes zoster of the right aspect of Figure 3. Herpes zoster of the right aspect of caused by nerve damage (5). the chest before treatment. the back before treatment.

PIERCE, WANAT, EGWUATU, WITHEE, ALLEN-SLABA, BEGERT, Page 44 SUGITA, KEENE, SCOTT, NOVION, SELSKI, MCCARROLL 7,8 lesions (Figures 4, 5) but marked post-herpetic shingles vaccine once they are 50 years or older. This References neuralgia over the affected dermatomes as well as vaccine has demonstrated the ability to reduce the 1. Drolet M, Brisson M, Schmader KE, et al. The dermatomes of the right trigeminal nerve and T₂ zoster-related burden of illness and the incidence of impact of herpes zoster and postherpetic neuralgia of the right arm. both zoster and PHN. Widespread vaccination could on health-related quality of life: a prospective study. significantly reduce infection, by a quarter of a million CMAJ. 2010 Nov;182(16):1731-6. cases annually, lowering both consequential costs and Discussion 8 The classic clinical presentation of a herpes zoster morbidity associated with VZV. 2. Gilden D, Nagel MA, Mahalingam R, et outbreak is a maculopapular rash followed by a painful 4 al. Clinical and molecular aspects of varicella vesicular eruption in the affected dermatomes. This PHN is challenging to treat. Choice of medication(s) is zoster virus infection. Future Neurol. 2009 may be accompanied by pain, itching, paresthesia, guided by a patient’s response to medication, preference, Jan;4(1):103-17. and/or allodynia.5 Usually the rash and associated comorbidities, and drug adverse effects.11 Treatment symptoms resolve within a few weeks, but a small options are aimed to attack the multiple mechanisms of 3. Wei JJ, Chotai S, Sivaganesan A, Archer KR, subset of patients may present with pain that disease. Combination therapy has been the standard in Schneider BJ, Yang AJ, Devin CJ. Effect of pre- continues for three months or more following the clinical practice, although there is no data that evaluates 2 injection opioid use on post-injection patient- resolution of the vesicular eruption. This condition a synergistic or additive benefit. Currently, the first line reported outcomes following epidural steroid is defined as postherpetic neuralgia (PHN). of treatment includes gabapentin and lidocaine patch injections for radicular pain. Spine J. 2018 5%, as they demonstrate tolerability profiles. In the past, May;18(5):788-96. Clinically, the presentation of PHN is similar to that tricyclic antidepressants were considered the first-line 11 of a herpes zoster outbreak, but the painful symptoms treatment for PHN. In addition to anticonvulsants and 4. Campbell SM, Winkelmann RR, Walkowski typically persist for months to years. The quality of tricyclic antidepressants, oral regimens have included S. Osteopathic Manipulative Treatment: Novel the pain in the affected areas is often described as pregabalin, opioids, steroids, and NSAIDS. Pregabalin 9 Application to Dermatological Disease. JCAD. burning, stabbing, or electric. Because many of the and opioids have been used for treatment of resistant 2012 Oct;5(10):24-32. symptoms of PHN are sensory, a neurologic exam PHN. Topical treatments have been used, often in testing dermatomal sensation bilaterally may be combination with oral medications like clonidine, 5. Lapolla W, DiGiorgio C, Haitz K, Magel G, useful in assessing patients with suspected PHN. gabapentin, capsaicin, diclofenac, amitriptyline, opioids, Mendoza N, Grady J, Lu W, Tyring S. Incidence of Age and past medical history may also provide useful ketamine, and botulinum toxin type A. Both topical and postherpetic neuralgia after combination treatment clues in the diagnosis of PHN. Incidence of PHN oral treatments have had varying and limited degrees of with gabapentin and valacyclovir in patients increases with age, affecting just 8% of patients aged success in pain management. with acute herpes zoster open-label study. Arch 50 to 54 years compared with 21% of patients aged 80 Dermatol. 2011 Apr;147(8):901-7. to 84 years.3 PHN may also occur more frequently in New and alternative therapies show promising results patients who suffered more severe symptoms in the in pain management and control of PHN. Physical 6. Yawn BP, Saddier P, Wollan PC, St Sauver JL, acute phase of infection, and some evidence suggests therapy, dry needling, trigger-point injections, and Kurland MJ, Sy LS. A population-based study of the incidence of PHN increases among patients with percutaneous nerve stimulation have been used as the incidence and complication rates of herpes 10 10 other chronic diseases, such as diabetes. alternative therapies for some patients. A newer zoster before zoster vaccine introduction. Mayo treatment option is narrowband ultraviolet B Clin Proc. 2007 Nov;82(11):1341-9. The optimal treatment of PHN is prevention. The (nbUVB) phototherapy.1 It may prevent or decrease herpes zoster vaccine (HZV) boosts cell-mediated the pain of PHN by suppressing inflammatory 7. Fazio S. Postherpetic Neuralgia. New Eng. J. immunity to both VZV and HZ. Children born after response surrounding sensory neurons due to HZ. Med NOW [blog]. 2014 Oct 17. [cited 2017 Sept 1995 should receive the VZV vaccine and avoid those Low-level laser therapy (LLLT) is another approach 14]. Available from: https://blogs.nejm.org/now/ affected with chicken pox. For those infected with VZV currently under review. Use of low-level laser therapy index.php/postherpetic-neuralgia/2014/10/17/. as a child, the latent VZV can cause HZ and PHN. within the first five days of HZ eruption significantly The best prevention for these patients, as long as they reduces the incidence of postherpetic neuralgia. LLLT 8. Betts RF, Vaccination strategies for the prevention are immunocompetent, is to receive the live attenuated may have the ability to prevent PHN, but further well- of herpes zoster and postherpetic neuralgia. J Am designed, randomized controlled trials are required.12 Acad Dermatol. 2007 Dec;(6 Suppl):S143-7.

It has been shown that patients with PHN exhibit 9. Kost RG and Straus SE. Postherpetic Neuralgia- myofascial pain, so osteopathic manipulative therapies Pathogenesis, Treatment, and Prevention. N Engl J may provide relief. Indirect techniques such as Med. 1996 July;335:32-42. counterstain, which positions stressed tissues at a point of balance and allows myofascial tissues to relax, 10. Johnson RW and Rice ASC. Postherpetic may facilitate relief of tender points and alleviate pain.4 Neuralgia. N Engl J Med. 2014 Oct; 371:1526-33. Indirect treatments may offer significant benefits to some patients when compared to the effectiveness and 11. Tyring S. Management of herpes zoster and risks associated with pain medications. postherpetic neuralgia. J Am Acad Dermatol. 2007 Jul;57:S136-42. PHN is the most common complication of herpes Figure 4. Herpes zoster of the right aspect of zoster disease, affecting up to one third of the 12. Chan YT, et al. Early application of low-level the chest after 10 days of treatment. approximately 1 million VZV patients in the United laser may reduce the incidence of postherpetic States. While not fatal, patients experiencing PHN neuralgia (PHN). J Am Acad Dermatol. 2016 have been shown to experience poor quality of life Sep;75(3):572-7. and dissatisfaction with treatment. 13. Brzezinski P, Cywinska E, Chiriac A. Treatment Research has shown that the best way to prevent of Postherpetic Neuralgia Using Narrow Band PHN is to avoid VZV infection in the first place. Ultraviolet B Radiation (UVB). Mædica. 2015 For children, this is accomplished via the chickenpox Sep;10(3):276-9. vaccination; for adults over age 50 who had chickenpox as children and now have latent VZV, vaccination 14. Progression of shingles. United States [cited: with the live attenuated shingles vaccine has resulted 2017 Sept 14]. Available from https://web.archive. in a 61.1% reduction in VZV disease reactivation.2 org/web/20010611001546/http:/www.fda.gov/ fdac/features/2001/301_pox.html. Emerging studies show evidence of relief through the use of phototherapy, physical therapy, dry needling, trigger-point injections and percutaneous Figure 5. Herpes zoster of the right thoracic nerve stimulation, and indirect osteopathic region of the back after 10 days of treatment. techniques may help alleviate pain.1,4,13

Page 45 PATTERNS AND TREATMENT OF POST-HERPETIC NEURALGIA: A CASE STUDY Primary Cutaneous Apocrine Carcinoma of the Scalp: A Case Presentation and Discussion Derek Hirschman, DO,* Cassandra Beard, DO,** Howard D. Lipkin, DO***

*Dermatology Resident, 1st year, Dermatology Residency Program, Beaumont Hospital - Farmington Hills, Farmington Hills, MI **Traditional Rotating Intern, Larkin Community Hospital, South Miami, FL ***Assistant Clinical Professor, Michigan State College of Osteopathic Medicine, East Lansing, MI; Board-Certified Dermatologist, Brighton Dermatology and Regenesis, Brighton, MI

Disclosures: None Correspondence: Cassandra Beard, DO; [email protected]

Abstract Primary cutaneous apocrine carcinoma (PCAC) is a rare, malignant adnexal neoplasm that tends to appear in the fifth decade of life with no predilection for sex or race. The diagnosis is complicated due to the vague clinical characteristics and the immunohistochemical similarities between PCAC and mammary apocrine carcinoma. Diagnosis relies on histologic examination, and treatment includes surgical excision with wide, clear margins. We report a case of PCAC in a cosmetically vulnerable location treated with Mohs micrographic surgery.

Introduction surgery. The patient will continue to be followed criteria among cutaneous apocrine carcinomas Primary cutaneous apocrine carcinoma (PCAC) with routine skin exams for local recurrence and reliably differentiate PCAC from other adnexal is an extremely rare, malignant adnexal tumor possible lymph node involvement. carcinomas: (1) decapitation secretion, (2) PAS- that presents a diagnostic challenge, as it shares positive diastase-resistant material in the cell or lumina, and (3) positive immunostaining for gross many features with ductal mammary carcinoma Discussion 7 1 PCAC is a rare adnexal tumor that arises in with cutaneous metastasis. PCAC typically arises cystic disease fluid protein. adults in the fifth decade of life and has a slight in areas of high apocrine-gland density, such as 4 2 male predominance. To our knowledge, there are The standard of care for this rare malignant tumor the axilla or anogenital region. There are reports, few reports of PCAC in the literature, with most has not been established; however, most cases are however, of PCAC arising on the eyelid, scalp, 3 reported cases arising in the axilla or anogenital managed with wide local excision with 1 cm to 2 ear, chest, and extremities. We report a case of 5 regions. The clinical presentation of the lesion cm surgical margins. Mohs micrographic surgery primary cutaneous apocrine carcinoma arising on 1,4,6 varies, but typical findings include erythema, firm or is an option for cosmetically sensitive areas. the parietal scalp of a 73-year-old male treated with cystic nodules, pruritus, and/or eczematous changes. Regional lymph node or sentinel Mohs micrographic surgery. The lesions are typically slow-growing, and in many lymph node biopsy is recommended for palpable cases, they are present for more than 10 years prior lymph nodes due to the high rate of lymph node Case Report to diagnosis.3 The tendency for a prolonged course metastasis at the time of diagnosis and the high A 73-year-old Caucasian male with a past medical 2,5 history including multiple basal cell carcinomas coupled with the latency to presentation increases rate of recurrence. Efficacies of radiotherapy and presented to an outpatient dermatology clinic for the likelihood of metastasis. Regional lymph nodes hormonal therapy as primary treatment methods a routine annual full-body skin exam. An 8 mm by are the most common location for metastasis; are unknown, but they may be used as adjunctive 5 mm, erythematous, asymptomatic but atypical- however, the lungs, brain, and may also be treatment modalities. Although PCAC responds affected.2 Up to 89% of patients demonstrate lymph poorly to conventional chemotherapy, there are appearing nodule was noted on the patient’s 5 right parietal scalp. The patient was unaware of node metastasis at the time of diagnosis. cases that demonstrate achievement of remission the lesion, so the duration was unknown. A deep with adjunctive chemotherapy following wide Upon presentation, PCAC is commonly 1 shave biopsy was performed, and the differential surgical resection. misdiagnosed clinically as basal cell carcinoma diagnosis included basal cell carcinoma, Merkel due to the indistinctive clinical findings and Cutaneous apocrine carcinoma is usually associated cell carcinoma, amelanotic melanoma, and 2 most physicians’ unfamiliarity with PCAC. with local recurrence and regional lymph node epidermal inclusion cyst. The pre-biopsy photo Histologically, PCAC mimics mammary apocrine metastasis, yet this tumor is infrequently fatal. was of poor quality and therefore was not included carcinomas, and in-depth knowledge of the Disease-specific five-year survival has been reported in this case report. 5,6 spectrum of stains necessary to differentiate the at 75% to 88%. The five-year local recurrence rate 1 Histologic sections demonstrated compact stratum two is required to make the proper diagnosis. Both is as low as 28%. corneum with a slightly atrophic epidermis with cutaneous and mammary apocrine carcinomas flattening of the rete ridge pattern. Extending demonstrate a strong androgen receptor (AR) Conclusion Cutaneous apocrine carcinomas can be difficult to from the superficial dermis and throughout the expression and positive estrogen receptor (ER) diagnose due to the vague clinical characteristics reticular dermis were basaloid islands of varying expression. Mammary apocrine carcinomas do and rarity of the disorder. Immunohistochemical sizes as well as duct formation with apocrine not demonstrate progesterone receptor (PR) analysis is similar to that found in mammary decapitation secretions. The basaloid islands expression, but PR expression is variable in primary apocrine carcinoma. Thus, the diagnosis of primary showed slight atypia and scattered mitosis. Based cutaneous apocrine carcinoma. Thus, an AR+/ cutaneous apocrine carcinoma relies on histologic on histology, a diagnosis of primary cutaneous ER+/PR+ immunoprofile favors the diagnosis of evaluation. In this case, microscopic findings adnexal carcinoma with apocrine differentiation cutaneous apocrine carcinoma, but an AR+/ER+/ were consistent with primary cutaneous apocrine (apocrine carcinoma) was favored. Because PR- immunoprofile does not rule it out. Strong carcinoma. We hope this review increases awareness the apocrine carcinoma did not connect to adipophilin expression is only seen in mammary 6 of this neoplasm as a potential differential diagnosis the epidermis, the histopathologic differential apocrine carcinoma, not in PCAC. Although not for cutaneous neoplasms and provides insight into included metastatic apocrine carcinoma; however, typically expressed in PCAC, presence of p63 is a useful marker in ruling out mammary apocrine therapeutic modalities for successful remission. that diagnosis was not favored based on patient 1 history and a lack of correlative clinical findings. carcinoma.

Due to the location of the lesion and the high rate Histopathological variation of structural disorder, of recurrence, the patient was subsequently treated cellular atypia, and mitotic activity complicate with Mohs micrographic surgery. Two stages were histologic grading for PCAC. Furthermore, required for complete removal, and the primary architectural patterns vary among different tumors, defect was closed with a single advancement flap. within tumors, and between primary tumors and No lymphadenopathy was noted at the time of recurrences. Despite this variability, three consistent

HIRSCHMAN, BEARD, LIPKIN Page 46 References 1. Schweitzer J, Vermeesch J, Zaleski T, Iacco M, Krach K, Ghaferi J, Cotton J. Primary cutaneous apocrine carcinoma: 2 cases and review of the pertinent histologic findings. JAAD Case Rep. 2016;2(5):411-4.

2. Miyagawa T, Kadono T, Taniguchi T, Nakamura K, Saigusa R, Yoshizaki A, Miyagaki T, Yamada D, Masui Y, Sato, S. Cutaneous apocrine carcinoma of the scrotum: a case with widespread subcutaneous induration. J Dermatol. 2015 Mar 20;42(8):815-7.

3. Li Y, Chen L, Tian X, Li Z. Unusual apocrine carcinoma with neuroendocrine differentiation: a cutaneous neoplasm may be analogous to neuroendocrine carcinoma with apocrine differentiation of breast. Diagn Pathol. 2015 Jun 10;10(1):64-70.

4. Loh S, Oh Y, Lew B, Sim W. Primary cutaneous apocrine carcinoma. Ann Dermatol. 2014 Dec 02;28(5):669-70.

5. Ogata D, Kiyohara Y, Yoshikawa S, Kasami M. Treatment strategy for cutaneous apocrine carcinoma. Int J Clin Oncol. 2013 Jul 31;19(4):712-5.

6. Piris A, Peng Y, Boussahmain C, Essary LR, Gudewicz TM, Hoang MP. Cutaneous and mammary apocrine carcinomas have different immunoprofiles. Hum Pathol. 2014 Feb 1;45(2):320-6.

7. Paties C, Taccagni L, Papotti M, Valente G, Zangrandi A, Aloi F. Apocrine Carcinoma of the Skin. Cancer. 1993 Jan 15;71(2):375-81.

Page 47 PRIMARY CUTANEOUS APOCRINE CARCINOMA OF THE SCALP: A CASE PRESENTATION AND DISCUSSION Treatment of Minocycline-Induced Dermal Pigmentation Deposition with the Q-Switched Alexandrite Laser John Feigner Linabury, DO,* Lisa Ann Zaleski-Larsen, DO, FAAD,** Mitchel P. Goldman, MD, FAAD***

*Dive Medical Officer, U.S. Navy, Falls Church, VA **Surgical Cosmetic Dermatologist, West Dermatology, San Diego, CA ***Surgical Cosmetic Dermatologist, Cosmetic Laser Dermatology, San Diego, CA

Disclosures: None Correspondence: John F. Linabury, DO; U.S. Navy, 7700 Arlington Blvd. Ste. 5113, Falls Church, VA 22042; Ph: 808.474.2532; [email protected]

The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, the Department of Defense, or the United States government. John Linabury is a military service member. This work was prepared as part of his official duties. Title 17, USC, x 105 provides that “Copyright protection under this title is not available for any work of the United States Government.” Title 17, USC, x 101 defines a U.S. Government work as a work prepared by a military service member or employee of the U.S. Government as part of that person’s official duties.

Abstract Minocycline hydrochloride-induced pigmentation (MIP) is a rare complication of sustained minocycline use. Cutaneous manifestations include a blue-grey pigmentation subdivided into three types that are differentiated both clinically and histologically. Immediate discontinuation of the minocycline is recommended, although a full resolution is rare. We describe a case of type 1 MIP successfully treated with the Q-Switched Alexandrite laser and discuss the various laser modalities used in the treatment of MIP.

Introduction Physical examination revealed 3 mm to 9 mm, grey- The patient did not report any side effects from the Unintended pigment changes in the skin are blue macules across the bilateral eyelids and eyebrows, treatments. The patient was advised of the benign disconcerting to patients. Pigment changes can be sclera, perioral area, and fingernails Figures ( 1, 2). nature of her scleral pigmentation and advised associated with various disease states, while others A test spot to the left thumbnail was successful. against laser treatments of the sclera due to a risk may be due to medications. Knowledge of these Subsequently, the patient’s fingernails, eyebrows and of blindness. She was referred back to her medical etiologies reduces the time to correct identification perioral areas were treated with a Q-switched (QS) dermatologist for further medical dermatologic care. and, if available, treatment. Minocycline is a alexandrite laser (Accolade, Cynosure, Westford, commonly used medication and rarely causes MA) at the following settings: 4 mm spot size, 5 J/ Discussion 2 Minocycline hydrochloride is a semi-synthetic pigment changes. cm , 1Hz . Significant improvement was noted by the patient and during skin examinations with a 75% tetracycline derivative with antimicrobial and 1-7 Minocycline is utilized for both antimicrobial clearance during the first treatment and nearly full anti-inflammatory applications. Minocycline and anti-inflammatory properties, commonly resolution with the second treatment one month hydrochloride-induced pigmentation (MIP) is a employed for use in acne, and autoimmune later. Figures 1 and 2 demonstrate the comparison. rare but known complication of the sustained use diseases. Minocycline hydrochloride-induced pigmentation (MIP) is a rare side effect that presents with cutaneous deposition of a black oxidized form of minocycline resulting in a blue, gray, or brown pigmentation.1-7 Three clinical distributions and histologic variations of MIP exist. Pigment deposition can have a permanent effect on numerous tissues, the most noticeable being the sclera, dermis, and fingernails. Immediate discontinuation of the medication is recommended if MIP is suspected; however, full resolution is rare. Lasers have been used to reduce the appearance of cutaneous pigments, including MIP.

We discuss several laser regimens employed in the literature and describe a regimen with the Q-switched alexandrite laser (Accolade, Cynosure, Westford, MA) that successfully treated a case of MIP, further refining the treatment of MIP. Case Report An 80-year old female, skin type II, with a past medical history of recurrent mycoplasma pneumonia Figure 1. 80-year-old female demonstrating type 1 MIP with grey-blue macules across the bilateral treated with minocycline intermittently over a six- eyelids, sclera, and perioral area. year period presented with blue-grey macules across the facial skin, sclera, and fingernails. The grey-blue discoloration of her bilateral thumbnails was first noted two months after starting minocycline when her dosage was increased from 100 mg daily to 100 mg twice daily. Over the following months, additional grey-blue macules appeared on the facial skin, sclera and fingernails. The minocycline was discontinued two years prior to her presentation with a persistence of her pigmentation. The patient was referred to this specialty laser clinic by her medical dermatologist for treatment of her blue- grey discoloration. Figure 2. Blue-grey discoloration noted in the bilateral fingernails.

LINABURY, ZALESKI-LARSEN, GOLDMAN Page 48 of minocycline. Minocycline is the most common one to two treatment sessions. Two of the three References medication in the tetracycline class associated with patients had the left half of the face irradiated 1. Alster TS, Gupta SN. Minocycline-induced cutaneous manifestations. Three types of MIP have with a picosecond 755-nm alexandrite laser and hyperpigmentation treated with a 755-nm been differentiated both clinically and histologically, the right half treated with an Nd:YAG laser. The 5 Q-switched alexandrite laser. Dermatol Surg. 2004 shown in Table 1. Our patient had clinical findings picosecond laser demonstrated superior clearance Sep;30(9):1201-4. consistent with type 1 MIP. Minocycline dosages of in both patients, achieving overall clearance of 100 mg daily over two months increases the risk of MIP, the right half of the face. A single patient had two 4-5,7 2. Green D, Friedman KJ. Treatment of as do cumulative doses in excess of 100 g. Ingestion picosecond 755-nm alexandrite laser sessions to the minocycline-induced cutaneous pigmentation with over four years carries a 20% incidence of MIP, with entire face with noticeable clearance.5 5-8 the Q-switched Alexandrite laser and a review of acne and rosacea representing 2.4% to 14.8% of cases. the literature. J Am Acad Dermatol. 2001 Feb;44(2 Autoimmune conditions may confer a higher incidence Nasir et al. compared the 1064-nm Nd:YAG Suppl):342-7. rate. Rheumatology studies have associated an increased laser (Palomar Spectrum RD1200), the 755-nm incidence of MIP with increasing age and rheumatoid QS alexandrite laser (Alex TriVantage, Syneron 3. Bernstein EF, Koblenzer C, Elenitsas R. arthritis as well as pemphigus and pemphigoid, at Candela), and the 694-nm ruby laser (Alex Minocycline pigmentation following carbon 36% and 77.0%, respectively.9-10 Prompt recognition TriVantage, Syneron-Candela) in the treatment of 6-7 dioxide laser resurfacing: treatment with the and subsequent discontinuation is recommended. MIP. The QS 755-nm alexandrite laser provided Q-switched Nd:YAG laser. J Drugs Dermatol. MIP can fade over time after the discontinuation a 50% clearance in a single treatment session with 2015 Apr;14(4):411-4. of minocycline, but topical treatments often prove minimal discomfort. The ruby laser was found 1-7 ineffective, and complete resolution is rare. Eisen et to have a 90% clearance in a single treatment but 4. Greve B, Schönermark MP, Raulin C. al. advocated for skin and oral mucosa screenings for with a greater degree of discomfort. Lastly, the Minocycline-induced hyperpigmentation: the development of hyperpigmentation in patients single Nd:YAG session was found to be ineffective. treatment with the Q-switched Nd:YAG laser. 8 receiving minocycline for greater than one year. Nisar et al. concluded the QS 755-nm alexandrite Lasers Surg Med. 1998;22(4):223-7. laser was the most acceptable based on percent of 6 Lasers can reduce the appearance of MIP both pigment clearance and patient comfort. 5. Rodrigues M, Bekhor P. Treatment of 1-6, 11 clinically and histologically. The putative Minocycline-Induced Cutaneous Pigmentation mechanism is extracellular and intracellular The Nd:YAG laser has been effective in other With the Picosecond Alexandrite (755-nm) Laser. pigment-complex dissolution to smaller fragments investigations. A single case reported by Bernstein Dermatol Surg. 2015 Oct;41(10):1179-82. for lymphatic removal.2,5 Investigations into laser et al. found that four treatment sessions with the applications, with intent for greatest percent clearance Nd:YAD laser (Con-Bio RevLite SI, Cynosure) 6. Nisar MS, Eyre K, Brodell RT, Lloyd JR, and cost considerations, have varied as to wavelengths, was effective in clearing MIP to the upper lip Shin TM, Ahmad A. Minocycline-induced irradiation intervals, and procedural side effects. following carbon-dioxide laser resurfacing. The hyperpigmentation: comparison of 3 Q-switched 3 degree of procedural discomfort was not noted. lasers to reverse its effects. Clin Cosmet Investig Q-switched 755-nm alexandrite lasers have achieved Similar results were obtained by Greve et al. with Dermatol. 2013 May 31;6:159-62. decreased pigmentation appearance.1,2,5,6 Alster et al. the application of the Nd:YAG laser (Medlite, utilized a QS 755-nm alexandrite laser (AlexLAZR, Continuum Biomedical), obtaining 90% clearance 7. Geria AN, Tajirian AL, Kihiczak G, Schwartz Candela Laser Corp) in the treatment of six patients after five sessions and complete clearance in eight RA. Minocycline-induced skin pigmentation: with slate-gray MIP distributed on the legs and sessions. A transient desquamation was noted with an update. Acta Dermatovenerol Croat. face. Durations of minocycline administration the procedure.4 2009;17(2):123-6. ranged from six months to 10 years. Five out of the six patients were female. A range of three to five Izikson et al. applied a fractional photothermolysis 8. Eisen D, Hakim MD. Minocycline-induced treatment sessions were completed bimonthly until regimen after two initial Nd:YAG laser treatment pigmentation. Incidence, prevention and pigmentation resolution. Transient side effects of sessions proved ineffective. Four fractional management. Drug Saf. 1998 Jun;18(6):431-40. purpura and desquamation were reported. Alster photothermolysis sessions using a 1550-nm diode et al. cited side effects of tissue splatter with the laser (Reliant Fraxel, Cynosure) and cooling device 9. Fay BT, Whiddon AP, Puumala S, Black NA, Nd:YAG laser and post-operative hypopigmentation (Zimmer) resulted in near-complete clearance. Pain O’Dell JR, Mikuls TR. Minocycline-induced with the ruby laser as influential in utilizing the QS was managed with topical anesthesia, and side effects hyperpigmentation in rheumatoid arthritis. J Clin 11 755-nm alexandrite laser in this study.1 were notable for transient edema and erythema. Rheumatol. 2008 Feb;14(1):17-20. Green et al. reported a case of successfully treated Conclusion 10. Ozog DM, Gogstetter DS, Scott G, Gaspari MIP on the bilateral legs with the QS 755-nm We report a case of type 1 MIP successfully treated AA. Minocycline-induced hyperpigmentation in alexandrite laser (VersaPulse-C, Coherent Medical with the 755-nm QS alexandrite laser in two patients with pemphigus and pemphigoid. Arch Systems) in nine treatment sessions with minimal treatment sessions spaced one month apart with Dermatol 2000;136:1133–8. desquamation and rare pin-point bleeding noted.2 minimal discomfort. The treatment of MIP with lasers is an exciting new use of the technology that 11. Izikson L, Anderson RR. Resolution of Recently, Rodrigues et al. utilized the picosecond dermatologists should be aware of. Additional blue minocycline pigmentation of the face after alexandrite laser (PicoSure, Cynosure) to studies are needed to fully assess the effectiveness fractional photothermolysis. Lasers Surg Med. successfully treat a series of three MIP patients in of various types of laser for the treatment of MIP. 2008 Aug;40(6):399-401. doi: 10.1002/lsm.20648.

Table 1. Clinical and histologic traits of MIP types5 Type Clinical Appearance Histologic Appearance - Bluish-black pigments - Predilection for previously inflamed tissue - Found intracellularly with macrophages 1 - Facial involvement most commonly noted - Stains positive for extracellular iron and melanin - Resolution may be protracted

- Bluish-gray pigments - Deposition in normal skin - Stains melanin in both basal keratinocytes and 2 - Frequently affects legs and forearms dermal macrophages - Resolution may be protracted - Muddy-brown pigments - Deposition in sun-exposed areas - Stains melanin in both basal keratinocytes and 3 - Least common dermal macrophages - Persists indefinitely

Page 49 TREATMENT OF MINOCYCLINE-INDUCED DERMAL PIGMENTATION DEPOSITION WITH THE Q-SWITCHED ALEXANDRITE LASER Understanding Livedo Reticularis: A Unique Case of Cutis Marmorata Telangiectatica Congenita and Discussion of Differential Diagnoses and Work-Up Rachel M. White, DO,* Sonya Zarkhin, DO,** Brad Glick, DO, MPH, FAOCD***

*Dermatology Resident, 2nd year, Larkin Community Hospital Palm Springs Campus, Hialeah, FL **Traditional Rotating Intern, Larkin Community Hospital Palm Springs Campus, Hialeah, FL ***Program Director, Dermatology Residency Program, Larkin Community Hospital Palm Springs Campus, Hialeah, FL

Abstract Livedo reticularis (LR) is a cutaneous vascular pattern that presents with reticular patch morphology. LR is a manifestation of a wide range of diseases, from idiopathic to systemic. We present a case with a rare distribution of congenital LR, or cutis marmorata telangiectatica congenita (CMTC). This is followed by a review of the extensive differential diagnoses to consider when LR is noted, in addition to work-up considerations and treatment options.

made clinically because the histology is nonspecific, measurements of affected limb(s) and ophthalmology Introduction demonstrating dilated . Inheritance is sporadic; exams along with consistent monitoring of any Livedo reticularis (LR) describes a cutaneous 4 cCCCC vascular pattern that presents in a reticular or net-like however, there are some familial reports. CMTC additional abnormalities, such as neurologic symptoms. configuration. The resulting mottled, reddish-blue to is often localized to one extremity and is associated with Improvement of CMTC often occurs as the child ages, soft-tissue atrophy and bone abnormalities underlying and 20% of cases eventually completely resolve. Of purple discoloration of skin is due to an accumulation 1,5 3 of deoxygenated blood.1 Decreased blood flow to the affected area. When localized to the abdomen, those with complete resolution, 50% resolve by age 2. the skin or decreased drainage from the skin results there is often a sharp demarcation line at midline. CMTC can also be generalized, in which case there Primary Livedo Reticularis in an increase in deoxygenated blood trapped in the 1 2 Cutis marmorata cutaneous venous plexus. While this reaction is most is a higher risk of associated anomalies. This form of Also known as physiologic LR, cutis marmorata commonly seen as a benign response to cold-induced LR may be associated with craniofacial, neurologic, cardiovascular, and ocular anomalies, such as cleft palate, is the most common manifestation of LR and vasospasm, known as cutis marmorata, LR can also 1 occurs as a response to cold. This condition is most be associated with congenital disease and systemic congenital glaucoma, delayed motor development, mental retardation, Sturge-Weber syndrome, and pronounced in neonates and infants and common disorders that alter blood flow. Therefore, LR can 7 in young children and fair-skinned females. Cold serve as an indicator of underlying disease, and these hypertrophy of affected limb, in addition to many 1,6 exposure produces a physiologic arteriolar vasospasm diseases should be considered with persistent LR. We others. Work-up should include regular-interval present a unique case of congenital LR, as well as a concise review of differential diagnoses, work-up, and treatment of the various causes of LR. The review aims to remind dermatologists to consider the many causes of this distinct pattern. Case A 69-year-old female with a past medical history of cutaneous squamous cell carcinoma, hypertension, anxiety, depression, and acid reflux presented to the dermatology clinic for a routine full body skin exam. On exam, red-purple patches and connecting rings in a lace-like pattern were noted on her bilateral upper (Figure 1) and lower extremities (Figures 2, 3). The findings were consistent with LR. The patient revealed that these lesions had been present since birth. She noted they worsen in cold temperatures and improve Figure 1. Livedo reticularis-like changes demonstrated on patient’s upper extremity. in warm temperatures but are always present and never completely resolve. The patient denied any associated symptoms including pain and tenderness. Family history revealed the patient’s sister and mother have persistent LR as well. Review of systems was unremarkable. Current medications included lisinopril, pantoprazole, venlafaxine, and alprazolam. She denied history of autoimmune disease, significant malignancy, or infectious disease. The patient denied any prior work-up for LR. Given the history of LR since birth and significant family history, the patient was diagnosed with cutis marmorata telangiectatica congenita. The patient displayed the rarer presentation of generalized LR on bilateral upper and lower extremities without any associated anomalies. The patient denied any neurologic, ocular, or developmental disorders or symptoms and therefore did not elicit any additional work-up. Discussion Congenital Livedo Reticularis Cutis marmorata telangiectatica congenita (CMTC) Figure 2 Figure 3 CMTC presents with and atrophy of skin at birth or soon after.3 A diagnosis of CMTC is Figures 2, 3. Livedo reticularis-like changes demonstrated on patient’s anterior and posterior lower extremities.

WHITE, ZARKHIN, GLICK Page 50 leading to the reversible skin changes seen in LR. Table 1. Vasculitides associated with livedo reticularis (LR) Cutis marmorata has a predilection for extremities, Small Vessel Medium Vessel Large Vessel particularly lower extremities. This condition resolves with re-warming. Avoiding cold exposure can Autoimmune Polyarteritis nodosa Takayasu’s 7 prevent or lessen the appearance of cutis marmorata. Temporal arteritis Idiopathic Livedo Reticularis Granulomatosis with polyangiitis When LR persists despite warming, idiopathic LR Microscopic polyangiitis should be considered. This form of LR is the result of arterial vasospasm resulting in dermal hypoxia. Nodular vasculitis While this condition is most commonly seen on Tromboangiitis obliterans lower extremities, involvement of the trunk and upper extremities can be seen. Limb elevation decreases Table 2. Vasculopathies associated with LR Table 3. Malignancies associated with LR the discoloration. This form of LR is temperature- 7 Hematologic/ Embolic Neoplasia Lymphoma independent and a benign finding. It is not associated Hypercoagulable Diseases with underlying disease or pathology and is therefore Renal-cell carcinoma Acute lymphocytic a diagnosis of exclusion.1 However, other forms of Livedoid vasculopathy leukemia persistent LR associated with underlying disease emboli Inflammatory breast Mycosis fungoides should be ruled out before making this diagnosis. Antiphospholipid syndrome Septic emboli cancer Secondary Livedo Reticularis Protein C and S deficiencies Calciphylaxis Angiotropic lymphoma Livedo reticularis vs. livedo racemosa Antithrombin III deficiency Atrial myxoma Chronic lymphocytic Livedo reticularis and livedo racemosa are often used lymphoma interchangeably to describe a livedo pattern. However, Factor V Leiden mutation Hyperoxaluria these terms imply different clinical presentations, Homocystinuria Table 4. distribution, and underlying disease. While both indicate a net-like configuration, broken or irregular Sneddon syndrome Infectious etiologies associated with LR rings characterize livedo racemosa. In addition Deep venous Hepatitis C to their geometric differences, livedo racemosa is Mycoplasma pneumonia commonly seen on the trunk and buttocks, whereas Disseminated intravascular LR is more common on the upper and lower coagulation Brucella 8 extremities. Livedo racemosa is always pathologic Thrombocythemia Coxiella burnetii and commonly associated with Sneddon syndrome9 10 and antiphospholipid syndrome. Livedo racemosa Parvovirus B19 can also be seen in other disorders, such as livedoid Cryoglobulinemia Tuberculosis vasculopathy, systemic lupus erythematosus, essential Cold agglutinins thrombocythemia, thromboangiitis obliterans, Meningococcemia 11 polycythemia vera, and polyarteritis nodosa. Cryofibrinogenemia Streptococcemia Erythema Ab Igne is suspected, skin biopsies should be performed and Rickettsia Erythema ab igne produces an LR-like pattern and preliminary labs initiated. Several cutaneous punch Rheumatic fever is caused by extended heat exposure. It is often found biopsies should be taken to increase diagnostic on the thighs due to heat from laptops; lower back yield.1 At least one biopsy should be taken from Typhus fever or abdomen due to heating pads; and feet due to the central blanched area and one from a peripheral Syphilis overheating from the fireplace or furnace.12 Erythema blue area. Biopsies from fixed or nodular areas are 1 Endocarditis ab igne histologically resembles an actinic keratosis recommended. Laboratory studies should reflect the with keratinocyte atypia confined to the epidermis. history and physical. Appropriate labs may include B19 is thought to cause LR due to the vasodilatory Removing and avoiding exposure to the heat source complete blood count, BUN/Cr, liver function tests, effects of viral particles on vascular smooth-muscle is the most effective treatment. However, areas that urinary analysis, ASO titers, hepatitis profile, ESR, 18 cells. Other evidence of infectious mechanisms do not resolve should be biopsied and evaluated for ANA, rheumatoid factor, c-ANCA, p-ANCA, for LR includes a case report of Brucella spp. that keratinocyte atypia and squamous cell carcinoma. If complement levels (C3 and C4), cryoglobulins, and induced lower extremity LR. The authors suggest atypia is seen histologically, topical 5-fluorouracil SPEP. If the biopsy is suggestive of vasculopathy, 19 13 a possible hypersensitivity reaction as the cause. cream should be considered for treatment. consider additional labs including cryofibrinogen, Furthermore, the deposition of immune complexes anticardiolipin antibodies, lupus anticoagulant, eliciting LR was reported in a case of Coxiella Vascular Causes of Livedo Reticularis PT/PTT, DIC panel, RPR, fibrin and fibrinogen 20 burnetii infection. LR is associated with many vascular disorders. As degradation products (FDP), D-dimer, fibrinogen, stated prior, LR results from pooling of deoxygenated protein C and S deficiencies, and antithrombin 3. Neurologic Causes of Livedo Reticularis blood in the cutaneous venous plexus. Vasculitides and Conditions that affect nerve conduction can lead vasculopathies that result in decrease blood flow to or Malignant Causes of Livedo Reticularis to LR. For example, trauma to the peripheral from the skin will consequentially increase the volume Neoplasms may result in LR due to various nerves seen in reflex sympathetic dystrophy results of deoxygenated blood in the venous plexus and result mechanisms characterized as vascular-occlusive. 1 in LR as well as sensory-motor dysfunction, pain, in LR. Livedoid vasculopathy, formerly known as Malignancies associated with LR are listed in Table 21 1,5 and dysautonomia. Similarly, irritation of the , is thrombosis and ulceration of the 3. The cause of LR in angiotropic lymphomas, brachial nerve plexus following insertion of a lower extremities due to hyalinizing vascular disease. such as cutaneous B-cell and T-cell lymphomas, is 15 midline catheter into the basilic has been The etiology is not completely understood; however, not identified. shown to cause LR in addition to edema, pain, and no true vasculitis is evident on biopsy. End-stage 22 weakness. livedoid vasculopathy results in atrophie blanche, a Infectious Causes of Livedo Reticularis 14 Infectious etiologies of LR are listed in Table 4.1 dermatologic finding of white stellate scars. Medication-induced Livedo Reticularis Mechanisms of vascular involvement are vast and LR is seen as a reaction to certain systemic A list of vasculitides associated with LR is not completely understood. Both Mycoplasma 1,5 medications. This side effect is most commonly summarized in Table 1. Vasculitis should be pneumonia and hepatitis C cause hyperviscosity documented with amantadine. Amantadine- considered when ulceration or nodules are present, that result in LR. Mycoplasma pneumonia can also 1 induced LR is highly variable, with incidence particularly on the lower extremities. Other vascular cause cold hemagglutinins, whereas hepatitis C can ranging from 2% to 90%, and is more common in disorders or vasculopathies that result in LR are result in mixed cryoglobulinemia. Both of these 23 1,5 16,17 women than men. Amantadine-induced LR clears summarized in Table 2. If vasculitis or vasculopathy secondary states lead to LR as well. Parvovirus

Page 51 UNDERSTANDING LIVEDO RETICULARIS:A UNIQUE CASE OF CUTIS MARMORATA TELANGIECTATICA CONGENITA AND DISCUSSION OF DIFFERENTIAL DIAGNOSES AND WORK-UP with discontinuation of the drug; however, it is not References 18. Dereure O, Montes B, Guilhou JJ. Acute necessary to discontinue the drug due to LR because 1. Gibbs MB, English JC, Zirwas MJ. Livedo generalized livedo reticularis with myasthenialike it does not result in long-term sequela. Treatments reticularis: an update. J Am Acad Dermatol. 2005 syndrome revealing parvovirus B19 primary to alleviate LR while continuing amantadine Jun;52(6):1009–19. infection. Arch Dermatol. 1995 Jun;131(6):744–5. include limb elevation and compression stockings.24 Other medications associated with drug-induced 19. Metin A, Akdeniz H, Buzgan T, Delice I. 1 2. Fleischer AB Jr, Resnick SD. Livedo reticularis. LR are listed in Table 5. The appearance of LR Dermatology Clin. 1990 Apr;(8):347–54. Cutaneous findings encountered in brucellosis subsides with discontinuation of drug. and review of the literature. Int J Dermatol. 2001 Jul;40(7):434–8. Table 5. 3. Amitai DB, Fichman S, Merlob P, Morad Y, Lapidoth M, Metzker A. Cutis marmorata Medications associated with LR telangiectatica congenita: clinical findings in 20. Le Quellec A, Sotto A, Bessis D, Ciurana AJ. Livedo réticulaire révélant une fièvre Q: Amantadine 85 patients. Pediatr Dermatol. 2000 Mar- Apr;17(2):100–4. responsabilité d’un anticoagulant circulant. La Minocycline Revue de Médecine Interne. 1993 Jun;14(6):558. Diphenhydramine 4. Spitz JL. Genodermatoses: A Clinical Guide to Genetic Skin Disorders. Philadelphia: Wolters 21. Freeman R, Dover JS. Autonomic Gemcitabine Kluwer Health; 2011. neurodermatology (Part I): , reflex sympathetic dystrophy, and livedo reticularis. Semin Heparin 5. Bolognia JL, Jorizzo JL, Schaffer JV. Dermatology. Neurol. 1992 Dec;12(04):385–93. Thrombolytics 3rd rev. ed. Elsevier; 2012. 22. Shrestha NK, Gordon SM, Isada CM. Livedo Interferon beta 6. Devillers AC, De Waard-van der Spek FB, reticularis associated with the use of a midline Erythromycin/lovastatin interaction Oranje AP. Cutis marmorata telangiectatica catheter. Scand J Infect Dis. 2002;34(11):845–6. Catecholamines congenita: clinical features in 35 cases. Arch of Dermatol. 1999 Jan;135(1):34–8. 23. Quaresma MV, Gomes AC, Serruya Bismuth A, Vendramini DL, Braga L, Buçard AM. Quinidine 7. Dean SM. Livedo reticularis and related Amantadine-induced livedo reticularis. An Bras disorders. Curr Treat Options Cardiovasc Med. Dermatol. 2015 Sep-Oct;90(5):745–7. Arsphenamine 2011 Apr;13(2):179–91. 24. Hayes BB, Cook-Norris RH, Miller JL, Conclusion 8. Lubach D, Schwabe C, Weissenborn K, Rodriguez A, Zic JA. Amantadine-induced livedo LR is a manifestation of a wide range of diseases, Hartung K, Creutzig A, Drenk F. Livedo racemosa reticularis: a report of two cases. J Drugs Dermatol. from idiopathic to systemic. LR most commonly generalisata: an evaluation of thirty-four cases. J 2006 Mar;5(3):288–9. is seen in cold-exposed areas, areas exposed to Am Acad Dermatol. 1990 Apr;22(4):633–9. long-term heat, and as an idiopathic finding. Other causes of LR that should be considered are 9. Housewright C, Butler D, Pike J. Sneddon vasculitis, vasculopathies, medication side effect, syndrome. J Amer Acad Dermatol. 2011 infectious diseases, neoplastic etiologies, and Feb;64(2):AB36. neurologic diseases. Lastly, LR at birth is seen in congenital genodermatoses such as cutis marmorata 10. Sajjan VV, Lunge VS, Swamy MB, Pandit AM. telangiectatica congenita (CMTC) and implies that Livedo Reticularis: A review of the literature. Indian a neuro-oculo-developmental work-up is necessary. Dermatol Online J. 2015 Sep-Oct;6(5):315–21. The patient presented here had findings consistent with CMTC in a rare bilateral distribution. No 11. Kraemer M, Linden D, Berlit P. The spectrum of evidence of neuro-oculo-developmental anomalies differential diagnosis in neurological patients with was noted and therefore no additional work-up livedo reticularis and livedo racemosa. J Neurol. was performed. It is important for clinicians to be 2005 Oct;252(10):1155–66. cognizant of the wide differential diagnoses of LR 12. Tan S, Bertucci V. Erythema ab igne: an old and rule out any underlying systemic disease or condition new again. CMAJ. 2000 Jan 11;161(1):77–8. drug exposure in persistent LR. 13. Sahl WJ Jr, Taira JW. Erythema ab igne: treatment with 5-florouracil cream. J Am Acad Dermatol. 1992 Jul;27(1):109–10.

14. Scheinfeld NS. Livedoid Vasculopathy [Internet]. [updated 2017 March 3; cited 2017 May 20]. Available from: https://emedicine.medscape. com/article/1082675-overview#a4.

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17. Durand JM, Lefevre P, Harle JR, Boucrat J, Vitviski L, Soubeyrand J. Cutaneous vasculitis and cryoglobulinaemia type II associated with hepatitis C virus infection. Lancet. 1991 Feb 23;337(8739):499–500.

WHITE, ZARKHIN, GLICK Page 52 Utilization of Ovine Collagen Extracellular Matrix in Surgical Excision of Recurrent Keloids Christopher Mancuso, MHS,* Megan Hemmrich,* Joseph K Francis, MD**

*Osteopathic Medical Student, College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL **Department of Dermatology, University of Florida, Gainesville, FL

Disclosures: None Correspondence: Christopher Mancuso, MHS, 3301 College Ave., Fort Lauderdale, FL 33314; [email protected]

Abstract Keloid scarring is a chronic, disfiguring condition that is diagnosed based on clinical presentation and history. While there is a large body of research on keloids, and treatments have been well established, recurrence rates remain high and variable. The goal of this case report is to demonstrate the use of xenografts in the reconstruction of keloid excisions on the ear.

no allergies or illnesses, and did not take any triamcinolone acetonide, surgical excision or both, Introduction medications. The lesions appeared two years after but ovine CECM dressings are not commonly used Keloid scarring is characterized as overproduction of 1 collagen caused by excessive fibroblast proliferation the patient pierced her ears and had been removed in their reconstruction. in response to dermal injury.1 It is a chronic, twice surgically, but they recurred both times. While there is a large body of research on keloids, disfiguring condition associated with lower quality Pathologic examination of excised tissue revealed an 1 and treatments have been well established, the of life. Keloids are distinguished from hypertrophic inflamed keloid scar. The recurrent keloids had been recurrence rates remain high and variable. The scars in that they are not confined to the boundaries present for several months, and the patient reported recurrence rates for intralesional triamcinolone of the wound and do not spontaneously regress inflammation, pain, and intense pruritus that came 1 and went. The intense pruritus was relieved with acetonide injections alone range from 50% to over time. While the pathogenesis of keloids and 3 triamcinolone acetonide (Kenalog) injections and 100%. For surgical excision alone, the recurrence hypertrophic scars is unclear, it is believed that the 3 rates have been reported to be 45% to 100%. problem stems from an alteration in the wound- surgical removal of the keloids. Treatment of keloids using a combination of healing process and, due to the high prevalence in Because of prior recurrences, it was decided to treat intralesional corticosteroids and surgical excision African and Asian populations, may have a genetic 1 using a combination of intralesional corticosteroid has been found to have a recurrence rate from 9% component. One of the greatest challenges in 3 injections and surgical excision. From March 8, to 50%. treating keloids is the high rate of recurrence. 2016, to July 28, 2016, the lesions were injected Some studies have investigated the use of ovine Fibroblast proliferation during wound healing is a monthly with triamcinolone acetonide 40 mg/cc on five separate occasions. On August 10, 2016, CECM in chronic wounds and support the idea highly regulated process that involves transforming 4,5 that these dressings may improve would healing. growth factor-beta (TGF-b), vascular endothelial the keloid on the right inferior posterior helix These ovine CECM dressings may be beneficial growth factor (VEGF) and connective-tissue measured 8.0 cm x 4.0 cm and was excised (Figure 1 2). On September 13, 2016, the keloid on the left to keloid wounds because they retain the three- growth factor (CTGF). In the normal healing of a 6 dimensional ECM architecture. This quality may wound, TGF-b activity decreases as would healing is crus of the helix measured 2.4 cm x 3.4 cm and 1 create a favorable environment for the wound to completed, but in keloids TGF-b is overproduced. was excised. An ovine collagen extracellular matrix (CECM) (Endoform dermal template) was used heal with less disruption to the tissue and greater Clinically, keloids are described as raised lesions with 5-0 fast absorbing gut (running) to achieve promotion of proper wound healing. that arise from the dermis up to one year following epidermal closure. The patient was sent home with 1 Wound healing is a process consisting of three minor injuries or inflammation. Diagnosis of dressings and instructions for moist wound care stages: inflammation, proliferation and remodeling. keloids is based on clinical presentation and history. and a bandage, and a follow-up appointment was Fibroblasts are responsible for making extracellular Treatment options include one or a combination scheduled (Figure 3). At three-month follow-up, matrix, which acts as a scaffold for tissue repair. It of the following: intralesional injections, topical the patient reported no pain, pruritus or thickening has been proposed that keloid scar formation results solutions, pressure therapy, cryotherapy, laser of the surgical scar. 1 when there is a prolonged inflammatory stage that therapy, radiation and surgery. It has been proposed creates increased fibroblast activity, greater protein that a combination of intralesional corticosteroid Discussion 1 deposition and overproduction of TGF-b. injections with surgical excision be considered as a Ovine collagen extracellular matrices (CECM) are first-line therapy for earlobe keloids.1 xenografts, which are acellular matrices of collagen from nonhuman sources that are used in surgical In wound healing, there is a bidirectional reconstruction.2 When treating keloids, it is crucial communication between cells and their Case Report to continue monitoring patients in order to detect microenvironment, called dynamic reciprocity A 35-year-old female presented with a chief 7 (DR). Through the DR process, it has been complaint of nodules on her earlobes bilaterally recurrences and treat them as soon as possible. predicted that excessive extracellular matrix (Figure 1). She was otherwise healthy, with Keloids are commonly treated with intralesional degradation leads to a prolonged inflammatory phase in healing and deprives cells of signals and

Figure 1. Pre-operative (right ear) Figure 2. Post-operative (right ear) Figure 3. Forty-day follow-up (right ear)

Page 53 UTILIZATION OF OVINE COLLAGEN EXTRACELLULAR MATRIX IN SURGICAL EXCISION OF RECURRENT KELOIDS attachment sites for differentiation, proliferation 7 References and migration. It is theorized that this disruption 1. Goldstein B, Goldstein A. Keloids and in DR may promote keloid formation. hypertrophic scars [Internet]. UpToDate. 2017 [cited 2017 Jun 29]. Available from: http://www. Conclusion uptodate.com/contents/keloids-and-hypertrophic- Xenografts, namely ovine CECM, shorten the scars. healing time for wounds by supporting protein degradation and remodeling of surrounding 2,8 2. Jacobsen G, Easter D. Allograft Vs. Xenograft tissue. This can be extremely beneficial for Practical Considerations for Biologic Scaffolds healing and may be helpful in preventing keloid [Internet]. San Diego, California: University of recurrence. Compared to secondary intention and California San Diego; c2008-2011 [cited 2017 allografts, xenografts require less healing by the Jun 29] Available from: https://cme.ucsd.edu/ body and do not require harvesting tissue from biologicscaffolds/. patients who may develop another keloid.2 Ovine CECM dressings are also relatively inexpensive 3. Bran GM, Brom J, Hormann K, Stuck BA. when compared to other options. In summary, Auricular Keloids: Combined Therapy with a we propose that by using ovine CECM dressings New Pressure Device. Arch Facial Plast Surg in combination with standard surgical excision [Internet]. 2012 Jan [cited 2017 Jun 29];14(1):20-6. and intralesional triamcinolone acetonide, keloid Available from: http://jamanetwork.com/journals/ recurrence can be mitigated. jamafacialplasticsurgery/fullarticle/1105714.

4. Bohn G, Gass K. Leg treatment outcomes with new ovine collagen extracellular matrix dressing: a retrospective case series. Adv Skin Wound Care [Internet]. 2014 Oct [cited 25 Sep 2017];27(10):448-54. Available from: https:// www-ncbi-nlm-nih-gov.ezproxylocal.library.nova. edu/pubmed/25198432.

5. Wiegand C, Buhren B, Bunemann E, et al. A novel native collagen dressing with advantageous properties to promote physiological wound healing. J Wound Care [Internet]. 2016 Dec 2 [cited 25 Sep 2017];25(12):713-20. Available from: https:// www-ncbi-nlm-nih-gov.ezproxylocal.library.nova. edu/pubmed/27974008.

6. Bohn G, Liden B, Schultz G, Yang Q, Gibson D. Ovine-based collagen matrix dressing: next- generation collagen dressing for wound care. Adv Skin Wound Care (New Rochelle) [Internet]. 2016 Jan 1 [cited 25 Sep 2017];5(1):1-10. Available from: https://www-ncbi-nlm-nih-gov.ezproxylocal. library.nova.edu/pubmed/26858910.

7. Schultz G, Davidson J, Kirsner R, Bornstein P, Herman I. Dynamic reciprocity in the wound microenvironment. Wound Repair Regen [Internet]. 2011 Mar-Apr [cited 2017 Jun 29];19(2):134-48. Available from: https://www. ncbi.nlm.nih.gov/pubmed/21362080.

8. Schultz G, Ladwig G, Wysocki A. Extracellular matrix: review of its roles in acute and chronic wounds [Internet]. World Wide Wounds. 2005 Aug [cited 2017 Jun 29]. Available from: http:// www.worldwidewounds.com/2005/august/Schultz/ Extrace-Matric-Acute-Chronic-Wounds.html.

MANCUSO, HEMMRICH, FRANCIS Page 54 Introducing New ULTRAVATE® Lotion HELP YOUR PATIENTS TAME THE BEAST OF PLAQUE PSORIASIS

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

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

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

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

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

SPTS1608A_Ultravate Lotion JA_JAOCD_FINAL2.indd 2 10/20/16 1:44 PM