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President: David Grice, DO, FAOCD President-Elect: Suzanne Rozenberg, DO, FAOCD First Vice President: Rick Lin, DO, FAOCD Second Vice President: Alpesh Desai, DO, FAOCD Third Vice President: Karthik Krishnamurthy, DO, FAOCD Secretary-Treasurer: Jere Mammino, DO, FAOCD (2010-2013) Editor-in-Chief Immediate Past President: Karthik Krishnamurthy, DO Bradley Glick, DO, FAOCD Trustees: Danica Alexander, DO, FAOCD (2012-2015) Reagan Anderson, DO, FAOCD (2012-2015) Mark Kuriata, DO, FAOCD (2010-2013) Sponsors: Daniel Ladd, DO, FAOCD (2012-2013) John Minni, DO, FAOCD (2011-2014) Bayer Bryan Sands, DO, FAOCD (2012-2014) Executive Director: Galderma Marsha Wise Resident Coordinator: Global Pathology Laboratory John Grogan

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Copyright © 2003 by the Journal of the American Osteopathic College of Dermatology

Print and layout by: The Dimensional Group, Mason City, IA 50401 Copy editing: Julia Layton, Freelance Writing and Editing able of Contents

Fall 2012, Volume 24 FEATUREDT ARTICLE Purpura: A Clinical Review Helia Eragi, DO, Khasha Touloei, BS, David C. Horowitz, DO, FAOCD...... 9

JAOCD Editors...... 4 Letter from the Editor-in-Chief...... 5 Letter from the Executive Director...... 6 Letter from the President...... 7 -Like On The Knee Zhi Zhong Wang, MD, MSc, Andrew A. Simone, MD...... 15 Day Spa Disasters: Patients' Injuries on the Rise Jonathan Crane, DO, FAOCD, Richard Flexner, JD, David Jackson, BS...... 16 Transient Reactive Aquagenic Acrokeratoderma on the Palms of a 62-Year-Old Female Brent Loftis, DO, Donna D. Tran, MSIV, Yoon Cohen, DO, Bill V. Way, DO, FAOCD...... 19 A 49-Year-Old Male With Tender Firm Nodules On His Posterior Lower Legs Paul Aanderud, DO, R. Scott Thomas, MSIV, George Murakawa, MD...... 21 Plaque of the Glans Penis: Differential Diagnosis Melinda F. Greenfield, DO, Joseph M. Dyer, BS...... 25 Advancement Flap for Distal Nasal Defects Albert E. Rivera, DO, FAOCD, Roger I. Ceilley, MD, Andrew K. Bean, MD, Joshua B. Wilson, MD...... 27 Amelanotic Spindle Cell in a Hispanic Male Charlotte Noorollah, DO, Suzanne Friedler, MD, Marvin Watsky, DO, FAOCD...... 29 Cutis Marmorata Telangiectatica Congenita: A Case Report and Discussion Mari M. Batta, DO, Brandon G. Shutty, BS, Stephen Kessler, DO, Ronald C. Hansen, MD ...... 31 A Suspicious Arising in a 28-Year-Old Female After Administration of Melanotan II Daniel Child, BS, Paul Aanderud, DO, Steven Grekin, DO, FAOCD...... 33 Vegetans: An Uncommon Presentation in Human Immunodeficiency Virus Infection Theresa Cao, DO, Angela Combs, DO, Tracy Favreau, DO, David Droller, MD, Eli Piatigorsky, MD...... 34 Microcystic Adnexal Carcinoma in a 7-Year-Old Female Cathy Koger, DO, Chris Weyer, DO, Lloyd J. Cleaver, DO, Michael B. Morgan, MD...... 36 Periocular Verruca Plana Following Use of a Carbon Dioxide Laser Roxanna Menendez, DO, Jacqui Thomas, DO, Matthew Uhde, PA-C, Layne Nisenbaum, DO, FAOCD...... 41 Hypopigmented Patches in a Young Columbian Boy Kurt Grelck, DO, Sheena Nguyen, BS, Andleeb Usmani, DO, Robin Shecter, DO, FAOCD...... 44 Reed Syndrome: Hereditary Leiomyomatosis and Renal Cell Cancer Peter J. Morrell, DO, FAOCD...... 46 Primary Cutaneous Anaplastic Large-cell Lymphoma Ali Daneshvar, Indira Misra-Higgins, DO, FAOCD...... 48 A Case of Segmental Neurofibromatosis Alison Himes, DO, Kristi Hawley, DO, Dawn Sammons, DO...... 50 Combined : and Justin Rubin, DO, Panagiotis Mitropoulos, DO, Carlos Gomez-Meade, DO, FAOCD, Evangelos Poulos, MD, Tracy Favreau, DO, FAOCD, Angela Combs, DO, FAOCD...... 55 A Case of Macularis Eruptiva Perstans (TMEP) Samuel M. Wilson, DO, R. Scott Thomas, Allison K. Divers, MD, Daniel S. Hurd, DO, FAOCD...... 57 Clinically Benign-appearing : A Treatment Conundrum Brooke Walls, DO, David Dorton, DO, FAOCD...... 63 Editor-in-Chief Founding Editor Copy Editor Karthik Krishnamurthy, DO Jay Gottlieb, DO Julia Layton, BA, MFA

Associate Editors

Aaron Bruce, DO Michelle Foley, DO Scott Wickless, DO Loveland, CO Ormond Beach, FL Durango, CO

Editorial Board

Melinda Greenfield, DO Albany, GA

Adriana Ros, DO Clifton, NJ

4 JAOCD Editors etter from the Editor-in-Chief L

Karthik Krishnamurthy, DO, FAOCD Editor-in-Chief, JAOCD Dear AOCD Members and Residents,

It is with great honor that I assume editorship of this fine journal. After 10 years of dedicated service, Dr. Jay Gottlieb has left our college with a proud legacy, and one that will continue to prosper.

The JAOCD and the AOCD, sharing the same not-for-profit status, are more intimately connected starting this year. Owing to this, and to foster transparency, I have created an Associate Editors Committee to serve as a resource for decision-making and future development.

Aaron Bruce, DO, Michelle Foley, DO, Michael Scott, DO, and Scott Wickless, DO, have graciously stepped up to this task. Each is fit to bring a fresh prospective and lend to the integrity of the articles we publish: Dr. Bruce in surgery, Dr. Foley in general dermatology and cosmetics, Dr. Wickless in dermatopathology, and Dr. Scott in dermatological wisdom that cannot be taught but only developed through experience. In addition, we continue to boast a robust Editorial Board, currently consisting of 55 reviewers! I am constantly amazed by the loyalty and dedication of the members of our College.

Please remember what a unique resource this journal is for our subspecialty college and the potential it possesses. Please continue to submit your articles and encourage your colleagues to do so, too. The better we make it, the broader its impact. “Continued quality” will be the first focus going forward, relying on the following litmus tests:

1) The article is written in brief language and in a professional, medical tone. 2) The submission includes clinical photographs and/or pathology, when applicable.

In the next year, with the implementation of stricter submission criteria, I hope to have the JAOCD approved for CME reading credits!

I would like to thank my family for their support of my involvement in the College, as well as Dr. Cindy Hoffman, my program director, without whom I would not be practicing dermatology and experiencing all the happiness that brings. I would also like to thank Marsha Wise, who is a fantastic resource in our home office. Dr. Gottlieb, thank you for all your dedication and for entrusting me with your “baby.” Thank you to Ranbaxy, Global, Bayer/Intendis, Medicis, and Galderma, whose generous donations keep the journal in print and coming to you. Finally, I would like to thank Julia Layton, our copy editor, who is a pleasure to work with and without whom the JAOCD could not exist.

Best, Karthik Krishnamurthy, DO, FAOCD Editor-in-Chief, JAOCD Third Vice President, AOCD

Letter from the Editor-in-Chief 5 etter from the Executive Director L

Marsha Wise Executive Director, AOCD

Greetings, everyone!

The 2012 Annual Meeting is now behind us, and new officers were elected at our annual business meeting on Monday, October 8, 2012. The AOCD has many committees working for the entire AOCD membership. If you would like to be a member of a commit- tee, please contact the AOCD office for more information.

AOCD OFFICE UPDATE The AOCD is excited to announce that the office will be moving to a larger space. The move should be completed by December 21, 2012. Our post office box, 7525, is our preferred mailing address, and all correspondence should be sent there. We will continue to accept shipments at our 1501 E. Illinois St. address until the move is completed, and notice of our new physical address will be sent to the membership.

2013 AOCD Dues Renewal Notices were handed out in San Diego to those who attended OMED. If you did not attend, or did not pick up a renewal notice, we will mail your notice to you.

In addition to renewing your AOCD dues, you may also designate additional funds to go to accounts earmarked for the AOCD Edu- cational Research Fund, the Koprince Award, AAD Camp Discovery, the Dermatopathology Fund (to help support fellowship candi- dates enrolled at the Ackerman Academy), and the Foundation for Osteopathic Dermatology.

Meetings Update AOCD Midyear Meeting 2013 will be held January 23-26, 2013, in Winter Park, CO. Please call the Winter Park Hotel directly for your room reservations.

Meeting Evaluations and Surveys AOA requirements for CME continue to evolve. Thank you to everyone for participating in the various surveys throughout the year and for returning meeting evaluations. The results are tabulated and reviewed by the Board of Trustees and the CME committee. Locations for future AOCD Midyear Meetings will be chosen based on survey results.

ACGME UPDATE The American Osteopathic Association (AOA), the Accreditation Council for Graduate Medical Education (ACGME), and the American Association of Colleges of Osteopathic Medicine (AACOM ) have entered into an agreement to pursue a single, unified accreditation system for graduate medical education programs in the United States beginning in July 2015.

As developments and details unfold, information for the osteopathic family can be found at www.osteopathic.org/acgme. There, you can find answers to frequently asked questions, the AOA’s joint press release, a timeline of the issue, and other resources.

The AOCD Board of Trustees and the staff at the National Office wish everyone a happy and healthy holiday season.

Marsha Wise Executive Director, AOCD

6 LEtter from the Executive Director etter from the President L

David L. Grice, DO, FAOCD President, AOCD

Our annual meeting in San Diego was filled with beautiful weather, great lectures and the opportunity to renew friendships. I would like to acknowledge my fellow Program Chairs, Brad Glick and Suzanne Rozenberg, for their assistance with putting together and running an outstanding meeting. I also want to thank the faculty and resident presenters who made this meeting both educational and interesting.

The AOCD Board of Trustees made several significant decisions while in San Diego. First, we approved the move of our national office in Kirksville to a larger building, a much-needed move for our cramped executive director, Marsha Wise, and staff. Second, we are looking to improve our website, with the goal of having a more user-friendly site for our members, residents, and the public. You should see some of these changes in 2013. In other technologic news, our college already has an iPhone App and is close to releas- ing an Android version. Three new members of the American Osteopathic Board of Dermatology were approved by the BOT: Rene Bermudez, Tanya Ermolovich, and Scott Wickless. At our annual business meeting, Reagan Anderson was re-elected as an AOCD trustee, and three new trustees were elected: Danica Alexander, Bryan Sands, and Dan Ladd.

On the political front, the AOCD is partnering with the AAD to stand firm against the new nurse practitioners’ doctorate degree, which would give nurses the title "doctor" and would therefore, we believe, deceive the public. Also, recently, the Women’s Derma- tologic Society had a bylaws change that reclassified osteopathic-trained dermatologists from active members to associate members. With the help of several leaders in the AOCD, the WDS President, Janet Hickman, M.D., and Immediate Past President Diane Ber- son, M.D., issued a letter stating that the Society leadership unanimously agrees to return osteopathic members to active status, pend- ing membership approval.

First VP and Program Chair Rick Lin is busy preparing an outstanding lineup of speakers for our upcoming Midyear meeting at the Winter Park Lodge in Winter Park, Colorado, January 23-26, 2013. Please join us for the meeting, and later on the slopes for some great skiing!

Best regards to you and your families, David L. Grice, DO, FAOCD President, AOCD

Letter from the President 7 Galderma: we know outside and in.

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

Galderma is a registered trademark. ©2011 Galderma Laboratories, L.P. Galderma Laboratories, L.P., 14501 N. Freeway, Fort Worth, TX 76177 GEN-316 Printed in USA. 08/11 Purpura: A Clinical Review

Helia Eragi, DO,* Khasha Touloei, BS,** David C. Horowitz, DO, FAOCD***

*Dermatology Resident, Second Year, Western University/Pacific Hospital of Long Beach, Long Beach, CA **4th-year Medical Student, Western University of Health Sciences, Pomona, CA ***Program Chairman/Dermatology Residency Director, Western University/Pacific Hospital of Long Beach, Long Beach, CA

ABSTRACT: Purpura is a common and nonspecific term used in medicine to describe the appearance of red or purple discoloration of the skin that does not blanch when pressure is applied. Purpura, petechiae and ecchymosis are caused by extravasation of red blood cells into the . Petechiae are less than 5mm, purpura 5mm to 1 cm, and ecchymosis greater than 1 cm. Purpura is a common presenting problem at both inpatient and outpatient medical settings, with an extensive variety of underlying causes. This paper will review different case scenarios for patients presenting with purpura, differential diagnoses, and workups and algorithms necessary to rule in or rule out the underlying cause for the presenting symptom. Case 1: Purpura secondary Thrombocytopenia is either due to Based on the history, physical exam decreased platelet production, increased findings and the algorithm above, the to thrombocytopenia platelet destruction, or platelet sequestration patient has immune thrombocytopenic (1) A 23-year-old female presents . Clinically, thrombocytopenia can manifest purpura (ITP). ITP presents as an isolated complaining of a two-day history of a as purpura, petechiae, ecchymosis, mucosal thrombocytopenia one to six weeks after a involving both lower extremities. She also bleeding, meno-metrorrhagia in females, viral infection, secondary to an autoimmune reports some gingival bleeding that she first easy bruising, epistaxis, gastrointestinal process, and undergoes spontaneous (4) noticed a couple of days ago. She states she bleeding, hematuria or intracranial bleeding resolution within two months . Among (2) just got over a severe flu, but is feeling better. . Bleeding doesn’t usually occur until adults under the age of 50, such as in the (3) Her past medical history is unremarkable, platelet count drops below 20,000 . Table 1 above case, the condition is more chronic she denies a family history of bleeding may be used to determine which tests should and persists longer than six months. The disorders, and she is taking no medications. be ordered to rule in or out a specific disease. disease mainly affects women between 20 Vital signs are normal. Physical examination demonstrates small, non-palpable, punctate Table 1 Purpura, normal platelet count Purpura, decreased platelet count Purpura with sepsis purple lesions involving bilateral lower extremities. CBC shows hemoglobin 14.0 Vitamin K deficiency Alloimmune thrombocytopenia Trauma during birth g/dL (normal 12-16g/dL), hematocrit Trauma Maternal autoimmune Septicemia 42% (normal 36-46%), leukocyte count 7,000/mm3 (normal 4,000-12,000/mm3), thrombocytopenia (MAT) 3 and platelet count 10,000/mm (normal In utero exposure to drugs Congenital amegakaryocytic Disseminated intravascular 150,000-400,000/mm3). Coagulation studies shows prothrombin time (PT) of thrombocytopenia coagulation (DIC) 10 seconds (normal 10-13 seconds), partial Hemophilia A/B Wiskott-Aldrich syndrome (WAS) TORCH infections thromboplastin time (PTT) of 35 seconds (normal 25-39 seconds), and international Child abuse Immune Osteopetrosis normalized ratio (INR) 1.5 (normal 0.8- (ITP) Leukemia 1.2). Fibrinogen and fibrinogen degradation products are both within normal limits. What is the diagnosis? Algorithim 1:

Differential Diagnosis: Immune thrombocytopenic purpura (ITP) Thrombotic thrombocytopenic purpura (TTP) Hemolytic uremic syndrome (HUS) Glanzmann disease (GD) Hermansky-Pudlak syndrome (HPS) Langerhans histiocytosisBernard Soulier disease (BS) von Willebrand disease (vWD)

Eragi, Touloei, Horowitz 9 and 40 years of age (5). Chronic ITP commonly occurs in patients Based on the history, physical exam, and the algorithm, the with a history of alcohol or heroin abuse and patients with AIDS patient has either hemophilia A or B, X-linked recessive bleeding and/or prior rubella exposure (6). Chronic ITP most often presents disorders secondary to deficiency of either factor VIII or IX, with scattered petechiae of the distal arms and legs and possibly with respectively. Spontaneous bruising occurs in patients with hemophilia deep-lying ecchymoses. One distinguishing factor of ITP is that it is and presents as palpable ecchymosis but is not as common as rarely accompanied by splenomegaly (7). hemarthrosis, observed most commonly in knee joints (13). Large-area Hemolytic uremic syndrome (HUS) presents with purpura in bruising occurs with vitamin K-dependent factor deficiency more so the lower extremities, hemolytic anemia, thrombocytopenia, and than with hemophilia. The vitamin K-dependent factors are II, VII, renal failure and is associated with E. coli 0157:H7. Thrombotic IX and X, protein C, and protein S. Causes of vitamin K deficiency thrombocytopenic purpura (TTP) has many similarities to HUS, but include cholestasis, fat malabsorption, prolonged antibiotic use, and (14) this disease mainly affects adults (8). TTP also exhibits neurological cystic fibrosis . A patient with DIC will have a history of septicemia, (15) defects and fever, which this patient did not exhibit. The patient in trauma, or shock . In liver failure, the liver is unable to synthesize (16) the above case did not have an increased partial thromboplastin coagulation factors . The findings are similar to DIC but will also time (PTT) or family history of bleeding disorders, which rules include decreased levels of the vitamin K clotting factors. This can out von Willebrand disease (6). Glanzmann disease (GD) is another also present with purpura, but more so with ecchymosis and other (17) differential that should be considered. The disease is characterized bleeding disorders . Liver function tests are helpful for diagnosis, by improper platelet aggregation and manifests with multiple bruises and risk factors for liver disease should be investigated. and purpura (9). Bernard Soulier manifests with severe bleeding during Case 3: Purpura in age group birth to 2 years injury or surgery (10). However, this patient had no history of trauma or surgery. Patients with Langerhans histiocytosis also present with A 12-month-old boy is referred for evaluation of white eye reflex. thrombocytopenia, but will have other physical manifestations His mother suspects a hearing problem because he does not such as , hepatosplenomegaly, anemia and a papular, respond when she calls out his name. The physical examination vesicular, and purpuric rash. This syndrome is diagnosed by skin (11). reveals a continuous, machine-like murmur over the second right intercostal space and purple lesions on his arms and chest that were Another disease that may present with purpura secondary to apparent since birth. The initial investigation reveals thrombocyto- platelet dysfunction is Hermansky-Pudlak syndrome (HPS), which penia. What is the most likely diagnosis? is a very rare genetic disorder characterized by and accumulation of ceroid lipofuscin, a lipid-protein Differential Diagnosis complex, in lysosomes. The disease is commonly found in albino Purpura, normal platelet count Purpura, decreased platelet count Purpura with sepsis Puerto Ricans. Diagnosis is made by clinical presentation, a platelet Vitamin K deficiency Alloimmune thrombocytopenia Trauma during birth function test, and electron microscopy to analyze the dense-body Trauma Maternal autoimmune Septicemia (12) granules in platelets . thrombocytopenia (MAT) Case 2: Purpura secondary to a coagulation disorder In utero exposure to drugs Congenital amegakaryocytic Disseminated intravascular thrombocytopenia coagulation (DIC) A 25-year-old male presents with a purpuric, swollen, tender Hemophilia A/B Wiskott-Aldrich syndrome (WAS) TORCH infections right thigh with some joint swelling after bumping into a table in Child abuse Immune thrombocytopenic purpura Osteopetrosis his living room. Pulsation is decreased over the left popliteal artery. (ITP) He has a family member who suffered from a clotting disease with Leukemia bleeding into joints. Given his family history of bleeding disorder, Algorithm 3: what is the diagnosis? Differential Diagnosis: Hemophilia A Hemophilia B Disseminated intravascular coagulation (DIC) Hematoma secondary to contusion/trauma Liver failure Vitamin K deficiency Algorithm 2:

The classic triad of congenital rubella syndrome is sensorineural deafness, cardiac malformations, and cataracts (18). The purpuric rash described in the above case, also known as blueberry muffin baby, along with history and physical exam is consistent with congenital rubella, which is one of the TORCH infections (toxoplasmosis, other [], rubella,

10 Purpura: A Clinical Review cytomegalovirus, herpes simplex virus). A baby with congenital Based on the CSF results and clinical symptoms, the patient in rubella infection can appear purpuric, but this condition must case 4 is suffering from meningitis. However, with the sudden onset be differentiated from purpura fulminans secondary to protein C of rash along with the other clinical symptoms, one must consider or S deficiency. Clinically, purpura fulminans manifests as large Waterhouse-Friderichsen syndrome secondary to a Neisseria ecchymoses, diffuse purpura, and of the extremities. The meningitides infection. This disease most commonly affects children ecchymoses become bullous and necrotic (19). Platelet typing should be between birth and 18 months but can also affect adults. Any patient ordered to rule out neonatal alloimmune thrombocytopenia (NAT), with meningitis and sudden onset of rash and purpura should have which can also present as diffuse purpura with a normal platelet count a culture and gram stain of blood and CSF. Initially, the patient and without coagulation abnormalities (20). Maternal autoimmune will have oropharyngeal petechiae and purpura that eventually thrombocytopenia (MAT) is different from NAT, as it has a lower become confluent. As the disease progresses, hemorrhagic bullae platelet count and typically presents after three months of age (21). If with ulcerations manifest. The disease can become fulminant as thrombocytopenia is present in the first year of life, and the family ecchymoses with irregular borders appear on the extremities. The history shows absent thumbs or absent radii, the diagnosis points lesions may form necrotic centers. This disease progresses rapidly toward absent radius syndrome (22). and is the only meningitis with skin manifestations, and it can be (28,29) A child with recurrent infections, , and fatal if not treated and recognized early in its course . Since the thrombocytopenia should point toward Wiskott-Aldrich syndrome patient has a history of recent outdoor activities, Rocky Mountain (WAS), a congenital, immune-mediated X-linked disorder. Patients spotted fever should also be in the differential. This disease manifests with WAS commonly present with atopic dermatitis and secondary with small, pink macules that evolve into petechiae and purpura skin infections due to pneumonia, Neisseria starting on the palms and soles, later migrating inward toward the meningitides, and Haemophilus influenza. The platelet count in WAS trunk. The disease occurs secondary to a tick bite from Dermacentor, is less than 50,000, and the mean platelet volume is also reduced. In Rhipicephalus or Amblyomma species. It is caused by the gram- WAS, the young child or infant may initially present with a reddish negative bacterium Rickettsia rickettsii and occurs in the eastern brown or blue, tender skin lesion which rapidly evolves into a two-thirds of the United States, Rocky Mountain states, Pacific violaceous, bulging mass with petechiae and purpura (23). If the patient coast, and southwestern United States. It most commonly affects has a history of a blue skin lesion prior to swelling and bruising, this children between the ages of 5 and 10. If the disease becomes too would warrant the diagnosis of Kasabach-Merritt syndrome (KMS) severe, it may present with extensive cutaneous necrosis due to DIC, (24). A newborn who has not been given vitamin K just following birth requiring amputation. The patient will also have other associated can experience severe purpura and bleeding within two to four days. symptoms including fever, headache, myalgia, and photophobia (30,31) These patients will have decreased factors II, VII, IX, and X (25). . secondary to can present clinically indistinguishable from meningococcemia. It In a patient with unexplained purpura and an inconsistent also manifests with desquamation, particularly on the palms and history, the clinician should perform an eye exam and a complete body soles, which can occur one to two weeks after onset of the illness(32) . scan for fractures, as child abuse should be suspected. Young children exposed to abuse or falls can exhibit purpura on various regions of the Case 5: Purpura not due to infection, body (26). After birth trauma, caput succedaneum may form and cause purpura on the head (27). thrombocytopenia or coagulation disorder A patient presents with purpura scattered on lower extremi- Case 4: Purpura secondary to infection ties. The patient is negative for infection, thrombocytopenia and An 18-year-old woman comes to the ER because of acute onset of coagulation disorders. What is the next step? headache, muscle pain, and nausea. These symptoms had been present Once infection, thrombocytopenia, and coagulation disorders for one day, arising soon after she returned from a camping trip. The have been ruled out as the cause of purpura, there are several illness started with fever and muscle pain that progressed to include methods that can be used to narrow the differential diagnosis. headache and nausea over the next several hours. She states that she The first step should be to obtain a thorough history of present went hiking twice during the trip and participated in many outdoor illness, including diet, medications, family history, complete review activities with her friends. She has no other medical problems. Her of systems, and physical exam. The following algorithm can be temperature is 102 F, blood pressure 90/60, pulse 120/min, and followed (see next page). respirations 18/min. Physical examination shows a stiff neck with pain A patient with a recent history of surgery, radiation or to passive flection. Her skin reveals few purpuric lesions on both legs. may exhibit purpura due to disruption in coagulation Examination of the cerebrospinal fluid (CSF) reveals: glucose 25mg/ or platelet activity. Cholesterol emboli can manifest with purpura dl, protein 175mg/dl, WBC 2000/cm. What is the likely diagnosis? in the lower extremities. Other findings include livedo reticularis, Differential Diagnosis gangrene, and occasionally ulceration of the skin (33). More Common Less Common The purpura in scurvy is usually found on the Meningococcemia lower extremities and manifests as perifollicular petechiae that coalesce to form ecchymoses, Scarlett fever Rickettsia prowazekii especially on the thigh and buttock regions. The Endocarditis caused by disease also presents with phlebothrombosis. Hemorrhaging can also occur in the joints, organs, Streptococcus viridans/Staphylococcus aureus Ehrlichiosis and beds. Other skin manifestations include Rocky Mountain spotted fever Hepatitis B scaly dermatitis, pallor, dry mouth, and poor wound healing (34). A diet history may allow you Staphylococcus-induced toxic shock syndrome Dengue hemorrhagic fever to diagnose vitamin B12 and/or folate deficiencies, both of which can cause thrombocytopenia. Both TORCH (covered in Case 3) Atypical measles syndromes present with megaloblastic anemia, but

Eragi, Touloei, Horowitz 11 Differential Diagnosis: Algorithm 5: Drugs Easy-bruising syndrome Schaumberg disease Ehlers-Danlos syndrome Scurvy (ascorbic acid deficiency) AmyloidosisAuto erythrocyte sensitivity Osler-Weber-Rendu syndrome Allergic purpura Systemic erythematosus (SLE) vitamin B12 deficiency also has neurological symptoms (35). Allergic purpura can appear secondary to foods such as wheat, eggs, milk, and chocolate. The most common cause of allergic purpura is streptococcal infection triggering an autoimmune reaction against the vasculature. Allergic purpura affects males more often and is most common in children from 3 to 7 years of age. It's usually preceded by an upper respiratory infection. As of yet, there are no lab tests to diagnose this disease. It does, however, present with elevated WBC and ESR counts. Patients will have a positive tourniquet test, while coagulation panels and platelet-function tests are normal females, and 50% of the time it appears after a URI(44) . Other palpable (36). A tourniquet test determines capillary fragility using an inflated purpuras include , Wegner's granulomatosis, blood pressure cuff for five minutes. The test is considered positive cryoglobulinemia and SLE immune-mediated thrombocytopenia (45). (37) if there are 10 or more petechiae per square inch . UA and stool Another diagnosis that can be made clinically is capillaritis, also guaiac usually test positive for blood. A small bowel X-ray may known as pigmented purpuric dermatosis, which results in cayenne- show areas of transient edema as well. This disease is a diagnosis of (36,38) pepper-like petechiae. There are several other clinical entities that exclusion . fall under the umbrella of capillaritis: Schamberg disease, purpura Medication-induced purpura manifests within 24 hours of annularis telangiectodes of Majocchi, eczematid-like purpura of exposure and disappears following discontinuation of the drug. Doucas and Kapetanakis, lichenoid purpura of Gougerot and Blum, Warfarin administered on its own can cause painful areas of and lichen aureus. Schamberg disease is characterized by yellow- that become purpuric and necrotic with a darkened eschar. brown patches with petechiae. Purpura annularis telangiectodes of Auto-erythrocyte sensitivity, which causes painful purpura and Majocchi is characterized by annular lesions, commonly reddish and ecchymoses, appears either as a single lesion or as several lesions brown, that can become atrophic. Lichenoid purpura of Gougerot and coalescing to form one lesion. The purpura and ecchymoses begin as Blum is characterized by symmetric purpuric papules and plaques pruritus, burning, or pain prior to their presentation. Furthermore, on distal legs. Both Schamberg’s disease and lichenoid purpura of one must consider drug-induced thrombocytopenia as a causative Gougerot and Blum can be pruritic. Eczematid-like purpura of Doucas factor for palpable purpura with medications such as quinidine, and Kapetanakis presents with scale and erythema with petechiae. trimethoprim-sulfamethoxazole, and gold, among others (38-42). Lichen aureus can present with solitary or multiple lesions (46). A thorough physical exam should be performed initially. The dysproteinemias that cause purpura include multiple Amyloidosis can manifest with purpura that occurs most commonly myeloma and cryoglobulinemia (hyperglobulinemic purpura of on the eyelids and mucous membranes (43). Henoch-Schonlein Waldenström). Multiple myeloma manifests with purpura, petechiae purpura (HSP) is the most common form of in children and ecchymoses, as well as gum bleeding and excessive bleeding and is a form of immune-mediated vasculitis syndrome in which the after surgery (47). Waldenström is characterized by recurrent crops of platelet count is not affected and the diagnosis is made clinically. It petechiae and purpura on the dependent areas of the body. Patients manifests with a symmetric, palpable, purpuric rash of the buttocks may be positive for IgG or IgA rheumatoid factor titers, antibodies to and lower extremities. The disease affects males more often than Ro/SS-A and La/SS-B, and elevated ESR (48).

12 Purpura: A Clinical Review Case 6: Purpura secondary to vasculitis/ The first test that should be conducted when suspecting LCV is a punch biopsy. The histology of leukocytoclastic vasculitis is autoimmune disease identified by the presence of fibrin deposits, fragmented nuclei A 47-year-old female presents complaining of a one-week history and neutrophils disrupting postcapillary venules and intravascular of rash involving both lower extremities. She also reports oral ulcers fibrin. HSP is restricted to the superficial dermis. Purpura secondary and hematuria. Her past medical history is unremarkable, she denies to a drug reaction will have severe fibrinoid necrosis of vessel walls a family history of bleeding disorders, and she takes no medications. but will have tissue eosinophilia. Sometimes a spongiotic interface (50) Vital signs are normal. Physical examination shows small, palpable, dermatitis may also be present . punctate purple lesions involving bilateral lower extremities. CBC and Once LCV is confirmed, systemic involvement must be coagulation studies are all within normal limits. What is the diagnosis? analyzed with a thorough history, CBC with differential, urine analysis, chemistry panel, erythrocyte sedimentation rate, Differential Diagnosis: antiphospholipid antibodies, immunoglobulin (IgG, IgA, and IgM) Leukocytoclastic vasculitis (LCV) levels, chest X-ray, fecal occult blood test and DIF. After a vasculitis Microscopic polyangiitis (MPA) is confirmed, infectious and rheumatologic etiologies can be ruled out by ordering ANA, anti-neutrophilic cytoplasmic antibody Cutaneous polyarteritis nodosa (CPAN) (ANCA), rheumatoid factor, anti-Ro, anti-La, complement levels, (49,51,52) Cryoglobulinemia cryoglobulins, hepatitis B and hepatitis C serology . Wegener's granulomatosis (WG) WG, CSS, and MPA are small-vessel vasculitides and have an absence of immune complexes (ICs). WG most commonly affects Churg-Strauss syndrome (CSS) the upper respiratory tract, lungs and kidneys. Patients may also Cocaine levamisole toxicity (CLT) present with hemoptysis and hematuria. IgG, IgM, Antiphospholipid antibody syndrome (AAS) and/or C3 in or around the Algorithm 6: vessels characterizes IC- mediated vasculitis, which includes cryoglobulinemic vasculitis, connective-tissue- disease vasculitis, and LV (52). In MPA and CSS, p-ANCA is seen; in WG, c-ANCA is commonly seen. However, these markers are not diagnostic (53). The histology of WG will have the presence of palisaded and neutrophilic granulomatous dermatitis. CSS patients will present with asthma, blood eosinophilia, and eosinophilic-rich and "red" necrotizing extra- vascular . MPA does not have granulomas, eosinophilia or asthma (49,51). Cutaneous PAN demonstrates a starburst appearance on physical exam. Secondary changes that may present include tender nodules, livedo reticularis or ulceration. Cutaneous PAN does not Purpura secondary to vasculitis can be caused by leukocytoclastic have peripheral gangrene, which is seen in systemic PAN. Histology vasculitis (LCV) or systemic vasculitis syndromes including Wegener will demonstrate neutrophilic muscular-vessel vasculitis in the granulomatosis (WG), Churg-Strauss syndrome (CSS), microscopic dermal-subcutis junction or in the subcutis (49,51). polyangiitis (MPA) and cutaneous polyarteritis nodosa (CPAN) (49). Based on the history, physical exam findings and the algorithm above, Cryoglobulinemia vasculitis is characterized by the triad the patient has WG. of purpura triggered by cold exposure or prolonged standing, weakness, and arthralgia. DIF will demonstrate deposits of IgM Nearly half of the cases of LCV are idiopathic and self-limited. and/or complement (49). The other half are due to drugs or infection. Cutaneous vasculitis may be the first initial symptom in CSS, MPA, and WG. Cutaneous Retiform purpura is a non-blanching purpura seen with vasculitis most commonly presents as palpable purpura, but can also antiphospholipid antibody syndrome (AAS) and cocaine levamisole present as other morphologies including livedo reticularis, nodules toxicity (CLT). AAS is an autoimmune disease characterized and ulcers (49). by elevated autoantibodies including the cardiolipin antibody, Eragi, Touloei, Horowitz 13 antiphospholipid antibody, and lupus 10. López JA, Andrews RK, Afshar-Kharghan V, Berndt 40. Cox NH, Piette W. (2010) Purpura and Microvascular MC. Bernard-Soulier syndrome. Blood. 1998 Jun Occlusion, in Rook's Textbook of Dermatology, anticoagulant, leading to thrombotic 15;91(12):4397-418. Eighth Edition (eds T. Burns, S. Breathnach, N. Cox (52) and C. Griffiths). Wiley-Blackwell, Oxford, UK. doi: 11. Newman B, Hu W, Nigro K, Gilliam AC. Aggressive conditions and recurrent fetal loss . 10.1002/9781444317633.ch49 histiocytic disorders that can involve the skin. J Am Acad CLT results from cocaine that has been Dermatol. 2007;56(2):302 41. Aster RH. Semin Can drugs cause autoimmune thrombocytopenic purpura? Hematol. 2000 contaminated with levamisole, leading to 12. Huizing M, Anikster Y, Gahl WA. Hermansky-Pudlak Jul;37(3):229-38. purpuric, tender skin eruptions. Other syndrome and related disorders of organelle formation. Traffic. 2000 Nov;1(11):823-35. 42. Mahboob A, Haroon TS. Drugs causing fixed symptoms include agranulocytosis and eruptions: a study of 450 cases. Int J Dermatol. 1998 13. Springhouse. Professional Guide to Diseases. Genetic Nov;37(11):833-8. neutropenia. It is common to see purpuric Disorders. Ninth edition. Philadelphia: Lippincott macules and papules on the helix of the ear or Williams & Wilkins, 2008. 1129-1130 43. Kyle RA, Bayrd ED. Amyloidosis: review of 236 cases. Medicine (Baltimore). 1975 Jul;54(4):271-99. cheeks. CLT is a diagnosis of exclusion, and 14. Pazirandeh S, Burns DL. Overview of vitamin K. In: UpToDate, D. Basow (Ed.). UpToDate, Waltham, MA, 44. Saulsbury FT. Henoch-Schönlein purpura. Curr Opin (53) urine toxicology may aid in diagnosis . 2011. Rheumatol. 2010 Sep;22(5):598-602. Review 15. Matsuda T. Clinical aspects of DIC--disseminated 45. Magro CM, Crowson AN. A clinical and histologic study Conclusion intravascular coagulation. Pol J Pharmacol 1996; 48:73. of 37 cases of immunoglobulin A-associated vasculitis. Am J Dermatopathol. 1999 Jun;21(3):234-40. 16. Violi F, Ferro D, Basili S. Coagulopathy of chronic liver Purpura, a very common and non- disease. N Engl J Med. 2011 Oct 13;365(15):1453; 46. Sardana K, Sarkar R, and Sehgal VN. (2004), author reply 1453-4. Pigmented purpuric dermatoses: An overview. specific term used in medicine, has a International Journal of Dermatology, 43: 482–488. 17. Reverter JC. Abnormal hemostasis tests and bleeding considerable number of possible underlying in chronic liver disease: are they related? Yes. J Thromb 47. Kois JM, Sexton FM, Lookingbill DP. Cutaneous etiologies. Since the differential diagnosis Haemost. 2006 Apr;4(4):717-20. manifestations of multiple myeloma. Arch Dermatol. 1991 Jan;127(1):69-74. can be very extensive, we have presented 18. Dudgeon JA. Congenital rubella. J Pediatr. 1975 Dec;87(6 Pt 2):1078-86. 48. Malaviya AN, Kaushik P, et al. Hypergammaglobulinemic six case scenarios with algorithms to review purpura of Waldenström: report of 3 cases with a short 19. Chu DZ, Blaisdell FW. Purpura fulminans. Am J Surg. review. Clin Exp Rheumatol. 2000 Jul-Aug;18(4):518-22. the history and physical exams, lab findings, 1982 Mar;143(3):356-62. 49. Chen KR, Carlson JA. Clinical approach to cutaneous and work-up necessary to determine the 20. Chakravorty S, Roberts I. How I manage neonatal vasculitis. Am J Clin Dermatol. 2008;9(2):71-92. Review. underlying causes of purpura. In summary, thrombocytopenia. Br J Haematol. 2011 Sep 27. doi: 10.1111/j.1365-2141.2011.08892.x. [Epub ahead of 50. Busam K. Dermatopathology. A volume in the series. purpura can be due to coagulation-factor print] Foundations in diagnostic pathology. 1st ed. Saunders; 2010 deficiencies, including hemophilia A/B; 21. van Leeuwen EF, Helmerhorst FM, Engelfriet CP, von dem Borne AE. Maternal autoimmune thrombocytopenia 51. Carlson JA, Ng BT, Chen KR. Cutaneous vasculitis von Willebrand disease; liver disease; or and the newborn. Br Med J (Clin Res Ed). 1981 Jul update: diagnostic criteria, classification, epidemiology, coagulopathic diseases including DIC and 11;283(6284):104. etiology, pathogenesis, evaluation and prognosis. Am J Dermatopathol 2005 Dec; 27 (6): 504-28 Kasabach-Merritt syndrome. Purpura 22. Toriello HV. Thrombocytopenia-absent radius syndrome. Semin Thromb Hemost. 2011 Sep;37(6):707-12. Epub 52. Sais G, Vidaller A, Jucgla A, et al. Prognostic factors in can present secondary to an acquired 2011 Nov 18. leukocytoclastic vasculitis: a clinicopathologic study of 160 patients. Arch Dermatol 1998; 134 (3): 309-15 thrombocytopenia caused by viral infections, 23. Ochs HD. The Wiskott-Aldrich syndrome. Isr Med Assoc vitamin B12 and folate deficiency, or a drug J. 2002 May;4(5):379-84. Review. 53. Weinstein S, Piette W. Cutaneous manifestations of antiphospholipid antibody syndrome. Hematol Oncol 24. Kelsch RD. Kasabach-Merritt syndrome: a case reaction. Purpura may also be the result of Clin North Am. 2008 Feb;22(1):67-77, vi. report and literature review. Compendium. 1994 thrombocytopenia secondary to platelet May;15(5):590-8. 54. Chung C, Tumeh PC, et al. Characteristic purpura of the ears, vasculitis, and neutropenia--a potential public 25. Lippi G, Franchini M. Vitamin K in neonates: facts destruction in diseases such as immune health epidemic associated with levamisole-adulterated and myths. Blood Transfus. 2011 Jan;9(1):4-9. doi: cocaine. J Am Acad Dermatol. 2011 Oct;65(4):722-5. thrombocytopenic purpura, connective- 10.2450/2010.0034-10. Epub 2010 Sep 13. Review. Epub 2011 Jun 11. tissue disease, leukemia, drugs, DIC, and 26. Ermertcan AT, Ertan P. Skin manifestations of child thrombotic thrombocytopenic purpura. abuse. Indian J Dermatol Venereol Leprol. 2010 Jul- Finally, purpura can be due to abnormal Aug;76(4):317-26. Review. 27. Uhing MR. Management of birth injuries. Pediatr Clin platelet function, observed with aspirin North Am. 2004 Aug;51(4):1169-86, xii. Review. ingestion, kidney and liver dysfunction, and 28. Harris P, Bennett A. Waterhouse-Friderichsen thrombocytosis. syndrome. N Engl J Med. 2001 Sep 13;345(11):841. 29. Wong VK, Hitchcock W, Mason WH. Meningococcal References infections in children: a review of 100 cases, Ped Infect Dis J 1989; 8:224 1. Ballem PJ, Segal GM, Stratton JR, Gernsheimer T, Adamson JW, Slichter SJ. Mechanisms 30. Walker DH. Rocky Mountain spotted fever: a seasonal of thrombocytopenia in chronic autoimmune alert. Clin Infect Dis. 1995 May;20(5):1111-7. thrombocytopenic purpura. Evidence of both impaired 31. Thorner AR, Walker DH, Petri WA Jr. Rocky mountain platelet production and increased platelet clearance. J spotted fever. Clin Infect Dis. 1998 Dec;27(6):1353-9; Clin Invest. 1987 Jul;80(1):33-40. quiz 1360. 2. Cines DB, McMillan R. Management of Adult 32. Stevens DL. Streptococcal toxic shock syndrome Idiopathic Thrombocytopenic Purpura. Annu Rev Med. associated with . Annu Rev Med. 2005;56:425-42. (2000) 3. Lacey JV, Penner JA. Management of idiopathic 33. Fine MJ, Kapoor W, Falanga V. Cholesterol crystal thrombocytopenic purpura in the adult. Semin Thromb embolization: a review of 221 cases in the English Hemost. 1977;3(3):160. literature. Angiology. 1987 Oct;38(10):769-84. 4. Lusher JM, Iyer R. Idiopathic thrombocytopenic purpura 34. Allen JI, Naas PL, Perri RT. Scurvy: bilateral lower in children. Semin Thromb Hemost. 1977 Jan;3(3):175- extremity ecchymoses and paraparesis. Ann Emerg 99. Med. 1982 Aug;11(8):446-8. 5. Segal JB, Powe NR. Prevalence of immune 35. Cooper BA, Lowenstein L. Vitamin B-12-folate thrombocytopenia: analyses of administrative data. J interrelationships in megaloblastic anaemia. Br J Thromb Haemost. 2006;4(11):2377. Haematol. 1966 May;12(3):283-96. 6. Springhouse. Professional Guide to Diseases. Platelet 36. Springhouse. Allergic Purpuras. Professional Guide Function Disorders. Ninth edition. Philadelphia: to Diseases. Ninth edition. Philadelphia: Lippincott Lippincott Williams & Wilkins, 2008. 530-533 Williams & Wilkins, 2008. 523-524 7. Thiagarajan P, Besa EC. (2009). Platelet Disorders. 37. Prevention and Control of Dengue and Dengue eMedicine. URL: http://emedicine.medscape.com/ Haemorrhagic Fever. World Health Organization. article/201722-overview. Accessed March 2011. Regional Publication, SEARO No.29 8. Amorosi EL, Ultmann JE. Thrombotic thrombocytopenic 38. Ackroyd JF. Allergic purpura, including purpura due purpura: Report of 16 cases and review of the literature. to foods, drugs and infections. Am J Med. 1953 Medicine 1966; 45: 139–159. May;14(5):605-32. 9. George JN, Caen JP, Nurden AT. Glanzmann's 39. Korbitz BD, Ramirez G, Mackman S, Davis HL Jr. thrombasthenia: the spectrum of clinical disease. Blood. Coumadin-induced skin necrosis in a sixteen-year-old 1990;75(7):1383. girl. Am J Cardiol. 1969 Sep;24(3):420-5.

14 Purpura: A Clinical Review Dermatofibroma-Like Glomus Tumor On The Knee

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

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

ABSTRACT: Glomus tumor is a rare benign and usually occurs under the fingernails. It can be misdiagnosed as other diseases when occurring in other body area. We reported a case of glomus tumor occurring on the knee. It was difficult to differentiate from dermatofibroma.

Pathological Examination Within the dermis, there was a tumor consisting of small vessels surrounded by several layers of small cuboidal cells, which are typical of glomus cells (Figures 1,2). Treatment: Surgical excision. Discussion Glomus tumor is a rare, benign neo- plasm arising from the glomus body. It usu- ally occurs as a solitary reddish spot under the fingernail, sometimes with a distal fis- sured nail plate or nail bed elevation. It often manifests with a classic triad of symp- Figures 1-2: The tumor is full of small vessels surrounded by typical glomus cells in the toms: pain, tenderness and temperature dermis. sensitivity. The pain can usually be repro- duced when the lesion is immersed in cold water. Glomus tumour may rarely occur in other body areas. In 1985, Macaluso et al. reported a U.S. case of glomus tumor on the glans penis.1 Park et al. reported another case of glomus tumor on the glans penis of a 19-year-old man in Korea in 2004.2 Lorber et al. reported a case of glo- mus tumor in gastric antrum in 2005.3 Clark et al. and many other authors reported several cases of glomus tumor causing knee pain in other years.4 They all concluded that glomus tumor can be a rare cause of knee pain. This case of glomus tumor occurred on the right knee without pain. Its location, A German male, 66 years old, com- previously treated with radioactive iodine appearance, tenderness, and lack of tem- plained of a firm, pinkish on his and was currently taking levothyroxine. perature sensitivity made it difficult to dif- right knee. This protuberance had been vis- He worked as a public transit driver for 28 ferentiate from dermatofibroma. The only ible for three years, grew slowly and was not years. Family history was non-contributory. diagnostic clue was the lack of dimpling. itchy. However, it felt painful when bumped against hard surfaces. There had been no Physical Examination References history of trauma to the knee. He'd had gout 1. Macaluso JN, Sullivan JW, Tomberlin S. Glomus tumor There was a solitary pink nodule on the of the glans penis. Urology. 1985;25(4):409-410. for 28 years and was taking allopurinol. medial side of the right knee, about 6 mm 2. Park DS, Cho TW, Kang H. Glomus tumor of the glans His was under good control in diameter and 3 mm in height. It was well- penis. Urology. 2004;64(5):1031. for five years through the use of ramipril. defined without in the 3. Lorber J, Kalish J, Farraye FA, Cerda S, Babineau TJ. Glomus tumor of the gastric antrum: case report. Curr The patient was diagnosed with periphery. It felt firm and tender when pres- Surg. 2005;62(4):436-8. type 2 one year prior and had since been sure was applied on the top of the nodule. 4. Clark ML, O’Hara C, Dobson PJ, Smith AL. Glomus taking metformin. He had also suffered There was no dimpling or pain when the tumor and knee pain: A report of four cases. The Knee. 2009;16(3):231-234. from hyperthyroidism 15 years ago, was nodule was squeezed from the sides.

wang, Simone 15 Day Spa Disasters: Patients' Injuries on the Rise

Jonathan Crane, DO, FAOCD,* Richard Flexner, JD,** David Jackson, BS***

*Atlantic Dermatology Associates, P.A., Wilmington, NC **The Law Offices of Richard Flexner, Wilmington, NC ***University of North Carolina at Wilmington, Wilmington, NC

ABSTRACT: Procedures including laser hair removal and chemical peels, termed "non-surgical medical procedures," have increased 749% from 1997 to 2008.1 Between 2005 and 2006 alone, injury from mishaps related to procedures at these "medical spas" rose 41% in clients of a Southern California law firm. 1 Some of these injuries include burns from hair-removal lasers, scarring from chemical peels, and even death. 1,2,3,4 From bodily harm caused by improperly-done procedures, lawsuits have dramatically risen as clients seek monetary repayment after suffering tremendously. 5 Here, we review the increase in day-spa related injuries stemming from this new and problematic beauty trend. Introduction History of Cosmetic Surgery This is especially prevalent among the aging “baby boomer” generation, and these Recently, there has been a boom in the Cosmetic surgery in some form has 1 spas are in turn offering anti-aging treat- business of “day spas”. Originally, day spas been done historically for thousands of ments including botulinum toxin type A offered traditional spa procedures such as years. Ancient Egyptians and Romans and laser hair removal.10 These medical massages and pedicures, but have recently both managed to use compounds such as spas have attempted to move away from the grown to provide “non-surgical medical fermented grape leaves and sour milk for “disease treatment” model to create a more procedures” or “small plastic surgery pro- chemical peels.7 Sanding of the skin was 1,6 hospitable environment with “memorable cedures.” These procedures include laser also done as an older form of dermabra- experiences” for clients, along with com- treatments, chemical peels, filling agents sion. In 1905, Kromayer invented a tech- bining various medical practices that range and the use of neurotoxins. Day spas pro- nique called “surgical planing,” which 7 from alternative and preventive medicine viding these treatments are the most rap- later became . Kurtin and to “mind-body” views.11 Also, physicians idly-growing portion of the spa industry Robbins created standardized dermabra- have been attracted to working in this field as noted by the International SPA Asso- sion in 1959 in order to treat “traumatic due to the promise of a large profit that will ciation, and have quadrupled in number injuries” that patients acquired in 5 7 boost income even with “declining insur- from 2004 to 2009 alone. Many of these World War II. In 1972, Baker and Gordon ance reimbursements.”10 businesses may seem official and similar to showed that phenol is beneficial in chemi- physicians’ offices, but are generally much cal peeling. Recently, plastic surgeons and Processes and Problems in less regulated, if at all.1,5 Some of these busi- dermatologists have improved upon chem- nesses call themselves “medical spas” or ical-peel methods in both safety and effec- Day Spas “med spas,” which in some states is allowed tiveness.7 Currently, the usual chemical peel Numerous medical procedures done at by law provided that certain criteria, most in a day spa is a “superficial or lunch-time day spas can result in serious injury. Acid importantly medical supervision, is met. variety,” which means that the penetration peels can result in atrophic scars, hypertro- Many states do have laws allowing surgical is not deep.8 In the 1980s, the process of phic scars, and . Postinflammatory procedures to be performed at a spa with a laser resurfacing emerged and was initially hyperpigmentation (PIH) and hypopigmen- supervising physician, but in practice the done with continuous-wave carbon-dioxide tation may occur from acid peels in spas. physician is often not present during the lasers.9 New techniques have since emerged Superficial peels, including salicylic acid procedure, and may not even be present on- that have fewer side effects. Some of these and glycolic acid, are commonly used in day site. Moreover, even with regulatory laws on techniques include nonablative resurfacing, spas. Some spas use more aggressive peels, the books, they are not uniformly enforced.6 which injures the dermis “to improve rhyt- such as trichloroacetic acid. Day spas using In other states where the law is silent ides and photodamage” without affecting trichloroacetic acid may injure and burn (such as in North Carolina), some busi- the ; and fractional resurfacing, patients. nesses present themselves as “med spas” which works over a fraction of the skin sur- 9 This is an example of a patient injured without any supporting basis in law. In face in order to shorten recovery time. in a day spa in Wilmington, North Caro- these cases, the purported “med spas” are History of Day Spas lina. She received a deep chemical peel unregulated by medical boards, and may from an esthetician, licensed only by the st in fact be wholly medically unsupervised, Around the beginning of the 21 North Carolina Board of Cosmetology, which would constitute a fraud upon the century, medical spas were few and far which licenses barbers and hairstylists as 10 patient and be actionable, along with other between. However, around 2003, the well. This esthetician and the day spa were theories of legal liability such as negligence medical spa industry began to rapidly completely unprepared to deal with the sec- 11 and medical malpractice, in lawsuits filed develop. This growth has been so mas- ond and third degree burns caused by the to seek compensation for injuries caused sive that between 2006 and 2007 alone, procedure that was being provided. Follow- by these procedures. Thus, as a result of medical spas increased by 50% to 1,250 ing the disastrous procedure, the esthetician 10 patients sustaining bodily harm from insuf- businesses. Numerous reasons have pro- involved a dentist friend who was not on ficiently supervised medical procedures, pelled these businesses to develop, but one scene and not apparently involved in any litigation is increasing; in particular, a spike main reason seems to be demand by clients, way in the supervision of either the day spa 10,12,13 in laser-related lawsuits has been noted.5,6 especially for anti-aging procedures. or the esthetician. The dentist undertook to 16 Day Spa disasters: Patients' Injuries on the Rise phentermine. spots (Figure 2), and the spa went bankrupt A 22-year-old as a result, which suggests that the spa did college student in not carry liability insurance. This form of North Carolina died litigation is predicted to increase dramati- 5 from a “violent reac- cally in the near future. Accordingly, many tion” to a numb- lawyers have advertised their field-related ing lidocaine cream services and have won cases in the area of 15,17 applied to her skin day-spa-related lawsuits. before a laser hair Regulations removal treatment.3 The lidocaine cream One critical problem is that while the caused lidocaine poi- majority of states require physicians to soning in this stu- supervise these medical procedures, many dent, and resulted of the procedures nevertheless go unregu- in her death. This lated.5 In some states, a person can per- tragedy led to a shut- form deep chemical peels without having a down of this spa, but medical degree.18,19 Due to this deficiency, not to additional reg- Florida, New York, Illinois, and other states ulation of the medi- are attempting to enact laws that would cal spa industry in impose tighter regulation on day spas that North Carolina. offer medical treatments.5 Due to the ris- Various states have different laws per- ing number of inju- taining to the use of lasers in a day spa set- ries from the greater ting.20 In California, state law provides that number of medi- a registered nurse or physician’s assistant cal spa procedures is allowed to give injections of botulinum being performed, toxin type A, as well as perform laser hair lawyers are filing removal, microdermabrasion, and an array more negligence and of other “non-surgical treatments.”1 How- malpractice lawsuits ever, Senator Liz Figueroa (D-Fremont) Figure 1 seeking redress for proposed bill 1423, which would make injuries caused by constant physician supervision mandatory prescribe medication for the burned patient improperly performed without ever seeing her to establish a doc- procedures. Claims Figure 2 tor-patient relationship, and without even have increased, espe- speaking with her. The dentist took no steps cially related to inju- to refer the patient to a qualified medical ries from laser hair specialist to treat her burns, thereby delay- removal and anti- ing the patient obtaining qualified medical wrinkle and scar care for her serious burns (Figure 1). treatments. In North Other examples include: Carolina, a claim A Southern California woman who was filed on behalf visited a day spa in a mall near her home of three women who was treated with a laser and suffered third- received unsuper- degree burns, which resulted in severe scar- vised injections for ring and nerve damage.1 buttocks enhance- ment that resulted in A woman in Arizona sued a spa there kidney failure in all in 2009 after having second-degree burns of them.5,15,16 Some and scars from improperly-done laser hair of these cases can 5 removal. result in major mon- A man sued a different Arizona spa etary recoveries for over a laser hair removal treatment done on the client, and cor- his back and shoulders.5 responding losses for 16 One woman in North Carolina became the businesses. In septic after undergoing stomach fat reduc- one case, a Chicago tion at a day spa.14 woman won $100,000 from a medical spa Three women in North Carolina devel- (Pure Med Spa) based oped kidney failure from receiving injec- on scarring on her 15 tions intended for buttocks enhancement. neck from laser treat- These injections were likely comprised of ment that was sup- hCG (human chorionic gonadotropin) and posed to remove age

Crane, Flexner, Jackson 17 for those types of treatments. The origi- their procedures for laser hair removal “safe, Medical_Spas/article/. nal bill has been delayed due to negative guaranteed, and FDA endorsed,”27 and oth- 13. Cherry Creek North. “Ageless Aesthetics Medical Spa: Shopping at Cherry Creek North.” 2011. 23 April comments from many California physicians ers offer a doctor’s office-like setting with 2011. http://cherrycreeknorth.com/shop/details/ageless- and medical spa employees, and has been the personnel in white coats, these claims aesthetics-medical-spa/. 21 14. DeMayo, MA. “Greensboro Spa Patient Wins $500,000 largely amended. In California, some of are empty and may increase the risk to a North Carolina Personal Injury Lawsuit Against the recently enacted laws allow physicians, patient.1,2,7 Alternative Medicine Spa.” 11 February 2009. 22 April 2011. http://www.northcarolinainjurylawyerblog. physician assistants, and registered nurses com/2009/02/greensboro_spa_patient_wins_50_1.html. to use cosmetic lasers and inject botulinum Conclusion 15. Alexander L. “Spa investigation slowed by need for toxin type A.22 Due to their lack of appro- coordination.” 21 August 2008. 22 April 2011. http:// Injuries and deaths from procedures www.news-record.com/content/2008/08/20/article/spa_ priate licenses, medical assistants are not performed in day spas are on the rise. investigation_slowed_by_need_for_coordination. allowed to perform these procedures. If Related lawsuits are on the rise, as well.1 16. Parker Waichman Alonso LLP. “Injuries from Laser Hair Removal, other Procedures Sparking Lawsuits Against an unlicensed person aids in performing Lawsuits have been increasing so much that Medical Spas.” 8 September 2009. 22 April 2011. these procedures, various punishments will comparisons are frequently made between http://www.yourlawyer.com/articles/read/16957. follow, ranging from “license discipline to laser cases and asbestos-exposure cases.28 17. The Law Office of Lee Arter. “Los Angeles Salon Injury Attorney.” 2011. 22 April 2011. http://www. criminal prosecution,” the second of which Some lawyers also forecast that the numbers losangelespersonalinjuryfirm.com/Personal-Injury/ would be for “aiding and abetting the unli- of this form of lawsuit will balloon, and say Beauty-Salon-Accidents.aspx. censed practice of medicine.”22 In Florida, 18. Howard County General Hospital. “Chemical Peel.” 22 that this is “the beginning of the industry April 2011. http://www.hcgh.org/content/greystone_837. similar legislation has been proposed by the being targeted.”28 Day spas offering medical htm. state’s dermatological society over the past treatments may have only recently arisen, 19. The Ohio State University Medical Center. “Chemical 23 Peel.” 22 April 2011. http://medicalcenter.osu.edu/ few years. but closely-linked problems have haunted patientcare/healthcare_services/skin_conditions/ this industry since its beginning, most nota- common_dermatological_procedures/chemical_peel/ In Mississippi, laser procedures are the Pages/index.aspx. bly the lack of regulation of these proce- responsibility of a physician, and cosmetol- 20. Kimbol AS, Conway CA. “The Medical Spa Movement 5,10,11 ogists and estheticians are forbidden by law dures. However, some states are already and Regulatory Uncertainty.” Health Law Perspectives. 8 June 2009. 24 April 2011. http://www.law.uh.edu/ to use lasers for any “cosmetic procedures” in the process of intensifying current regu- healthlaw/perspectives/2009/(CC)%20Medical%20 unless under physician supervision.24 The lations, thereby beginning to address the Spas.pdf. Kansas Medical Society intends to create severe problems associated with facilities 21. Whitman C. California State Bill 1423 has been temporarily held back. 24 April 2011. legislation for its state that would require with questionable staff offering procedures http://www.medicalspaassociation.org/index. a spa to have “a medical director who is including chemical peels and laser treat- asp?submenu=legislation. ments.5 22. Aristelguieta C, Greenberg M, Yaroslavsky B, Fantozzi licensed by the Healing Arts Board,” mak- RD, Gregg LC, Chang H. “Action Report – Medical ing the business physician-run and sanitary, Board of California – Use of Mid-level Practitioners For References Laser, Dermabrators, Botox, and Other Treatments.” 24 and holding the physician in the position April 2011. http://www.medicalspaassociation.org/index. 1. Allen, Flatt, Ballidis & Leslie, Inc. “Day Spas asp?submenu=legislation. of medical director of a day spa responsible Accounting for 41% Increase in Personal Injury to for ensuring the legality of the practice as Clients.” 25 February 2008. 22 April 2011. http://www. 23. Pensa P. “New Laws Regulates Med Spa Operation californiainjurylawyerblog.com/2008/02/day_spas_ Businesses Make Beauty Convenient.” 2 July 2006. 24 opposed to only supervising and delegat- accounting_for_41_inc.html. April 2011. http://www.medicalspaassociation.org/index. asp?submenu=legislation. ing to those who work there.25 New Jersey 2. Fitts Zehl, LLP. “Laser Hair Removal Burn Injuries.” 2010. 22 April 2011. http://www.fittszehl.com/practice- 24. Luckett N. “Mississippi State Board of Cosmetology states that “only doctors licensed by the areas/personal-injury/laser-hair-removal-burn-injuries. Position Statement Topic: The use of Laser Devices state board of medical examiners” may use html. in Cosmetic Practices.” 27 February 2006. 24 April 2011. http://www.medicalspaassociation.org/index. 20 3. Lamb A. “Clinic Tied to N.C. State Student’s Death lasers, and delegation is illegal. Finally, asp?submenu=legislation. Shuts Down.” 31 January 2005. 22 April 2011. http:// a “state task force” in Massachusetts has www.wral.com/news/local/story/115269/?print_friendly. 25. Kansas Medical Society. “Medical Spas.” 1 May 2010. 24 April 2011. http://kmsonline.org/advocacy/ proposed that Massachusetts medical spas 4. Zhang AY, Obagi S. “Diagnosis and management of kms-policy-statements/34-2010-policy-statements/255- Skin Resurfacing-Related Complications.” Oral and medical-spas. should be licensed by the state’s Depart- Maxillofacial Surgery Clinics of North America. Vol. 21, ment of Public Health, and that those who Issue 1. Pages 1-12. February 2009. 26. Zneimer and Zneimer Law Office, P.C.. A. “Estheticians and Cosmetologists Cannot Perform Laser Hair 5. Baldas T. “Unwanted Lawsuits Grow from Laser Hair perform the procedures have appropriate Removal.” 8 March 2010. 22 April 2011. http://www. Removal.” The National Law Journal. 2 September 20 chicagoaccidentlawyerblog.com/burn_injury/. licensing. 2009. 22 April 2011. http://www.law.com/jsp/article. jsp?id=120243351813. 27. Zneimer and Zneimer Law Office, P.C.. B. “Laser Hair Greater enforcement of the laws Removal Can Cause Burn Injuries.” 7 March 2010. 22 6. “Injuries From Laser Hair Removal, Other Procedures April 2011. http://www.chicagoaccidentlawyerblog.com/ already on the books would also serve to Sparking Lawsuits Against Medical Spas.” 9 September burn_injury/. reduce the risk to patients from potentially 2009. 22 April 2011. http://www.injury911law.com/ personal-injury/injuries-from-laser-hair-removal-other- 28. “Is Laser-Hair Removal the New Asbestos?” The Wall life-threatening injuries due to procedures procedures-sparking-lawsuits-against-medical-spas. Street Journal. 2 September 2009. 22 April 2011. html. http://blogs.wsj.com/law/2009/09/02/is-laser-hair- improperly done by those with no expertise removal-the-new-asbestos/tab/print/. 7. Clark E, Scerri L. “Superficial and medium-depth in techniques such as laser hair removal. chemical peels.” Clinics in Dermatology. Vol. 26, Issue Illinois’ “Barber, Cosmetology, Esthetics, 2. Pages 209-218. March-April 2008. and Nail Technology Act of 1985” states 8. Taub AF. “Procedures Offered in the Medical Spa Environment.” Dermatologic Clinics. Vol. 26, Issue 3. that licensed cosmetologists “are prohib- Pages 341-358. July 2008. ited from using any technique, product, or 9. Alexiades-Armenakas MR, Dover JS, Arndt KA. “The practice intended to affect the living lay- spectrum of laser skin resurfacing: Nonablative, fractional, and ablative laser resurfacing.” Journal of the 26 ers of the skin.” By implementing more American Academy of Dermatology. Vol. 58, Issue 5. severe punishment for breaking this and Pages 719-737. May 2008. 10. Dolan PL. “Medispa industry continuing growth.” 12 other regulatory laws, more of these proce- March 2007. 23 April 2011. http://www.ama-assn.org/ dures would be done by physicians who are amednews/2007/03/12/bisc0312.htm. experienced in this field of cosmetic pro- 11. Feed-Back.com E-zine. “Medical Spas.” April 2006. 23 April 2011. http://www.feed-back.com/ezine_ cedures, and fewer errors would be made. archive/2006/april_06ezine.html. Also, while many of these day spas state that 12. Anderson P. “The Growth of Medical Spa in the they “use FDA approved lasers” and call Hospitality Industry.” 10 July 2006. 23 April 2011. http://www.spatrade.com/knowledge/idx/80/242/

18 Day Spa disasters: Patients' Injuries on the Rise Transient Reactive Aquagenic Acrokeratoderma on the Palms of a 62-Year-Old Female

Brent Loftis, DO,* Donna D. Tran, MSIV,** Yoon Cohen, DO,*** Bill V. Way, DO, FAOCD****

*3rd year resident, Northeast Regional Medical Center Texas Division, Dermatology Institute, Duncanville, TX **4th year medical student, University of North Texas Health Science Center, Fort Worth, TX ***Intern, University Hospitals Richmond Medical Center, Cleveland, OH ****Dermatology Residency Program Director, Northeast Regional Medical Center Texas Division, Dermatology Institute, Duncanville, TX

ABSTRACT: Transient reactive aquagenic acrokeratoderma is a rare condition characterized by rapid development of white to translucent papules on the palms following immersion in water. Histopathologically, hyperkeratosis and dilated eccrine ducts are seen. We describe a case of a 62-year-old Caucasian female who presented with a 3-year history of pebble-like palmar eruptions following exposure to water. We discuss the clinical and histopathologic features, etiology, and treatment of the disease.

Introduction In 1996, English and McCullough described the first case of transient reactive aquagenic acrokeratoderma in a report of two sisters with symmetric, flesh-colored to white papules on the palms and lateral fingers, which, upon re-exposure to water, evolved into translucent white papules with dilated puncta.1 Since then, more than 30 cases have been described under different names, including “aquagenic palmoplantar ,” “aquagenic syringeal acro- keratoderma,” “aquagenic keratoderma,” “aquagenic wrinkling of the palms,” and “aquagenic acrokeratoderma.”2 Herein, we report a case of transient reactive aquagenic acrokeratoderma arising on the palms of a 62-year-old female, and characterize the histopathological fea- tures and pathogenesis of the disease. Figures 1-2: Appearance of pebble-like papules on the palms Case Report following immersion in water for a few minutes. A 62-year-old Caucasian female presented to our dermatology clinic for evaluation of a palmar eruption. She noted a three-year history of bumps under the skin of her hands after brief immersion in water. The lesions were associated with a burning sensation and resolved within minutes after drying her hands. She denied any concomitant hyperhidrosis. She had no family history of similar problems and denied any personal or family history of cystic fibrosis or atopy. Her past medical history was noted for hypertension and hypothyroidism. Her medications included hydrochlorothiazide, thy- roxine and multivitamins. Physical examination was remarkable for hyperlinearity of the palms as well as palmar erythema. Following exposure to warm water for a few minutes, she developed pebble-like papules with dilated puncta (Figures 1-2). The soles of her feet were not involved. A shave biopsy of the right palm was performed. Histopatho- tion characterized by rapid development of white-to-translucent logic examination revealed acanthosis and hyperkeratosis (Figure 3). papules on the palms following immersion in water.3 It has a Focally, a discrete focus of orthokeratotic hyperkeratosis was identi- predilection for females, with a mean age of 22.1 years.4 Preferen- fied with slight epidermal invagination. There were local fibrosis and tial involvement of the hands and not the feet, as in our patient, lymphocytic infiltrate. The granular layer was intact, and no viral is unclear. The “hands-in-the-bucket” sign, which is not clearly inclusions were identified. visible until the hand is immersed in water, is considered to be Based on the clinical and histopathologic findings, a diagnosis of pathognomonic. The lesions appear within a few minutes of 6 aquagenic acrokeratoderma was made. A trial of topical aluminum exposure to water and subside with drying of the skin. A burning chloride was prescribed. Within one week, the patient noticed dra- sensation, pain, tingling, or pruritus may be present, although the 4 matic improvement. At the time of submission, we plan to continue condition may be asymptomatic. to monitor her condition with the current therapy. Histologically, aquagenic acrokeratoderma is characterized by orthokeratotic hyperkeratosis and dilated eccrine ducts.1,2,6,7 How- Discussion ever, the dermis and epidermis may appear normal. In our patient, Transient reactive aquagenic acrokeratoderma is a rare condi- biopsy after water exposure showed acanthosis and a discrete focus

Loftis, Tran, Cohen, Way 19 Figure 3: Histopathology reveals acantho- sis and hyperkeratosis.

Trait Transient Reactive Aquagenic Hereditary Papulotranslucent Acrokeratoderma Acrokeratoderma Table 1: Features differentiating transient Sex Females predominately Females and males reactive aquagenic acrokeratoderma from Inheritance pattern Sporadic in most cases Autosomal dominant hereditary papulotranslucent acrokerato- Distribution Hands Edges of hands and feet derma. Clinical features Symptomatic translucent white papules Asymptomatic papules after exposure to water, associated with and plaques burning, tingling or pruritus Trauma associated No Yes History of atopy No Yes Abnormal hair No Yes Course Transient Permanent of orthokeratotic hyperkeratosis with slight hair and an atopic diathesis. After puberty, keratoderma: 3 new cases and a review of the literature. Actas Dermosifiliogr. 2008; 99(5): 399-406. epidermal invagination. new lesions fail to arise, but existing lesions 5. Itin PH, Lautenschlager S. Aquagenic syringeal 1 do not disappear or decrease in size. The acrokeratoderma (transient reactive papulotranslucent The pathogenesis of the disease acrokeratoderma). Dermatol. 2002;204:8-11. remains unclear. MacCormack et al. condition exhibits an autosomal-dominant pattern of inheritance. Histologically, the 6. Neri I, Bianchi F, Patrizi A. Transient aquagenic palmar hypothesized that aquagenic acrokerato- hyperwrinkling: the first instance reported in a young derma develops as a result of a defect in lesions show focal hyperkeratosis, acantho- boy. Pediatr Dermatol. 2006; 23(1): 39-42. 6 8 sis, and normal eccrine ducts. Males and 7. Betlloch I, Vergra G, Albares MP, et al. Aquagenic the sweat duct due to friction or occlusion. keratoderma. J Eur Acad Dermatol Venereol. Betlloch et al., on the other hand, proposed females are equally affected. 2003;17:306-7. that a transitory structural or functional Most treatment regimens for transient 8. MacCormack MA, Wiss K, Malbotra R. Aquagenic syringeal acrokeratoderma: report of two teenage cases. alteration of the stratum corneum elements reactive aquagenic acrokeratoderma focus J Am Acad Dermatol. 2001;45:124-6. (proteins, lipids, humectant substances, etc.) on decreasing the hyperkeratosis associ- 9. Diba VC, Cormack GC, Burrows NP. Botulinum toxin 7 is helpful in aquagenic . Br J leads to the disease. Itin et al. suggested an ated with the condition, or with providing Dermatol 152: 394-395, 2005. increase in water absorption capacity due to a water barrier to prevent exposure. Topical a defect in barrier function of the stratum treatment with aluminum chloride, ionto- corneum as the etiology and pathogenesis phoresis, and botulinum toxin have been of the disease.5 Aquagenic acrokeratoderma reported as effective options.5,9 Spontane- has also been reported in association with ous amelioration or remission after water cystic fibrosis and as an adverse effect of withdrawal has been described.5 Our patient cyclooxygenase-2 (COX-2) inhibitors.4 responded well to topical aluminum chlo- Several features help to differentiate ride. transient reactive aquagenic acrokerato- References derma from hereditary papulotranslucent 1. English JC III, McCollough ML. Transient reactive acrokeratoderma (Table 1). HPA appears papulotranslucent acrokeratoderma. J Am Acad soon after puberty and is characterized Dermatol 1996;34:686-7. 2. Luo DQ, Zhao YK, Zhang WJ, et al. Aquagenic by persistent, asymptomatic papules and acrokeratoderma. Int J Dermatol. 2010; 49:526-31. plaques that appear on the pressure and/ 3. Rizzo C, Bragg J, Soldano AC, Cohen D, Soter NA. or trauma points of the hands and feet, Hereditary papulotranslucent acrokeratoderma. Dermatol Online J. 2008;15:14:3. and is associated with fine-textured scalp 4. Pastor MA, Gonzalez L, KilmurrayL, et al. Aquagenic

20 Transient Reactive Aquagenic Acrokeratoderma on the Palms of a 62-Year-Old Female A 49-Year-Old Male With Tender Firm Nodules On His Posterior Lower Legs

Paul Aanderud, DO*, R. Scott Thomas, MSIV**, George Murakawa, MD***

*PGY-III Dermatology Resident, Oakwood Southshore Medical Center, Trenton MI **MSIV, A.T. Still University/Kirksville College of Osteopathic Medicine, Kirksville, MO ***Dermatology Private Practice, Troy, MI

ABSTRACT: is a disease process that belongs to a group known as tuberculids; diseases caused by a silent or active focus of tuberculosis. We present a 49 year-old man from India who presented with recurring tender nodules on the posterior aspects of his legs. He had a BCG vaccination as a child and previously positive PPD. Initial lab work, and chest X-ray were all unremarkable. A skin biopsy resulted in findings consistent with Erythema Induratum and the patient was subsequently referred to infectious diseases to begin treatment and investigate any other possible evidence of TB.

Examination Physical exam revealed multiple hyperpigmented patches and erythematous tender nodules on the posterior lower legs, and admixed areas of poorly defined violaceous-to-erythematousmacules (Figures 1-2). No regional lymphadenopathy was identified. The remainder of the exam was unremarkable. Laboratory Laboratory work showed a negative quantifer on gold test. A PPD was not performed due to history of BCG vaccination and a positive PPD in the past. All other labs including CBC and CMP were normal. An AFB culture was performed on a tissue sample from the right leg and showed no growth of any bacteria. Histopathology Figures 1 & 2 A 1.0 by 1.0 cm excision biopsy of the posterior right leg and a punch biopsy of the right ankle were performed. Histopathology revealed a septal-lobular panniculitis consisting of a mixed infiltrate of acute suppurative and granulomatous inflammation with foreign body-type giant cells. The inflammation extended into the overlying deep reticular dermis. Focal fat necrosis was also observed. There was also involvement of large vessels. Course And Therapy The patient received a diagnosis of erythema induratum and was referred to infectious disease in an attempt to uncover any unseen tuberculosis infection and begin treatment. The patient began a rifampin, isoniazid, pyrazinamide, and ethambutol (RIPE) regimen and experienced a gradual resolution of symptoms within the first two months. History Discussion A 49-year-old Indian male presented to the clinic with complaints of tender, Pierre-Antoine-Ernest Bazin from France first purple, lumps on his legs for over 15 years. He said that at times he would clear up used the term erythema induratum (EI) nearly 150 but then new lesions would appear on his legs. He also stated that similar lesions years ago to represent the chronic disorder of painful, had presented on his hands. The patient denied any complaints of chills, fever, violaceous, indurated, and sometimes even ulcerated night sweats, myalgias, or shortness of breath. He emigrated from India in 1998 nodules found on the lower extremities of patients. and received the BCG vaccination as a child. A recent chest X-ray was normal. The Initially he classified the disorder as a scrofula or patient had a history of sulfa allergies. A review of systems was otherwise normal scrofulid. With the discovery of Mycobacterium and family history was non-contributory. tuberculosis years later and subsequent findings of

Aanderud, Thomas, Murakawa 21 mycobacteria in lymph nodes of patients latent TB infection, an incisional skin biopsy exist as well. These include more supportive with EI, the association between the two with H&E and stains for acid-fast organisms, methods such as rest with spontaneous began. In 1898, fellow Frenchman Audry and labs such as a complete blood count with resolution, compression and supportive began to challenge such an association differential, erythrocyte sedimentation rate, bandages, and NSAIDS. after encountering similar patients lacking liver function tests, and hepatitis C serology. Additionally, success has stemmed tuberculoid granulomas on biopsy, acid-fast Though 60% of patients with EI have a from potassium iodide, dapsone, gold bacilli within lesions, and even a history of positive tuberculin skin test and/or evidence salts, colchicine, and doxycyline (1, 5, 8). (1) previous TB exposure . Whitfield reported of TB exposure, lack of these findings does Pegylated interferon and ribavirin use have similar cases in patients without evidence not in any way negate a diagnosis of EI. In also demonstrated the ability in treating Think of me of tuberculosis and postulated that EI contrast, more reliance should be placed on patients with concomitant hepatitis C (4). consisted of two entities dependent on the the combination of clinical and histological Unfortunately, a prospective comparison of (2) presence of TB or lack thereof . Thus, a findings with M. tuberculosis DNA PCR RIPE therapy versus such alternatives has Bazin and Whitfield variation respectively results acting as a strongly supportive test not been conducted. emerged. Montgomery and colleagues (7, 8) . The patient in this case presented with References further described the Whitfield type as a both the clinical and histological evidence non-tubercular nodular vasculitis (3). Various 1. Mascaró JM, Baselga E. Erythema Induratum of Bazin. consistent with EI. The negative quantiferon Dermatol Clin 26 (2008) 439-445. authors continue using the term erythema gold test in this case points to a Whitfield 2. Whitfield A. On the nature of the disease known as induratum to represent either variant rather variant. It could also represent a false erythema induratum scrofulosorum. Am J Med Sci 1901;122:828-834. than utilizing different names for the two negative or a rare true negative finding in the distinct processes (4, 5, 6). 3. Montgomery H, O’Leary PA, Barker NW. Nodular Bazin type of EI. vascular diseases of the legs: erythema induratum and allied conditions. JAMA 1945;128:335-45. EI currently belongs to a group of As mentioned previously, tuberculosis 4. Fernandes SS, Carvalho J, Leite S, Afonso M, Pinto diseases known as tuberculids, which are does not always represent the sole etiology. J, Veloso R, Duarte R, Ferreira E, Fraga J. Erythema skin conditions thought to result from either Nevertheless, multiple authors have found induratum and chronic hepatitis C infection. J Clin Virol. a silent or active focus of tuberculosis. In 2009;44(4):333-336. success utilizing the anti-tubercular regimen 5. Gilchrist H, Patterson JW. and some cases patients do not present with of rifampin, isoniazid, pyrazinamide, and erythema induratum (nodular vasulitis): diagnosis Specifi cally Designed symptoms or positive test results consistent and management. Dermatol Ther. 2010 Jul- ethambutol (RIPE). This combination was Aug;23(4):320-327. with a tuberculosis infection. Many authors used by Schneider and colleagues in treating 6. Segura S, Pujol RM, Felicidade T, Requena L. Vasculitis would advocate the use of M. tuberculosis a group of 20 patients diagnosed with EI. in erythema induratum of Bazin: A histopathologic study DNA PCR on skin biopsy of EI lesions to of 101 biopsy specimens from 86 patients. J Am Acad with in Mind They reported that only five of the group had Dermatol 2008; 59(5):839- 851. (7) Tolerability prove the association in this setting . positive PCR results for MTB DNA. Despite 7. Alothman A, Mohammed AQ, Al-Khenalzan S. Erythema induratum: What is the role of Mycobacterium Along with the reported association that, the entire group of patients experienced tuberculosis? Annals of Saudi Medicine 2007;27(4):298- with both active and latent TB, many resolution of symptoms within one to 300. possible etiologies have coexisted and have six months (9). Alothman and colleagues 8. Sharon V, Goodarzi H, Chambers CJ, Fung MA, Armstrong AW. Erythema induratum of Bazin. been thought to be triggers for EI. Cases successfully treated two different female Dermatology Online Journal 2010;16(4). • Indicated for the topical treatment of acne vulgaris in patients 12 years or older. exist linking EI with rheumatoid arthritis, patients with negative medical and family 9. Schneider JW, Jordaan HF, Geiger DH, et al. Erythema • Suspended crystalline tretinoin in vehicle designed to deliver the active ingredients to the skin.2 history of TB, negative mycobacterium induratum of Bazin: a clinicopathological study of Crohns’ disease, chronic lymphocytic 20 cases and detection of MTB DNA in skin lesions 1 leukemia, hypothyroidism, and hepatitis B tuberculosis cultures, and negative PCR for by polymerase chain reaction. American Journal of • Hydrogel alcohol-free aqueous base. and C (6). In addition, cases of EI have been MTB DNA. They utilized the same anti- Dermatopathology 1995;17:350-3. 10. Vera-Kellet C, Peters L, Elwood K, Dutz JP. Usefulness reported in totally healthy individuals with tubercular therapy and witnessed excellent of Interferon- Release Assays in the Diagnosis of Important Safety Information for ZIANA Gel no known underlying co-morbidities. clinical results as well as gradual declines in Erythema Induratum. Arch Dermatol. 2011;147(8):949- their respective erythrocyte sedimentation 952. That there exists more than one single • Diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) have been reported with the use of topical rate values (7). The current recommended etiologic cause for EI, a diagnosis should regimen consists of either two months clindamycin. ZIANA Gel should be discontinued if signi cant diarrhea occurs. Systemic absorption of clindamycin has rest on the clinical pathological correlation. of RIPE with four subsequent months of been demonstrated following topical use of this product. Patients with EI present with recurrent flares isoniazid and rifampin, or two months of • If a reaction suggesting sensitivity or chemical irritation occurs, use of the medication should be discontinued. of cold violaceous nodules on the posterior rifampin, isoniazid, pyrazinamide, with • Avoid exposure to sunlight and sunlamps. Patients with sunburn should not use the product. Use with caution in patients and anterolateral surfaces of the lower legs. seven proceeding months of rifampin and These nodules may or may not be painful who require considerable sun exposure due to occupation or who are inherently sensitive to the sun. Avoid excessive exposure isoniazid (8). Unfortunately, the possible and can have a predisposition to centrally to the sun, cold, and wind, which can irritate skin. Daily use of sunscreen and protective clothing are recommended. adverse effects of these antitubercular ulcerate, leaving behind scars and/or post- • Keep away from eyes, mouth, angles of nose, and mucous membranes. drugs are well known (e.g. hepatotoxicity, inflammatory hyperpigmentation. The agranulocytosis, drug-induced systemic nodules that ulcerate can also present as lupus erythematosus, peripheral neuropathy, • Concomitant use of topical medications with a strong drying e ect can increase skin irritation. Use with caution. superficial crusts with rolled erythematous optic neuritis, gout, etc.) and have raised borders (1). This ulceration is thought to To learn more, contact your Medicis, The Dermatology Company representative. some debate as to whether or not such a result from the caseous necrosis induced by treatment plan should wait for positive vascular damage that progressively migrates evidence of TB involvement. Some have even to the overlying dermis and epidermis. The recommend the use of interferon-gamma nodules can share similarities in appearance release assays to aid in diagnosing patients with other diseases such as erythema with TB positive EI before beginning anti- See reverse side for a Brief Summary of the Full Prescribing Information. nodosum, polyarteritis nodosa, and perniosis tubercular treatment, especially in patients References: 1. (3). EI becomes chronic with recurrences with previous BCG vaccination or known 2. NDA 50-802 for ZIANA Gel; Sections 4.4.4.1 & 4.2.5. 2006. Data on le, Medicis Pharmaceutical Corporation. taking place in 4-month intervals. TB exposure (10). Workup includes testing for an active or ZIANA is a registered trademark of Medicis Pharmaceutical Corporation. Other efficacious treatment options ZNA 12-024 06/30/13

22 A 49-Year-Old Male With Tender Firm Nodules On His Posterior Lower Legs Think of me

Specifi cally Designed with Tolerabilityin Mind

• Indicated for the topical treatment of acne vulgaris in patients 12 years or older. • Suspended crystalline tretinoin in vehicle designed to deliver the active ingredients to the skin.2 • Hydrogel alcohol-free aqueous base.1

Important Safety Information for ZIANA Gel

• Diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) have been reported with the use of topical clindamycin. ZIANA Gel should be discontinued if signi cant diarrhea occurs. Systemic absorption of clindamycin has been demonstrated following topical use of this product. • If a reaction suggesting sensitivity or chemical irritation occurs, use of the medication should be discontinued. • Avoid exposure to sunlight and sunlamps. Patients with sunburn should not use the product. Use with caution in patients who require considerable sun exposure due to occupation or who are inherently sensitive to the sun. Avoid excessive exposure to the sun, cold, and wind, which can irritate skin. Daily use of sunscreen and protective clothing are recommended. • Keep away from eyes, mouth, angles of nose, and mucous membranes.

• Concomitant use of topical medications with a strong drying e ect can increase skin irritation. Use with caution. To learn more, contact your Medicis, The Dermatology Company representative.

See reverse side for a Brief Summary of the Full Prescribing Information. References: 1. 2. NDA 50-802 for ZIANA Gel; Sections 4.4.4.1 & 4.2.5. 2006. Data on le, Medicis Pharmaceutical Corporation.

ZIANA is a registered trademark of Medicis Pharmaceutical Corporation. ZNA 12-024 06/30/13

23 BRIEF SUMMARY DRUG INTERACTIONS (see package insert for Full Prescribing Information) Concomitant Topical Medication Concomitant topical medication, medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect, and products with high concentrations of alcohol, astringents, spices or lime should be used with caution. When used with ZIANA® Gel, there may be increased skin irritation. Erythromycin ZIANA® Gel should not be used in combination with erythromycin-containing products due to its clindamycin component. In vitro studies have shown antagonism between these two antimicrobials. The clinical significance of this in vitro antagonism is not known. Neuromuscular Blocking Agents Clindamycin has been shown to have neuromuscular blocking properties that may enhance the action RX ONLY of other neuromuscular blocking agents. Therefore, ZIANA® Gel should be used with caution in patients FOR TOPICAL USE ONLY receiving such agents.

INDICATIONS AND USAGE USE IN SPECIFIC POPULATIONS ZIANA® Gel is indicated for the topical treatment of acne vulgaris in patients 12 years or older. Pregnancy Pregnancy Category C. There are no well-controlled trials in pregnant women treated with ZIANA® Gel. CONTRAINDICATIONS ZIANA® Gel should be used during pregnancy only if the potential benefit justifies the potential risk to ® ® the fetus. ZIANA Gel was tested for maternal and developmental toxicity in New Zealand White Rabbits ZIANA Gel is contraindicated in patients with regional enteritis, ulcerative colitis, or history of ® antibiotic-associated colitis. with topical doses of 60, 180 and 600 mg/kg/day. ZIANA Gel at 600 mg/kg/day (approximately 12 times the recommended clinical dose assuming 100% absorption and based on body surface area WARNINGS AND PRECAUTIONS comparison) was considered to be the no-observed-adverse-effect level (NOAEL) for maternal and developmental toxicity following dermal administration of ZIANA® Gel for two weeks prior to artificial Colitis insemination and continuing until gestation day 18, inclusive. For purposes of comparisons of the animal Systemic absorption of clindamycin has been demonstrated following topical use of this product. exposure to human exposure, the recommended clinical dose is defined as 1 g of ZIANA® Gel applied Diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) have been reported with the daily to a 60 kg person. use of topical clindamycin. When significant diarrhea occurs, ZIANA® Gel should be discontinued. Clindamycin Severe colitis has occurred following oral or parenteral administration of clindamycin with an onset of up Teratology (Segment II) studies using clindamycin were performed orally in rats (up to 600 mg/kg/ to several weeks following cessation of therapy. Antiperistaltic agents such as opiates and diphenoxylate day) and mice (up to 100 mg/kg/day) (583 and 49 times amount of clindamycin in the recommended with atropine may prolong and/or worsen severe colitis. Severe colitis may result in death. clinical dose based on a body surface area comparison, respectively) or with subcutaneous doses of Studies indicate a toxin(s) produced by clostridia is one primary cause of antibiotic-associated colitis. clindamycin up to 180 mg/kg/day (175 and 88 times the amount of clindamycin in the recommended The colitis is usually characterized by severe persistent diarrhea and severe abdominal cramps and may clinical dose based on a body surface area comparison, respectively) revealed no evidence of be associated with the passage of blood and mucus. Stool cultures for difficile and stool teratogenicity. assay for C. difficile toxin may be helpful diagnostically. Tretinoin Ultraviolet Light and Environmental Exposure In oral Segment III studies in rats with tretinoin, decreased survival of neonates and growth retardation Exposure to sunlight, including sunlamps, should be avoided during the use of ZIANA® Gel, and patients were observed at doses in excess of 2 mg/kg/day (~ 78 times the recommended clinical dose assuming with sunburn should be advised not to use the product until fully recovered because of heightened 100% absorption and based on body surface area comparison). susceptibility to sunlight as a result of the use of tretinoin. Patients who may be required to have With widespread use of any drug, a small number of birth defect reports associated temporally considerable sun exposure due to occupation and those with inherent sensitivity to the sun should with the administration of the drug would be expected by chance alone. Thirty cases of temporally exercise particular caution. Daily use of sunscreen products and protective apparel (e.g., a hat) are associated congenital malformations have been reported during two decades of clinical use of another recommended. Weather extremes, such as wind or cold, also may be irritating to patients under formulation of topical tretinoin. Although no definite pattern of teratogenicity and no causal association treatment with ZIANA® Gel. have been established from these cases, 5 of the reports describe the rare birth defect category, holoprosencephaly (defects associated with incomplete midline development of the forebrain). The ADVERSE REACTIONS significance of these spontaneous reports in terms of risk to the fetus is not known. Clinical Studies Experience Because clinical trials are conducted under prescribed conditions, adverse reaction rates observed in Dermal tretinoin has been shown to be fetotoxic in rabbits when administered in doses 40 times the the clinical trial may not reflect the rates observed in practice. The adverse reaction information from recommended human clinical dose based on a body surface area comparison. Oral tretinoin has been clinical trials does, however, provide a basis for identifying the adverse reactions that appear to be shown to be fetotoxic in rats when administered in doses 78 times the recommended clinical dose based related to drug use for approximating rates. on a body surface area comparison. The safety data presented in Table 1 (below) reflects exposure to ZIANA® Gel in 1,853 patients with acne Nursing Mothers vulgaris. Patients were 12 years and older and were treated once daily for 12 weeks. Adverse reactions It is not known whether clindamycin is excreted in human milk following use of ZIANA® Gel. However, that were reported in ≥ 1% of patients treated with ZIANA® Gel were compared to adverse reactions in orally and parenterally administered clindamycin has been reported to appear in breast milk. Because patients treated with clindamycin phosphate 1.2% in vehicle gel, tretinoin 0.025% in vehicle gel, and the of the potential for serious adverse reactions in nursing infants, a decision should be made whether to vehicle gel alone: discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. It is not known whether tretinoin is excreted in human milk. Because many drugs are excreted in Table 1: Adverse Reactions Reported in at Least 1% of Patients Treated human milk, caution should be exercised when ZIANA® Gel is administered to a nursing woman. with ZIANA® Gel: 12-Week Studies ZIANA® Gel Clindamycin Tretinoin Vehicle Pediatric Use ® N=1853 N=1428 N=846 N=423 Safety and effectiveness of ZIANA Gel in pediatric patients under the age of 12 have not been N (%) N (%) N (%) N (%) established. PATIENTS WITH AT LEAST ONE AR 497 (27) 342 (24) 225 (27) 91 (22) Clinical trials of ZIANA® Gel included patients 12–17 years of age. Nasopharyngitis 65 (4) 64 (5) 16 (2) 5 (1) Geriatric Use Pharyngolaryngeal pain 29 (2) 18 (1) 5 (1) 7 (2) Clinical studies of ZIANA® Gel did not include sufficient numbers of subjects aged 65 and over to Dry skin 23 (1) 7 (1) 3 (<1) 0 (0) determine whether they respond differently from younger subjects. Cough 19 (1) 21 (2) 9 (1) 2 (1) Manufactured for: Sinusitis 19 (1) 19 (1) 15 (2) 4 (1) Medicis, The Dermatology Company Note: Formulations used in all treatment arms were in the ZIANA® vehicle gel. Scottsdale, AZ 85256 Cutaneous safety and tolerance evaluations were conducted at each study visit in all of the clinical trials U.S. Patents 5,721,275 and 6,387,383 by assessment of erythema, scaling, itching, burning, and stinging: ZIANA is a registered trademark of Medicis Pharmaceutical Corporation. Table 2: ZIANA® Gel-Treated Patients with Local Skin Reactions Prescribing Information as of October 2008. Local Reaction Baseline End of Treatment 300-13B N=1835 N=1614 N (%) N (%) Erythema 636 (35) 416 (26) Scaling 237 (13) 280 (17) Itching 189 (10) 70 (4) Burning 38 (2) 56 (4) Stinging 33 (2) 27 (2)

At each study visit, application site reactions on a scale of 0 (none), 1 (mild), 2 (moderate), and 3 (severe), and the mean scores were calculated for each of the local skin reactions. In Studies 1 and 2, 1277 subjects enrolled with moderate to severe acne, 854 subjects treated with ZIANA® Gel and 423 treated with vehicle. Analysis over the twelve week period demonstrated that cutaneous irritation scores for erythema, scaling, itching, burning, and stinging peaked at two weeks of therapy, and were slightly higher for the ZIANA®-treated group, decreasing thereafter. One open-label 12-month safety study for ZIANA® Gel showed a similar adverse reaction profile as seen in the 12-week studies. Eighteen out of 442 subjects (4%) reported gastrointestinal symptoms.

24 Plaque of the Glans Penis: Differential Diagnosis

Melinda F. Greenfield, DO,* Joseph M. Dyer, BS** *Board-certified dermatologist, Albany Dermatology Clinic, Albany, GA **OMS-III, Philadelphia College of Osteopathic Medicine – Georgia Campus, Suwanee, GA

ABSTRACT: We offer the case of an erosive penile plaque in an elderly male that follows a relapsing and remitting course and discuss the differential diagnosis. Case Report Figure 1 healing. Lesions vary from asymptomatic to pruritic and painful. Offending medica- A 77-year-old African American male tions include tetracyclines, sulfonamides, complained of a sore on his penis for several NSAIDs, anticonvulsants, quinine, and phe- years. The lesion appeared intermittently, nolphthalein.2 Limited anecdotal evidence healed, then recurred, always on the glans. suggests that an FDE may be elicited in an He stated it was irritated by sexual inter- individual after sexual contact with a part- course. Of note, the patient uses a vacuum ner who has taken a sensitizing drug.3 erection device (VED) to achieve tumes- inversus (PI) is the most cence. When present, the lesion lasted two common noninfectious dermatosis occur- to three months. The patient reported an ring on the glans penis. Distribution of PI initial that would subsequently "bust includes intertriginous areas, such as the and stay raw." He stated that the lesion did submammary folds, axillae, gluteal cleft, not but was tender. The patient had and genital region. Examination reveals sampled a variety of creams, none of which erythematous, fissured plaques with clearly gave relief. delineated margins. Lesions may appear Review of systems was non-contribu- macerated, lacking the typical scaling of tory except for osteoarthritis. The patient psoriasis, due to increased moisture content reported taking non-steroidal anti-inflam- of these areas. Microscopically, psoriasis matory drugs (NSAIDs). demonstrates parakeratotic hyperkeratosis, Past medical and surgical history was where cornified cells in the thickened epi- unremarkable except for prostatectomy. Differential Diagnosis dermis retain pyknotic nuclei. The dermis The patient was a non-smoker and non- displays swollen, tortuous capillaries that Fixed drinker, with no known drug allergies. are grossly evident through bleeding when the superficial layer of the plaque is scraped Additionally, the patient provided a Psoriasis inversus away (Auspitz's sign).4 pathology report from a penile biopsy of a Zoon's Zoon's balanitis (ZB) is a rare, idio- similar lesion taken six months prior. The Erythroplasia of Queyrat report described fibrosis involving subcu- pathic dermatosis occurring almost exclu- 5 taneous tissue and corpus spongiosum. It sively in the uncircumcised penis. It characterized the specimen as having mild Syphilitic presents as a mildly pruritic, mildly tender, epithelial and focal dystrophic red-orange plaque on the glans or prepuce. calcifications. Further, the report noted a Histologically, plasma cell infiltration of moderate number of pigmented cells con- Herpes genitalis the dermis attests to ZB's alternate name, plasma cell balanitis. Although calcineurin sistent with either melanophages or hemo- Erosive siderophages. No significant inflammatory inhibitors and carbon dioxide lasers have component was apparent. No dysplasia or et atrophicus been reported as beneficial therapies, cir- malignancy was identified. This original Vacuum-associated penile injury cumcision is usually curative. biopsy was read by a general pathologist. Erythroplasia of Queyrat (EoQ) is Physical examination of the lesion Discussion: Differential in situ (Bow- revealed an erythematous, scaly, eroded Diagnosis en's disease) that presents on the penis. It appears as a glistening, velvety, red plaque plaque of the right penile tip (Figure 1). Fixed drug eruption (FDE) is a spe- The penis was circumcised. Inguinal on the glans, prepuce, or urethral meatus of cial type of drug sensitivity where exposure elderly males. The lesion gradually enlarges lymphadenopathy was not appreciated. The to an inciting medication causes recurrent plaque was moderately tender to palpation. over time. Symptoms include bleeding, lesions at the same location. Any area of pain, and itching. Management of EoQ The initial assessment was chronic skin or mucous membrane may be involved, involves 5-fluorouracil, Mohs micrographic dermatitis. The patient was treated with 1 although the glans penis is a typical site. surgery, or partial . clobetasol 0.05% cream BID for one week. Lesions begin as solitary or multiple dusky- The patient was asked to follow up in one red, demarcated plaques and may become Contact dermatitis occurs after physi- week. If there was no clinical improvement, bullous or erosive. Characteristically, the cal exposure to an irritating or sensitizing another biopsy might have been indicated. affected area appears hyperpigmented after substance. There are several categories of

Greenfield, Dy er 25 common materials that may induce a skin genital region of females ten times as often exposure to a sexually transmitted infec- reaction: metals, such as nickel; preserva- as men.8 Involved areas may appear as tion? Is his partner taking any medications? tives, such as formaldehyde; rubber ingre- ivory-white plaques, indurations overlain What brand of vacuum erection device does dients, such as thiurams; plants, such as with skin that is thin and fragile like tissue he use? How does he use it? Was he cir- poison ivy; or medications, such as topical paper. Purpura and telangiectasia may be cumcised at birth? Late circumcision con- . With regard to the glans penis, associated. When present on the penis, fers risk for balanitis xerotica obliterans. latex condoms and diaphragms are com- LSA is renamed balanitis xerotica obliterans Does he self-administer any medications mon culprits. Clinically, pruritus and (BXO). Lesions of BXO are usually con- or creams before coitus? What medica- edema are significant features of allergic fined to the glans and prepuce. Symptoms tions does he take for osteoarthritis? Does contact dermatitis, and expression of symp- include pruritus, pain, and, in the uncir- the patient take any other over-the-counter toms is especially florid when this entity cumcised male, . Complaints may drugs, prescription medications, or supple- affects the genitalia. be heightened by intercourse. Once irri- ments? Three sexually transmitted infections tated, plaques may erode and heal with con- If the lesion had persisted, a repeat deserve mention. First, a syphilitic chancre traction. BXO occurs most frequently in biopsy would have been necessary, with is the primary manifestation of the disease uncircumcised, middle aged men and shows evaluation by a dermatopathologist. no racial predilection. Potent topical gluco- caused by the spirochete Treponema pal- In general, the goal in this situation lidum. This lesion is described as a pain- corticoid preparations, such as clobetasol, are effective treatments. is to rule out malignancy (erythroplasia of less ulceration with an elevated border and Queyrat), treat infections (syphilitic chan- scanty serous exudate. Discrete, rubbery Vacuum-associated penile injury bears cre, chancroid, and herpes genitalis), avoid lymph nodes may be palpated regionally special consideration in this case. Common inciting substances or scenarios (fixed drug and are commonly unilateral. side effects from VED use include numb- eruption, contact dermatitis, and vacuum- 9 develop around three weeks after inocula- ness, pain, penile bruising, and petechiae. associated penile injury), manage other tion and persist for approximately three Anecdotally, penile hematoma, hyperpig- conditions (psoriasis inversus, Zoon's bala- to six weeks before resolving. Syphilis mentation, and Fournier’s gangrene have nitis, erosive lichen planus, and lichen scle- progresses with serious systemic and neu- been reported. Surprisingly, penile blister rosus et atrophicus), and allay the patient's rologic sequelae, if untreated. Another formation is not a known complication of anxiety. infectious consideration is chancroid, a vacuum therapy in , painful genital caused by Haemophilus although it remains a theoretical concern. References ducreyi. Tender, suppurative lymphadenop- Although VEDs vary considerably among 1. Habif TP. Clinical Dermatology: A Color Guide to Diagnosis and Therapy, 5th Ed. Philadelphia: Mosby, athy occurs in 50% of patients. Chancroid manufacturers, time required to achieve a 2010. is most common among young males in suitable penile erection ranges from 30 sec- 2. Gendernalik SB, Galeckas KJ. Fixed drug eruptions: tropical and subtropical developing coun- onds to 7 minutes at negative pressures of a case report and review of the literature. Cutis. Oct 2009;84:215-219. tries. Finally, herpes genitalis classically 100 to 225 mm Hg. Deliberate induction of 3. Zawar V, Chuh A. may be sexually manifests as grouped vesicles on an ery- suction in vivo takes at minimum 1 induced. Int J Dermatol. Aug 2006;45(8):1003-4; author thematous base. More commonly, though, to 2 hours at negative pressures of 300 mm reply 1004. 10 4. Wolff K, Johnson RA. Fitzpatrick's Color Atlas and it progresses from plaque to vesicles, with Hg. Thus, without gross misuse, VEDs Synopsis of Clinical Dermatology, 5th Ed. New York: erosions and fissuring culminating in ulcer- would seem incapable of generating suction McGraw-Hill, 2005: 56, 134, 556, 898-904, 911, 925, 1038, 1046. ations. These lesions heal in two to four blisters. 5. Mallon E, Hawkins D, Dinneen M, et al. Circumcision weeks. Again, inguinal and femoral lymph and genital dermatoses. Arch Dermatol. 2000;136:350- nodes are usually enlarged and firm. Case Follow-Up 354. 6. Van Dijk F, Thio H, Neumann H. Non-oncological and An inflammatory condition of skin and After one week, the patient returned non-infectious disease of the penis. EAU-EBU Update mucous membranes, typical lichen planus for evaluation. The penile plaque dem- Series. 2006;4(1):13-19. onstrated improvement after applying 7. Moyal-Barracco M, Edwards L. Diagnosis and (LP) presents as pruritic, purple, polygo- therapy of anogenital lichen planus. Dermatol Ther. nal, planar papules. Close inspection of the clobetasol. The patient stated that his 2004;17(1):38-46. papules frequently reveals pathognomonic symptoms were resolving. Re-biopsy was 8. Weller R, Hunter J, Savin J, Dahl M. Clinical Dermatology, 4th Ed. Malden: Blackwell, 2008. Wickham striae, a whitish reticular pattern deemed unnecessary at that time. 9. Yuan J, Hoang AN, et al. Vacuum therapy in that may be better visualized with immer- erectile dysfunction – science and clinical evidence. Conclusion International Journal of Impotence Research. sion in oil. Usual locations of LP include 2010;22:211-219. flexor surfaces of wrists and forearms, shins A recurrent penile plaque in an elderly 10. Gupta S, Kumar B. Suction blister induction time: and ankles, and the lumbar region. Buccal patient warrants a thorough investigation 15 minutes or 150 minutes? Dermatol Surg. Aug 2000;26:8. mucosa is also a site of predilection. One into the differential diagnosis. in four patients with lichen planus displays If the initial assessment and treatment 6 involvement of the male genitalia. Here, had proved inadequate in our case, the LP papules are often nonspecific, less shiny, patient's history would have been re-visited. poorly demarcated, and may instead appear Does he always have sexual intercourse erosive. Erosive LP may mimic FDE, but a with the same partner? Is contraception chronic rather than recurrent course sug- employed, such as condom, sponge, dia- 7 gests the former. Biopsy submission to a phragm, spermicide, or intrauterine device dermatopathologist may be necessary to (IUD)? Contact dermatitis may be impli- yield a definitive diagnosis. cated by accelerators used in latex condom Lichen sclerosus et atrophicus (LSA) manufacture or metallic ions eluted from is a cutaneous disorder affecting the ano- an IUD. Has the patient had any known

26 Plaque of the Glans Penis: Differential Diagnosis Advancement Flap for Distal Nasal Defects

Albert E. Rivera, DO, FAOCD,* Roger I. Ceilley, MD,** Andrew K. Bean, MD,* Joshua B. Wilson, MD*

*Dermatology P.C., West Des Moines, Iowa **University of Iowa Department of Dermatology, Iowa City, Iowa

ABSTRACT: Skin cancers involving the distal one half of the nose are commonly encountered in dermatology. Herein we present an example of a nasal advancement flap to expand the dermatologic surgeon's alternatives for restoring both the aesthetic and functional characteristics of such a surgical site after tumor removal. The following technique provides a simple, single-stage option with a high survival rate that maximizes use of cosmetic unit borders and minimizes functional concerns. Intro deficits, size of the defect, patient comorbidities and Skin cancers involving the distal half prior procedures (or tumors) of the nose are commonly encountered in at or near the same location. dermatology. Herein we present an exam- ple of a nasal advancement flap to expand Surgical Technique the dermatologic surgeon’s alternatives for Figure 1 illustrates a rep- restoring both the aesthetic and functional resentative defect that is well characteristics of such a surgical site after suited for this repair. Figure 2 tumor removal. Mohs micrographic sur- shows the appropriate design. gery is often the treatment option chosen From the most lateral mar- for tumor clearance due to its tissue sparing gin of the defect, an incision properties. Once a tumor is totally resected, down to the subcutaneous tis- the repair of the resulting defect must sue, or submuscularly if the be addressed. Various techniques exist defect allows, is made running depending on the defect location, cosmetic cephalad along the junction concerns, patient tolerance of procedures, of the nasal sidewall and the comorbidities and previous interventions. nasal dorsum. This location Being familiar with the range of reliable allows for camouflage of the repair alternatives is essential. The follow- suture line once healed. At ing technique provides a simple, single- the junction of the nasal dor- stage option with a high survival rate that sum, nasal root and sidewall, maximizes use of cosmetic unit borders and the incision is carried laterally, Figure 1 minimizes functional concerns. again hiding the line within Repair Concerns the cosmetic unit borders. A Figure 2 Burrow’s triangle is taken from There are several factors that deserve this location to allow for the consideration when surgically restoring later caudal advancement. A the functional and cosmetic aspects of a second Burrow’s triangle is patient’s nose. The primary concern is to then removed from the pri- maintain the nasal valve function. Cos- mary defect, contralateral to metically, symmetry is also essential due to the original incision to allow the midfacial location of the nose. Respect optimal approximation of the for the cosmetic units is a key component in original defect. Both pieces achieving an optimal result and minimizing of removed skin are placed in suture line visibility. Sites that are of par- sterile saline should an unex- ticular concern include the nasal tip, nasal pected need for tissue arise. dorsum, bilateral nasal alae, bilateral nasal Extensive undermining of the sidewalls and the soft triangle. Depending entire flap in the subcutane- on patient preference or physician recom- ous or, as allowed, submuscu- mendation, a single- or multi-staged pro- lar plane is then performed. cedure might be favored. If considering a Meticulous hemostasis is graft, the color, adnexae, thickness and skin achieved to ensure prevention quality (ultraviolet exposure or damage) are of hematoma or ecchymoses. variables. Other relevant considerations The cephalad secondary defect include the overall healing time, wound care is closed using subcutaneous required, anatomic variations, functional dissolvable sutures, essentially Rivera, Ceilley, Bean, Wilson 27 Discussion donor defect. In addition, it is a multi- staged procedure and requires additional The described advance- visits and wound care by the patient. ment flap is best suited for Other flaps could be considered. One defects of the distal nose less would include the dorsal nasal rotation than approximately 2 centime- (Hatchet) flap.1 It has excellent survival, ters in diameter. Benefits of but it crosses multiple cosmetic units. The this particular flap variation bilobed flap utilizes similar local tissue but include a robust random vas- can often develop “pincushioning” at the cular supply and thus excellent suture lines. Though more commonly used survival. Also, the incision for alar defects, the nasolabial flap has good lines tend to respect the cos- survival, but it is a multi-staged procedure. metic units, allowing for bet- Island pedicle flaps (unilateral or bilateral) ter cosmetic results, and the have been suggested due to use of adja- local tissue is a superb match cent tissue.2 The Rintala flap is a good skin for color, adnexae and qual- match but is for midline lesions only and ity. It is a favorable option can distally necrose.3 A horizontal advance- to patients since it is a single ment flap is more difficult to utilize for stage procedure. Slight lateral smaller noses or defects that are too far lat- or upward pull can occur, but eral.4 Use of a rhombic flap usually does not it usually returns to baseline utilize the cosmetic units. A less frequently within a few weeks. Overall, encountered option would be the orbicu- Figure 3 it is an easily performed and laris oculi musculocutaneous flap.5 The tolerated procedure with good survival is improved because of the infra- cosmetic and functional out- orbital artery supply, but the multi-staged comes. nature makes it a less attractive option. There are a number of In summary, there are multiple designs other options for repair of to consider when repairing a defect of the the type of lesion discussed. distal nose. Any consideration will have Secondary intention could positive and negative aspects. Our sugges- be considered but is usually tion is a simple, single-stage procedure with reserved for more superficial a high survival rate that maximizes use of defects and primarily on con- cosmetic unit borders and has minimal cos- cave areas rather than convex metic or functional concerns. The addition sites. Primary linear closure of this flap to the dermatologic repair arse- is another proposed option for nal will hopefully expand the possibilities repair of smaller defects. If the and improve outcomes within the appropri- lesion is not centrally located, ate surgical patient population. there can be lateral nasal devi- ation or sometimes alar flar- References ing. Defects of great size that 1. Tremblay JF, Bernstein SC. Hatchet flap. Dermatol are closed primarily can very Surg. 2001 Dec;27(12):1049-51. 2. Papadopoulos DJ, Trinei FA. Superiorly Based commonly result in a “saddle Nasalis Myocutaneous Island Pedicle Flap with Bilevel nose” deformity where the Undermining for Nasal Tip and Supratip Reconstruction. central area of the incision line Dermatol Surg. 1999; 25:530-536. Figure 4 3. Rintala AE, Asko-Seljavaara S. Reconstruction of is depressed. Midline Skin Defects of the Nose. Scandinavian Journal pushing the flap into place. The remainder of Plastic and Reconstructive Surgery and Hand Full thickness grafts may also be uti- of the flap is then sutured subcutaneously Surgery. 1969; 3(2):105-108. lized. Burrow’s grafts tend to match the using careful technique to produce optimal 4. Goldberg LH, Alam M. Horizontal advancement flap local skin more closely but often alter or for symmetric reconstruction of small to medium-sized wound edge eversion and approximation. cutaneous defects of the lateral nasal supratip. J Am cross cosmetic units. The survival rate Acad Dermatol. 2003 Oct;49(4):685-9 Once the flap is in place with minimum is lower because a new, viable blood sup- 5. Cö loğlu H, Koçer U, Kankaya Y, Sungur N, Oruç M. wound edge tension, superficial running ply must develop to sustain the metabolic Lower eyelid orbicularis oculi Musculocutaneous flap for or interrupted sutures are utilized with reconstruction of nasal tip and supratip defects. Plast needs. Grafts from other locations dem- Reconstr Surg. 2006 Jan;117(1):239-46. particular attention to maintaining wound onstrate these same difficulties in addition edge eversion and precise approximation to creating an additional secondary donor (Figure 3). Of course, this flap can also be defect. Also, the thicker sebaceous skin of performed laterally since it is essentially the nose is a difficult match when using a relocation of the excised tissue redun- remote tissue. With delayed grafts, there dancy. Suture removal should be planned is a higher chance of survival and usually a for 5-7 days to allow ample healing time smaller size requirement because of wound while also preventing suture scars from contraction and granulation. It is still bur- prolonged placement. Figure 4 is a three- dened by occasional graft failure, cosmetic month postoperative photo to demonstrate unit disruption, matching difficulty and early results.

28 Advancement Flap for Distal Nasal Defects Amelanotic Spindle Cell Melanoma in a Hispanic Male

Charlotte Noorollah, DO,* Suzanne Friedler, MD,** Marvin Watsky, DO, FAOCD***

*Dermatology Resident, PGY II, St John's Episcopal Hospital South Shore, Far Rockaway, NY **Dermatology Attending, Brookdale Hospital, Jamaica, New York ***Program Director, St John's Episcopal Hospital South Shore, Far Rockaway, NY

ABSTRACT: Spindle cell melanoma is a rare form of melanoma that is locally aggressive and tends to have a high recurrence rate. The clinical appearance can be highly variable and may mimic a variety of lesions. In this case, a Hispanic male presented with a lesion clinically resembling a . The diagnosis of of the spindle cell type was achieved via histopathology and histochemical markers. are less common and often under recognized in patients of color. This case demonstrates the need to maintain a high index of suspicion for melanoma even in non-pigmented lesions and especially in patients of color. mon variant of melanoma that is Case Presentation locally aggressive and tends to have a An 83-year-old Hispanic male high recurrence rate even with treat- from the Dominican Republic pre- ment. , neu- sented with the chief complaint of a rotropic melanoma, and spindle cell growth on his face for approximately melanoma form a continuum without 5-6 months. His past medical his- a discrete separation, and the terms tory was significant for hypertension are often used interchangeably. The and cancer. Review of sys- terms are more histologically rather tems was non-contributory; the patient than clinically defined.1 Desmoplastic denied pain, neuropathy, and bleeding melanoma accounts for 1-5% of all or constitutional symptoms. He was cases of melanoma reported.2,3 not on any medications and had no This form of melanoma has a pre- known drug allergies. Family history dilection for sun-exposed areas such as was non-contributory, and he denied Figure 1: Pictures taken after incisional biopsy. Ery- the head and neck region and mainly smoking or alcohol use. Physical thematous nodule with rolled border, telangectasias affects elderly males. Lesions usu- examination revealed a 2 x 2 cm ery- and a central keratotoic plug. ally present as firm, fibrous masses of thematous nodule with rolled border, tumor and vary in color from amela- telangectasias and a central keratotic notic to brown-black. The clinical plug (Figure 1). An incisional biopsy appearance of this type of melanoma was performed with clinical suspi- is highly variable, making the initial cion of keratoacanthoma verses squa- diagnosis difficult. In a clinicopatho- mous cell carcinoma. Histopathology logic analysis of 113 cases of desmo- showed a tumor comprised of a highly plastic malignant melanoma, 71% of cellular proliferation of plump spindle cases were histologically amelanotic.4 cells arranged in nests, intersecting Lesions can develop de novo or in fascicles and confluent sheets. Cells pre-existing nevi. When arising de had large, hyperchromatic nuclei with novo, they can appear as flesh-colored, frequent mitoses present. The adja- indurated, papules, plaques or nod- cent dermis had severe actinic elasto- ules with pigmentation usually being sis, and there was no pigment absent; when present, pigment is usu- present (Figure 2). The tumor cells Figure 2: Highly cellular proliferation of plump spin- ally sparse or irregularly distributed.5 were strongly and diffusely positive dle cells arranged in nests, intersecting fascicles and A lesion may arise in conjunction with for S100 protein and vimentin, and confluent sheets. Cells have large, hyperchromatic a maligna, further suggesting negative for specific melanoma mark- nuclei with frequent mitoses present. Severe actinic a link to sun-exposure. When found ers HMB 45 and MelanA. There was elastosis is present in the adjacent dermis without in association with another cancer, it strong reactivity with CD68, a mac- presence of melanin pigment. Staining diffusely for usually exhibits the characteristics of rophage marker, and neuron specific S100. that cancer, so presentation may vary enolase, which can label melanomas from a basal cell carcinoma to a squamous as well as other neural crest tumors. closed with a rotational Z plasty flap. Final cell carcinoma, keratoacanthoma, dermato- Histochemical staining in addition to histo- diagnosis of the specimen revealed a Bres- , or a plaque resembling a pathology allowed us to make the diagnosis low’s depth of 6.35 mm with a Clark’s level scar.6 When there is clinical suspicion of a of spindle cell melanoma. The patient was of V and a mitotic count of 12 per mm2. , palpation of the lesion may referred for immediate surgical excision and Blood vessel, lymphatic and neural invasion reveal a dermal component or area of indu- metastatic workup. ACT PET scan showed were not identified; however, ulceration was ration and should heighten the clinician’s no evidence of metastatic disease, and labs present and measured greater than 1 centi- suspicion of a spindle cell melanoma. These including complete blood count, compre- meter. types of melanoma may be more symptom- hensive metabolic panel and lactate dehy- Discussion atic, as there may be secondary perineural drogenase were all within normal limits. invasion. The mass was excised, and the defect was Spindle cell melanoma is an uncom- Noorollah, Friedler, Watsky 29 Histologically, lesions are usually large, local recurrence. In a study of 49 patients Conclusion poorly circumscribed and can extend to with desmoplastic melanomas of the head the subcutaneous tissue, fascia and nerves.6 and neck, the local recurrence rate was 4% Spindle cell melanomas are frequently Desmoplastic melanomas show a lentigi- (2 of 49 patients). Surgical margins greater mistaken for a non-melanocytic prolifera- nous melanocytic proliferation with atypia than or equal to 2cm were obtained for head tion; diagnosis is often delayed, and pre- and pleomorphic spindle cells in the der- and neck lesions that measured > 1mm in sentation at an advanced stage is quite mis.7 There are dermal and/or subcutaneous depth. In this study, wide excision alone common.4 This case demonstrates the need infiltrates of spindle-shaped cells arranged was found to produce excellent results with- to maintain a high index of suspicion for in fascicles or singly within a prominent out the need for adjuvant radiation.14 melanoma even in non-pigmented lesions 6 and especially in patients of color, in whom collagenous or mixoid stroma. There is Desmoplastic melanoma is locally melanoma is less common. This diagnosis variability among tumors classified as des- aggressive and often has an advanced Bre- should be kept in mind when faced with moplastic melanomas. Desmoplasia can be slow’s thickness at the time of presenta- suspicious growths particularly in patients prominent throughout the entire tumor, tion, possibly due to late diagnosis. These with a history of excessive sun exposure. classified as a “pure” desmoplastic mela- tumors carry a high risk of local recurrence, Perhaps better education of patients of noma, or it can represent a portion of a while the incidence of distant metastasis is lower socioeconomic status is needed to aid nondesmoplastic melanoma, referred to as a low. Desmoplastic neurotropic melanomas in diagnosis of melanoma in the non-white “combined” desmoplastic melanoma. Some present at a more advanced stage locally population. tumors have prominent nerve involvement, and may be associated with a better survival in which case they are termed desmoplastic than other forms of non-desmoplastic mela- References neurotropic melanomas.8 nomas of equal Breslow’s depth of invasion. 1. Bolognia JL, Jorizzo JL. Dermatology. 2nd ed. Vol. 2. Immunohistochemical staining In an analysis of 28 cases of desmoplastic [S.l.]: Mosby becomes important in these cases. S100 is melanoma by Carlson et al., actual 5-year 2. Elsevier, 2008. Print. a reliable marker with high sensitivity for survival for tumors greater than 4mm thick- 3. Chang P, Fischbein N, Mccalmont T. "Perineural Spread of Malignant Melanoma of the Head and Neck: identifying spindle cell melanomas and is ness was 72%, which was greater than that Clinical and Imaging Features." American Journal of often positive; however, its usefulness is for other types of melanoma with greater Ophthalmology 137.6 (2004): 1173-174. limited by its low specificity. Newer studies than 4mm thickness.15 Although this par- 4. Busam KJ, Zhao H, Coit DG. "Distinction of Desmoplastic Melanoma from Non-Desmoplastic reveal that p75 nerve growth factor receptor ticular type of melanoma does portend a Melanoma by Gene Expression Profiling." Journal of staining could prove beneficial in cases of better prognosis, it can be fatal if local inva- Investigative Dermatology 124.2 (2005): 412-19. S100-negative desmoplastic or neurotropic sion is deep enough. 5. De Almeida LS, Requena L, Rutten A. "Desmoplastic Malignant Melanoma: A Clinicopathologic Analysis of melanomas and should be used as well to As with all types of melanoma, close 113 Cases." Am J Dermatopathol 30.3 (2008): 207-15. increase diagnostic sensitivity. P75 nerve follow-up is recommended. The rate of 6. Mihm MC Jr. Desmoplastic Melanoma. Massachusetts growth factor receptor is a member of the General Hospital, Harvard Medical School, 01 May local recurrence is higher with incomplete 2000. Web. . tumor necrosis family and is one of the ear- excision of the primary lesion, greater 7. Lens MB. "Desmoplastic Malignant Melanoma: A liest markers expressed by cells of the neu- tumor thickness, and the presence of neu- Systematic Review." The British Journal of Dermatology 9 ral crest. Staining for HMB-45, a marker rotropism.6 152.4 (2005): 673-78. Medscape. for premelanosomes and a more specific 8. www.medscape.com/viewarticle/503442 marker for melanoma, is often absent; how- This particular type of tumor should be 9. Tsao H, Sober AJ, Barnhill RL. "Desmoplastic considered when faced with an elderly indi- Neurotropic Melanoma." Semin Cutan Med Surg 16.2 ever, when present, tumors tend to have (1997): 131-36. 10,11,12 vidual who presents with a tumor arising in more aggressive behavior. CD 68, a 10. Busam KJ. "Cutaneous Desmoplastic Melanoma." Adv macrophage maker, has been demonstrated a background of sun-damaged skin. Mela- Anat Pathol 12.2 (2005): 92-102. in a minority of cases and was positive in nomas are less common in people of color 11. Lazova R, Tantcheva-Poor I, Sigal AC. "P75 Nerve 5 when compared with Caucasians. Melano- Growth Factor Receptor Staining Is Superior to S100 in the case described. The tumor cells are Identifying Spindle Cell and Desmoplastic Melanoma." positive for vimentin in all cases and for mas are also under-recognized in patients Journal of the American Academy of Dermatology 63.5 (2010): 852-58. neuron-specific enolase in about 95% of of color and often do not present the same 12 way they would in Caucasian populations. 12. Skelton H, et al. "Desmoplastic Malignant Melanoma." cases. Journal of the American Academy of Dermatology 32.5 Age adjusted incidence rates, per 100,000, (1995): 717-25. As with most forms of melanoma, sur- for melanoma in Hispanics, Blacks and 13. Kanik AB, Yaar M, Bhawan J. "P75 Nerve Growth gery is the first line of treatment as this non-Hispanics are approximately 4.5, 1.0, Factor Receptor Staining Helps Identify Desmoplastic tumor is both highly infiltrative and locally 16 and Neurotropic Melanoma." Journal of Cutaneous and 21.6, respectively. Skin cancers in skin Pathology 23.3 (1996): 205-10. UK Pubmed Central. aggressive. Optimal margins for exci- of color often present at a more advanced 14. "Desmoplastic/Spindle Cell/Neurotropic Melanoma." sion have not been established owing to stage. This may be attributed to socioeco- Histopathology-India.net. Web. 01 Feb. 2011. . the smaller number of reported cases as nomic factors including less frequent medi- compared with other types of melanoma. 15. Su L, Fullen DR, Lowe L. "Desmoplastic and cal visits, screening programs Neurotropic Melanoma." Cancer 100.3 (2004): 598-604. Metastasis to regional lymph nodes is and less skin cancer prevention education in 16. Arora A, Lowe L, Su L. "Wide Excision without Radiation uncommon, and elective lymph node dis- Hispanics, blacks and Asians.17 Pollitt et al. for Desmoplastic Melanoma." Cancer 104.7 (2005): 1462-467. section is not usually indicated. However, examined data for Hispanic and non-His- sentinel lymph node biopsy (SLNB) can 17. Carlson JA, Dickersin, GR, Sober AJ, Barnhill panic white patients who were diagnosed RL. "Desmoplastic Neurotropic Melanoma. A be used to detect subclinical metastases to with invasive cutaneous melanoma from Clinicopathologic Analysis of 28 Cases." Cancer 75.2 (1995): 478-94. regional lymph nodes. Su et al. examined 1988 to 2007 in California and found that 33 patients with desmoplastic and neuro- 18. Rouhani P, Hu S, Kirsner RS. "Melanoma in Hispanic tumor thickness at diagnosis was higher in and Black Americans." Cancer Control 15.3 (2008):248- tropic melanoma without clinical evidence Hispanics, and that lower socioeconomic 53. of metastatic disease who underwent senti- status was associated with thicker tumors.18 19. Bradford PT. “Skin Cancer in skin of Color.” Dermatol Nurse. (2009):170-7. nel lymph node biopsy; 4 of the 33 patients Specific epidemiologic data on incidence of had at least one positive sentinel lymph 20. Pollitt RA, Clarke CA, Swetter SM. "The Expanding melanoma in non-whites is limited, neces- Melanoma Burden in California Hispanics: Importance 13 node. Some authors recommend adjuvant sitating the need for further awareness and of Socioeconomic Distribution, Histologic Subtype, and Anatomic Location." Cancer 1st ser. 1.117 (2011):152- post-operative radiation therapy to control patient education. 61. v

30 Amelanotic Spindle Cell Melanoma in a Hispanic Male Cutis Marmorata Telangiectatica Congenita: A Case Report and Discussion

Mari M. Batta, DO,* Brandon G. Shutty, BS,** Stephen Kessler, DO,*** Ronald C. Hansen, MD****

* Dermatology Resident, 1st year, Alta Dermatology / LECOMT, Mesa, AZ; Scottsdale Healthcare System – Osborn Campus, Scottsdale, AZ ** Medical Student, 4th year, Lake Erie College of Osteopathic Medicine, Bradenton, FL *** Program Director, Alta Dermatology / LECOMT, Mesa, AZ; Scottsdale Healthcare System – Osborn Campus, Scottsdale, AZ **** Pediatric Dermatologist, Phoenix Children’s Hospital, Phoenix, AZ

ABSTRACT: Persistent cutis marmorata and phlebectasia presenting at birth describe cutis marmorata telangiectatica congenita (CMTC). The etiology is unknown for this uncommon disorder. Associated anomalies are numerous and may include limb asymmetry, port wine stains, as well as glaucoma. The differential diagnosis includes physiologic cutis marmorata, capillary malformations, as well as vascular defects. The diagnosis is primarily ascertained clinically. Management involves careful evaluation for associated disorders, supportive care, and routine follow-up visits at least until age 3. This article presents a case of a young boy diagnosed with extensive cutis marmorata telangiectatica congenita. Following is a discussion including the hypothesized pathogenesis, clinical findings, potential associated abnormalities, differential diagnoses as well as management of CMTC. Case Report A 12-month-old Caucasian male was born full-term via Caesarian section at 39 weeks gestation without complications. At birth, he was sent to the neonatal intensive care unit for evaluation of a “skin condi- tion” described as “diffuse ecchymosis” and areas of “skin necrosis.” Upon examination by hematology, the patient was thought to have protein C/S deficiency, and a dissemi- nated intravascular coagulation panel was ordered. The patient was started on fresh frozen plasma pending work-up, as well as ampicillin and gentamicin due to suspected sepsis. Dermatology was consulted on day 4 of life. Physical exam revealed numer- ous reticulate purpuric plaques with cen- tral depression noted over the right upper extremity, trunk, left lower back, and bilat- Figure 1: Reticulated purpuric plaques with central depression over chest, right arm and eral lower extremities (Figures 1-3). Sub- left leg. cutaneous tissue was diminished over the right arm and leg, and erosions were noted within the purpuric areas. Faint linear purpura was noted over the forehead and cheeks. Skin biopsy was not performed, and the laboratory results from earlier work-up were non-contributory. He did not have protein C/S deficiency. Based on the history and physical exam, the diagnosis of cutis marmorata telangiectatica congenita was established and supportive treatment instituted. For eroded areas, petroleum jelly and hydrocol- Figure 2: Reticulated purpuric plaques Figure 3: Diminished subcutaneous tissue loid dressings were applied, with healing with central depression over back. within purpuric areas. occurring over the following months. At 12 months of age, the patient continues to by Maarten van Lohuizen, a Dutch pedia- sporadic condition, although there are case show improvement with fading of the mar- trician. It is a relatively uncommon con- reports of familial associations, suggesting morated plaques. genital characterized a possible genetic link.4 The pathogenesis by persistent cutis marmorata along with is unknown; however, hypotheses regard- Discussion variable presence of telangiectasia, phle- ing its etiology include genetic mosaicism, Cutis marmorata telangiectatica con- bectasia, cutaneous atrophy and ulcer- peripheral neural dysfunction, or an envi- genita (CMTC) was first described in 1922 ation.1,2,3 It is generally recognized as a ronmental teratogenic agent.3, 5 There does Batta, Shutty, Kessler, Hansen 31 not appear to be any gender predilection.3 heimer syndrome presents in infancy and able presence of cutaneous atrophy, tel- 2 Greater than 90% of patients present progresses to diffuse painful phlebectasia. angiectasias and ulcerations. Associated at birth with reticulated blue-violet to red Capillary malformations, such as port wine abnormalities may affect cutaneous, ocular, stains, may present in a reticulated pattern neurologic, musculoskeletal, hematologic, patches, but lesions can appear anywhere from 3 months to 2 years after birth.3 The and be localized and unilateral without gastrointestinal or genitourinary systems. livedo reticularis-like pattern preferen- crossing the midline; however, they are not The differential includes physiologic cutis associated with atrophy and do not fade marmorata, capillary malformations such tially affects the extremities (in particu- 7 lar the legs), followed by the trunk and with time. Klippel-Trenaunay syndrome as port-wine stains, vascular defects such as face.2,3 Although the sharply demarcated presents with port wine stains, prominent Klippel-Trenaunay syndrome, and CMTC- varicosities, and bony or soft-tissue hyper- inclusive syndromes such as Adams-Oliver reticular erythema can be generalized, it 2 is more commonly localized, unilateral, trophy. There is a questionable association syndrome. This entity carries a good prog- and does not appear to cross the midline.2,3 between CMTC and neonatal lupus erythe- nosis and usually resolves within the first The lesions are relatively fixed, and while matosus, wherein CMTC affects bilateral two years of life. more prominent with cooling and crying, extremities symmetrically and the infant References has the presence of anti-Ro antibodies, sug- the mottling does not resolve with warm- 1. Van Lohuizen CHJ. Uber eine seltene angerborene 6 gesting that CMTC may be a part of the ing of the skin. These major features are Haut-anomalie [Cutis marmorata telangiectatica 11,12 congenital]. Acta Derm Venereol. 1922;3:202-11. often accompanied by focal areas of atrophy cutaneous spectrum of neonatal lupus. Finally, macrocephaly-cutis marmorata syn- 2. Kienast AK, Hoeger PH. Cutis marmorata telangiectatica within the reticulated bands, resulting in congenita: a prospective study of 27 cases and review limb circumference discrepancy as well as drome (previously known as macroceph- of literature with proposal of diagnostic criteria. Clin Esp Dermatol. 2009;34:319-23. varying degrees of vein prominence, telan- aly-CMTC syndrome) must be considered 3. Amitai DB, Fichman S, Merlob P, Morad Y, Lapidoth M, 7,8 when there is concomitant macrocephaly, giectasia, and ulceration. Metzker A. Cutis marmorata telangiectatica congenita: as these patients are at significant risk for clinical findings in 85 patients. Pediatr Dermatol. 2000 The rate of associated anomalies, neurologic abnormalities.12 While initially Mar-Apr;17(2):100-4. both cutaneous and extracutaneous, range believed to be associated with CMTC, this 4. Pehr K, Moroz B. Cutis marmorata telangiectatica 7 congenital: long-term follow-up, review of literature from 20-80%. The large discrepancy in syndrome, which presents with neonatal and report of a case in conjunction with congenital hypothyroidism. Pediatr Dermatol. 1993 Mar;10(1):6-11. reported rates may be due to an overestima- hypotonia, developmental delay, segmen- tion from purely coincidental findings.3,9 5. Rogers M, Peyzer KG. Cutis marmorata telangiectatica tal overgrowth, syndactyly and connective congenita. Arch Dermatol. 1982;118:895-899. The most common finding associated with tissue defects, is in fact associated with a 6. Kapoor S. Systemic abnormalities associated with cutis CMTC is body asymmetry, with limb hypo- capillary malformation or persistent nevus marmorata telangiectatica congenita. Hong Kong Med J. 2008 Feb;14(1):490-492. or hyperplasia confined to areas affected simplex.7,9,11,14 7. Levy R, Lam JM. Cutis marmorata telangiectatica by CMTC, often with overlying cutane- congenita: a mimicker of a common disorder. Can Med 2 Diagnosis of CMTC is primarily clini- ous atrophy. Also commonly seen are Assoc J. 2011 Mar 8;183(4):E249-51. cal. Although a biopsy may be performed, vascular anomalies, including port wine 8. Way BH, Herrmann J, Gilbert EF, Johnson SA, Opitz the histopathologic findings are generally JM. Cutis marmorata telangiectatica congenita. J Cutan stains, and . Pathol. 1974;1:10–25. non-specific, revealing dilated capillaries Although not exhaustive, other associa- 9. Garzon MC, Schweiger E. Cutis marmorata tions include underlying musculoskeletal in the deep dermis with hyperplasia and telangiectatica congenital. Semin Cutan Med Surg. 2004 3 Jun;23(2):99-106. defects (e.g., syndactyly, tendinitis steno- swollen endothelial cells. Performing a careful clinical examination is important to 10. Gonzalez ME, Burk CJ, Barouth DS, Connelly EA. sans, hip dysplasia, clubfoot, cleft palate), Macrocephaly-capillary malformation: a report of exclude possible associations. Along with three cases and review of literature. Pediatr Dermatol. ocular malformations (glaucoma, especially 2009;26:342-6. in association with facial lesions), neuro- a thorough medical history and cutaneous exam, the musculoskeletal system should be 11. Dar NR, Ghafoor T, Awan Z. Cutis marmorata logic anomalies (e.g., macrocephaly, mental telangiectatica congenita. JCPSP 2003;13(11):653-655. retardation, seizures), and cardiovascular, evaluated for body asymmetry, such as limb 12. Heughan CE, Kanigsberg N. Cutis marmorata hypoplasia.2 When the head is affected, telangiectatica congenita and neonatal lupus. Pediatr gastrointestinal and genitourinary abnor- Dermatol. 2007 Mar-Jun;24(3):320-1. 3,4,10,11 both an ophthalmologic and neurologic malities. There does not seem to be 13. Dadzie OE, Tyszczuk L, Holder SE, Teixeira, Charakida any correlation between the severity or examination must be performed to assess A, Scarisbrick J, Chu A. Adams-Oliver syndrome for glaucoma, head circumference, and with widespread CMTC and fatal pulmonary vascular disease. Pediatr Dermatol. 2007 Nov-Dec;24(6):651-3. extent of skin lesions and the presence of 7 12 developmental delays. associated anomalies. Of note, a finding 14. Write DR, Frieden IJ, Orlow S, et al. The misnomer “macrocephaly-cutis marmorata telangiectatica seen in many patients with Adams-Oliver Limb asymmetry, if present, tends to congenita syndrome”: report of 12 new cases and syndrome is CMTC. These patients present persist; however, in approximately 50% of support for revising the name to macrocephaly-capillary malformations. Arch Dermatol. 2009;145:287-293. with generalized CMTC, heart anomalies, cases, the reticular pattern remits by the limb defects, and calvarium malformations.9 second year of life, conferring a favorable 3,7 The differential diagnosis is extensive prognosis. Thus, treatment is primar- and must be differentiated from other retic- ily supportive, including wound care reg- ulated vascular lesions. Physiologic cutis imens for ulcerations and consideration of the pulsed-dye laser for persistent marmorata, a common benign neonatal 9 response to cooling, can be differentiated lesions. Patients should be seen annually from CMTC by the finer reticulated pattern, for a minimum of three years, and long- term follow-up is indicated with associated resolution with heat application as well as 2 lack of atrophy and ulceration.3,6,9 Physi- abnormalities. ologic cutis marmorata, when persistent, Conclusion often co-exists with genetic syndromes, including Down syndrome, Cornelia de CMTC is a rare congenital vascular Lange syndrome, homocystinuria, and anomaly characterized by persistent cutis Divry-Van Bogaert syndrome.9 Bocken- marmorata and phlebectasia, with vari-

32 Cutis Marmorata Telangiectatica Congenita: A Case Report and Discussion A Suspicious Lesion Arising in a 28-Year-Old Female After Administration of Melanotan II

Daniel Child, BS,* Paul Aanderud, DO,** Steven Grekin, DO, FAOCD***

* Third-year Medical Student, ATSU/KCOM, Kirksville, Missouri ** Second-year Dermatology Resident, Oakwood Southshore Medical Center, Trenton, Michigan ***Program Director, Oakwood Southshore Medical Center Dermatology Residency Program, Trenton, Michigan

ABSTRACT: Melanotan I and Melanotan II are synthetic peptides analogous to naturally occurring alpha stimulating horomone (α-MSH). Despite potential benefits of these peptides with tanning and treatment of erectile dysfunction, the safety of such drugs has been questioned. We present a case of a 28 year-old female with history of frequent tanning and Melanotan II use that presented to our clinic with multiple irregularly hyperpigmented papules and plaques on her abdomen, back, chest, and breasts. Case Report every cutaneous cell type and is the target of the synthetic analogues Melanotan I and II. Its activa- A 28-year-old Caucasian female with no his- tion leads to increased melanogenesis and pig- tory of previous dysplastic nevi presented to our mentation of the skin.4 This receptor has also been clinic with a suspicious lesion on her abdomen. found to be over-expressed in melanoma.5 The patient noticed the lesion began to enlarge, but denied any change in color or bleeding. Inter- Despite the initial belief that Melanotan estingly, she had a history of subcutaneous injec- actually had a protective role, inhibiting mela- tion of Melanotan II, an analog of α-MSH, which noma cell proliferation by reducing cell migration she purchased without prescription from an Inter- and invasion, evidence exists that may contradict net web site. Over a period of five months, she Figure 1 the initial findings. α-MSH not only has been injected doses of Melanotan II to increase her tan shown to have direct stimulatory effects on mela- and improve her sexual performance. She initially noma cells by inducing change in cell shape and injected the substance every other day during a increased dendrigicity,6 but it also down-regulates loading phase and then subsequently every other adhesion molecules that would normally allow week for a maintenance phase. She also visited the interaction of the immune cells with melanoma. tanning salon every five days to accelerate her tan. This interaction may allow melanoma to escape During the months following the injections, she immune detection and increase its survival.7 experienced marked darkening of her skin tone, Studies have also suggested a decreased level of ephelides, and nevi. The patient also reported α-MSH is actually a good prognostic factor for a long history of visiting tanning salons with an response to immunotherapy of melanoma. estimation of biweekly visits over a 10-year period. Recent reports of the appearance of atypical Figure 2 A review of systems was negative for preceding nevi and changing of appearance of pre-existing illness, recent weight loss, or constitutional symp- Course And Therapy nevi in Melanotan users has called into question toms. the safety of such drugs. One case of melanoma Examination This patient returned to our clinic for exci- has been reported in a Melanotan user but with sion of her lesion and has remained free from any no clear evidence of the causative factor.8 Cau- Physical examination revealed a well- sign of recurrence for two months. She continues tion should be taken in pursuing the use of these appearing patient with a darkened skin tone and to get full-body skin checks every three months, potent melanocortins due to the possible serious multiple irregularly hyperpigmented papules and and has stopped the self-administration of Mela- unknown risks associated with them. plaques on her abdomen, back, chest, and breasts, notan II and the practice of tanning. ranging in size from 0.5 to 1.5 cm. Axillary and Discussion References inguinal lymph nodes were palpated and were not 1. Hadley ME, Dorr RT. Melanocortin peptide therapeutics: enlarged. On the left lower abdomen was a 1.2 The synthetic peptides known as Melanotan historical milestones, clinical studies and commercialization. cm hyperpigmented, multicolored plaque with I and Melanotan II are analogues of the naturally Peptides 2006; 27(4):921-930 2. Dorr RT, Lines R, Levine N, et al. Evaluation of melanotan-II, irregular borders. occurring alpha melanocyte stimulating hormone a superpotent cyclic melanotropic peptide in a pilot phase-I Histopathology (α-MSH). These peptides are up to 1,000 times clinical study. Life Sci 1996; 58(20):1777-1784. more potent than their endogenous counterpart.1 3. Dorr RT, Dvorakova K, Brooks C, et al. Increased eumelanin A biopsy of the patient’s left lower abdomi- expression and tanning is induced by a superpotent Initial clinical trials confirmed the assumed effects melanotropin [Nle4-D-Phe7]-α-MSH in humans. Photochem nal lesion was sent to a dermatopathologist for of these peptides on the tanning of the skin (Mela- Photobiol 2000; 72(4):526-532. interpretation. According to the pathology report, notan I) and the treatment of male erectile dys- 4. Virador VM, Muller J, Wu X, et al. Influence of α-melanocyte- the results displayed superficial spreading malig- 2,3 stimulating hormone and ultraviolet radiation on the transfer function (Melanotan II). The potential benefits of melanosomes to keratinocytes. FASEB J. 2002; 16(1):105- nant melanoma, Clark’s level II. Both peripheral of such drugs have caused an increase in the use 107. and deep margins were involved. Microscopic of unlicensed melanotropic hormones, further 5. Raposinho PD, Xavier C, Correia JD, et al. Melanoma findings showed atypical disposed targeting with alpha-melanocyte stimulating hormone analogs complicating the presentation and diagnosis of labeled with fac- [99mTv(CO)3]+: effect of cyclization on as solitary units and in nests unevenly distrib- pigmented lesions. tumor-seeking properties. J Biol Inorg Chem 2008; 13:449-59. uted within the epidermis and extending into the 6. Thody AJ. A-MSH and the regulation of melanocyte function. upper dermis. Single cells in a pagetoid array were α-MSH is the most potent of the melano- Ann N Y Acad Sci. 1999; 885: 217-229. found in the upper layers of the epidermis as well. tropic hormones. Produced by an array of cells 7. Hedley SJ, Murray A, Sisley K, et al. Alpha-Melanocyte found in the body, including keratinocytes, it acts stimulating hormone can reduce T-cell interaction with Melanocytes did not mature with progressive melanoma cells in vitro. Melanoma Res. 2000; 10(4):323-330. through activation of the melanocortin receptors.4 descent into the dermis, and melanophages were 8. Ellis R, Kirkham N, Seukeran D. Malignant melanoma in a noted in the superficial dermis (Figures 1 & 2). Melanocortin 1 receptor is present in virtually user of melanotan I [E-Letter publication]. Br Med J 2009.

Child, Aanderud, Grekin 33 Herpes Simplex Vegetans: An Uncommon Presentation in Human Immunodeficiency Virus Infection

Theresa Cao, DO,* Angela Combs, DO,** Tracy Favreau, DO,*** David Droller, MD,**** Eli Piatigorsky, MD*****

* Third-year Dermatology Resident, Nova Southeastern University/Broward General Medical Center Dermatology Residency, Fort Lauderdale, FL ** Assistant Clinical Professor, Nova Southeastern University/Broward General Medical Center Dermatology Residency, Fort Lauderdale, FL *** Assistant Program Director, Nova Southeastern University/Broward General Medical Center Dermatology Residency, Fort Lauderdale, FL **** Infectious Disease Specialist, Broward General Medical Center, Fort Lauderdale, FL ***** Dermatopathologist, Associate Clinical Professor, Nova Southeastern University/Broward General Medical Center Dermatology Residency, Fort Lauderdale, FL

ABSTRACT: Herpes infections in immunocompromised individuals can demonstrate unusual clinical presentations. Herpes vegetans is an uncommon manifestation of herpes simplex infection that presents as an exophytic mass mimicking a large verrucous tumor or alignancy. We report a case of herpes simplex vegetans in a 54-year-old human immunodeficiency virus (HIV)-positive man caused by both herpes simplex virus (HSV) types 1 and 2. Figure 1: Round, 4 cm x 4 cm x 1 cm, exophytic, pink and flesh-col- ored, nontender, partially-erosive, papillomatous tumor on the left lower buttock with serous drainage.

Figure 2: H&E. At low power there is pseudoepitheliomatous hyperplasia with erosions. In the dermis there is a dense, mixed inflammatory infiltrate and numer- ous dilated papillary dermal vessels. (Orig- inal magnification 40x) Case Report diagnosis of herpes simplex vegetans with herpes simplex virus immunoperoxidase A 54-year-old Haitian man with HIV studies demonstrating both HSV-1 and infection diagnosed two years prior pre- HSV-2 infections (Figures 2-5). Other lab- sented with an asymptomatic, oozing oratory data included CD4 count of 382, growth on the left buttock present for at HIV viral load undetectable at less than least six months. He had been treated by his 48 copies/mL, non-reactive rapid plasma primary care physician with oral antibiotics reagin (RPR), and unremarkable complete without improvement. The patient had no blood count, comprehensive metabolic other relevant past medical or family his- panel and urinalysis. Recommended treat- tory. He was married and denied tobacco, ment was destruction or surgical debulking alcohol, or recreational drug use. He had of the mass combined with long-term oral no known drug allergies. His medications antiviral therapy and continued control of included darunavir 600 mg twice daily, rito- underlying HIV infection with highly active Figure 3: H&E. At high power there is navir 100 mg twice daily, emtricitabine/ antiretroviral therapy (HAART) as managed a dense mixed inflammatory infiltrate tenofovir 200/300 mg daily, and a multivi- by infectious disease team. consisting of neutrophils, lymphocytes, tamin daily, with which he was compliant. eosinophils, histiocytes, and plasma cells Review of systems was negative for fever, Discussion as well as viropathic changes including multinucleated giant cells, nuclear mold- chills, night sweats, or weight loss. Herpes virus infections can present ing, and margination of chromatin. (Origi- in unusual ways in immunocompromised Physical examination revealed a well- nal magnification 400x) developed, well-nourished black man in individuals, such as chronic ulcerations no acute distress. Skin exam revealed a or erosions, hyperkeratotic lesions, or in round, 4 cm x 4 cm x 1 cm, exophytic, pink non-traditional locations.1 There have been 2-5 and flesh-colored, nontender, partially- few reports of herpes vegetans in the lit- cutaneous lymphoid leukemia. Unlike erosive, papillomatous tumor on the left erature, with cases associated with HIV, conventional genital herpes infections that lower buttock with mild serous drainage B-cell chronic lymphocytic leukemia, com- present with painful grouped vesicles on an (Figure. 1). There was no inguinal lymph- mon variable immunodeficiency, congeni- erythematous base, herpes vegetans pres- adenopathy. A skin biopsy confirmed a tal T-cell immunodeficiency, and chronic ents as an exophytic, proliferative lesion that

34 Herpes Simplex Vegetans: An Uncommon Presentation in Human Immunodeficiency Virus Infection Figure 4: HSV-1 immunoperoxidase study highlighting infected keratinocytes. (Orig- inal magnification 400x)

Figure 5: HSV-2 immunoperoxidase study highlighting infected keratinocytes. (Orig- inal magnification 400x)

resembles a verrucous or malignant growth, lymphocytic leukemia. J Dtsch Dermatol Ges. 2008 Oct;6(10):865-7. Epub 2008 May 21. most often found on the digits, genitalia, 4. Beasley KL, Cooley GE, Kao GF, Lowitt MH, Burnett 1 or perioral skin. The differential diagnosis JW, Aurelian L. Herpes simplex vegetans: atypical genital herpes infection in a patient with common may include squamous cell carcinoma, giant variable immunodeficiency. J Am Acad Dermatol. 1997 condyloma of Buschke-Lowenstein vari- Nov;37(5 Pt 2):860-3. ant of verrucous carcinoma, or 5. Meunier L, Guillot B, Lavabre-Bertrand T, Barnéon G, Izarn P, Meynadier J. Chronic herpes of the vegetans. pyodermatitis vegetans type in chronic cutaneous lymphoid leukemia. [French]. Ann Dermatol Venereol. Histopathology of herpes vegetans may 1986;113(12):1199-204. show a hyperproliferative epithelium with 6. Abbo L, Vincek V, Dickinson G, Shrestha N, Doblecki S, ulceration, virocytopathic changes at the Haslett PA. Selective defect in plasmacytoid dendritic cell function in a patient with AIDS-associated atypical periphery including multinucleated giant genital herpes simplex vegetans treated with imiquimod. Clin Infect Dis. 2007 Feb 1;44(3):e25-7. Epub 2006 cells, and a dense mixed inflammatory infil- Dec 29. trate of neutrophils, eosinophils, lympho- 7. Patel P, Bush T, Mayer KH, Desai S, Henry K, Overton cytes, histiocytes, and plasma cells.1 The ET, Conley L, Hammer J, Brooks JT. Prevalence and risk factors associated with herpes simplex virus-2 presence of eosinophils may be secondary infection in a contemporary cohort of HIV-infected to the TH2 cytokine response character- persons in the United States. Sex Transm Dis. 2012 Feb;39(2):154-60. istic of advanced HIV disease.6 Although the exact pathogenesis of these lesions is unknown, the hypothesized mechanisms include immune dysregulation related to concomitant HSV and HIV as well as immune reconstitution following HAART.1 Prior cases of herpes vegetans in the literature were often partially resistant to acyclovir and thus responded more favor- ably to valacyclovir, foscarnet, cidofovir, or surgical removal.1 Imiquimod has also been proposed as an alternative treatment in resistant cases, effectively stimulating self-healing by increasing alpha interferon response.6 Although a large, exophytic lesion would not normally prompt suspicion for HSV, HSV-2 seroprevalence is three times higher among HIV-infected adults than in the general U.S. population. Awareness of the possible unusual presentations of HSV in HIV and other immunocompromised states may broaden the differential diagno- sis of such vegetative, exophytic lesions and facilitate early diagnosis and institution of effective antiviral therapy. References 1. Patel AB, Rosen T. Herpes vegetans as a sign of HIV infection. Dermatol Online J. 2008 Apr 15;14(4):6. 2. Blieden LS, Chévez-Barrios P, Yen MT. Herpes simplex vegetans presenting as an eyelid mass. Ophthal Plast Reconstr Surg. 2011 May-Jun;27(3):e58-9. 3. Römer A, Greiner A, Enk A, Hartschuh W. Herpes simplex vegetans: atypical genital herpes infection with prominent plasma cell infiltration in B-cell chronic

Cao, Combs, Favreau, Droller, Piatigorsky 35 Microcystic Adnexal Carcinoma in a 7-Year-Old Female

Cathy Koger, DO,* Chris Weyer, DO,** Lloyd J. Cleaver, DO,*** Michael B. Morgan, MD****

* First-Year Dermatology Resident, Northeast Regional Medical Center, Kirksville, MO ** Board Certified Dermatologist and Mohs Surgeon, The Cleveland Clinic Dermatology and Plastic Surgery Institute, Cleveland, OH *** Dermatology Residency Program Director, Northeast Regional Medical Center, Kirksville, MO **** Board Certified Dermatopathologist, Dermpath Diagnostics, Tampa, FL

ABSTRACT: Microcystic Adnexal Carcinoma (MAC) is an uncommon locally aggressive neoplasm that tends to invade deeply and recur but rarely metastasizes. First described by Goldstein et al in 1982, MAC tends to have a predilection for the left side of the face but may also present in sun-exposed or radiation treated areas. It can appear as a flesh-colored, red, or yellow papule or as an indurated plaque and is often misdiagnosed clinically. The pathogenesis of MAC remains unclear, but it is thought to arise from pluripotent keratinocytes capable of differentiating into sweat glands or hair follicles. It most commonly arises in older adults with less than a dozen pediatric cases reported to date. We present a case of MAC in a 7 year old female as well as a discussion of diagnosis and treatment for this rare tumor. erythema or indu- uniform cells and central keratinous micro- ration was appreci- cysts. In one section these cysts were broad, ated surrounding but in subsequent sections interconnected the lesion. She had smaller nests were noted. Desmoplastic multiple benign- was still favored at this appearing nevi point, but a final diagnosis was deferred to on her upper and dermatopathology. The margins of the first lower extremi- section appeared free of tumor, so the fam- ties, along with a ily agreed to defer further intervention until 4x2.3cm café au a more definitive diagnosis was reached. lait spot on her The defect site was closed primarily, and the right lower back. procedure was well tolerated by the patient. The remainder of The Mohs specimen was re-sent to the her skin and physi- original reporting dermatopathologist for cal exam was nor- further evaluation. After comparison with mal. Given the the initial biopsy slides, microcystic adnexal lesion’s persistence carcinoma (MAC) was the favored primary and resistance to biopsy diagnosis. The final dermatopathol- any treatment, a ogy report indicated free margins with no biopsy was taken to residual MAC. The patient was to follow rule out pilomatri- up with our dermatology clinic one month Figure 1 coma based on the after her Mohs procedure and every three Case Presentation patient’s age and months thereafter for a year. Her surgi- clinical presentation. The clinical differen- cal site continued to heal well with slight In January 2008, a 7-year-old Cauca- tial diagnoses included syringoma, desmo- hypertrophy but no recurrence of the lesion. sian female was referred to our dermatol- plastic trichoepithelioma or other adnexal The patient regularly follows up with our ogy clinic by her nurse practitioner for a tumors. clinic and remains tumor free. lesion on her left lower lip. The patient’s The biopsy showed an infiltrative, mother stated the lesion had been present asymmetrical, epithelial neoplasm occupy- Discussion for approximately four years. Previously ing all levels of the dermis. The neoplasm Microcystic adnexal carcinoma it had been biopsied by a dermatologist was disposed into cords, nests, and angu- (MAC), also called sclerosing sweat duct with unknown results. Her mother had used lated glandular foci containing inspissated carcinoma (SSDC), is an uncommon, various home remedies on the area with material, which was consistent with a diag- locally aggressive tumor that may invade the thought that it might be a . The nosis of a desmoplastic follicular neoplasm. deeply and has the propensity to recur.1 lesion was asymptomatic. The patient had Re-excision of the lesion to obtain clear Though the exact pathogenesis of MAC no previous history of skin disease and her margins and definitive diagnosis was rec- remains unclear, it is thought to arise from other medical, family, surgical, and social ommended, and Mohs surgery was deter- pluripotent keratinocytes capable of dif- history were unremarkable. She took a mul- mined to be the best course of action. ferentiation to either sweat glands or hair tivitamin daily but otherwise used no medi- follicles. No gender predilection has been cations and had no allergies. The patient was brought back for Mohs micrographic surgery approximately one shown in studies, and the vast majority of On physical exam, a firm, flesh-colored month later. The dermatologist took a first reported MAC cases has been in Cauca- plaque measuring approximately 0.8x0.5cm stage, and based on the microscopic find- sians, although rarely it has been seen in was identified on the left lower lip, near the ings, consulted pathology. The pathologist other ethnicities.9 MAC typically involves vermillion border (Figure 1). No associated noted a follicular neoplasm with nests of the face of older adults but also has been 36 microcystic Adnexal Carcinoma in a 7-Year-Old Female reported on the scalp, axilla, trunk and tasias.10 In the two congenital cases cited extremities.1,5,6,7 Chiller et al. found a above, both lesions had firm, subcutane- slight predominance for the left side of the ous, nodular components along with the face (specifically the lip) and postulated accompanying plaque/papule.9,10 The most this to be from sun exposure to drivers on consistent diagnostic feature has been the left side of cars in the United States.1 its frequent location on the face. Due to MAC is extremely uncommon in chil- its difficulty in diagnosis, MAC should dren, making the case reported here very always be considered in the differential for unique.6 any slow-growing tumor of the head and 13 To date there are still very few neck region. reported cases of MAC in any age demo- Microcystic adnexal carcinoma has a graphic. A total of 223 were identified relatively bland microscopic appearance, by Surveillance, Epidemiology, and End especially in superficial biopsy specimens, Results registry from 1973–2004.12 A more which can also complicate the pathologi- recent case study done in 2011 reported cal identification and lead to misdiagno- still only 300 cases in the literature, with sis.8 Thin biopsy specimens are commonly fewer than a dozen involving children inadequate as they capture only the under the age of 18.9 From the major- superficial cystic or ductal component, ity of accounts, the predilection site of which may be misinterpreted as a benign MAC is still predominantly in the head adnexal neoplasm such as syringoma or and neck area (74%) in all ages.5 A review desmoplastic trichoepithelioma.1 Thus a by Nelson and colleagues done in 2008 deep shave, punch, or excisional biopsy is cited a lesion diagnosed as SSDC in the recommended if MAC is in the differen- pre-auricular area of a 6-year-old African Figure 2 tial diagnosis. 6 American girl. This had been the young- Other diagnostic tools used with est known MAC patient until recently, identification of MAC have included com- when two congenital cases were reported puted tomography or magnetic resonance in the literature. The first was from Smart imaging. Due to the infiltrative growth et al., detailing a malar lesion diagnosed as pattern and perineural invasion often seen 9 MAC on a 3-day-old Caucasian female. with MAC tumors, these modalities have The second was provided by Fu et al. and sometimes been implemented preopera- described a 1cm verrucous-like plaque on tively to determine the extent of inva- 10 the temple of a 2-week-old female. In sion.6,7 CT/MRI has also been utilized to both cases, the tumor involved the nearby detect the presence of metastatic disease, muscle and extended almost to the peri- which is still relatively rare despite the osteal zygoma. As a result, re-excisions infiltrative nature of MAC. Only five local were necessary to ensure clear margins, and three distant metastases have been and both patients have remained free of reported, and only one death has been recurrence upon close follow-up. To date, attributed to MAC. 9 formal pediatric management protocols for MAC do not exist. Histopathology One risk factor for MAC is postu- In 1982, Goldstein et al. first lated to be exposure to ultraviolet light, described MAC as a malignant append- given the tumor’s common appearance age tumor with distinct histologic features in sun-exposed areas.1,8 Yet another risk that were necessary to distinguish it from factor seems to be related to prior radi- benign tumors with a similar appear- ation treatment, as several MAC cases ance.13 Histologically, MAC tends to have been reported in patients who have exhibit a biphasic pattern of both eccrine undergone radiation for acne or vari- Figure 3 and follicular structures, but apocrine and 7,8 cystic adnexal carcinoma is often misdi- ous cancers. Curiously, the tumors in sebaceous differentiation have also been agnosed clinically and may be mistaken patients with a history of radiation exposure described.4,8,13 The tumor usually involves on physical exam for morpheaform basal have not been more aggressive or histologi- the dermis and subcutis, with paisley- cell carcinomas, desmoplastic trichoepi- cally more atypical than those in patients tie tadpole-shaped ducts and keratinous 7 theliomas, syringomas, cysts, squamous without prior radiation exposure. MAC horn cysts common in the upper dermis, cell carcinomas, or even lichen simplex has also been seen in immunocompromised and small basaloid strands and nests with chronicus.1 MAC lesions may appear flesh- patients and may possibly have a genetic pilar differentiation and benign-appear- colored, yellowish, or red, are sometimes link. Abbate et al. did report sibling cases of ing keratinocytes or squamous cells in the blanchable, and often are asymptomatic. MAC, thus suggesting that there may be an deeper dermis 3,13 (Figures 2, 3). The stroma In some instances MAC will present as a increased risk in immediate family mem- is densely pink-to-red and sclerotic. The 8 firm, indurated, slow-growing plaque, while bers for developing the tumor. tumor cells themselves are bland with mini- other times it may be an ill-defined round mal atypia or mitoses.9 As mentioned above, papule.5 One case report described a ver- Diagnosis MAC is deeply invasive and tends to exhibit rucous plaque with peripheral telangiec- Due to its varying presentation, micro- lymphoid aggregates along with perineural

Koger, Weyer, Cleaver, Morgan 37 invasion.3 ress by local invasion rather than meta- collaborative series review and update. J Am Acad Dermatol. Aug 1999;41(2 Pt 1):225-31. static spread.12 If left undiagnosed for a Histologically, the differential diagnosis 8. Abbate M, Zeitouni NC, Seyler M, Hicks W, Loree T, of MAC includes desmoplastic trichoepithe- long period of time, MAC may infiltrate Cheney RT. Clinical course, risk factors, and treatment the subcutaneous fat tissue, muscles, peri- of microcystic adnexal carcinoma: a short series report. lioma (DTE), morpheaform basal cell car- Dermatol Surg. Oct 2003;29(10):1035-8. 13 3 chondrium, periosteum, or perineurium. cinoma (MBCC), or syringoma. All have 9. Smart DR, Taintor AR, Kelly ME, Lyon VB, Segura A, For your patients with mild to moderate atopic dermatitis In approximately 80% of cases, exten- Jensen JN, Drolet BA. Microcystic Adnexal Carcinoma: similar histologic features, including duct- The First Reported Congenital Case. Pediatric like structures, round cells with high N:C sive perineural spreading has also been Dermatology. 2011;28(1):35–38. 13 ratio, and dense sclerotic stroma.5 However, observed. Thus these tumors frequently 10. Fu T, Clark FL, Lorenz HP, Bruckner AL. Congenital require extensive surgical resection, and Microcystic Adnexal Carcinoma. Arch Dermatol. Feb DTE commonly shows micro-calcifications, 2011;147(2):256-257. even lesions treated with MMS can lead to rarely has lymphoid aggregates in the der- 11. Vidal CI, Goldberg N, Burstein DE, Emanuel HJ, mis, displays no perineural extension, and a four-fold increase in defect size. However, Emanuel PO. p63 Is a Useful Desonate (desonide) Gel 0.05% simple wide excision can lead to equal if Adjunct in Distinguishing Sclerosing Cutaneous Tumors. does not involve the deeper dermis as MAC The American Journal of Dermatopathology. May 12 does. MBCC can be histologically very not greater overall defect sizes. Due to the 2010;32(3):257-261. is a Choice with locally aggressive nature of MAC and the 12. Yu JB, Blitzblau RC, Patel SC, Decker RH, Wilson similar to MAC but will only occasionally LD. Surveillance, Epidemiology, and End Results 1,2 display the paisley-tie tadpole ducts and often extensive surgery required to extricate (SEER) Database Analysis of Microcystic Adnexal Carcinoma (Sclerosing Sweat Duct Carcinoma) of typically does not contain horn cysts. Syr- it, radiotherapy may play an adjuvant role No Generic Equivalent. 12 the Skin. American Journal of Clinical . April ingomas display clear cell changes, show no in treatment. Radiation as primary treat- 2010;33(2):125-127. perineural invasion, and do not exhibit a ment has been reported in a small number 13. Fischer S, Breuninger H, Metzler G, Hoffmann J. Microcystic Adnexal Carcinoma: An Often Misdiagnosed, 3,6,8 of patients, but almost all cases reported deep infiltrative growth pattern. The dif- Locally Aggressive Growing Skin Tumor. Journal of ficulties in identifying MAC both clinically recurrences of MAC. In fact, there has been Craniofacial Surgery. January 2005;16(1):53-58. and histologically may often lead to late a report of radiation possibly converting 14. Merritt B, Snow S, Longley J. Desmoplastic 12 Trichoepithelioma, Infiltrative/Morpheaform BCC, and diagnosis and the danger of a more infiltra- MAC to a more aggressive neoplasm. Microcystic Adnexal Carcinoma: Differentiation by Another case study by Abbate et al. docu- Immunohistochemistry and Determining the Need for tive and potentially inoperable tumor. Mohs Micrographic Surgery. Cutis. May 2010;85(5):254- mented five cases of MAC on the face in 258. Immunohistochemistry staining has which all patients had had prior radiation shown MAC will stain most consistently exposure.8 As a result, most literature rec- with carcinoembryonic antigen stain ommends eliciting a careful radiation his- (CEA), epithelial membrane antigen (EMA) tory from individuals diagnosed with MAC stain, as well as cytokeratin AE1/AE3 but or if MAC is suspected in the differential.7 is nonreactive to S100 and BerEP4.8,9 Cyto- keratin 15 can be helpful in distinguishing The preferred method of treatment for 6 MAC from MBCC.5 One source suggested MAC in children has yet to be elucidated. utilizing CK20 to differentiate DTE from In the few literature case reports available, Desonate Gel offers these benefi ts: either MBCC or MAC in an attempt to both wide local excision and Mohs surgery have been performed.6,9,10 MMS has also determine whether further surgical exci- • Proven effi cacy in clinical studies1,3,4 INDICATION AND USAGE sion is necessary. With an adequately deep been the most favored initial modality in Desonate Gel is indicated for the treatment of mild to moderate atopic • Approved for use in patients 3 months of age and older1 biopsy, competent dermatopathology children, but sometimes the need for anes- dermatitis in patients 3 months of age and older. (For pediatric safety information, see ISI and the following page evaluation, and clinical correlation, light thesia, the child’s age, or lack of availability for Brief Summary) IMPORTANT SAFETY INFORMATION microscopy remains the gold standard for of a Mohs surgeon dictates the wide exci- 6,10 Desonate is contraindicated in those with a history of hypersensitivity sion option over MMS. In either case, 5 diagnosis, with immunohistochemistry • Helps maintain the stratum corneum barrier function to any of the components of the preparation. Topical corticosteroids used only rarely.8 no recurrences in children have yet to be • Copay assistance programs that make the average can produce reversible hypothalamic pituitary adrenal (HPA) axis reported in the literature. Despite this, rec- suppression, Cushing’s syndrome and unmask latent diabetes. Systemic Treatment ommendation for follow-up in children has cost comparable to or lower than generics* absorption may require evaluation for HPA axis suppression. Modify been inspection and palpation of the sur- use should HPA axis suppression develop. Potent corticosteroids, use The treatment options for MAC gical site as well as regional lymph nodes on large areas, prolonged use or occlusive use may increase systemic include surgical excision, Mohs micro- * $0 copay with patient’s fi rst every three months for several years.10 prescription. Most patients absorption. graphic surgery (MMS), and radiotherapy.7 Overall survival in all patients with MAC pay $10 each for 3 refi lls. Pediatric patients may be more susceptible to systemic toxicity when Although Mohs surgery has been reported COPAY* has been excellent, and most have lived a on your first fill See eligibility requirements. treated with topical corticosteroids due to their larger skin surface-to- AND to be the preferred first-line therapy, stan- 12 pay no more than $10* Maximum benefi t of $200 for 3 additional fills *See eligibility requirements. Up to a body mass ratios. Unless directed by a physician, do not use on the 6 normal lifespan. maximum benefit of $200 per fill. dard treatment is still unclear. Mohs sur- SeSeee reevererssee foforr importanportantt prograogramm information. on each fi ll. underarm or groin area of children. Do not use to treat diaper dermatitis. gery and simple excision show comparable References Use in children less than 3 months of age is not recommended. complication rates, but Mohs tends to pro- 1. Chiller K, Passaro D, Scheuller M, Singer M, McCalmont Local adverse reactions may include atrophy, striae, irritation, acneiform duce clearer margins in fewer procedures/ T, Grekin RC. Microcystic adnexal carcinoma: forty- Models used for illustrative purposes only. eight cases, their treatment, and their outcome. Arch. eruptions, hypopigmentation and allergic contact dermatitis and may be 1,12 References: 1. Desonate Gel 0.05% [package insert]. Morristown, NJ: Intendis Inc; 2010. 2. US Food Dermatol. Nov 2000;136(11):1355-9. office visits with smaller recurrence rates. and Drug Administration. Drug details. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index. more likely with occlusive use or more potent corticosteroids. The most In one study of patients undergoing either 2. Bolognia JL, Jorrizo JL, Rapini RP. Dermatology: cfm?fuseaction=Search.DrugDetails. Accessed July 18, 2012. 3. Fitzgerald N, Decker R. Clinical Study common adverse reactions (incidence ≥ 1%) are headache, application Mosby Elsevier Publishing; 2008. Report #7001-G3HP-01-05. Dow Pharmaceutical Sciences, Inc, Petaluma, CA. November 22, 2005. MMS or simple excision, 30% of patients 4. Fitzgerald N, Lemke S. Clinical Study Report #7001-G3HP-04-03. Dow Pharmaceutical Sciences, Inc, site burning and rash. To report SUSPECTED ADVERSE REACTIONS, treated with surgical excision required at 3. Elston DM, Ferringer T. Dermatopathology: Saunders Petaluma, CA. May 10, 2005. 5. Trookman NS, Rizer RL, Ford RO, Gotz V. The stratum corneum and atopic contact Bayer HealthCare at 1-866-463-3634 or FDA at 1-800- Elsevier Publishing; 2010. dermatitis: moisturizing advantages of a novel desonide hydrogel treatment. Poster presented at: 66th FDA-1088 or www.fda.gov/medwatch. least one other procedure and hence one 4. Rapini RP. Practical Dermatopathology: Elsevier Mosby Annual Meeting of the American Academy of Dermatology: February 1-5, 2008; San Antonio, TX. other office visit, compared with 0% treated Publishing; 2005. Not for ophthalmic, oral or intravaginal use. As with other corticosteroids, by MMS.1 Several other studies have dem- 5. Sasis S, Andrew WS, Bijal A. Cytologic features of therapy should be discontinued when control is achieved. Safety beyond microcystic adnexal carcinoma. Cytojournal. Published 4 weeks has not been established. onstrated similar results when comparing online 2011 March;8:5. 7 MMS to wide excision. Regardless of the 6. Nelson PS, Bourgeois KM, Nicotri T, Chiu ES, Poole JC. See following page for Brief Summary of full Sclerosing sweatduct carcinoma in a 6-year-old African Prescribing Information. treatment modality, long-term and consis- American child. Pediatr. Dermatol. 2008;25(1):38-42. tent follow-up of the patient is advocated. 7. Friedman PM, Friedman RH, Jiang SB, Nouri K, © 2012 Bayer HealthCare. Bayer and the Bayer Cross are registered trademarks of Bayer. The Desonate logo is a registered trademark of Intendis GmbH. All rights reserved. DES-10-0001-12 August 2012 Printed in USA MAC has been known to prog- Amonette R, Robins P. Microcystic adnexal carcinoma: 38 microcystic Adnexal Carcinoma in a 7-Year-Old Female For your patients with mild to moderate atopic dermatitis

Desonate (desonide) Gel 0.05% is a Choice with No Generic Equivalent.1,2

Desonate Gel offers these benefi ts:

• Proven effi cacy in clinical studies1,3,4 INDICATION AND USAGE Desonate Gel is indicated for the treatment of mild to moderate atopic • 1 Appr oved for use in patients 3 months of age and older dermatitis in patients 3 months of age and older. (For pediatric safety information, see ISI and the following page for Brief Summary) IMPORTANT SAFETY INFORMATION Desonate is contraindicated in those with a history of hypersensitivity • Helps maintain the stratum corneum barrier function5 to any of the components of the preparation. Topical corticosteroids • Copay assistance programs that make the average can produce reversible hypothalamic pituitary adrenal (HPA) axis suppression, Cushing’s syndrome and unmask latent diabetes. Systemic cost comparable to or lower than generics* absorption may require evaluation for HPA axis suppression. Modify use should HPA axis suppression develop. Potent corticosteroids, use * $0 copay with patient’s fi rst on large areas, prolonged use or occlusive use may increase systemic prescription. Most patients absorption. pay $10 each for 3 refi lls. Pediatric patients may be more susceptible to systemic toxicity when COPAY* on your first fill See eligibility requirements. treated with topical corticosteroids due to their larger skin surface-to- AND pay no more than $10* Maximum benefi t of $200 *See eligibility requirements. Up to a body mass ratios. Unless directed by a physician, do not use on the for 3 additional fills maximum benefit of $200 per fill. SeSeee reevererssee foforr importanportantt prograogramm information. on each fi ll. underarm or groin area of children. Do not use to treat diaper dermatitis. Use in children less than 3 months of age is not recommended. Local adverse reactions may include atrophy, striae, irritation, acneiform Models used for illustrative purposes only. eruptions, hypopigmentation and allergic contact dermatitis and may be References: 1. Desonate Gel 0.05% [package insert]. Morristown, NJ: Intendis Inc; 2010. 2. US Food and Drug Administration. Drug details. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index. more likely with occlusive use or more potent corticosteroids. The most cfm?fuseaction=Search.DrugDetails. Accessed July 18, 2012. 3. Fitzgerald N, Decker R. Clinical Study common adverse reactions (incidence ≥ 1%) are headache, application Report #7001-G3HP-01-05. Dow Pharmaceutical Sciences, Inc, Petaluma, CA. November 22, 2005. 4. Fitzgerald N, Lemke S. Clinical Study Report #7001-G3HP-04-03. Dow Pharmaceutical Sciences, Inc, site burning and rash. To report SUSPECTED ADVERSE REACTIONS, Petaluma, CA. May 10, 2005. 5. Trookman NS, Rizer RL, Ford RO, Gotz V. The stratum corneum and atopic contact Bayer HealthCare at 1-866-463-3634 or FDA at 1-800- dermatitis: moisturizing advantages of a novel desonide hydrogel treatment. Poster presented at: 66th FDA-1088 or www.fda.gov/medwatch. Annual Meeting of the American Academy of Dermatology: February 1-5, 2008; San Antonio, TX. Not for ophthalmic, oral or intravaginal use. As with other corticosteroids, therapy should be discontinued when control is achieved. Safety beyond 4 weeks has not been established. See following page for Brief Summary of full Prescribing Information.

© 2012 Bayer HealthCare. Bayer and the Bayer Cross are registered trademarks of Bayer. The Desonate logo is a registered trademark of Intendis GmbH. All rights reserved. DES-10-0001-12 August 2012 Printed in USA DESONATE® (desonide) Gel for topical use only corticosteroids. Reactions may include skin atrophy, striae, , burning, itching, irritation, dryness, Initial U.S. Approval: 1972 , acneiform eruptions, hypopigmentation, BRIEF SUMMARY perioral dermatitis, allergic contact dermatitis, secondary CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION infection, and . Some local adverse reactions may be irreversible. 1 INDICATIONS AND USAGE 5.3 Concomitant Skin Infections Desonate is indicated for the treatment of mild to moderate atopic dermatitis in patients 3 months of age If concomitant skin infections are present or develop and older. during treatment, an appropriate antifungal or antibacterial agent should be used. If a favorable response does not Patients should be instructed to use Desonate for the occur promptly, use of Desonate should be discontinued minimum amount of time as necessary to achieve the until the infection is adequately controlled. desired results because of the potential for Desonate to suppress the hypothalamic-pituitary-adrenal (HPA) axis 5.4 Skin Irritation [see Warnings and Precautions (5.1)]. Treatment should If irritation develops, Desonate should be discontinued not exceed 4 consecutive weeks [see Dosage and and appropriate therapy instituted. Allergic contact Administration (2)]. dermatitis with corticosteroids is usually diagnosed by 4 CONTRAINDICATIONS observing failure to heal rather than noting a clinical Desonate is contraindicated in those patients with a exacerbation as with most topical products not containing history of hypersensitivity to any of the components of corticosteroids. Such an observation should be the preparation. corroborated with appropriate diagnostic patch testing. 5 WARNINGS AND PRECAUTIONS 6 ADVERSE REACTIONS 5.1 Effects on Endocrine System Because clinical trials are conducted under widely varying Systemic absorption of topical corticosteroids can conditions, adverse reaction rates observed in the clinical produce reversible hypothalamic-pituitary-adrenal trials of a drug cannot be directly compared to rates in the (HPA) axis suppression with the potential for clinical clinical trials of another drug and may not reflect the rates glucocorticosteroid insufficiency. This may occur during observed in practice. treatment or upon withdrawal of the topical corticosteroid. In controlled clinical studies of 425 Desonate-treated The effect of Desonate on HPA axis function was subjects and 157 Vehicle-treated subjects, adverse investigated in pediatric subjects, 6 months to 6 years old, events occurred at the application site in 3% of subjects with atopic dermatitis covering at least 35% of their body, treated with Desonate and the incidence rate was not who were treated with Desonate twice daily for 4 weeks. higher compared with vehicle-treated subjects. The One of 37 subjects (3%) displayed adrenal suppression most common local adverse events in Desonate treated after 4 weeks of use, based on the cosyntropin stimulation subjects were application site burning in 1% (4/425) and test. As follow-up evaluation of the subject’s adrenal axis rash in 1% (3/425) followed by application site pruritus in was not performed, it is unknown whether the suppression <1% (2/425). was reversible [see Use In Specific Populations (8.4) and Adverse events that resulted in premature discontinuation Clinical Pharmacology (12.2)]. of study drug in Desonate treated subjects were Pediatric patients may be more susceptible than adults to telangiectasia and worsening of atopic dermatitis in one systemic toxicity from equivalent doses of Desonate due subject each. Additional adverse events observed during to their larger skin surface-to-body mass ratios [see Use clinical trials for patients treated with Desonate included In Specific Populations (8.4)]. headache in 2% (8/425) compared with 1% (2/157) in those treated with vehicle. Because of the potential for systemic absorption, use of topical corticosteroids may require that patients be The following additional local adverse reactions have periodically evaluated for HPA axis suppression. Factors been reported infrequently with topical corticosteroids. that predispose a patient using a topical corticosteroid They may occur more frequently with the use of occlusive to HPA axis suppression include the use of more dressings, especially with higher potency corticosteroids. potent steroids, use over large surface areas, use over These reactions are listed in an approximate decreasing prolonged periods, use under occlusion, use on an order of occurrence: folliculitis, acneiform eruptions, altered skin barrier, and use in patients with liver failure. hypopigmentation, perioral dermatitis, secondary infection, skin atrophy, striae, and miliaria. An ACTH stimulation test may be helpful in evaluating patients for HPA axis suppression. If HPA axis suppression is documented, an attempt should be made to gradually withdraw the drug, to reduce the frequency of application, or to substitute a less potent . Manifestations of adrenal insufficiency may require supplemental systemic corticosteroids. Recovery of HPA axis function is © 2010, Intendis, Inc. All rights reserved. June 2010 generally prompt and complete upon discontinuation of Manufactured by Contract Pharmaceuticals Limited, Buffalo, topical corticosteroids. NY 14213 Cushing’s syndrome, hyperglycemia, and unmasking of latent diabetes mellitus can also result from systemic Distributed by: absorption of topical corticosteroids. Morristown, NJ 07962 Use of more than one corticosteroid-containing product at the same time may increase the total systemic corticosteroid exposure. 5.2 Local Adverse Reactions with Topical Corticosteroids 6706903BS 09-0081 Local adverse reactions may be more likely to occur with The Desonate logo is a registered trademark of Intendis, Inc. occlusive use, prolonged use or use of higher potency Covered by US Patent No. 6,387,383 Periocular Verruca Plana Following Use of a Carbon Dioxide Laser

Roxanna Menendez, DO,* Jacqui Thomas, DO,** Matthew Uhde, PA-C,*** Layne Nisenbaum, DO, FAOCD****

*3rd-year Dermatology Resident, Columbia Hospital, West Palm Beach, FL **Dermatologist, The Skin Institute, Ft. Lauderdale, FL ***3rd-year Medical Student, NSU-COM, Ft. Lauderdale, FL ****Program Director, Columbia Hospital Dermatology Residency, West Palm Beach, FL

Abstract: The carbon dioxide laser is utilized in a variety of situations for dermatologic use. Several complications can occur with these laser treatments; however, clinical manifestations of verruca plana are uncommon. We report a case of an elderly woman who presented to the clinic with verruca plana on the periocular regions of the face after a recent carbon dioxide laser resurfacing procedure. She was successfully treated with imiquimod 5% cream. The lesions were theorized to occur secondary to prior inoculation from latent human papillomavirus, the causative agent of verruca plana. Although the skin can appear without evidence of clinical infection, human papillomavirus can lie dormant and be reactivated secondary to the induced trauma by a laser procedure.

Figure 2

Case Report Figure 1 A 69-year-old female presented with multiple, symmetric, bilateral, flesh- colored, 0.4mm flat-topped papules surrounding the periocular and temple regions of the face, present for several months. Evidence of mild pink erythema and inflammation was noted on the physical exam (Figure 1). They appeared shortly after a periocular carbon dioxide laser resurfacing treatment more than six months prior, which was performed at another location by an unknown medical professional. She fully healed from the carbon dioxide laser procedure, but the papules remained present. She denied a history of herpes simplex virus and did not remember taking an oral antiviral prior to the procedure. The Figure 3 differential diagnosis included lichen planus and scar tissue. The biopsy revealed verruca plana (Figures 2 and 3). The patient refused different laser treatments or liquid nitrogen. Treatment consisted of imiquimod 5% cream twice per week for 16 weeks. Two weeks later, the areas appeared flatter and smaller. The patient increased imiquimod 5% cream to three times per week for the remainder of the course of therapy. Four months later, the majority of the areas were clear; however, there were four small 0.2mm papules on the right malar crescent and one small 0.2mm papule on the left temple region near the hairline (Figure 4). The patient refused further treatment and was satisfied with the resulting outcome. Introduction Verruca plana (VP), also known as flat or plane , are caused by human papillomavirus (HPV) types 3 and 10.1 They are most often seen on sun-exposed areas of children, young adults and the immunosuppressed. Flat warts are typically asymptomatic, with cosmetic disfiguration being the only associated Figure 4

Menendez, Thomas, Uhde, Nisenbaum 41 morbidity. They are characteristically nevi and lentigines should be considered in of CO2 laser treatments have been well smooth, flat-topped, pink, light brown, or the differential. documented. The thermal tissue breakdown light yellow papules. VP warts vary between is emitted in the smoke by-product, which 0.1 to 0.5cm in size and are generally Skin Resurfacing with CO2 Lasers contains intracellular components that were numerous on the following typical sites: carbonized or underwent vaporization. Carbon dioxide (CO2) lasers have forehead, perioral, dorsal hands and shaved been shown to be safe, precise and reliable, This process produces gas contents areas such as the beard region and the lower but complications can arise. One of the including carbon monoxide, benzene legs.2 Koebnerization may occur. most common post-treatment infections and hydrogen cyanide. These substances Once VP undergoes clinical is herpes simplex virus, found in up to can cause respiratory inflammation and 15 manifestation, the papule can last for several 2% of cases. In patients without a prior have mutagenic potential. In addition, weeks or for years.2 Regression is usually history, this risk can be decreased to 0.5% studies have confirmed the risk of HPV 26-28 heralded by an erythematous change to the with antiviral medications one day before transmission from contaminated smoke. lesion, inflammation and sometimes the treatment and continued for five to seven A study conducted by the Mayo Clinic found 3 15 CO laser surgeons are at an increased risk development of depigmented haloes. days following the procedure. Erythema is 2 expected for several days after the procedure of nasopharyngeal lesions, particularly those Histopathology and can be reduced with a light-emitting treating genital warts.27 The study concluded 16 that inhalation of plume smoke carries VP lesions display hyperkeratosis and diode. There is also the possibility of both infectious particles into the upper airway, acanthosis without the papillomatosis or hyperpigmentation and hypopigmentation displaying various levels of contagion.27 parakeratosis seen with verrucae vulgaris.4 from laser procedures. Fitzpatrick III-VI skin types have an increased risk for developing Smoke removal is one of the best The stratum corneum has a characteristic 17 basket-weave appearance.4 Infected cells post-inflammatory hyperpigmentation. ways to decrease papillomavirus particle have a “bird’s eyes” appearance, containing Acne, milia, ectropion formation, contact transmission. Smoke evacuators are 98.6% dermatitis and hypertrophic scarring have effective at removing the virus when placed large vacuoles and shrunken nuclei with 17-19 condensed basophilic chromatin located in also been reported. Many complications 1 cm from the treatment site, with efficacy the upper malpighian layer.4 In cases where can be avoided with patient education and decreasing by half when moved to 2 cm VP spontaneously resolves, a lymphocytic preoperative and postoperative skin care. from the treatment site.29 Several federal infiltrate, cell exocytosis and apoptosis In the case presented herein, VP agencies, national societies and institutes occur.5,6 appeared secondary to skin-resurfacing have recommended measures to minimize particle transmission.30-32 Such measures treatment with a CO2 laser. There have been Transmission similar published case reports. One such include local exhaust ventilation procedures Transmission is through skin-to-skin study describes a patient who developed and wearing approved N-95 respiratory contact, with an incubation period of one to an exacerbation of plane warts to her masks. six months.2 The source can be individuals nose, glabella and left periocular following Management There are several experiencing clinical or subclinical infection treatment with a CO2 laser to the same approaches to VP therapy, including surgical or viral particles on fomites.2 HPV can resist region for active VP and skin irregularities destruction, topical treatments, and laser 20 desiccation, freezing and prolonged time caused by acne. New-onset verruca vulgaris resurfacing procedures. When treating the outside of its host.2 Infections can be latent to the facial cheeks resulting from full-face patient, location and severity of the lesions 7 21 in normal-appearing skin. CO2 resurfacing has been reported. To along with patient compliance should be these authors’ knowledge, no accounts of There are a variety of cases found in the considered in choosing the appropriate new-onset VP following periocular CO literature describing unusual transmission. 2 management. Topical medications such as resurfacing have been reported in the In one case, VP developed over a port wine imiquimod, tretinoin and 5-fluorouracil English literature. 1 stain being treated with a pulsed dye laser.8 cream can be applied. Kim et al. showed There are reported cases associated with We theorize the virus disseminated successful results in 73% of patients using 33 tattooing and eyebrow threading as well.9-12 from prior inoculation in the presented 5% imiquimod cream for VP. Although case. Evidence of HPV has been detected in imiquimod can initially cause severe Differential Diagnosis random sites on healthy human skin.22 Animal inflammation, desirable clinical and cosmetic results are documented.34 A recent There are multiple diseases that can models have demonstrated significant 23 report showed glycolic acid 15% topical mimic VP lesions. Epidermodysplasia evidence for HPV latency and reactivation. gel plus salicylic acid 2% was found to be verruciformis (EV) results from the same HPV infects basal epithelial cells and can effective within eight weeks of treatment.35 HPV subtypes as flat warts.1 EV lesions are remain undetectable until triggered to 23,24 Sun protection should be stressed due to more persistent and widespread, and plaques differentiate for wound healing. Dormant HPV may have been reactivated by the CO phototoxic effects. Liquid nitrogen, an are present. Acrokeratosis verruciformis 2 electrocautery needle or laser resurfacing of Hopf, a associated with laser procedure. We conclude the breakdown may be performed for more immediate Darier’s disease, resembles plane warts on of the epidermal layer allowed latent HPV results.36 Nontraditional methods such as the dorsum of the hands.13 Histologically to proliferate, rather than it resulting from vitamin B12 acupoint injections and the it contains papillomatous changes, direct inoculation from the laser system, Chinese herbal medication Qu You Ding hyperkeratosis and acanthosis causing a operator or any other environmental source. have also been described in the literature.37,38 prominent granular layer that has a church Nanni and Alster found this to be the cause spire appearance.13 Lichen planus has flat- of many herpes simplex virus infections after 25 Conclusion topped papules that can be differentiated resurfacing treatments. from verruca plana by the presence of lacy Verrucae are rare complications from 14 CO Laser Plume Smoke fractional CO laser resurfacing. The specific oral lesions and Wickham's striae. In 2 2 addition, scar tissue, seborrheic , The hazards resulting from plume etiology of this patient's VP is undetermined. 42 Periocular Verruca Plana Following Use of a Carbon Dioxide Laser Once the skin is damaged by the laser, a 18. Fife DJ, Fitzpatrick RE, Zachary CB. Complications of fractional CO2 laser resurfacing: four cases. Lasers number of sources can be implicated in the Surg Med 2009;41:179–184. HPV transmission: latent HPV, the laser 19. Ragland HP Mcburney EI. Complication of resurfacing. operator, or plume smoke. Semin Cutan Med Surg 1996;15:200-207. 20. Van der Lei B, van Schijndel AW, Blanken R. This case illustrates an unusual Exacerbation of multiple plane warts following laser skin resurfacing. Aesthet Surg J 2006 May- complication of CO2 laser resurfacing. Jun;26(3):297-299. Operators should be mindful of the 21. Torezan LA, Osorio N, Neto CF. Development of multiple potential for viral spread between patients if warts after skin resurfacing with CO2 laser. Dermatol Surg 2000 Jan;26(1):70-72. inappropriate handling of laser handpieces 22. Antonsson A, Erfurt C, Hazard K, Holmgren V, between patients occurs, although many et al. Prevalence and type spectrum of human papillomaviruses in healthy skin samples collected in handpieces do not make contact with the three continents. J Gen Virol 2003;84:1881-1886. patient’s skin. Patients need to be thoroughly 23. Maglennon GA, McIntosh P, Doorbar J. Persistence of informed of the expected treatment viral DNA in the epithelial basal layer suggests a model for papillomavirus latency following immune regression. outcome, anticipated recovery period, and Virology. 2011;414(2):153–163. treatment risks, including viral infection, 24. Chow LT, Broker TR, Steinberg BM. The natural history prior to resurfacing. Pre-treatment antiviral of human papillomavirus infections of the mucosal epithelia. APMIS. 2010;118(6–7):422–449. therapy may reduce the chance of infection. 25. Nanni CA, Alster TS. Complications of carbon dioxide It is important for patients to understand an laser resurfacing: an evaluation of 500 patients. opportunistic infection can result with any Dermatol Surg 1998;24:315-320. 26. Garden JM, O’Banion MK, Bakus AD, Olson C. Viral breakdown of the body's natural protective disease transmitted by laser-generated plume (aerosol). system. Once the epidermis is exposed, it Arch Dermatol 2002;138:1303-1307. is susceptible to local spread or an outside 27. Gloster HM Jr, Roenigk RK. Risk of acquiring human papillomavirus from the plume produced by the carbon element. dioxide laser in the treatment of warts. J Am Acad Dermatol 1995;32:436-441. Acknowledgement 28. Garden JM, O’Banion K, Sheinitz LS, Pinski KS, Bakus AD, Reichmann ME. Papillomavirus in the The authors are indebted to Drs. Shawna vapor of carbon dioxide laser treated verrucae. JAMA Flanagan and Les Rosen for their support. 1988;259:1199-1202. 29. Sawchuk WS, Weber PJ, Lowy DR, Dzubow LM. Infectious papillomavirus in the vapor of warts treated References with carbon dioxide laser or electrocoagulation: 1. Jablonska S. Wart viruses: Human papillomaviruses. detection and protection. J Am Acad Dermatol Semin Dermatol 1984;3:120-129. 1989;21:41-49. 2. Carr J, Gyorfi T. Human papillomavirus. Epidemiology, 30. Edwards BE, Reiman RE. Results of a survey on current transmission, and pathogenesis. Clin Lab Med 2000 surgical smoke control practices. AORN J 2008;87:739- June;20(2):235-255. 749. 3. Berman A. Depigmented haloes associated with the 31. American National Standards Institute, Inc. American involution of flat warts. Br J Dermatol 1977;97:263-265. national standard for safe use of lasers in facilities. Orlando (FL): Laser Institute of America; 4. Gross G, Pfister H, Hagedorn H, Gissman L. Correlation 2005.p. 18-19. between human papillomavirus (HPV) type and histology of warts. J Invest Dermatol 1982;78:160-164. 32. American Society for Laser Medicine and Surgery. Smoking guns. Available from: URL:http://www.aslms. 5. Tagami H, Takigawa M, Ogino A, et al. Spontaneous org/public/smokingguns1.shtml. Accessed October 20, regression of plane wart after inflammation: clinical 2011. and histologic studies in 25 cases. Arch Dermatol 1977;113:1209-1213. 33. Kim M, Ko H, Jang H, Oh C, Kwon K. Treatment of flat warts with 5% imiquimod cream. J Eur Acad Dermatol 6. Weedon D, Robertson I. Regressing plane warts-an Venereol 2006 Nov;20(10):1349-1350. ultrastructural study. Australas J Dermatol 1978;19:65- 68. 34. Greenberg HL, Cohen JL, Rosen T, Orengo I. Severe reaction to 5% imiquimod cream with excellent clinical 7. Gravitt P. The known unknowns of HPV natural history. J and cosmetic outcomes. J Drugs Dermatol 2007 Clin Invest 2011 Dec 1;121(12):4593-4599. Apr;6(4):452-458. 8. Chen T, Frieden I. Development of Extensive Flat Warts 35. Dall'Oglio F, D'Amico V, Nasca MR, Micali G. Treatment after Pulsed Dye Laser Treatment of a Port-Wine Stain. of cutaneous warts. American Journal of Clinical Dermatol Surg 2007;33:734-735. Dermatology. 2012;13(2):73-96. 9. Jung JY, Shin HS, Won CH, Cho S. Facial verruca 36. Rodríguez-Cerdeira C, Sánchez-Blanco E. Glycolic plana that developed after semipermanent tattooing. Acid 15% plus salicylic Acid 2%: a new therapeutic Ann Dermatol 2009 Feb;21(1):92-94. pearl for facial flat warts. J Clin Aesthet Dermatol 2011 Sep;4(9):62-64. 10. Baxter SY, Deck DH. Tattoo-acquired verruca plana. Am Fam Physician 1993;47:732. 37. Hu Y, Zhang W, Chen L. The effect of Vit. B12 injection into acupoints in the treatment of verruca 11. Halder S, Halder A. Verruca plana following eyebrow plana. Zhonghua Kou Qiang Yi Xue Za Zhi 1998 threading. Indian J Dermatol Venereol Leprol Mar;33(2):122-123. 2009;75:196-197. 38. Wu J, Wang J, Huang Y, Zhou J. Clinical observation 12. Kumar R, Zawar V. Threading warts: A beauty parlour on the therapeutic effects of Qu You Ding on flat wart. J dermatosis. J Cosmet Dermatol 2007;6:279-282. Tradit Chin Med 2005 Sep;25(3):206-208. 13. Schueller WA. Acrokeratosis verruciformis of Hopf. Arch Dermatol 1972 Jul;106(1):81-3. 14. Scully C, el-Kom M. Lichen planus: review and update on pathogenesis. J Oral Pathol 1985; 14:431. 15. Setyadi HG, Jacobs AA, Markus RF. Infectious complications after nonablative fractional resurfacing treatment. Dermatol Surg 2008;34:1595–1598. 16. Alster TS. Improvement of post-fractional laser erythema with light-emitting diode photomodulation. Dermatol Surg 2009;35:813–815. 17. Metelitsa AI, Alster TS. Fractionated laser skin resurfacing treatment complications: a review. Dermatol Surg 2010;36:299–306.

Menendez, Thomas, Uhde, Nisenbaum 43 Hypopigmented Patches in a Young Columbian Boy

Kurt Grelck, DO,* Sheena Nguyen, BS,** Andleeb Usmani, DO,*** Robin Shecter, DO, FAOCD****

*Third-year dermatology resident, Columbia Hospital, West Palm Beach, FL **Second-year medical student, Touro College of Osteopathic Medicine, NY, NY *** Dermatologist, The Children’s Skin Center, Weston, FL ****Program director, Columbia Hospital Dermatology Residency, West Palm Beach, FL

ABSTRACT: is an increasingly uncommon disease that is characterized by polymorphic patches of hyper or hypopigmentation. The etiologic agent of pinta, Treponema carateum is not endemic to the United States, however due to increasing international travel this topical disease occasionally presents in the United states and should remain in the differential diagnosis of hypopigmented patches. We present a case of pinta in a young boy and his family members who were successfully treated with penicillin. Case Study A 12-year-old, healthy Columbian boy presented with several slowly enlarging, hypopigmented patches with faint erythema and scale that were located on the right cheek, chest and back (see Figures 1-3). The areas were asymptomatic, and he and his family denied any preceding illnesses, topical medication use, or prior treatments. His medical history and family history were unremarkable, and he was not taking any medications or supplements. Further inquiry of the patient’s mother revealed that a few weeks prior to presentation, they had a biopsy performed in Columbia prior to immigrating to South Florida, for which the results were unknown. The biopsy report was recovered, and it revealed trepo- nemes present within the epidermis, a find- ing compatible with a diagnosis of pinta. The patient was subsequently treated with Figure 1: A 12-year-old Columbian boy with enlarging hypopigmented patches. penicillin G benzathine 1.2 million units intramuscularly (IM) for one dose and sent home. However, the patient’s mother and brother returned three weeks later for eval- uation of newly forming hypopigmented macules similar to the first boy’s previ- ous lesions. They were subsequently also treated with penicillin G benzathine 2.4 million units IM, with eventual resolution of the hypopigmented areas over the ensu- ing months. Discussion Figure 2: Hypopigmented patch to the Figure 3: H&E; Hypopigmented patch to The onset of hypopigmented patches is cheek with central faint erythema. the left upper back. often a disturbing event for patients, and the clinical differential diagnosis is broad (see lidum, the etiologic agent of syphilis. Table 1). However, as in this case, a focused Pinta’s incidence over the last few Treponema carateum, the species respon- decades has declined precipitously for history combined with histopathologic sible for pinta, is morphologically and analysis can often yield a correct diagnosis. unknown reasons, with some calling it antigenically indistinguishable from T. pal- extinct worldwide aside from a few scat- Pinta is unique among the treponematoses lidum.2 Interestingly, in recent attempts to in that it causes only skin manifestations.1 tered endemic areas in Central and South sub-classify the treponemes, no differences America, as well as a more recent case iden- Pinta is one of the three non-vene- were detected by either the Western or the 3,5-9 3 tified in Cuba. Also known as puru- real treponematoses, along with bejel and Southern blot hybridization techniques. puru or carate, the disease has been known . All three diseases' causative organ- T. carateum cannot be cultured in vitro but th 4 to exist since the 16 century in Aztec and isms closely resemble Treponema pal- can be transmitted to chimpanzees. Carib Amerindians.8 Rural areas in Mexico, 44 Hypopigmented patches in a young Columbian boy 14 Table 1 a “mottled” appearance. and for patients 6-15 years of age 1.2 mil- All three stages may result lion units IM for disease of less than two • • Pityriasis versicolor in hypopigmented patches; years duration. For those with penicillin • however, only within the allergy, tetracyclines or erythromycin can be • Chemical leukoderma first two stages can organ- used (tetracycline 500 mg four times a day • Hypopigmented isms (which are highly for 15 days in adults, or erythromycin 250 • Lymphomatoid papulosis infectious) be found within mg four times a day in children <15 years • Morphea lesions. old). Lesions become non-infectious 24 • Onchocerciasis Dark-field exami- hours after treatment. Following treatment, • nation of specimens will treponemal titers will slowly decline, and • Discoid lupus erythematosus reveal numerous T. cara- pigmentary abnormalities typically resolve • Sarcoidosis teum organisms in early slowly in primary and secondary lesions. • Pigmentary demarcation lines lesions, the number of which The patient discussed herein presented • Post-kala-azar leishmaniasis • declines with the lesion’s with multiple hypopigmented patches that • Physical agents (heat or freezing, lasers, radiation) overall age. Biopsy with were a manifestation of a rare but still pres- • Melanoma-associated leukoderma visual microscopy of pri- ent tropical disease. With increased glo- • Lichen sclerosus mary or secondary lesions balization, people in areas of the world that • Idiopathic guttate hypomelanosis by hematoxylin and eosin are not known to be endemic for this dis- • Progressive macular hypomelanosis staining is relatively non- ease may have to be more wary. The astute • Bier’s spots specific. Acanthosis with clinician should continue to include this • spongiosis is seen in the unusual, communicable, and easily treat- • Woronoff’s ring epidermis, and there is a able entity in the differential diagnosis of • Nutritional disorders sparse dermal infiltrate of hypopigmented patches. • Treponematoses (yaws, bejel, pinta) lymphocytes, plasma cells, References and neutrophils scattered 1. Engelkens HJ, Niemel PL, van der Sluis JJ, Meheus among dilated blood ves- A, Stolz E. Endemic treponematoses. Part II. Honduras, Venezuela, Bolivia, Peru, Colom- sels within the dermis. Lichenoid inflam- Pinta and endemic syphilis. Int J Dermatol. 1991 Apr;30(4):231-8. bia, Guatemala, and Brazil are believed to mation with basal layer vasculopathy and 2. Koff AB, Rosen T. Nonvenereal treponematoses: yaws, be endemic foci. pigment incontinence is also sometimes endemic syphilis and pinta. J Am Acad Dermatol. seen. Tertiary-stage lesions typically have 1993;29:519-535. The mode of transmission is as yet numerous melanophages within the der- 3. Woltsche-Kahr I, Schmidt B, Aberer W, Aberer E. Pinta unknown; however, most believe it to be in Austria (or Cuba?): import of an extinct disease? Arch mis, along with epidermal atrophy and Dermatol. 1999 Jun;135(6):685-8. spread by touch. As described in the case 14 perivascular lymphocytic infiltrates. Anti- 4. Chandler FW Jr, Kaufmann AF, Kuhn US. The above, it is classically described as spread- treponemal immunohistochemical stains or histopathology of experimental pinta in the chimpanzee. ing between family members. Older case J Invest Dermatol. 1972;58:103-108. silver stains may be employed to visualize reports emphasize a variety of specific cul- 5. Castro LG. Nonvenereal treponematoses. J Am Acad organisms in all but late, chronic lesions. Dermatol. 1994;31:1075-1076. tural customs, such as ritualistic whipping Treponemal laboratory tests (rapid plasma 6. Sosa-Martinez J, Peralta S. An epidemiologic study of ceremonies among Indian tribes, as meth- pinta in Mexico. Am J Trop Med. 1952;10:556-565. 10,11 reagent [RPR], Venereal Disease Research ods of transmission; however, insect 7. Edmundson WF, Rico AL, Olansky S. A study of pinta Laboratory [VDRL] test) will be positive as bites or other physical factors which dis- in the Tepalcatepec Basin, Michoacán, Mexico. Am J in syphilis in all stages of disease and are Syphilol. 1953;37:201-225. rupt the natural skin barrier likely play a not able to discriminate between species 8. Lupi O. Tropical dermatology: bacterial tropical more pertinent role.8 Typically, children diseases. J Am Acad Dermatol. 01-APR-2006; 54(4): of Treponema. Confirmatory tests such 559-78. and young adults are affected, with a typical as T. pallidum hemagglutination (TPHA), 9. Talhari S. Pinta. In: Talhari S, Garrido Neves R, editors. age of onset of 15-30 years. Both sexes are microhemagglutination T. pallidum (MHA- Dermatologia tropical. Rio de Janeiro: Ed Medsi; 1997. affected equally.1 pp. 291-300. TP), and fluorescent treponemal antibody 10. Biocca E. Estudo etno-biolo´gico sobre os ı´ndios Clinically, pinta’s primary lesion is absorption (FTA-Abs) will also be positive.15 do alto Rio Negro, Amazonas. Transmissão ritual e transmissão criminosa da espiroquetose discrômicas characterized by an erythematous papule The difficulty in differentiating trepone- (pupu-puru, pinto). entre os indios do Rio Icana. Arq Biol surrounded by erythematous, squamous mal species strictly by laboratory testing (S Paulo) 1945;29:7-12. plaque or halo that appears one to eight alone lies in the strikingly similar genetic 11. Talhari S, Maleville J, Basset A. Epidemiology of 8,12 endemic non-venereal treponematoses. Bull Mem Acad weeks after inoculation. By direct exten- sequences between T. pallidum and the R Med Belg 1992;147:149-59. sion or fusion of satellite lesions, the pri- non-venereal treponemal species.16 Clinical 12. Padilha-Goncalves A. Pinta experimental. Bol Soc Bras mary site may grow to a diameter of 12 cm diagnosis with histopathologic confirmation Derm Sif 1949;1:190-1. or larger, forming an ill-defined erythema- 13. Lapeere H. Chapter 73. “Hypomelanoses and currently remains the most practical means hypermelanoses.” In Wolff K, Goldsmith LA, Katz SI, tous plaque with hypopigmentation. Occa- of differentiation. Gilchrest B, Paller AS, Leffell DJ (Ed.), Fitzpatrick's sional local lymphadenopathy can be seen.8 dermatology in general medicine (7th ed., ). New York: Treatment of pinta is most easily McGraw Hill, (2008), p 627. Secondary lesions, or “pintids,” manifest accomplished with a single injection of pen- 14. Crowson N, Magro C, Mihm M. Histology of the skin. as initially erythematous patches that turn In: Elder DE, Elenitsas R, Johnson B, Murphy G, icillin G benzathine 2.4 million units IM editors. Lever's histopathology of the skin. 9th ed. brown, slate blue, gray or black.13 After sev- for disease of less than 2 years duration. Philadelphia:JB Lippincott; 2005. p. 584-585. eral years, a mix of depigmented and hyper- For those cases with duration >2 years, 2.4 15. Klein N, Cunha. “Pinta.” eMedicine. WebMD, Aug 3, pigmented lesions may result. The tertiary 2011. Available at: http://emedicine.medscape.com/ million units of penicillin G benzathine article/225576-overview Accessed Feb. 2 2012. stage is evident with the development of is recommended IM, three times in one 16. Smajs D, Norris SJ, Weinstock GM. Genetic diversity multiple hypopigmented, symmetric areas in Treponema pallidum: implications for pathogenesis, week for adults. The dose for patients on the bony prominences over the wrists, evolution and molecular diagnostics of syphilis and under six years of age is 600,000 units IM, yaws. Infect Genet Evol. 2012 Mar;12(2):191-202. Epub elbows, ankles and knees, giving patients 2011 Dec 15. Grelck, Nguyen, Usmani, Shecter 45 Reed Syndrome: Hereditary Leiomyomatosis and Renal Cell Cancer

Peter J. Morrell, DO, FAOCD

Kirksville College of Osteopathic Medicine - Mohs Surgery Fellow, Tulsa, OK

ABSTRACT: Reed Syndrome or Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is catalogued in the Online Mendelian Inheritance in Man Database (OMIM 150800) and was first reported in 1973. This condition is associated with significant, aggressive internal malignancies, and thus is an important genodermatosis for dermatologists and other clinicians to recognize. Herein, we present a characteristic clinical presentation of this syndrome and review pertinent treatment options and screening recommendations.

Figure 1 – Numerous seen as small, skin-colored Figure 2 – Close-up to pink, dermal-based papules grouped on the right upper back view of a represen- and shoulder. tative skin-colored on the Case Report right upper back. Patient ML, a 54-year-old Caucasian male, presented to our dermatology clinic with a chief complaint of a few small painful “bumps” on the right upper back. He had noticed many simi- lar small, persistent, pink papules which had first arisen in this same area years ago. It was only recently, however, that they had become more bothersome and symptomatic. His medical history was unremarkable other than remote past treatment for , now in remission. Fam- ily history revealed a father who was deceased after battling “some problem with his kidney.” The Figure 3 – 4x power H&E view of the biop- patient was unsure if this problem was kidney cancer. Physical exam showed numerous small, sied leiomyoma from the right upper back. 5-10mm pink, firm, dermal-based papules, with no overlying epidermal change, segmentally Note the poorly demarcated dermal-based clustered over the right upper back and shoulder (Figures 1-2). At this point, a punch excisional proliferation of cells with pink cytoplasm, biopsy was taken around a representative symptomatic lesion and sent off for histopathological round nuclei and peri-nuclear vacuoliza- analysis, which revealed a leiomyoma (Figures 3-4). Taking into account the multi-focal nature tion. of these leiomyomas, along with a possible family history of kidney cancer, it was decided that genetic testing for Reed syndrome (HLRCC) would be prudent. Whole blood samples were then sent for laboratory sequencing, which ultimately revealed the patient to be heterozygous for an A117P missense mutation in the fumarate hydratase gene, confirming the diagnosis. Genetic counseling was provided at length for the patient along with a discussion concerning the impli- cations for any living blood-relatives. Baseline CT of the abdomen, with and without contrast, was negative for any kidney abnormality and will be repeated, per urology, at 1-2 year intervals. Finally, as to symptomatic treatment, the few particularly bothersome leiomyomas have been punch excised without complication, and the patient has been pleased. Figure 4 – 10x power H&E view of the same biopsied leiomyoma. Note the characteristic bundles of cells with pink cytoplasm, round nuclei and peri-nuclear vacuolization. Those cells in longitudinal section also nicely demonstrate the classic cigar-shaped nuclei seen in these benign smooth-muscle proliferations.

46 Reed Syndrome: (Hereditary Leiomyomatosis and Renal Cell Cancer) Discussion nitroglycerin, NSAIDS, analgesics, gabapen- tin, doxazosin, phenoxybenzamine, prega- First reported in 1973, Reed syndrome balin, duloxetine, and even Botox injections (HLRCC) has been linked to the fumarate have all been advocated.1,3,4,11,13 The effective hydratase gene on chromosome 1q42.3- 1-4 dosing regimen for these medications varies q43. Mutations in this gene lead to short- and is anecdotal. Partial rather than com- ages of the fumarate hydratase enzyme, plete resolution of symptoms tends to be the which is part of the Krebs cycle. The exact rule. Our patient, though not completely pathogenesis of how this defect leads to symptom-free, was more than satisfied with proliferation and renal can- our procurement of a definitive diagnosis cer is unknown. In the autosomal-dom- and partial relief of his pain. inant, heterozygous form, it displays the Finally, comprehensive genetic coun- typical findings of Reed syndrome, while seling should be provided to the patient and the rare autosomal-recessive variety mani- family. Taking into account the autosomal- fests as fumarate hydratase deficiency with dominant nature of this condition, if pos- severe neurological disease absent cutane- sible, blood-relatives should be clinically ous signs. examined and offered genetic screening as Reed syndrome typically presents with well. multiple cutaneous or uterine leiomyomas starting in the third decade of life. In the References 1. Alam NA, Bevan S, Churchman M, et al. Localization of skin, these benign cutaneous smooth-mus- a gene (MCUL1) for multiple cutaneous leiomyomata cle characteristically arise from and uterine fibroids to chromosome 1q42.3-Q43. American Journal of Human Genetics 2001; 68(5); the arrector pili muscle and are visualized 1264-1269. as smooth, firm, pink to skin-colored pap- 2. Holst VA, Junkins-Hopkins JM, Elenitsas R. Cutaneous ules or nodules that are symptomatically smooth muscle neoplasms: clinical features, histologic findings, and treatment options. J Am Acad Dermatol painful in the majority of patients. These 2002; 46: 477-490. recurrent painful episodes can be triggered 3. Kostopanagiotou G, Arvaniti C, Kitsiou MC, et al. Successful pain relief of cutaneous leiomyomata due by pressure, cold, or rubbing, or they may to reed syndrome with the combination treatment 5-6 occur spontaneously. Uterine leiomyomas of pregabalin and duloxetine. Journal of Pain and (fibroids) in these patients tend to have a Symptomatic Management 2009; 39(3)e3-e5. 4. Mitchum MD, Adams EG, Holcomb KZ, Wisniewski JD, slightly earlier age of onset (20-35) com- et al. JAAD grand rounds quiz. J Am Acad Dermatol pared to the general population (35-44) 2012; 66(2); 337-339. and are more symptomatic, often needing 5. Garcia MP, Pujol RM, Alomar A, Calaf J, de Moragas 4,7-9 JM. Familial leiomyomatosis cutis et uteri (Reed’s hysterectomy. Cutaneous leiomyomas Syndrome). Arch Dermatol Res 1988; Suppl:S29-S32. generally precede the uterine fibroids by 6. Butler DF. Pathology quiz case: cutaneous leiomyoma about seven years.4 (familial). Archives of Dermatology 1984; 120: 1618-20. 7. Garg K, Tickoo SK, Soslow RA, Reuter VE. Morphologic The kidney tumors associated with features of uterine leiomyomas associated with Reed syndrome tend to be very aggressive hereditary leiomyomatosis and renal cell carcinoma syndrome: a case report. Am J Surg Pathol 2011; 35(8); compared to other cutaneous-renal geno- 1235-1237. dermatoses such as Birt–Hogg–Dubé syn- 8. Alam NA, Rowan AJ, Wortham NC, et al. Genetic drome. These tumors are thought to arise and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary 7,10 in around 15% of patients with HLRCC. leiomyomatosis and renal cancer, and fumarate hydratase deficiency. Hum Mol Genet 2003; 12; 1241- The most common types that have been 1252. definitively linked are papillary renal 9. Stewart L, Glenn GM, Stratton P, et al. Association cell carcinoma and collecting duct carci- of germline mutations in the fumarate hydratase gene and uterine fibroids in women with hereditary noma. Rarely, have been leiomyomatosis and renal cell cancer. Arch Dermatol reported as well. Owing to the aggressive 2008; 144; 1584-1592. nature of these associated renal malignan- 10. Toro JR, Nickerson ML, Wei MH, et al. Mutations in the fumarate hydratase gene cause hereditary cies, periodic imaging with MRI or CT is leiomyomatosis and renal cell cancer in families in North suggested, while ultrasound alone is con- America. Am J Hum Genet 2003; 73; 95-106. 4 11. Stapp L, Thomas J, Weiss E, Combs A. Multiple sidered inadequate. There is currently no piloleiomyomas associated with fumarate hydratase definitive consensus as to the optimum rec- gene mutation: a case report and review of the literature. Journal of the American Osteopathic College ommended screening interval. of Dermatology 2012; 22; 32-34. Treatment of these leiomyomas is 12. Haugen R, Tharp M. The use of gabapentin for recurrent classically dependant on symptomatol- painful attacks with multiple piloleiomyomas. J Drugs Dermatol 2008; 7; 401-402. ogy. Options range from simple excision 13. Thompson JA. Therapy for painful cutaneous to numerous pharmacologic possibilities, leiomyomas. J Am Acad Dermatol 1985; 13; 865. all with varying degrees of success. Some reports have shown that excision tends to be associated with high recurrence rates approaching 50%.11-12 Other destructive modalities such as and electro- coagulation, however, tend to be even more disappointing.2,11 Drugs such as nifedipine,

MORRELL 47 Primary Cutaneous Anaplastic Large-cell Lymphoma

Ali Daneshvar,* Indira Misra-Higgins, DO, FAOCD **

*OMS-IV, Michigan State University College of Osteopathic Medicine, East Lansing, Michigan ** Private Practice Dermatology, Beverly Hills, Michigan

ABSTRACT: Anaplastic large-cell lymphoma (ALCL) is a disorder of abnormal proliferation of lymphoid cells with highly variable cytological features; it expresses the lymphocyte activation marker CD30.1 There are both primary cutaneous and systemic forms of ALCL. Three variants of ALCL include the common type, the lymphohistiocytic type, and the small-cell type. Primary cutaneous anaplastic large-cell lymphoma (PCALCL) is a rare, anaplastic T-cell lymphoma originating in and usually confined to the skin, characterized by solitary or multiple, erythematous or brown nodules and tumors. Although a small number of cases resolve spontaneously, the vast majority of primary cutaneous anaplastic large-cell lymphomas require treatment. We present a case of a 36-year-old Caucasian male who presented to the clinic with a three-week history of a nodular plaque on his right nasolabial fold. The typical clinical presentation, pathogenesis and management of primary cutaneous anaplastic large-cell lymphoma will be reviewed in this case study.

Case Description of the right nasolabial fold. At this time, he was started on a course of sulfamethoxazole A 36-year-old Caucasian male with an and trimethoprim. In addition, the fungal unremarkable medical history presented to cultures came back negative, and the bacte- our clinic with a nodular plaque on his right rial gram stain showed gram-positive bacilli nasolabial fold as well as an erythematous along with other polymorphonuclear leuko- lesion on his left mid-back. The lesions arose cytes. In an effort to identify the nature of the spontaneously two and a half weeks prior to lesion, the patient was referred to plastic sur- his visit. They began as flesh-colored papules gery, where an excisional biopsy of the lesion and subsequently enlarged and transformed was done and sent for pathology. into firm, erythematous nodules. There was The pathology from the biopsy speci- slight pain associated with the lesions. He men is shown in Figures 1-3. The biopsy denied any trauma or previous injuries to the shows lymphocytes infiltrating into follicu- areas. The patient also noted two patches of lar epithelium where there is associated fol- Figure 1 hair loss on his legs occurring over the past licular mucinosis (Figure 1). The infiltrate few years. He denied any previous treatment is comprised of large lymphoid cells with prior to his presentation. The patient had vesicular indented nuclei as well as promi- no personal history or family history of skin nent nucleoli. There are numerous mitotic cancer. He also denied any history of fever, changes with atypia (Figures 2, 3). Also, the weight loss, night sweats, or fatigue. infiltrate shows the presence of eosinophils On physical examination, a fairly tender, and neutrophils. Immunochemical stains erythematous, nodular plaque in the right showed positive labeling of the folliculotropic nasolabial fold was noted. In addition, there lymphocytes for CD2, CD3, CD4, CD5, was a slightly tender erythematous papule and CD30 and negative for CD7 and CD8. on his left mid-back. Grossly, both lesions Additional immunohistochemical stains appeared acneiform and were presump- were done and showed anaplastic lymphoma tively treated as such. The lesions were each kinase (ALK-1) negative, epithelial mem- treated with a triamcinolone 10mg injection, brane antigen (EMA) negative, and MUM1 Figure 2 clindamycin/benzoyl peroxide topical, as well and MIB1 positive. Given these findings, a as 0.1% tazarotene topical gel. subsequent diagnosis of CD30+/ALK- pri- At his two-week follow-up appointment, mary cutaneous anaplastic large-cell lym- the patient reported no significant relief of phoma was made. his symptoms. The papule on his back had With the diagnosis of PCALCL, the decreased in size and had some clearing of patient was referred to a cutaneous T-cell erythema; however, the nodule on his naso- lymphoma clinic for treatment. A PET CT labial fold had developed marked induration scan of the neck, thorax, abdomen, and and erythema. The lesion was incised and was done to look for any metastatic drained with minimal pus expression, and lesions, and came back negative. A number bacterial and fungal cultures were obtained. of treatment options were discussed with A course of cephalexin 500mg antibiotics the patient including bexarotene gel, intra- four times a day was initiated for a presump- lesional corticosteroids, and radiotherapy. tive facial . A week later, the patient Due to its irritating properties, bexarotene returned to the clinic with progression of was not used on the face. Since two sessions Figure 3 erythema, ulceration, and marked swelling of intralesional corticosteroids offered no 48 Primary Cutaneous Anaplastic Large-cell Lymphoma improvement to the lesions, localized radio- One particular PCALCL case study as in our patient’s case, PCALCL typically therapy was chosen. The patient successfully showed on histology a diffuse infiltration of has an excellent prognosis in the initial stage completed 20 treatments of local radiation lymphocytes and macrophages seen in the when it is confined to the skin; however, therapy to the right cheek. He also denied dermis associated with hypertrophied hair it carries a grim prognosis once systemic any symptoms of pain, headache, drainage, follicles, follicular mucinosis, and marked spread has occurred. or any new skin lesions. Since subsequent folliculotropism, leading to follicular dis- Management of primary cutaneous lym- 6 radiotherapy, the lesion on the patient’s face ruption. Cohesive groups of CD30+ large, phomas often requires a multidisciplinary has regressed, and close follow-up has been atypical lymphocytes with a high prolif- approach. Although one quarter of PCALCL maintained. erative index were seen focally. Similarly, cases resolve spontaneously, the vast major- our patient's biopsy showed the follicular 3,5,10 Discussion ity require treatment. Choice of therapy epithelium to be expanded and containing depends on two factors: disease dissemina- The group CD30+ cutaneous lympho- mucin. The infiltrate showed large lym- tion, and the presence of localized or mul- proliferative disorders (CLPD) includes a phoid cells with vesicular indented nuclei tifocal lesions. For a solitary lesion, local spectrum of disorders such as lymphoma- as well as prominent nucleoli. Lymphocytes radiotherapy is the preferred treatment.1,3,10 toid papulosis, borderline cases of CD30+ were also noted in the expanding follicular Surgical excision is an alternative approach CLPD, and primary cutaneous anaplastic epithelium, as well scattered mitoses. Con- for localized lesions and in conjunction with large-cell lymphoma (PCALCL).2 These lym- sequently, PCALCL may present with differ- radiotherapy leads to an excellent prognosis. phomas comprise the second most common ent histologic features, including a follicular Single-agent therapy using low-dose metho- group of cutaneous lymphomas after mycosis variant, that may mimic both benign and trexate is effective for patients with multifo- fungoides. Three variants of CD30+ ana- malignant conditions such as mycosis fun- cal disease or for those who do not respond 6 plastic large-cell lymphoma (ALCL) include goides or Sézary syndrome. Histology of well to surgical and radiation treatment.10 the common, lymphohistiocytic, and small- PCALCL typically shows cohesive sheets of Consequently, physicians must be keen and cell types.4 Primary cutaneous CD30+ T-cell neoplastic cells with anaplastic morphol- clinically suspicious if patients present with lymphoproliferative disorders as a group are ogy, including round to irregularly shaped non-healing recurring ulcers. Cutaneous one of the more common types of T-cell lym- nuclei, prominent nucleoli, and abundant lymphoma should be considered as a dif- 7 phoma, comprising around 30% of the total cytoplasm. When an ulcer is present, it is ferential diagnosis in these instances, and number of cases.7 More specifically, PCALCL accompanied by an abundant inflammatory further clinical workup should be initiated. is the second most common cutaneous T-cell infiltrate consisting of reactive T-cells, neu- lymphoma.7 trophils, eosinophils, and histiocytes, similar References 8 to the histology in our patient. PCALCL is 1. Asha L, Thomas D, Binitha M, Nandakumar G. Primary Primary cutaneous anaplastic large- cutaneous multifocal CD 30+ anaplastic large cell difficult to recognize histologically, since it cell lymphoma is a rare anaplastic CD30+ lymphoma. Indian Journal of Dermatology, is characterized by variable histopathologi- and Leprology. 2006;72(5):376-8. large T-cell lymphoma originating in and cal presentations and a broad cytomorpho- 2. Nandini, A, et al. Primary Cutaneous Anaplastic Large usually confined to the skin, character- Cell Lymphoma Arising from Lymphomatoid Papulosis, logic spectrum.4 It can be classified according ized by solitary or multiple, erythematous Responding to Low Dose Methotrexate. Journal of to histologic features (i.e., pleomorphic, Cutaneous and Aesthetic Surgery 2.2 (2009): 97-100. or brown nodules and tumors with a ten- immunoblastic, monomorphic, small-cell 3. Rao SD, Ravi R, and Govindarajan M. Primary dency to ulcerate.2 Typically, progression to Cutaneous CD30+ Anaplastic Large Cell Lymphoma. predominant, Hodgkin-disease related), Indian Journal of Surgery 72.00195650 (2010): 283-5. extracutaneous sites is rare. In general, the immunophenotype, and clinical features, 4. Massone C, El-Shabrawi-Caelen L, Kerl H, Cerroni prognosis of CD30+ cutaneous T-cell lym- L. The morphologic spectrum of primary cutaneous such as ALCL occurring after another lym- phoma (CTCL) is more favorable than that anaplastic large T-cell lymphoma: a histopathologic study phoproliferative disorder (i.e., mycosis fun- on 66 biopsy specimens from 47 patients with report of its CD30- counterparts, and spontaneous of rare variants. Journal of Cutaneous Pathology. 2008 goides or lymphomatoid papulosis) or arising Jan;35(1):46-53. regression is observed in up to 25% of cases 2,7,9 5 in HIV-positive patients. 5. Tchernev G, et al. "Extrinsic Apoptotic Pathways: A New of PCALCL. These disorders are more com- Potential "Target" for More Sufficient Therapy in a Case mon in middle-aged males than in females. Clinically, physicians must be aware of of Cutaneous Anaplastic Large CD30+ ALK-T--Cell Lymphoma." Indian journal of dermatology 56.1 (2011): Typically, lesions present on the face, trunk, differential diagnoses when approaching a 87-91. or extremities as , plaques, nodules cutaneous lesion similar to that seen in this 6. Bittencourt AL, de Oliveira RF, Santos JB. Primary and/or tumors with central ulceration and patient. PCALCL can present in benign and cutaneous folliculotropic and lymphohistiocytic anaplastic large cell lymphoma. Journal of Cutaneous Medicine and may undergo spontaneous regression; how- malignant forms and appear similar to other Surgery. 2011 May-Jun;15(3):172-6. 1 ever, they maintain a high recurrence rate. common dermatological diagnoses. It can 7. McNab PM, Jukic DM, Mills O, Browarsky I. Primary present like lymphomatoid papulosis, myco- cutaneous CD30+ T-cell lymphoproliferative disorder Histology of ALCL typically shows dif- presenting as : a case report and review sis fungoides (MF), and Sézary syndrome of the literature. Dermatology Online Journal. 2011 Jul fuse, non-epidermotropic infiltrates with (SS). It can also present similarly to the 15;17(7):3. cohesive sheets of large CD30+ tumor cells, more common cases of cellulitis, eczema or 8. Ralfkiaer E, et al. Primary cutaneous CD30+- oval or irregularly shaped nuclei, prominent positive T-cell lymphoproliferative disorders, in WHO even acne, as in our patient. Lymphomatoid Classification of Tumours of Haematopoietic and eosinophilic nucleoli and abundant cyto- Lymphoid Tissues, S.H. Swerdlow, et al., Editors. 2008, papulosis is a self-healing papulonecrotic or plasm with a high mitotic index.6 Immuno- International Agency for Research on Cancer (IARC) papulonodular skin disease with histologic Press: Lyon. p. 300-301. histochemistry is essential in determination features suggestive of a (CD30+) malignant 9. Kempf W, et al. CD30+ T-cell Lymphoproliferative Disorders., in WHO Classification of Tumours. Pathology of CTCL subtypes, and in the differentiation 11 lymphoma. Mycosis fungoides also presents and Genetics of Skin Tumours, P.E. Leboit, et al., Editors. between primary and secondary disease.6 with different stages including pre-MF, patch, 2006, International Agency for Research on Cancer PCALCL more frequently expresses the cuta- (IARC) Press: Lyon. plaque, and tumor, similar to the patch on neous lymphocyte antigen (CLA) but lacks 10. Diamantidis MD, Myrou AD. Perils and pitfalls regarding our patient’s face. Other differentials include differential diagnosis and treatment of primary cutaneous the epithelial membrane antigen (EMA), and anaplastic large-cell lymphoma. Scientific World Journal. B-cell lymphoma, Hodgkin disease, meta- ALK expression is negative in most cases, as 2011 May 5;11:1048-55. static carcinoma, granulocytic sarcoma, and in our patient’s case.10 11. Habif TP. Cutaneous T-Cell Lymphoma. In Clinical even malignant melanoma. If detected early, Dermatology. Philadelphia: Mosby, Inc. 2004. p.754-762.

Daneshvar, Misra-Higgins 49 A Case of Segmental Neurofibromatosis

Alison Himes, DO,* Kristi Hawley, DO,** Dawn Sammons, DO***

*PGY-5, O’bleness Memorial Hospital, Athens, Ohio **PGY-1, O’bleness Memorial Hospital, Athens, Ohio ***Oakview Dermatology, O’bleness Memorial Hospital, Athens, Ohio

ABSTRACT: Segmental neurofibromatosis is a rare variant of neurofibromatosis type 1 and is characterized by café-au-lait macules, and/or cutaneous that are limited to a circumscribed body segment. This subset of neurofibromatosis type 1 is considered to be the result of a somatic mosaicism and is believed to be underreported. We report a case of localized segmental neurofibromatosis in a 54-year-old female who presented with a 10 year history of painful papules clustered in a dermatomal distribution on the right posterior shoulder. In this case study we will discuss the pathogenesis, clinical findings, and consequences of segmental neurofibromatosis. Introduction Segmental neurofibromatosis (SNF) is a rare variant of the common genodermatosis neurofibromatosis type 1 (NF1). SNF is characterized by café-au- lait macules (CALMs), freckles and/or cutaneous neurofibromas that are limited to a circumscribed body segment.1-5 Fewer than 150 cases have been reported in the literature4 since the first case was described in 1931 by Gammel,6 with a prevalence estimated to be 0.002%.2 SNF is thought to be underreported due to its absence of symptoms and complications in most patients.2,4 Here we present a 54-year- old female with SNF localized to the right scapula. Case Report A 54-year-old Caucasian female Figure 1: Multiple scattered, pink and flesh-toned papules on posterior right shoulder. presented to the dermatology clinic Scars are present from years of cryotherapy. complaining of painful lesions on her right posterior shoulder. She stated that the first lesion appeared more than 10 years ago and had gradually progressed into multiple lesions confined to the back of her right shoulder. She reported stinging, pruritus, and pain with palpation of the papules. She noted that her primary care physician had tried removing them with cryotherapy in the past. Her past medical history was significant for hepatitis C and bipolar disorder, but she denied any history of seizures or other neurologic disorders. Family history was non-contributory, and the patient had no children. Examination revealed approximately 15 discrete, flesh-toned and pink papules on the posterior right shoulder in a dermatomal distribution (Figures 1 and 2). The papules ranged in size from 2mm to 8mm. Full body exam revealed no other significant lesions, including CALMs or axillary freckling. A 4mm punch biopsy Figure 2: Closer view of soft papules.

50 A Case of Segmental Neurofibromatosis was performed on one of the lesions, which demonstrated proliferation of spindle cells in the superficial dermis surrounding eccrine ducts. The cytoplasm of the cells was pale, wavy and eosinophilic with no cytologic atypia or capsule present (Figures 3 and 4). The clinical and histopathological findings were consistent with neurofibromas in a segmental distribution. Discussion This patient demonstrates features that are consistent with localized segmental neurofibromatosis. This rare variant of NF1, in which lesions are confined to a circumscribed body segment, is a non- inherited form of NF1 caused by a postzygotic mutation of the NF1 gene resulting in mosaicism.3,6-8 Mosaicism is the consequence of a sporadic mutation that occurs in a single, genetically homogenous zygote, resulting in more than one genetically distinct cell line Figure 3: Histopathology at 100x. Note the proliferation of spindle cells in the superfi- in an individual. The timing of the mutation cial dermis surrounding eccrine ducts. (early versus late embryonic development) determines the clinical effect of the disease; early mutations lead to generalized disease, whereas mutations occurring later (after cell differentiation) give rise to segmental disease.2,6,9 Despite the sporadic nature of mutations, familial occurrence has been reported in several cases.10-12 This can be explained by germ-line mutations referred to as gonosomal mosaicism.6,9,13 Neurofibromatosis has been previously classified by Riccardi into seven different types.1 The segmental type, demonstrated by our patient, was referred to as NF-type 5 and was defined as the occurrence of cutaneous lesions (café-au-lait spots, freckling, and/ or neurofibromas) restricted to a single side of the body, with no crossing of the midline, in a patient with no family history of neurofibromatosis.1 This definition has since been adjusted as different clinical subtypes continue to be reported.2,14 Roth et al. has proposed a new classification system Figure 4: Histopathology at 400x. The cytoplasm of the cells are pale, wavy and eosino- to further encompass the different types philic with no cytologic atypia or capsule present. of SNF,14 in which our patient is classified as true segmental (i.e., meets Riccardi’s Neurofibromas are the most common relatively superficial nerves, neurofibromas criteria). True segmental neurofibromatosis manifestation of SNF and are most often present as subcutaneous nodules that are is the form that is most commonly reported unilateral and located on the right side of the often only painful when touched. They tend in the literature.2,5 body.2,17 The lesions tend to occupy a single to have a characteristic violaceous color and dermatome,2 most commonly cervical or may be pruritic.2 SNF has a prevalence of 1 in 36,000 to thoracic.17 Patients suffering from SNF are 40,000 individuals in the general population,5 Extracutaneous manifestations of SNF typically asymptomatic, and the lesions are 2,5,17-19 with the majority of cases occurring in white are rare but have been described. A discovered incidentally, with the exception females.15-16 A review of 82 SNF patients by study of ophthalmological manifestations of patients with spinal neurofibromas Hager et al. revealed the median age of onset in 72 patients with SNF by Ruggieri et al. or lesions on major peripheral nerves. to be 28 years (range, birth to 83) with a revealed no Lisch nodules or hypertelorism 17 These patients often present with pain in any of their patients,18 findings commonly female predominance of 59%. A review of or neurologic deficits. Common dermal 20-21 124 SNF patients by Ruggieri and Huson in seen in NF1. One study reported a neurofibromas, as seen in our patient, lie 2001 demonstrated a mean age of onset of higher prevalence of short stature and within the dermis and epidermis and move 19 17.4 years (range, 4 to 70) with a slight male macrocephaly. The review by Ruggieri passively with the skin. When they are on predominance of 53%.2 and Huson demonstrated specific NF1

Himes, Hawley, Sammo ns 51 complications in 5.6% of their patients, 9. Hall JG. Review and hypotheses: somatic mosaicism: observations related to clinical genetics. Am J Hum Genet which included learning difficulties, 1988;43:355-363. plexiform neurofibromas, optic pathway 10. Lazaro C, Ravella A, Gaona A, Volpini V, Estivill X. 2 Neurofibromatosis type 1 due to germ-line mosaicism in gliomas, and pseudarthrosis. SNF has a clinically normal father. N Engl J Med 1994;331:1403–7. been reported to occur in association with 11. Oguzkan S, Cinbis M, Ayter S, et al. Familial Segmental a variety of conditions, including renal Neurofibromatosis. J Child Neuro 2004;19(5):392-394. agenesis,22 adenocarcinoma of the colon,23 12. Boltshauser E, Stocker H, Machler M. Neurofibromatosis 24 type 1 in a child of a parent with segmental partial unilateral , agenesis neurofibromatosis (NF-5). Neurofibromatosis of the corpus callosum,25 and nevus 1989;2:244–5. sebaceous of Jadasshon.26 Malignancies 13. Consoli C, Moss C, Green S, Balderson D, et al. Gonosomal mosaicism for a nonsense are rare, but reported cases include adrenal mutation (R1947X) in the NF1 gene in segmental 27 neurofibromatosis type 1. J Invest Dermatol ganglionueroma and peripheral nerve 2005;125:463–6. 28 sheath tumors. 14. Roth R, Martines M, James W. Segmental Management of SNF is simple. Patients neurofibromatosis. Arch Dermatol 1987;123:917-920. should be aware that disease-associated 15. Sanchez Conejo-Mir J, Herrera Saval A, Camacho complications are very rare in localized Martinez F. Segmental neurofibromatosis. J Am Acad Dermatol 1989;20:681–682. SNF. 2 Regardless, all patients suspected 16. Niiyama S, Satoh K, Kaneko S, Aiba S, Mukai H. of having this disorder should undergo Segmental neurofibromatosis. Acta Derm Venereol a thorough skin and ophthalmologic 2005;85:448-9. 29 17. Hager CM, Cohen PR, Tschen JA. Segmental exam. If the neurofibromas cause neurofibromatosis: Case reports and review. J Am Acad discomfort, create cosmetic disfigurement, Dermatol 1997;37(5):864-9. or compromise adjacent structures, they 18. Ruggieri M, Pavone P, Polizzi A, et al. Ophthalmological 30 manifestations in segmental neurofibromatosis type 1. Br may be surgically removed. With regard to J Ophthalmol 2004;88:1429-1433. genetic counseling, those considering having 19. Hix K, Rothner D, Cohen B. Segmental children have a very small risk of having a neurofibromatosis: analysis of 14 cases. Ann Neurol 1998;44:575-576. child with generalized NF1, although the 20. Friedman JM, Gutmann DH, MacCollin M, Riccardi 2 exact risk is unknown. VM, eds. Neurofibromatosis: phenotype, natural history and pathogenesis. 3rd ed. Baltimore: Johns Hopkins Conclusion University Press; 1999. 21. Huson SM. Neurofibromatosis 1: a clinical and genetic SNF is a rare but probably underreported overview. In: Huson SM, Hughes RAC, Eds. The neurofibromatoses: pathogenetic and clinical overview. disorder, as the majority of patients are London: Chapman & Hall; 1994: p. 160-203. 2 asymptomatic. This condition is thought 22. Demierre MF, Gerstein W. Segmental neurofibromatosis with ipsilateral renal agenesis. Int J Dermatol to be secondary to a sporadic postzygotic 1996;35:445-7. mutation resulting in mosaicism, making it 23. Kim SE, Heo EP, Yoon TJ, Kim TH. Segmentally incapable of spreading to offspring unless distributed neurofibromatosis associated with involving the germ-cell line.3,6-9,13 Our adenocarcinoma of the colon. J Dermatol 2002;29:350-3. 24. Wong SS. Bilateral segmental neurofibromatosis patient is an example of the most common with partial unilateral lentiginosis. Br J Dermatol presentation documented in the literature:2,17 1997;136:380-3. Unilateral neurofibromas present in a 25. Hassan I, Shah PA, Malik GM. Segmental neurofibromatosis with agenesis of corpus callosum. J dermatomal pattern on the right side of Assoc Physics Ind 2000;48:1125-6. the body in an individual without a family 26. Lupton JR, Elgart ML, Sulica VI. Segmental neurofibromatosis in association with nevus sebaceus of history. Our patient does not currently suffer Jadassohn. J Am Acad Dermatol 2000;43:895-7. from any extracutaneous manifestations. 27. Darie H, Veran Y, Le Guyadec T, Gros P, et al. Cutaneous splanchnic neurofibromatosis. Ann Dermatol Venereol References 1998;125:509-11. 1. Riccardi VM. Neurofibromatosis: clinical heterogeneity. 28. Schwarz J, Belzberg AJ. Malignant peripheral Curr Probl Cancer 1982;7:1-34. nerve sheath tumours in the setting of segmental neurofibromatosis. Case report. J Neurosurg 2. Ruggieri M, Huson SM. The clinical and diagnostic 2000;92:342-6. implications of mosaicism in the neurofibromatoses. Neurology 2001;56:1433-43. 29. Goldberg NS. What is segmental neurofibromatosis? J Am Acad Dermatol 1992;26:638-640. 3. Redlick FP, Shaw JC. Segmental Neurofibromatosis Follows Blaschko’s Lines or Dermatomes Depending 30. Krishnan R, Angel T, Orengo I, et al. Bilateral segmental on the Cell Line Affected: Case Report and Literature neurofibromatosis: a case report and review. Inter J Review. J Cutan Med Surg 2004;353-56. Dermatol 2001;40:401-414. 4. Kumar S, Kumar RP. Multi-segmental neurofibromatosis. Indian J Dermatol Venereol Leprol 2004;70(6):361-3. 5. Huson SM, Ruggieri M. The neurofibromatoses. In: Harper J, Oranje JM, Rose M, eds. Textbook of pediatric dermatology. Vol. 2. Oxford: Blackwell Science; 2000. P. 1204-1224. 6. Happle R. Principles of genetics, mosaicism and molecular biology. In: Harper J, Oranje JM, Rose M, eds. Textbook of pediatric dermatology. Vol. 2. Oxford: Blackwell Science; 2000. P. 1037-56. 7. Happle R. Mosaicism in human skin. Understanding the patterns and mechanisms. Arch Dermatol 1993;129:1460-70. 8. Itin PH, Buechner SA. Segmental forms of autosomal dominant skin disorders: the puzzle of mosaicism. Am J Med Genet 1999;85:351-54.

52 A Case of Segmental Neurofibromatosis 53

Combined Nevus: Blue Nevus and Balloon Cell Nevus

Justin Rubin, DO,* Panagiotis Mitropoulos, DO,* Carlos Gomez-Meade, DO, FAOCD,** Evangelos Poulos, MD,*** Tracy Favreau, DO, FAOCD,**** Angela Combs, DO, FAOCD*****

*1st-year Dermatology Resident, NSUCOM/Broward Health, Fort Lauderdale, Florida **Mohs fellow, Skin Institute of South Florida, Coral Springs, Florida ***Dermatopathologist, Faculty Instructor, Global Pathology, Miami Lakes, Florida ****Chairman, Department of Dermatology, NSUCOM/Broward Health, Fort Lauderdale, Florida *****Interim Program Director, NSUCOM/Broward Health, Fort Lauderdale, Florida

ABSTRACT: A blue nevus with histological evidence of balloon cells is underreported and rare in scientific literature. This histological case report illustrates the rare occurrence of this combined nevus and discusses the importance of recognizing this change to avoid misinterpreting the lesion as malignant. Case metastasis is the lymph nodes. Malignant blue nevi can arise A 68-year-old male with history of in a previously benign cellular basal cell carcinoma presented to an outpa- blue nevus, in a or tient office for routine screening. A shave Ito, or de novo.3 Histologically, biopsy of a well-defined blue papule on his it is more densely cellular and right jaw was performed. The subsequent contains atypical melanocytes, histological diagnosis of a combined nevus necrosis, and more inflam- (blue nevus and balloon cell nevus) was mation compared to the non- made. (See histology photos.) malignant blue nevus. Discussion There are many variations of the blue nevus, including cel- The blue nevus was first described in lular blue nevus (Jadassohn’s 1906 by Tiesche and is clinically described nevus or nevus coeruleus), 1 as a well-defined blue papule or nodule. deep penetrating nevus (Seab’s Histologically, it consists of a normal epi- nevus), blue neuronevus (Mas- dermis, and spindle-shaped, dendritic son’s nevus), amelanotic blue melanocytes in the dermis associatied with nevus (hypomelanotic blue abundant, fine granules of melanin, mela- nevus), epithelioid blue nevus, 2 nophages and sclerosis of collagen. Blue compound blue nevus, and nevi are usually acquired and have their combined nevus.4 onset most commonly in childhood and adolescence, although up to one-fourth of The term "combined nevus" cases arise in middle-aged adults.3 Blue nevi is applied to the association of consist of benign tumors of dermal mela- a blue nevus with an overlying nocytes. The melanocytes disappear from or to other 5 the dermis during the second half of gesta- combinations of benign nevi. tion, but some residual melanin-producing Histologically, one component is cells remain. The scalp, sacral region, and often a congenital pattern nevus dorsal aspect of the distal extremities are the in which pigmented spindle most common sites for blue nevi. The blue cells form a focal collection of coloration of these nevi is the result of the fascicles among nests of ordi- 5 Tyndall phenomenon.3 The Tyndall effect nary nevus cells. The fascicles modifies the color of skin and of lesions by tend to be organized along the the selective scattering of light waves of dif- lines of a blue nevus, which may ferent wavelengths. This also explains why be either a common or a cellular 5 the brown melanin in the dermis appears blue nevus. The other compo- blue-gray clinically.4 nent may be an overlying nevus of the junctional, compound, The malignant form of the blue nevus or intradermal type, or rarely is known as malignant blue nevus. This is Spitz.5 a rare form of melanoma and most com- monly arises in cellular blue nevi. Malignant The balloon cell nevus blue nevi tend to show progressive enlarge- was first described in 1901 by 6 ment and have a multinodular or plaque- Judalewitsh. Histologically, like appearance. The most common site it consists of large, ballooned is the scalp, and the most common site of melanocytes with a central RUBIN, MITROPOLUS, GOMEZ-MEADE, POULOS, FAVREAU, COMBS 55 nucleus and a pale granular cytoplasm with 9. McGowan JR, et al. Proliferative nodules with balloon- cell change in a large congenital melanocytic nevus. J of or without ordinary nevus cells. Balloon Cutaneous Pathology. 2006 March(33)253-255. cells are altered melanocytes with clear, vac- 10. Laaff H, et al. Hautarzt. 1992 Sep; 43(9):566-8. German. uolated cytoplasm caused by a defect in 11. Requena L, et al. Malignant Combined Nevus. Am J of the process of melanogenesis.7 Clinically, Dermatopathol. 1991 Apr;13(2):169-73. balloon cell nevi are indistinguishable from ordinary nevi.3 Balloon-cell change has been reported in cases of intradermal mela- nocytic nevi, large congenital melanocytic nevus, dysplastic nevi, and melanoma.1,7,8,9 In 2006, McGowan reported a case of an 18-year-old female who presented with multiple nodules developing in a pre- viously stable giant congenital nevus that involved the left side of her neck, shoulder, and upper back.9 Three of these nodules were biopsied, and two of the three were diagnosed as large congenital melanocytic nevi with balloon-cell change.9 In 1992, Laaff reported seven cases of HMB-45 positive balloon cells in a com- bined nevus, which can make the differen- tiation between benign and malignant more challenging.10 In the balloon-cell mela- noma, the nuclei are large and pleomorphic, mitotic figures are present, and there is an absence of intervening stroma.10 In 1991, Requena reported a case of a combined nevus with malignant transfor- mation. The clinical impression was blue nevus.11 Histologically, the lesion was com- posed of a cellular blue nevus in the retic- ular dermis and an overlying compound melanocytic nevus. The junctional compo- nent of the melanocytic nevus showed tran- sition to malignant melanoma in situ. Presence of the balloon-cell phenom- enon is predominantly determined by the dermatopathologist. Treatment can vary from reassurance to surgical excision with appropriate margins, depending on the degree of atypia. The purpose of this case report is to convey an enhanced awareness of the combined nevus (blue nevus and bal- loon cell nevus). References 1. Tièche M. Über bénigne Melanome (Chromatophorome) der Haut-Blaue Naevi. Virchows Arch. f. path. Anat. 186: 212–229, 1906. 2. Rapini RP. Melanocytic Neoplasms. Practical Dermatopathology. 2005. 261-280. 3. Bolognia JL, et al. Dermatology 2nd Ed. 2003. 1722- 1739. 4. James WD, et al. Melanocytic Nevi and Neoplasms. Andrews’ Diseases of the Skin: Clinical Dermatology. 10th Ed 2006, 685-700. 5. Elder DE, et al. Combined Nevus. Lever’s Histopathology of the Skin: 10th Ed 2009, 704. 6. Judalewitsch G. Zur Histogenese der weichen Nevi. Arch Dermatol Syph 1901;58:15-18. 7. Perez M, et al. Balloon cell change in cellular blue nevus. Am J Dermatopathol. 1999 Apr;21(2):181-184. 8. Cagnano E, et al. Compound nevus with congenital features and balloon cell changes-an immunohistochemical study. Annals of Diagnostic Pathology. 2008 Oct (12)362-364.

56 Combined Nevus: Blue Nevus and Balloon Cell Nevus A Case of Telangiectasia Macularis Eruptiva Perstans (TMEP)

Samuel M. Wilson, DO,* R. Scott Thomas,** Allison K. Divers, MD,*** Daniel S. Hurd, DO, FAOCD**** *Dermatology Resident, PGY2, VCOM/LewisGale Hospital-Montgomery, Blacksburg, VA **Medical Student, OMSIV, KCOM-ATSU, Kirksville, MO ***Clinical Professor of Dermatology, VCOM/LewisGale Hospital-Montgomery, Blacksburg, VA; The Art and Science of Dermatology, Roanoke, VA ****Program Director, VCOM/LewisGale Hospital-Montgomery, Blacksburg, VA

ABSTRACT: represents a wide spectrum of disorders that result in the accumulation of mast cells in one or more organ systems. The organ most commonly involved is the skin. The spectrum of cutaneous mastocytosis includes; cutaneous , , diffuse cutaneous mastocytosis and telangiectasia macularis eruptive perstans (TMEP). TMEP is a rare form of mastocytosis that often presents in adulthood and carries an indolent course. Treatment is often focused on symptomatic relief and avoidance of exacerbating triggers. We describe a case of a 20-year-old Caucasian female that presented with a one-year history of multiple asymptomatic tan to pink telangiectatic macules. Darier's sign was mildly positive. The cutaneous H&E biopsy confirmed the diagnosis of TMEP. Clinical and laboratory findings failed to demonstrate systemic involvement. Case Report to the age of onset. Given the patient’s asymptomatic presen- A 20-year-old Caucasian female pre- tation and a pertinent negative sented to the dermatology clinic for a one- review of systems, the initial year history of persistent “red spots” on work-up included only a CBC her breasts, abdomen and upper thighs. with differential. The labora- The lesions were described as asymptom- tory findings failed to reveal atic. The patient’s primary concern was that any abnormalities. The diag- new lesions were appearing while the old nosis and disease course were ones were not “going way.” Review of sys- discussed in detail with the tems failed to reveal any history of fevers, patient. The patient was edu- unintentional weight loss, reflux, diarrhea, cated on the potential triggers flushing, bone pain, difficulty breathing, and activators of her disease. swelling of the lips, dysphagia, or anaphy- This included the risk of car- laxis. Past medical history included: lin- diovascular collapse secondary ear scleroderma requiring treatment with to anesthesia. She was ulti- methotrexate at the age of 8, generalized mately prescribed an epineph- anxiety, and occasional headaches. Med- rine injector as a precautionary ications included: alprazolam as needed measure. Regular follow-up by and dextroamphetamine/amphetamine as the dermatologist and primary needed. Family history was non-contribu- care provider was advised, as tory. was a yearly CBC. Physical exam revealed a well-devel- oped, well-nourished 20-year-old female History with multiple 2-3mm, tan to pink, blanch- Having an increased able, telangiectatic macules scattered over number of mast cells in one the breasts, lower abdomen and upper or more organs indicates the thighs (Figure 1). The oral, genital, and diagnosis of mastocytosis.1 Figure 1: Tan to pink telangiectatic macules on the lat- ocular mucosa and face were uninvolved. Mastocytosis represents a wide eral breast. Similar lesions were seen on the abdomen and upper thighs. Darier’s sign was mildly positive. No spectrum of disorders that are lymphadenopathy of the cervical, axillary, clinically very heterogeneous. The with TMEP. Rare occurrences in infancy and inguinal regions was appreciated. A organ most commonly involved is the skin. and childhood have been reported. The 4mm punch biopsy of the skin from the The spectrum of cutaneous mastocytosis course is often indolent in nature, unlike left lateral chest demonstrated a sparse (CM) includes: solitary mastocytoma, dif- other forms of CM (such as urticaria pig- paucicellular infiltrate consisting predom- fuse CM (erythroderma), urticaria pigmen- mentosa) that often resolve by adoles- inantly of mast cells around dilated ves- tosa, and telangiectasia macularis eruptiva cence.4,5 Familial cases have been reported sels of the superficial vascular plexus. The perstans (TMEP) (Table 1).2 TMEP is the as well, with a particular family exhibit- immunohistochemical stain for mast-cell rarest form of CM, originally described by ing a possible autosomal-dominant form of tryptase confirmed the presence of mast F. Parkes Weber more than 80 years ago as a inheritance.1,4,6 3 cells. The suggestive clinical findings com- variant of urticaria pigmentosa. The exact etiology of CM has yet to bined with the histopathology findings Epidemiology/Etiology be fully determined. Evidence has shown confirmed the diagnosis of telangiectasia that multiple cell types, including epidermal macularis eruptive perstans (TMEP). A It has been estimated that TMEP keratinocytes, produce mast-cell growth serum tryptase level was entertained as part occurs about 1 percent of all cases of CM.4 factor (steel factor, stem-cell growth factor of the patient’s diagnostic evaluation due Adults represent the majority of patients Wilson, Thomas, Divers, Hurd 57 Type Clinical evidence Pathological evidence Demographics Telangiectasia 2-6 mm irregular, Slight increase in mast Almost always affects macularis eruptiva red/brown telangiectatic cells perivascularly and adults, rare: less than perstans macules/papules. in upper third of dermis, 1% of patients Commonly found on dilation of superficial diagnosed with trunk and extremities. capillaries. mastocytosis. Darier’s sign often negative. Urticaria pigmentosa 0.5-3.5 mm red-brown Increase in mature mast Most common type of macules and papules, cell population. cutaneous mastocytosis, associated flushing and bimodal peak pruritus, positive distribution in childhood Darier’s sign and and 3rd decade but can dermatographism. be seen in any age. Mastocytoma 1 cm or smaller reddish Large group of densely Rarely seen in adults, brown nodules/plaques packed mast cells. usually present within with positive Darier’s first 3 months. sign. Diffuse cutaneous Red/brown thick, Generalized mast cell Seen in infants and mastocytosis edematous skin with infiltration, band-like. children before the age orange peel texture, of 3. Table 1: Types of positive Darier’s sign cutaneous and dermatographism. mastocytosis Adapted from Watkins CE, Bokor WB, Leicht S, Youngberg G, Krishnaswamy G. Telangiectasia macularis eruptive perstans: more than skin deep. Dermatology Reports, 2011; 3(1) ! or kit ligand). For normal mast-cell devel- Clinical Presentation Histopathology and Diagnostic opment and differentiation, interaction Skin findings usually consist of ill- between mast-cell growth factor and the Evaluation defined erythematous telangiectatic mac- protein product of the c-KIT proto-onco- Skin findings resembling those of CM ules/patches that range in size from 2-6 mm gene appears to be essential. The c-KIT require a skin biopsy in order to establish with an underlying tannish-brown color.9 proto-oncogene encodes KIT (CD117), a a definitive diagnosis and to differentiate These most often appear symmetrically tyrosine kinase that is the receptor for mast- among the various types. While performing arranged on the trunk and extremities, usu- cell growth factor. KIT is expressed within this, some authors suggest avoiding the use ally sparing the face, palms, and soles.1,2,5,14 multiple cell types including mast cells of local anesthetic containing epinephrine The telangiectasia also exhibits a reticu- and melanocytes. In CM, studies suggest during skin biopsy due to the ability of epi- lar pattern alignment when examined with an alteration in both the distribution and nephrine to stimulate mast-cell degranula- a dermatoscope.15 Physical stroking or metabolism of mast-cell growth factor. This tion.16 application of heat to the affected areas may is thought to result in reactive hyperplasia illicit a local urtication response, a positive TMEP usually possesses less apparent versus neoplasia. Interestingly, mast-cell Darier’s sign. However, in TMEP, Darier’s histopathological findings, as mentioned growth factor stimulates the production sign is typically negative or only slightly above. There usually exists a mild increase of melanin by melanocytes. It is thought positive compared to other forms of CM. in mast cells, particularly in the interstitial that this finding may explain the mela- This is demonstrated by the smaller number collagen and around the superficial plexus nin pigment in the epidermis in lesions of of mast cells involved.4,5,16 Laboratory find- blood vessels of the top third of the der- urticaria pigmentosa. In cases of systemic 5,19 ings can show increased levels of mast cell mis. With TMEP, authors have found the mastocytosis and sporadic cases of adult products like histamine, histamine metabo- value of mast cells per high-power field to mastocytosis, studies have shown that a lites, tryptase, heparin, and prostaglandin be around 15-20, though a simple contrast- somatic mutation (postzygotic) in the c-KIT D2.17 This disease process rarely presents ing difference of mast cells when comparing proto-oncogene, especially within codon with systemic involvement. Symptoms sug- normal and affected skin can suffice for 816V, leads to enhanced receptor function 5,16,20 gestive of systemic disease include fever, diagnosis. Stains used to visualize mast of KIT. The constitutive activation of KIT unintentional weight loss, headaches, flush- cells and their cytoplasmic metachromatic is believed to ultimately enhance mast-cell ing, palpitations, pruritus, gastrointestinal granules include Giemsa and toluidine proliferation, differentiation and prevention blue. Chloroacetate esterase (Leder stain) 7,8 complaints, dyspnea, syncope, anaphylaxis, of apoptosis. 14 bone pain, and hepatosplenomegaly.14 Sys- may also be used to identify mast cells. Different case reports have shown rare temic involvement may directly correlate Additionally, monoclonal antibodies that cases of TMEP associated with other disease with increasing serum tryptase levels. A recognize KIT (CD117) and/or trypase are processes such as polycythemia rubra vera, study showed that a tryptase level of 75 ng/ more sensitive and useful in confirming the myelofibrosis, Sjogren syndrome, multiple ml represented a threshold for 100-percent diagnosis of mastocytosis.16,21 9-13 myeloma, and renal cancer. positivity, whereas tryptase levels 20-75 ng/ It is also vital to rule out any systemic ml demonstrated 50-percent positivity.18 involvement. Serum tryptase is a reliable

58 A Case of Telangiectasia Macularis Eruptiva Perstans (TMEP) initial test to investigate for systemic mas- au-lait macules.21 The presence of systemic the risk of anaphylaxis with contrast dyes tocytosis.22 Tryptase is the main protein symptoms such as episodic flushing may and anesthesia.16 Providing an epinephrine component of mast-cell secretory gran- necessitate the ruling out of disease pro- injector for emergency use, along with a ules.23 Those presenting with purely cuta- cesses such as syndrome, endo- medical alert bracelet, is recommended.16,17 neous disease process often demonstrate crine tumors secreting vasoactive peptides, Frequent examinations and yearly monitor- serum tryptase levels within normal ranges. pheochromocytoma, and medullary thyroid ing of CBC, serum trypase and 24-hour Authors have found that most patients with carcinoma. Urinary 5-hydroxyindoleacetic urinary histamine has been advised.16 systemic mastocytosis reveal tryptase levels acid (5-HIAA) and metanephrine concen- If only CM is observed, then simple 24,25 greater than 20 μg/L. Another prelimi- trations within normal limits would help to conservative management and observation nary test is the 24-hour urinary histamine. differentiate and pheo- are appropriate. When systemic symptoms Due to its non-specific nature, authors rec- chromocytoma from mastocytosis, as the are present, H1 antagonists can be used to ommend the use of the more sensitive hista- latter usually has normal urinary concentra- alleviate pruritus and/or flushing.14 Oral 23 14,15,17,19 mine metabolite N-methylhistamine. tions. disodium cromoglycate can aid with gastro- A bone marrow biopsy can also aid Treatment intestinal symptoms and may be useful in in uncovering a systemic process as well patients who fail to respond to other forms as provide evidence of mutations such as Unfortunately, there is no cure or an of treatment.17,27 Some have demonstrated c-kit (D816V) and FIP1L1.16 While these established first-line therapy for TMEP. the efficacious use of psoralen plus ultravio- types of usually follow symptoms Symptomatic treatment, with the emphasis let-A light therapy in alleviating the cutane- suggesting systemic mastocytosis, an older on avoidance of triggers, is the primary ous “stinging” sensations. This treatment study recommends the practice of routine treatment goal. According to the literature, works to inhibit the release of histamine by bone marrow biopsies and aspirates in all the combination of symptomatic treatment mast cells.4,16 Given that mast cells release adult patients with CM with or without and avoidance of triggers minimizes the a variety of pro-inflammatory mediators, such symptoms in order to establish a base- release of mast-cell mediators and helps cytokines, and signaling molecules, includ- line for staging purposes.26 In adolescents block the effects of these mediators.16 ing cysteinyl leukotrienes, some authors and children with CM, systemic involve- Potential triggers and activators include: have recommended a trial of leukotriene ment is much less likely, and bone marrow physical exercise, temperature extremes, antagonists such as montelukast.27 Tempo- biopsies should not be performed unless bacterial toxins, bee stings/insect bites, eth- rary but effective results have also followed clinically warranted.16 Additional testing anol intake, emotional and physical stress, the use of a 585-nm flashlamp-pumped for suspected systemic mastocytosis may morphine, codeine, penicillin, acetyl sali- pulsed dye laser. The flashlamp-pumped include bone scan, DEXA study/bone min- cylic acid, amphotericin B, and NSAIDS pulsed dye laser may act to decrease local eral density, gastrointestinal endoscopy, and (Table 2).4,27 Patients should be educated on vasculature rather than affect the number CT of the chest, abdomen and pelvis.16,21 avoidance of the common triggers as well as

Additionally, some authors have devel- Table 2: oped a three-part evaluation scoring index Known mast Ethanol known as the SCORMA (SCORing MAsto- cell releas- Psychological/emotional stress cytosis) index. This takes into account the ing triggers Physical exertion following three main components: the per- Bacterial toxins cent of total skin involvement; the intensity Food allergens (e.g., shellfish, peanuts) of the disease process based on pigmenta- tion/erythema, vesiculation, elevation, and Immunologic stimuli (e.g., IgE) a positive Darier's sign; and five subjective Solar radiation symptoms such as flushing, diarrhea, pru- Hot/cold temperature extremes ritus, bone pain, and having known spe- Venoms (e.g., hymenoptera) cific triggers. A formula is then utilized Other insect bites to generate a score that can both establish Pharmaceutical agents: initial severity and follow disease progres- Acetylsalicylic acid sion. This index is considered comparable • to serum tryptase levels in predicting sys- • Amphotericin B temic involvement.25 • d-tubocurarine • Dextromethorphan Differential Diagnosis • Gallium Other CM-related processes deserve • Iodine-based contrast dyes consideration, especially due to the rar- • Narcotics (e.g., morphine, meperidine, codeine) ity of TMEP. Clinical presentation, age of • Nonsteroidal anti-inflammatory drugs onset, and exam findings will often point to this heterogeneous group of disorders. • Polymyxin B Often, the lesions seen in mastocytosis are • Polymeric eye drops so characteristic that they are rarely mis- • Quinine taken for other skin disorders. At initial • Reserpine glance, lesions may appear similar to mela- • Scopolamine nocytic nevi or lentigines. Mastocytosis in Adapted from Watkins CE, Bokor WB, Leicht S, Youngberg G, Krishnaswamy G. children may be confused with pseudolym- Telangiectasia macularis eruptive perstans: more than skin deep. Dermatology phoma, juvenile xanthogranuloma, or café- Reports, 2011; 3(1).

Wilson, Thomas, Divers, Hurd 59 of mast cells present, and therefore mainly 1609-1614 improves cosmesis. Such an option may 9. Turchin I, Barankin B, Schloss E. Unusual cutaneous findings of urticaria pigmentosa and telangiectasia need a pretreatment with histamine-recep- macularis eruptiva perstans associated with marked myelofibrosis. International Journal of Dermatology, tor blockers to prevent any laser-induced 2006; 45:1215-1217. 14,28 mediator release. Systemic therapy for 10. Suzuki K, Konishi N, Tokura Y, Takigawa M. aggressive/severe systemic mastocytosis Telangiectasia macularis eruptiva perstans in polycythemia rubra vera. European Journal of may include interferon-α-2b, radiation and Dermatology, 2002; 12(2): 201-203 chemotherapeutic agents. Chemothera- 11. Erbay SK, Stewary C, Hassanein A, Fletcher A, peutics agents have been used with little Bhattacharyya I, Cohen D, Wesson SK, Weinstein J, Lyons R, Reeves WH. Cutaneous mastocytosis in a success. Intravenous cladribine (2-chloro- patient with primary Sjogren’s syndrome. J Rheumatol, deoxyadenosine) was reported to be effec- 2006; 33(8)1697-1700 12. Bachmeyer C, Guillemaette J, Blum L, Turc Y, Dhote tive in reducing bone-marrow mast cells R, Fermand JP, Aractiniqi S. Telangiectasia macularis and eliminating skin lesions in one patient.21 eruptiva perstans and multiple myeloma. J Am Acad Imatinib mesylate, an oral tyrosine kinase Dermatol 2000; 43: 972-4. 13. Pascual JC, Banuls J, Albares MP, Vergara G, Belinchon inhibitor, has been used for the treatment I, Silvestre JF, Betlloch I. Presentation of telangiectasia of systemic mastocytosis. However, adults macularis eruptive perstans as a long-standing solitary plaque associated with renal carcinoma. J Cutan Med with the common D816V mutation often Surg, 2003; 7(5):399-402 respond poorly to imatinib. Isolated case 14. Chung-Leddon J. Telangiectasia macularis eruptive reports have shown that adults with muta- perstans. Dermatology Online Journal, 2000; 6(1): 6 15. Akay BN, Kittler H, Sanli H, Harmankaya K, Anadolu tions outside of the exon 17 (location of the R. Dermatoscopic findings of cutaneous mastocytosis. codon 816V) were treated successfully with Dermatology, 2009; 218(3):226-230 imatinib.21 16. Watkins CE, Bokor WB, Leicht S, Youngberg G, Krishnaswamy G. Telangiectasia macularis eruptive perstans: more than skin deep. Dermatology Reports, Conclusion 2011; 3(1) 17. Golkar L, Bernhard JD. Mastocytosis. The Lancet, 1997; TMEP is rare form of cutaneous mas- 349(9062):1379-1385 tocytosis that often presents in adults. The 18. Schwartz LB, Irani AM. Serum tryptase and the course is often indolent in nature. The laboratory diagnosis of systemic mastocytosis. Hematol pathogenesis is not fully understood and Oncol North Am, 2000; 14:641 19. Betti R, Vergani R, Tolomio E, Martino P, Crosti C. requires further clinical studies. Treatment Telangiectasia macularis eruptive perstans involving is often centered on controlling symptoms the upper arms in an adult male. European Journal of Dermatology, 2000; 10(7):563-564 and avoiding triggers. Although rare, case 20. Altiner A, Tzu J, Patel R, Meehan S, Sanchez M. reports of systemic involvement have been Telangiectasia macularis eruptiva perstans. Dermatology associated with TMEP, so a thorough his- Online Journal, 2011; 17(10):7 21. Bolognia JL, Jorizzo JL, Rapini RP, editors. Dermatology. tory and physical exam are essential. In Edinburgh: Mosby, Inc; 2008; pg 1851-52 the aforementioned case, the patient pre- 22. Valent P, Akin C, Sperr WR, Horny HP, Metcalfe DD. sented without any concerning symptoms Mast cell proliferative disorders: current view on variants recognized by the World Health Organization. Hematol or laboratory findings to suggest underlying Oncol Clin North Am 2003;17:1227-41. systemic involvement. Given the asymp- 23. Liu AY, Lowe RC, Levy BD, Katz JT, Loscalzo J. Clinical tomatic nature of her disease, the patient problem-solving. A rash hypothesis. N Engl J Med, 2010;363:72-8 was advised on the importance of frequent 24. Horny HP, Sotlar K, Valent P. Mastocytosis: state of the examinations by her primary care provider art. Pathobiology, 2007;74:121-32. and dermatologist along with a yearly CBC. 25. Heide R, Van DK, Mulder PG, van Toorenenbergen AW, Beishuizen A, de Groot H, Tank B, Oranje AP. If the patient develops any systemic symp- Serum tryptase and SCORMA (SCORing MAstocytosis) toms, additional testing will be completed. Index as disease severity parameters in childhood and adult cutaneous mastocytosis. Clin Exp Dermatol, References 2009;34:462-8. 26. Tebbe B, Stavropoulos PG, Krasagakis K, Orfanos CE. 1. Nguyen NQ. Telangiectasia macularis eruptive perstans. Cutaneous mastocytosis in adults. Evaluation of 14 Dermatology Online Journal, 2004; 10(3): 1 patients with respect to systemic disease manifestations. 2. Soter NA. The skin in mastocytosis. J Invest Dermatol, Dermatology, 1998;197:101-8. 1991; 96(3 suppl):32S-38S 27. Cengizlier R, Hucumenoglu S, Ozen A, Tulin Sayli R. 3. Weber PF, Hellenschmied R. Telangiectasia macularis Treatment of telangiectasia macularis eruptiva perstans eruptiva perstans. Br J Dermatol Syph 1930; 42: 374-82 with montelukast. Allergol Immunopathol, 2009; 37(6): 334-336 4. Oliveira CR, Albuquerque GC, Simon EF, Quinete SS, Carvalho CRS. Caso para diagnostic. Telangiectasia 28. Ellis DL. Treatment of telangiectasia macularis eruptive macularis eruptive perstans. An Bras Dermatol. 2009; perstans with the 585-nm flashlamp-pumped dye laser. 84(1):87-89 Dermatol Surg, 1996; 22:33-37 5. Chang A, Tung RC, Schlesinger T, Bergfeld WF, Dijkstra J, Kahn TA. Familial cutaneous mastocytosis. Pediatr Dermatol, 2001; 18(4): 271-276 6. Gibbs NF, Friedlander SF, Harpster EF. Telangiectasia Macularis Eruptiva Perstans. Pediatric Dermatology, 2000; 17(3):194-197 7. Longley BJ, Morganroth GS, Tyrrell L, Ding TG, Anderson DM, Williams DE, Halaban R. Altered metabolism of mast-cell growth factor (c-kit ligand) in cutaneous mastocytosis. N Engl J Med, 1993; 328(18):1302-7 8. Longley BJ, Metcalfe DD, Tharp M, Wang X, Tyrrell L, Lu SZ, Heitjan D, Ma Y. Activating and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis. Proc Natl Acad Sci, 1999; 96(4):

60 A Case of Telangiectasia Macularis Eruptiva Perstans (TMEP)

Clinically Benign-appearing Papule: A Treatment Conundrum

Brooke Walls, DO,* David Dorton, DO, FAOCD**

*Nova Southeastern University College of Osteopathic Medicine, Largo Medical Center, Largo, FL **Bay Dermatology, Tampa, FL

ABSTRACT: Superficial (SLMS) is a rare sarcoma which is further classified into either cutaneous or subcutaneous based on dermal location and site of origin.Cutaneous SLMS has an excellent outcome with rare recurrence whereas subcutaneous SLMS has a high incidence of recurrence and metastatses. Wide excision with 2-5 cm margins has historically been advocated for treatment for both subtypes. However, due to the low recurrence and metastatic potential of cutaneous SLMS more conservative excisional margins may be more appropriate and is supported by recent institutional based studies.

Figure 1: Normal epidermis with a highly Figure 2: Interwoven fascicles of spindle Figure 3: Pleomorphic, blunt-ended nuclei cellular dermis cells with effacement

Case Report including irritated , cysts, , neurofibro- A 74-year-old Caucasian man presented with an asymptom- mas, , and carcinoma. Histologic examination is atic lesion of six months duration on his right upper back. Physical strikingly significant for a proliferation of pleomorphic fascicles of examination revealed a 5 mm, tan-colored papule. His past derma- spindle cells in the dermis. Immunohistochemistry is necessary tologic history was significant for actinic keratoses, and his medical for diagnosis, as many spindle-cell neoplasms mimic SLMS, such history was non-contributory. He denied a history of non-melanoma as spindle-cell squamous cell carcinoma, , skin cancer or other cutaneous neoplasms. A shave biopsy was and melanoma.3,4 SLMS is further subdivided into cutaneous and performed with dermatopathologic examination and immunohis- subcutaneous SLMS, and this distinction is based on the location tochemistry staining. Histological examination revealed atypical in the dermis and presumed site of origin (Table 2).4 This clas- spindle cells and fascicles present within the dermis (Figures 1 & sification is of prognostic significance, as the biologic behavior of 2). Cells contained hyperchromatic and pleomorphic nuclei (Figure these two subtypes diverges greatly.3-6 Cutaneous SLMS is postu- 3). Immunohistochemical stain for desmin was strongly positive, lated to arise from the arrector pili muscles and is located in the and there was weak staining for smooth-muscle actin. A diagnosis dermis, whereas subcutaneous SLMS arises from the endothelium of cutaneous SLMS was rendered. Treatment included wide local of dermal vessels and extends into the subcutaneous tissues.7 excision with 1 cm margins and en face histologic evaluation (Figure Furthermore, cutaneous SLMS has an excellent prognosis with 4). Temporary wound closure was maintained with subcutaneous variable recurrence rates and only isolated reports of metasta- sutures (Figure 5). Histologic examination of the surgical specimen ses, whereas subcutaneous SLMS has a grimmer prognosis, with revealed the margins free of tumor, and the defect was then closed reported recurrence of 50% and 30-40% reported incidence of primarily with subcutaneous sutures and a running, interrupted metastases.6,8-10 subcuticular suture with excellent wound approximation and tissue Surgical excision is the standard of care for SLMS; how- eversion (Figure 6). ever, recommended excisional margins and follow-up are poorly defined. Historically, recommended margins ranged from 2-5 Discussion cm for both cutaneous and subcutaneous SLMS, with no criteria Leiomyosarcomas are of smooth muscle that are clas- outlined for narrower verses wider margins. As the prognosis dif- sified as superficial or metastatic depending on the site of origin fers significantly between these two subtypes, excisional margins (Table 1).1 Superficial leiomyosarcoma (SLMS) is an extremely should be recommended for each separately. A recent analysis rare sarcoma, and the incidence is not known or reported in the of 33 patients with cutaneous SLMS showed excellent outcomes literature due to its rarity. If often arises on hair-bearing skin of with wide local excision with 1 cm margins and no reported recur- middle-aged men.2 SLMS is often asymptomatic but may present rences nor metastases at a median follow-up time of 15.5 months.6 with mild tenderness, pruritus, bleeding and slow growth. Clinically, This observation is supported by other large, institution-based the differential diagnosis includes many benign cutaneous tumors studies in the literature.5,9 We recommend pathologic evaluation

Walls, Dort on 63 Figure 4: Surgical excision margins and mapping Figure 5: Temporary Sutures status post excision of sarcoma Table 1: Classification of Leiomyosarcoma1 Figure 6: 7.3 cm closure with an inter- rupted subcuticular I. Superficial leiomyosarcoma a) Cutaneous leiomyosarcoma b) Subcutaneous leiomyosarcoma

II. Metastatic leiomyosarcoma from visceral sites (, retroperitoneum) Adapted from Annest et al.

Table 2: Comparison of Cutaneous vs. Subcutaneous SLMS1-10 Cutaneous SLMS Subcutaneous SLMS ORIGIN Arrector pili Vascular endothelium LOCATION Dermis with some extension into Localized predominantly in the superficial subcutaneous tissue subcutaneous tissues MITOTIC RATE +/- Present to a greater degree S-100 Occasionally + - IHC + in the majority of cases + less frequently, esp. in higher- vimentin, desmin, smooth grade lesions RECURRENCE RATE 0-50% 50-70% METASTATIC RATE - 30% using the en face technique of the peripheral and deep margin with 4. Cany L, Stoeckle E, Coindre JM, Kantor G, Bonichon F, and Bui BN. "Prognostic Factors in Superficial Adult Sarcomas: Analysis of a Series of 105 Patients." Journal of immunohistochemical staining, as this would allow for more com- Surgical Oncology. 1999;4-9. 11 plete margin assessment. Although this was not performed in this 5. Svarvar C, Bohling, T, Berlin O, Gustafson P, Bjerkehagen B, Domanski H, Hall KS, Tukiainen E, and Blomqvist C. "Clinical Course of Nonvisceral Soft Tissue Leiomyosarcoma case, it was requested. This should result in high cure rates and bet- in 225 patients from the Scandinavian Sarcoma Group." Cancer. 2006; 282-291. ter margin control. 6. Deneve JL, Messina JL, Salmasinia D, Marzban SS, Bui M, Letson DG, Cheong D, Gonzalez, RJ, Sondak VS, Zager JS. "Cutaneous Leiomyosarcoma: a single institution In conclusion, superficial leiomyosarcoma is a rare soft-tissue experience with treatment and outcome." Pigment Cell and Melanoma. 2011;1074. sarcoma with poorly defined treatment algorithms. Cutaneous 7. Porter CJW, Januszkiewicz JS. "Cutaneous Leiomyosarcoma." Plastic and Reconstructive SLMS has an excellent prognosis and low recurrence rates with Surgery. 2002;109(3): 964-967. narrow excisional margins. Dermatopathology-controlled surgical 8. Oliver GF, Reiman HM, Gonchoroff NJ, Muller SA, Umbert IJ. "Cutaneous and subcutaneous leiomyosarcoma: a clinicopathologic review of 14 cases with reference to antidesmin staining excision proves to be a viable approach to decrease recurrence and and nuclear DNA patterns studied by flow cytometry." Br J Dermatol. 1991;124: 252-7. increase patient outcomes. 9. Fauth CT, Bruecks AK, Temple W, Arlette JP, DiFrancesco LM. "Superficial leiomyosarcoma: a clinicopathologic review and update." J Cutan Pathol. 2010;37:269-276. References 10. Humphreys TR, Finkelstein DH, Lee JB. "Superficial Leiomyosarcoma Treated with Mohs Micrographic Surgery." Dermatol Surg. 2004;30:108-112. 1. Annest NM, Grekin SJ, Stone MS, Messingham MJ. “Cutaneous Leiomyosarcoma: A tumor of the Head and Neck.” Dermatol Surg. 2007;33:628-633. 11. Smith-Zagone MJ, Schwartz MR. “Frozen Section of the Skin.” Arch Pathol Lab Med. 2005;129:1536-1543. 2. Holst VA, Junkins-Hopkins JM, Elenitsas R. “Cutaneous smooth muscle neoplasms: Clinical features, histologic findings, and treatment options.” J Am Acad Dermatol. 2002;46:477-90. 3. Fields EB and JP Helwig. "Leiomyosarcoma of the Skin and Subcutaneous Tissue." Cancer. 1981;156-169.

64 Clinically Benign-appearing Papule: Treatment Conundrum