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Volume 28

JAOCDJournal Of The American Osteopathic College Of

Common Phototherapy Mistakes & How to Avoid Them

Also in this issue: Nodular Kaposi’s in an Immunocompetent Female Beyond ? The Growing Problem of Exposure Perspective: The Forgotten Tool for Rhytides last modified on March 24, 2014 5:25 PM

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

2013-2014 AOCD OFFICERS

PRESIDENT Suzanne Sirota-Rozenberg, DO, FAOCD

PRESIDENT-ELECT Rick Lin, DO, FAOCD

FIRST VICE-PRESIDENT Alpesh Desai, DO, FAOCD

SECOND VICE-PRESIDENT Karthik Krishnamurthy, DO, FAOCD

THIRD VICE-PRESIDENT Daniel Ladd, DO, FAOCD

Editor-in-Chief SECRETARY-TREASURER Karthik Krishnamurthy, DO Jere J. Mammino, DO, FAOCD TRUSTEES John P. Minni, DO, FAOCD Bryan Sands, DO, FAOCD Danica Alexander, DO, FAOCD Reagan Anderson, DO, FAOCD Sponsors: Michael Whitworth, DO, FAOCD Tracy Favreau, DO, FAOCD

Bayer Immediate Past-President AuroraDx David L. Grice, DO, FAOCD EEC Representatives Ranbaxy James Bernard, DO, FAOCD Michael Scott, DO, FAOCD

Finance Committee Representative Steven K. Grekin, DO, FAOCD

AOBD Representative Stephen Purcell, DO, FAOCD

Executive Director Marsha A. Wise, BS

AOCD • 2902 N. Baltimore St. • Kirksville, MO 63501 800-449-2623 • FAX: 660-627-2623 • www.aocd.org COPYRIGHT AND PERMISSION: Written permission must be obtained from the Journal of the American Osteopathic College of Dermatology for copying or reprinting text of more than half a page, tables or figures. Permissions are normally granted contingent upon similar permission from the author(s), inclusion of acknowledgement of the original source, and a payment of $15 per page, table or figure of reproduced material. Permission fees are waived for authors wishing to reproduce their own articles. Request for permission should be directed to JAOCD c/o AOCD, PO Box 7525, Kirksville, MO 63501. Copyright © 2003 by the Journal of the American Osteopathic College of Dermatology Print and layout by: S&S Printing and Graphics LLC, 401 N. Marion St., Kirksville, MO 63501 Copy editing by: Julia Layton, Freelance Writing and Editing Page 2 JOURNAL OF THE AMERICAN OSTEOPATHIC COLLEGE OF DERMATOLOGY TABLE OF CONTENTS Volume 28

JAOCD Editors...... 4 Letter from the Editor-in-Chief...... 5 Letter from the Executive Director...... 6 Letter from the President...... 7 FEATURE ARTICLE: Common Phototherapy Mistakes and How to Avoid Them Monica Huynh, BA, Maya G. Debbaneh, BA, Ethan Levin, MD, Daniel Butler, BS, Rishu Gupta, BS, Argentina Leon, MD, John Koo, MD...... 13

EDITOR’S PICKS: An Unusual Case of Nodular Kaposi’s on the Dorsal Hand in a Non-HIV Latina Female Mayha Patel, DO, Melissa Camouse, DO, FAOCD, Paul Shitabata, MD...... 15 Asymptomatic in an Elderly Male Christopher Cook, DO, Lacey Elwin, BS, David Cleaver, DO, Lloyd Cleaver, DO ...... 19 Manual Dermabrasion: The Forgotten Tool for Perioral Rhytides Adam J. Taylor, BS, Derrick H. Adams, DO, FAOCD...... 21

ORIGINAL ARTICLES AND CASE REPORTS A Novel Case of Scrotal Angiolymphoid Hyperplasia Renee N. Lucero, BS, Derrick H. Adams, DO, FAOCD...... 23 Verrucous Intertriginous Plaques in a Young Female Joseph Dyer, DO, Kathleen P. Soe, DO, FAOCD, George Gibbons, MD ...... 24 Pernio: A Case Presentation and Review of Treatment Options Teresa Ishak, DO, Mayha Patel, DO, David Horowitz, DO, FAOCD ...... 26 Cutaneous Rosai-Dorfman : A Case Report and Review Khasha Touloei, DO, Adam Wiener, DO, Angela Macri, DO, Bradley P. Glick, DO, MPH, FAOCD ...... 28 A Case of Punctate Porokeratotic : Manifestation of Uncontrolled Hyperlipidemia or Delayed Paraneoplastic Syndrome? Charisse McCall, DO, Sanjosh Singh, DO, Michael Berry, MD...... 30 Multiple Eruptive Following Immunosuppressive in a Patient with Systemic Lupus Erythematosus Maria Tempera, BS, Peter Saitta, DO, FAOCD, Cherise Khani, DO, Cindy Hoffman, DO, FAOCD, Ronald Brancaccio, MD, FAAD...... 32 Darier’s Disease: A Case Study and Review of the Literature Jeffrey Kushner, BA, David A. Kasper, DO, FAOCD, MBA...... 34 Erythrodermic : A Case Report and Literature Review Jacqueline Fisher, DO, Nanda Channaiah, DO, FAOCD...... 36 Iatrogenic Kaposi’s Sarcoma Arising After Renal Transplant Immunosuppression Katherine Johnson, DO, Jessica Garelik, DO, Howard D. Lipkin, DO...... 41 Pagetoid Reticulosis (Woringer-Kolopp Disease) in a 43-Year-Old Woman Helia Eragi, DO, Matthew Koehler, DO, Paul Shitabata, MD, David Horowitz, DO, FAOCD ...... 43 Blue Vein at the Nasal Root: A Case Presentation and Discussion A Case Report and Review of the Literature Adam Sorensen, DO, Harper Price, MD, Stephen Kessler, DO, Rebecca E. Fisher, PhD...... 47 Combination of Photodynamic Therapy with Blue Light for Treating Pyoderma Faciale in a Post-partum, Breast-feeding Patient: A Case Report and Literature Review Dorene Niv, BS, Patrick Keehan, DO...... 48 A Case of (PXE) in a 14-year-old Female: A Case Report and Review of the Literature D. Ryan Skinner, DO, Samuel Ecker, BS, Daniel Hurd, DO, FAOCD...... 50 Vibrio Vulnificus Septicemia Presenting as Fevers, Bullae, and Compartment Syndrome: A Case Presentation and Review of the Literature Alissa T. Lamoureux, DO, Brad P. Glick, DO, MPH...... 52 JOURNAL OF THE AMERICAN OSTEOPATHIC COLLEGE OF DERMATOLOGY Page 3 Editor-In-Chief Founding Editor Assistant Editor Karthik Krishnamurthy, DO Jay Gottleib, DO Julia Layton, BA, MFA Associate Editors

Aaron Bruce, DO Michelle Foley, DO Michael Scott, DO Scott Wickless, DO Bozeman, Montana Ormond Beach, FL Seattle, WA Dallas, Texas

Editorial Board

Sami Abbasi, DO Marcus Goodman, DO Chava Lustig, DO Richard Rudnicki, DO Brownstown, MI Roswell, GA Weston, FL Mesquite, TX

Brad Abrams, DO Melinda Greenfield, DO Jere Mammino, DO Amara Sayed, DO Sarasota, FL Albany. GA Winter Springs, FL San Marcos, TX

Derrick Adams, DO Denise Guevara, DO Chris Manlio, DO Joseph Brant Schneider, DO Red Bluff, CA Weston, FL Loxahatchee, FL Shawnee Mission, KS

Kevin Belasco, DO Andrew Hanly, MD John Minni, DO Gregg Severs, DO Milwaukee, WI Miami, FL Port St. Lucie, FL Scranton, PA

Brett Bender, DO Joel Harris, DO Tony Nakhla, DO Sean Stephenson, DO Farmington Hills, MI Madison Heights, MI Orange County, CA Troy, MI

Ryan Carlson, DO Heather Higgins, DO Navid Nami, DO Jacqueline Thomas, DO Hilliard, OH Troy, MI Newport Beach, CA Fort Lauderdale, FL

Igor Chaplik, DO David Horowitz, DO Jon Keeling, DO Jim Towry, DO Aventura, FL Torrence, CA Lexington, KY Ocala, FL

Michael P. Conroy, MD Matt Leavitt, DO Dimitria Papadopoulos, DO Columbus, OH Maitland, FL Bellmore, NY

Matthew Elias, DO Mark Lebwohl, MD John Perrotto, DO Lighthouse Point, FL New York, NY West Palm Beach, FL

Merrick Elias, DO Angela Leo, DO Stephen Purcell, DO Delray Beach, FL New York, NY Allentown, PA

Brad Glick, DO Scott Lim, DO Andrew Racette, DO Margate, FL Erie, PA Phoenix, AZ

Page 4 JAOCD EDITORS Letter from the Editor-in-Chief

Karthik Krishnamurthy, DO, FAOCD Editor-in-Chief

Dear Colleagues,

I am just getting back from our Dallas Midyear Meeting and couldn’t be happier. Thank you for the positive feedback. Our attendance was among the highest it has ever been for a Midyear Meeting. In addition, we had more exhibitors than we have ever had at any meeting, which translates to our ability to host a great event in a great venue.

All of the wonderful talks from the meeting are available online. To access them, just log into the members area of the AOCD website (www.aocd.org). Apart from the invaluable updates on conditions like , lymphoma, and psoriasis, and treatment modalities like Mohs, we also learned about avoiding medical errors, creating cosmetic workflows, dealing with potential legal dilemmas, complying with OCC requirements, adopting the ICD-10, embracing future changes to the practice of , and how to maintain personal and practice finances. (And perhaps most important, we learned from Dr. Brown to “never take a sleeping pill and a laxative in the same night.”) All of this knowledge is geared toward helping us achieve our greatest long-term goal: delivering the best care we can to our patients and being happy while doing it.

Finally, we have some potentially exciting news for those reading this right now: The process for CME reading credit approval for the JAOCD is in its final stages. Our journal is currently being reviewed by the AOA CCME, and I anticipate that at some point this year, the JAOCD will be able to start providing credits to make it just a little bit easier to get to those 120 hours.

Fraternally, Karthik Krishnamurthy, DO Editor-in-Chief, Journal of the American Osteopathic College of Dermatology 2nd Vice President, American Osteopathic College of Dermatology

LETTER FROM THE EDITOR-IN-CHIEF Page 5 Letter from the Executive Director

Marsha Wise Executive Director, AOCD

Greetings, everyone!

Our Dallas Midyear Meeting was a huge success! Dr. Karthik Krishnamurthy put together a fabulous program for the attendees.

Our next Annual Meeting, taking place in Seattle, is being chaired by Dr. Rick Lin, and we can surely expect another great event. Look for meeting information on our web site, www.AOCD.org. We will also update everyone through the regular Thursday Bulletin.

Save the Dates! Our 2014 Fall Meeting will take place October 25th through 28th. Please note the first day of lectures will be Sunday, October 26th. This is a new meeting cycle the AOA is implementing. Monitor the AOCD and AOBD web sites (www.aobd-derm. org) for updates concerning the conference schedule and testing dates and locations.

Our 2015 Midyear Meeting will take place from April 23rd through 26th at the Ritz Carlton in Charlotte, North Carolina. The Program Chair is Dr. Daniel Ladd.

Staying In-the-Know We have several avenues for our members to remain updated on all things AOCD. In addition to the JAOCD, the Dermline publication provides valuable information. As of 2014, we are switching to an online-only Dermline. We will be monitoring member feedback to decide whether this change is permanent or we go back to a printed newsletter, so please make your opinion known.

The AOCD Insights is a weekly newsletter full of recent articles related to dermatology.

The Thursday Bulletin is intended to keep members updated regarding AOCD news and events. Please let me know if you have information you think would be helpful to our membership, and we can include it in an upcoming Thursday Bulletin.

As always, if you have questions or concerns, please feel free to contact me (see “Contact Us” at AOCD.org), and I will be happy to assist you.

Sincerely, Marsha Wise Executive Director, American Osteopathic College of Dermatology

Page 6 LETTER FROM THE EXECUTIVE DIRECTOR Letter from the President

Suzanne Sirota Rozenberg DO, FAOCD President, AOCD

Dear Members of the AOCD,

I write my letter to you now during a period of great transition. What lies in store for the AOCD will be determined by you, our membership. As of publication time, the ACGME and AOA have entered into an agreement for a unified accreditation system. This, in short summary, will allow all graduating DO students to go into allopathic or osteopathic residency programs. The same is true for all graduating MD students.

This has come about for several reasons, including a government push for one system and the fact that there will be insufficient residency slots for DO graduates by the year 2022.

With this comes many changes, and change is not easy for many. I believe the AOCD will prevail in this new system. The AOA web site (www.osteopathic.org) has all the current facts about the merger, but there is still much to be worked out. We know the transition will take place over the next five years, during which all AOA programs will apply for ACGME accreditation. By the year 2020, there will no longer be standalone DO residencies, although there will be osteopathic-focused residencies. All DO program directors will be working with their MD counterparts.

So, where does this leave us?

I believe in osteopathic medicine and in the AOCD. We have a transition committee in place already. A document for comparison of residencies will be available soon and can be used by programs to help meet ACGME standards. Some of our own standards will be included in the overall process, as well.

We will need to redefine ourselves and our mission in this new system. Our new strategic plan will reflect our future goals. Ultimately, though, we are who we are and we are proud of it, and we will capitalize on our uniqueness to establish ourselves amongst our colleagues. Our approach to the patient will not change. Our membership must persevere. We are committed to CME and to all of you.

We are DO dermatologists, and we stand strong!

I am truly proud to be one of us and your president.

Sincerely, Suzanne Sirota-Rozenberg, DO, FAOCD President, American Osteopathic College of Dermatology

LETTER FROM THE PRESIDENT Page 7 Letter from the President

Released January 6, 2014 1560 Sherman Avenue, Evanston, IL 60201-4808 Voice: (847) 328-2256 Fax: (847) 328-0509 Dermatology [email protected] Foundation www.dermatologyfoundation.org Shaping the Future of Dermatology

For More Information Contact: Chris Boris, Deputy Executive Director

Charles and Daneen Stiefel Give $1 Million for Dermatologic Research

The Dermatology Foundation’s Board of Trustees is pleased to announce and recognize Charles and Daneen Stiefel for their recent gift of $1 million, the largest single contribution ever received by the DF.

“We have enormous respect for the work of the Dermatology Foundation, and we wanted to do something special to support its mission,” Mr. Stiefel explains. At the Stiefels’ request, these funds will be dedicated to advancing research in autoimmune and/or through a new research award intended for early to mid-career investigators. They hope their gift will lead to better treatments for these diseases and to an improved understanding of their causes and their association with cancer. “My primary philanthropic focus has been—and continues to be—cancer research,” Mr. Stiefel notes. This holds deep personal significance for him, because many members of his family have battled cancer. He himself has suffered from two different types of cancer.

Mr. Stiefel’s unwavering support of the DF has long been part of both his private and public lives. He is a member of the Annenberg Circle and Fitzpatrick Legacy Fund, and is the former Chair and CEO of Stiefel Laboratories, a Corporate Honor Society member and supporter of the DF.

Mr. Stiefel’s dedication to the Foundation reflects his belief that building the scientific base of dermatology is critically important. “Throughout its 50-year history, the Foundation has played a prominent role in advancing the science and the practice of dermatology,” he says—“and I strongly believe it will continue to do so.”

The DF Trustees extend their deep gratitude to Charles and Daneen Stiefel for their exceptional generosity, and their decision to support the future of the specialty.

The Dermatology Foundation was established in 1964 and is the leading private funding source for disease research. It provides funding that helps develop and retain tomorrow’s teachers and researchers in dermatology, enabling advancements in patient care.

Page 8 DERMATOLOGY FOUNDATION PRESS RELEASE LETTER FROM THE PRESIDENT Page 9 6.2 Post-Marketing Experience The following adverse reactions have been identified post approval of FINACEA Gel. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure: Eyes: iridocyclitis upon accidental exposure of the eyes to FINACEA Gel Finacea® 7 DRUG INTERACTIONS There have been no formal studies of the interaction of FINACEA Gel with other drugs. (azelaic acid) Gel,15% 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Pregnancy Category B For Dermatologic Use Only–Not for Ophthalmic, Oral, or Intravaginal Use There are no adequate and well-controlled studies in pregnant women. Therefore, FINACEA Gel should Rx only be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. BRIEF SUMMARY Dermal embryofetal developmental studies have not been performed with azelaic acid, CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 15% gel. Oral embryofetal developmental studies were conducted with azelaic acid in rats, rabbits, 1 INDICATIONS AND USAGE and cynomolgus monkeys. Azelaic acid was administered during the period of organogenesis in all FINACEA® Gel is indicated for topical treatment of the inflammatory and pustules of mild to three animal species. Embryotoxicity was observed in rats, rabbits, and monkeys at oral doses of moderate . Although some reduction of which was present in patients with papules azelaic acid that generated some maternal . Embryotoxicity was observed in rats given 2500 and pustules of rosacea occurred in clinical studies, efficacy for treatment of erythema in rosacea in mg/kg/day [162 times the maximum recommended human dose (MRHD) based on body surface the absence of papules and pustules has not been evaluated. area (BSA)], rabbits given 150 or 500 mg/kg/day (19 or 65 times the MRHD based on BSA) and cynomolgus monkeys given 500 mg/kg/day (65 times the MRHD based on BSA) azelaic acid. No 5 WARNINGS AND PRECAUTIONS teratogenic effects were observed in the oral embryofetal developmental studies conducted in rats, 5.1 Skin Reactions rabbits and cynomolgus monkeys. Skin irritation (i.e. pruritus, burning or stinging) may occur during use of FINACEA Gel, usually during An oral peri- and post-natal developmental study was conducted in rats. Azelaic acid was administered the first few weeks of treatment. If sensitivity or severe irritation develops and persists, discontinue from gestational day 15 through day 21 postpartum up to a dose level of 2500 mg/kg/day. Em- HALOG Cream and Ointment treatment and institute appropriate therapy. bryotoxicity was observed in rats at an oral dose of 2500 mg/kg/day (162 times the MRHD based There have been isolated reports of after use of azelaic acid. Since azelaic acid has on BSA) that generated some maternal toxicity. In addition, slight disturbances in the post-natal are designed for a difference not been well studied in patients with dark complexion, monitor these patients for early signs of development of fetuses was noted in rats at oral doses that generated some maternal toxicity hypopigmentation. (500 and 2500 mg/kg/day; 32 and 162 times the MRHD based on BSA). No effects on sexual your patients can truly feel. 5.2 Eye and Mucous Membranes Irritation maturation of the fetuses were noted in this study. 1,2 Avoid contact with the eyes, mouth and other mucous membranes. If FINACEA Gel does come in 8.3 Nursing Mothers BIPHASIC CREAM for sustained relief. contact with the eyes, wash the eyes with large amounts of water and consult a if eye It is not known whether azelaic acid is excreted in human milk; however, in vitro studies using equilibrium PLASTIBASE® OINTMENT for enhanced irritation persists [see Adverse Reactions (6.2)]. dialysis were conducted to assess the potential for human milk partitioning. The studies demonstrated spreadability and appeal.3 6 ADVERSE REACTIONS that, at an azelaic acid concentration of 25 µg/mL, the milk/plasma distribution coefficient was 0.7 6.1 Clinical Trials Experience and the milk/buffer distribution was 1.0. These data indicate that passage of drug into maternal milk Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed may occur. Since less than 4% of a topically applied dose of 20% azelaic acid cream is systemically in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug absorbed, the uptake of azelaic acid into maternal milk is not expected to cause a significant change INDICATIONS AND USAGE: HALOG (Halcinonide, and may not reflect the rates observed in practice. from baseline azelaic acid levels in the milk. Nevertheless, a decision should be made to discontinue USP) 0.1% is indicated for the relief of the nursing or to discontinue the drug, taking into account the importance of the drug to the mother. In two vehicle-controlled and one active-controlled U.S. clinical trials, treatment safety was monitored inflammatory and pruritic manifestations of in 788 subjects who used twice-daily FINACEA Gel for 12 weeks (N=333) or 15 weeks (N=124), or 8.4 Pediatric Use -responsive dermatoses. the gel vehicle (N=331) for 12 weeks. In all three trials, the most common treatment-related adverse Safety and effectiveness of FINACEAGelin pediatric patients have not been established. events were: burning/stinging/tingling (29%), pruritus (11%), scaling/dry skin/xerosis (8%) and For topical use only. 8.5 Geriatric Use erythema/irritation (4%). In the active-controlled trial, overall adverse reactions (including burning, Clinical studies of FINACEA Gel did not include sufficient numbers of subjects aged 65 and over to For Important Safety Information, please stinging/tingling, dryness/tightness/ scaling, itching, and erythema/irritation/redness) were 19.4% determine whether they respond differently from younger subjects. see Brief Summary on reverse. For full (24/124) for FINACEA Gel compared to 7.1% (9/127) for the active comparator gel at 15 weeks. Prescribing Information see Product 17 PATIENT COUNSELING INFORMATION Table 1: Adverse Events Occurring in ≥1% of Subjects in the Rosacea Trials by Treatment Group Package Insert at HalogRx.com Inform patients using FINACEA Gel of the following information and instructions: and Maximum Intensity* REFERENCES: 1. Blecker, J. Double-blind comparison between two FINACEA Gel, 15% Vehicle Use only as directed by your physician. new topical steroids, halcinonide 0.1% and clobetasol propionate cream N=457 (100%) N=331 (100%) •For external use only. 0.05%. Curr Med Res Opin. 1975;3:225-228. 2. Bagatell FK. Halcinonide: •Before applying FINACEA Gel, cleanse affected area(s) with a very mild soap or a soapless cleansing a new potent anti-inflammatory drug.Cutis. 1974:14:459-462. Mild Moderate Severe Mild Moderate Severe 3. Thau P, Fox C. A new procedure for the preparation of polyethylene- lotion and pat dry with a soft towel. n=99 n=61 n=27 n=46 n=30 n=5 oil gels. J Soc Cosmet Chem. 1965;16:359-363. (22%) (13%) (6%) (14%) (9%) (2%) •Avoid use of alcoholic cleansers, tinctures and astringents, abrasives and peeling agents. Burning/ 71 (16%) 42 (9%) 17 (4%) 8 (2%) 6 (2%) 2 (1%) •Avoid contact with the eyes, mouth and other mucous membranes. If FINACEA Gel does come in stinging/ contact with the eyes, wash the eyes with large amounts of water and consult your physician if eye tingling irritation persists. •Wash hands immediately following application of FINACEA Gel. Pruritus 29 (6%) 18 (4%) 5 (1%) 9 (3%) 6 (2%) 0 (0%) •Cosmetics may be applied after the application of FINACEA Gel has dried. Scaling/ 21 (5%) 10 (2%) 5 (1%) 31 (9%) 14 (4%) 1 (<1%) •Avoid the use of occlusive dressings or wrappings. dry skin/ •Skin irritation (e.g., pruritus, burning, or stinging) may occur during use of FINACEA Gel, usually xerosis during the first few weeks of treatment. If irritation is excessive or persists, discontinue use and Erythema/ 6 (1%) 7 (2%) 2 (<1%) 8 (2%) 4 (1%) 2 (1%) consult your physician. irritation •Report abnormal changes in skin color to your physician. Contact 2 (<1%) 3 (1%) 0 (0%) 1 (<1%) 0 (0%) 0 (0%) •To help manage rosacea, avoid any triggers that may provoke erythema, , and blushing. These triggers can include spicy and thermally hot food and drinks such as hot coffee, tea, or alcoholic 3 (1%) 2 (<1%) 0 (0%) 3 (1%) 0 (0%) 0 (0%) beverages. 3 (1%) 1 (<1%) 0 (0%) 1 (<1%) 0 (0%) 0 (0%) © 2012, Bayer HealthCare Pharmaceuticals Inc. All rights reserved. * Subjects may have >1 cutaneous adverse event; thus, the sum of the frequencies of preferred HALOG® is a registered trademark terms may exceed the number of subjects with at least 1 cutaneous adverse event. of Ranbaxy Laboratories Inc. In patients using azelaic acid formulations, the following adverse events have been reported: worsening All other trademarks are property of asthma, , , small depigmented spots, hypertrichosis, reddening (signs of Manufactured for: of their respective owners. ) and exacerbation of recurrent herpes labialis. HLGJI1Aa 01/14 Local Tolerability Studies FINACEA Gel and its vehicle caused irritant reactions at the application site in human dermal safety studies. FINACEA Gel caused significantly more irritation than its vehicle in a cumulative irritation Bayer HealthCare Pharmaceuticals Inc. Wayne, NJ 07470 study. Some improvement in irritation was demonstrated over the course of the clinical trials, but this improvement might be attributed to subject dropouts. No phototoxicity or photoallergenicity were Manufactured in Italy reported in human dermal safety studies. 6706805BS HALOG Cream and Ointment are designed for a difference your patients can truly feel.

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

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

HALOG® is a registered trademark of Ranbaxy Laboratories Inc. All other trademarks are property of their respective owners. HLGJI1Aa 01/14 Page 12 Common Phototherapy Mistakes and How to Avoid Them

Monica Huynh, BA,* Maya G. Debbaneh, BA,** Ethan Levin, MD,*** Daniel Butler, BS,**** Rishu Gupta, BS,***** Argentina Leon, MD,*** John Koo, MD******

*Medical Student, 3rd year, Chicago College of Osteopathic Medicine, Chicago, IL **Medical Student, 4th year, University of California, Irvine, School of Medicine, Irvine, CA ***Psoriasis Research Fellow, Department of Dermatology, University of California, San Francisco, San Francisco, CA ****Medical Student, 4th year, University of Arizona, College of Medicine, Tucson, AZ *****Medical Student, 4th year, University of Southern California, Keck School of Medicine, Los Angeles, CA ******Professor and Vice Chairman, Department of Dermatology, University of California, San Francisco, San Francisco, CA

Abstract Phototherapy is one of the oldest therapeutic modalities to treat psoriasis. Even after decades of use, phototherapy continues to maintain its long track record for safety and efficacy. Optimization of phototherapy, however, requires both time and effort in order to define the ideal therapeutic dose for each individual patient. Therein lies the art of the process: achieving the right balance between dosage requirement and tolerance. It is not uncommon for missteps to occur before the appropriate dosimetry for a patient is determined. If not recognized and addressed, missteps may precipitate adverse effects or premature termination of therapy. We outline some of the more common missteps, as identified at the University of California Psoriasis and Skin Treatment Center under Director John Koo, MD, and discuss how they can be avoided. We also provide an overall phototherapy treatment algorithm.

Failure to adequately Phototherapy: Treatment Algorithm determine optimal dosimetry Though skin type and ethnic background are suggestive as to the optimal dosimetry, each individual can differ significantly from the expected light tolerance. Moreover, the threshold for improvement (and phototoxic reaction) is different not only between individuals but also within the same individual. The extremities (especially the legs) typically need many times the dosimetry of the trunk. In fact, difficult-to- treat areas like the elbows and shins can have a minimal erythema dose that is two to three times greater than that of the trunk. At the University of California Psoriasis and Skin Treatment Center, we typically divide phototherapy into three sequential exposures to ensure that an adequate dosimetry is provided for each body part. First, the whole body is treated (including the face if involved with disease). Second, the face is covered from forehead to chin, and the remaining area is treated. Third, the face and trunk are covered, and only the extremities are treated. By assessing the skin’s reaction to each treatment and taking into account differences in regional dose requirements, the practitioner can determine whether the patient has reached his or her ideal therapeutic light dose. Further, it may be helpful to counsel patients before their first treatment that it is common to experience a mild phototoxic reaction during the course of phototherapy. In fact, these reactions are helpful, because they ensure that an appropriate dosimetry is being used.

HUYNH Page 13 therapeutic need while avoiding a phototoxic Correspondence: Monica Huynh, 3950 N. Lake Failure to recognize initiation burn reaction. During this process, patients may Shore Dr., Chicago, IL 60613; Ph: 408-242-7618; Some patients may experience a burn or other experience a phototoxic reaction, such as an [email protected] sensitivity to light very early in the course initiation burn. If this happens and the patient of phototherapy with low dosimetry. This is has not been counseled about the possibility experienced most frequently in patients with of irritation and discomfort from a phototoxic . When a patient cannot tolerate reaction, the patient may become noncompliant very low fluences of light early on in treatment, or discontinue phototherapy altogether. this may not indicate a failure of the therapy; rather, this may indicate “initiation burn.” Proactively educating the patient can help. A patient who knows from the outset that a mild It is frequently possible to get around this burn helps to define the level of optimal dosimetry “initiation burn” by reducing the dosimetry and and thus is actually helpful in improving the skin then, after multiple exposures to a tolerable condition is less likely to become excessively dosimetry, re-challenging the patient by increasing fearful of phototherapy when a phototoxic the dose incrementally. When the clinician finally reaction does occur. Another effective strategy is “breaks through” the barrier of the initiation burn, reassurance of control: reminding phototherapy the dosimetry can often be increased to a level patients that the dosimetry is always under the far higher than that which caused the initiation direct control of the clinician. If the patient burn. Eventually, the real limit of the patient’s experiences a phototoxic reaction to the current tolerance -- the minimal erythema dose, or MED dose of light, the dose can always be lowered, -- is reached. By using this strategy, we can avoid and future phototoxic reactions will be avoided. the pitfall of erroneously labeling the patient as a This knowledge is reassuring to the patient and “phototherapy failure.” helps prevent premature discontinuation of phototherapy. Failure to distinguish between pruritus from disease and Failure to address anatomical pruritus from treatment peculiarity in terms of light Patients with pruritic skin disorders often tolerance respond well to phototherapy; however, pruritus There is an extremely rare subset of patients that is also one of the most common side effects may experience burning from phototherapy in experienced by patients exposed to narrowband a highly unusual anatomical distribution. For UVB. One of the most challenging nuances to example, a patient may experience a phototoxic grasp as a phototherapy provider, then, is the reaction only in one horizontal dermatome on distinction between the primary disease process the trunk. Failure to recognize this possibility and and the side effects of treatment. Since pruritus adjust for the anomalous reaction can ultimately from the primary disease process is often highly lead to phototherapy failure. unpredictable both in anatomical distribution and chronology, it can be easily misinterpreted as With knowledge that these rare reactions do a side effect of treatment with narrowband UVB. occur, once recognized, the sensitive region of the body can be selectively covered after a limited The timing of onset provides valuable information, light exposure, allowing the clinician to continue as pruritus from treatment with narrowband UVB to steadily increase the dosimetry for the rest usually begins four to eight hours after treatment. of the body. Eventually, the sensitive area may Outside of this time period, pruritus is likely a become more tolerant of higher dosimetry. It may manifestation of active disease. If the origin of even “catch up” to the rest of the body. pruritic symptoms is ambiguous, one distinction strategy is to slightly increase the dosimetry and monitor the response to the light. If the pruritus Conclusion is secondary to a phototoxic reaction, then an Phototherapy offers the advantage of a safe, incremental increase in dosimetry may cause whole-body treatment for generalized psoriasis, erythema. Although it may be intimidating to even during a prolonged maintenance phase of increase dosimetry in fear that it will lead to a management. Although the majority of patients phototoxic reaction, it may be better to cause a respond to phototherapy, this response often mild burn and successfully define the maximal relies on the patience and skill of the practitioner. tolerable dose than to chronically undertreat the The successful delivery of phototherapy is an art, patient. and by developing an awareness of some common pitfalls and strategies to avoid them, clinicians may be able to help a subset of patients who Failure to educate might otherwise miss out on the benefits of the (Once burned, twice shy) treatment. Phototherapy often requires carefully pushing the dosimetry close to the MED in order to define the optimal dosimetry to meet a patient’s

Page 14 COMMON PHOTOTHERAPY MISTAKES AND HOW TO AVOID THEM An Unusual Case of Nodular Kaposi’s Sarcoma on the Dorsal Hand in a Non-HIV Latina Female

Mayha Patel, DO,* Melissa Camouse, DO, FAOCD,** Paul Shitabata, MD***

*PGY-1, Pacific Hospital of Long Beach/Western University, Long Beach, CA **Dermatologist, Private Practice, Downey, CA ***Director of Dermatopathology, Harbor-UCLA Department of Dermatology, Torrance, CA

Abstract Kaposi’s sarcoma (KS) is a multicentric neoplasia of microvascular origin with four main subtypes: classic KS, endemic African KS, immunosuppression (iatrogenic) KS, and AIDS-KS. KS is commonly found in HIV-infected, elderly, Eastern European and Mediterranean males. We present the unusual case of a -proven Kaposi’s sarcoma of the left dorsal hand in an immunocompetent, HIV-negative woman. Although there have been several reports in the literature discussing atypical cases of KS, there are very few reports of nodular Kaposi’s in HIV-negative women. Knowledge of atypical presentations of KS is important for proper assessment, biopsy, diagnosis and treatment of this condition.

was referred to our dermatology office two weeks Introduction later when this treatment failed. The patient Kaposi’s sarcoma (KS) is a multifocal denied shortness of breath, cough, oral lesions, of the reticuloendothelial system that is seen pain, swollen lymph nodes, hematuria or any most commonly in elderly Eastern European other skin lesions. She had a past medical history and Mediterranean males. Since 1979, KS has of hypercholesterolemia and but been found to occur with greater frequency in denied any history of immunodeficiency. immunosuppressed individuals, such as organ transplant recipients and patients infected A deep shave biopsy was performed and revealed with the human immunodeficiency virus a diagnosis of nodular Kaposi’s sarcoma (Figure Figure 1 (HIV). In 1872, Moritz Kaposi, a Hungarian 2, 20x magnification). Immunohistochemistry dermatologist, first talked about findings of staining showed neoplastic cells positive for an aggressive “sarcoma idiopaticum multiplex CD31 (Figure 3, 40x magnification) and human hemorrhagicum” and published case reports of herpesvirus-8 (Figure 4, 40x magnification). The five elderly men with skin lesions.1 The clinical neoplastic cells were negative for cytokeratin course of this classic KS is protracted and usually 34bE12, S-100 and melan-A, consistent with benign. Since then, three more variants have the diagnosis. An ANA screen, ASO titer, been identified. The endemic African variant rheumatoid factor, chlamydia, gonorrhea, RPR often affects HIV-negative adults and children, and HIV test were all negative. and in its aggressive form affects the lymph The patient was referred to with the nodes.2 The immunosuppressive (iatrogenic) diagnosis of a classic, nodular, low-risk Kaposi’s Figure 2 form of KS occurs in patients status post solid sarcoma. As of this paper’s submission, she has on immunosuppressive undergone 23 days of external beam radiation to therapy. In 1981, AIDS-associated KS was first the dorsal hand with complete resolution of the described, with visceral and mucosal involvement tumor. occurring in 10 percent of these patients in the fifth and sixth decades of life.2 KS is commonly Discussion found in HIV-infected males and seldom seen in Kaposi’s sarcoma (KS) is a mesenchymal tumor HIV-negative or immunocompetent women. We involving blood and lymphatic vessels. The report the unusual case of an immunocompetent, pathogenesis of KS involves viral oncogenesis HIV-negative woman with biopsy-proven and cytokine-induced growth, together with Kaposi’s sarcoma of the left dorsal hand, focusing some state of immunocompromise.3 In 1994, a on the rarity of this finding. Figure 3 previously unknown virus was discovered and termed human herpes virus 8 (HHV8), also Case Report known as Kaposi’s sarcoma-associated herpes A 56-year-old Latina woman presented to her virus.3 The modes of transmission of HHV8 are PCP with a three-month history of a rapidly yet to be fully described. In the United States, enlarging, painful red on the left dorsal sexual transmission may be an important route; hand (Figure 1). Incision and drainage (I&D) however, throughout sub-Saharan Africa, KS and a bacterial culture were performed for a has been seen in children since before the era suspected infected . The culture yielded of AIDS, suggesting other possible routes of heavy growth of Staphylococcus aureus, and transmission, including mother-to-child or the patient was treated with a course of oral child-to-child via saliva. Figure 4 clindamycin and topical mupirocin. The patient

PATEL, CAMOUSE, SHITABATA Page 15 In immunocompetent children, HHV8 occurs cutaneous disease, which looks like classic KS channels with erythrocytes.11 Hemosiderin with a febrile maculopapular skin . In and is predominantly seen in young adults deposits and eosinophilic hyaline globules with adults, it is associated with bone marrow failure, around 35 years of age; aggressive localized a perivascular inflammatory infiltrate are seen.11 splenomegaly and fever in organ transplant cutaneous disease, which targets Histiocytes with the phenotype of either factor patients. and bone and is fatal within five to seven years; XIIIa or S-100 dermal dendritic cells are present, 11 It appears that HHV8 initiates and promotes florid mucocutaneous and visceral disease; and as are T-cells and B-cells, including plasma cells. fulminant lymphadenopathic disease, occurring the development of KS lesions through the viral The third stage is the nodular stage, composed in children around 3 years of age and spreading interleukin-6 (vIL-6) and the vascular endothelial of sheets and fascicles of spindle cells with 4 rapidly to lymph nodes and visceral organs with growth factor (VEGF) it produces. There is 3 moderate atypia, single-cell necrosis, and trapped an important difference in the pathogenesis no signs of cutaneous manifestation. erythrocytes within an extensive network of of KS in HIV-negative versus HIV-positive Immunosuppressive KS occurs 500 times more slit-like vascular spaces.12 The spindle cells individuals. KS in immunocompetent persons often in recipients of organ transplants currently present in all KS lesions are thought to represent runs a more indolent course than in patients on immunosuppressive therapy. The clinical the neoplastic component, and most express infected with HIV. In HIV-infected patients, the appearance of KS in patients status post organ endothelial markers CD31 and CD34, along 7 HHV8 virus interacts synergistically with the transplant is limited to the skin. with cell markers.12 It was recently Tat protein produced by the HIV, promoting the AIDS-KS presents quickly, in a few days, reported that all KS spindle cells express vascular migration and proliferation of cytokine-activated beginning as macules and evolving to papules endothelial growth factor (VEGFR-3), which is 5 endothelial cells and stimulating KS cell growth. and tumors. Before the HAART treatment usually only expressed by lymphatic endothelium Similarly, a latency-associated nuclear antigen protocol became the standard of care for AIDS and neoantigenic vessels, showing that KS spindle from the HHV8 virus activates long terminal patients, oral KS lesions were the first clinical cells probably belong to the endothelial lineage repeats of HIV through the Tat protein. HIV- that can differentiate into lymphatic cells.12 5 sign in 25 percent of patients. KS involving ocular negative persons do not possess this protein. adnexal structures has been reported in up to 20 They also overexpress matrix metalloproteinases This difference in pathogenesis shows that the 8 percent of patients with AIDS-KS. AIDS-KS (MMP), which are enzymes that facilitate the evolution and progression of KS relies on different lesions often disappear spontaneously, with new destruction of extracellular matrix proteins. cofactors and mechanisms in HIV-positive versus lesions appearing at neighboring sites. AIDS-KS In summary, the main histologic features of all HIV-negative patients. causes significant morbidity and mortality, with forms of KS include irregularly shaped, slit-like The four most common forms of KS are: classic lymphatic obstruction and rapidly progressive vascular spaces lined by spindled cells with well- KS, endemic African KS, immunosuppression pulmonary failure.3 The clinical characteristics defined borders, extravasated erythrocytes, a (iatrogenic) KS, and AIDS-KS. Other less and treatments of each variant are summarized lymphoplasmacytic infiltrate, hemosiderin-laden common forms of KS include: telangiectatic in Table 1. macrophages, and intracellular and extracellular KS, presenting with translucent nodules and A study of 438 patients by Hiatt et al. compared eosinophilic hyaline globules representing telangiectasia; ecchymotic KS, appearing as classic KS in HIV-negative patients to AIDS-KS erythrocyte breakdown products. periorbital ecchymoses with a large number over a two-decade time period and found 354 In addition, immunohistochemistry and in situ of extravasated red blood cells; keloidal KS, cases of AIDS-KS. Of those 354 patients, there hybridization studies have shown oxytocin- demonstrating brown-violaceous nodules with a was a male predominance characterized by more expression in the cells of classic and keloidal component; cavernous KS, a rare type of aggressive behavior and higher rates of visceral AIDS-KS. Oxytocin can stimulate KS cell locally aggressive KS that histologically resembles and disseminated disease.9 This further illustrates proliferation and may be a pathogenic growth cavernous ; and lymphangioma-like the rarity of KS in HIV-negative women. factor involved in the development of Kaposi’s KS, presenting with bullous-like, compressible sarcoma.13 eruptions in vascular spaces on the lower legs.3 The histological differential diagnosis of Classic KS is seen in elderly men of Histology cutaneous KS includes fibrous , Mediterranean, eastern European, or Jewish The histology of KS can be broken into three targetoid haemosiderotic haemangioma, decent with a peak incidence occurring after stages: patch, plaque and nodular. Some studies acroangiodermatitis (pseudo-Kaposi’s), the sixth decade of life. It originally appears as have reported slight histopathologic differences of Mibelli, cutaneous angiosarcoma, erythematous, violecous macules that progress to between HIV-associated KS and non-HIV- spindle-cell hemangioendothelioma, benign multiple, firm, purple-reddish-brown plaques and associated KS . In HIV-negative patients, lymphangioendothelioma, angiolipoma, and nodules on the lower extremities, occasionally mitoses and cellular anaplasia are more common, 3 whereas AIDS-KS lesions tend to display more bacillary angiomatosis. associated with and . 10 Within this variant there are three subtypes: extensive dissecting vessels. cutaneous, which runs a prolonged course with The patch-stage clinically appears as a macule Treatment a mean survival of eight to 13 years; nodular, and arises in the reticular . A proliferation Treatment for KS depends on the variant of disease. with aggressive, fungating, exophytic, ulcerating of small, irregular endothelium-lined spaces Patients with classic KS typically respond well to growths that infiltrate through large areas of the surrounding normal dermal vessels and local therapy such as excision, laser, cryotherapy skin and subcutaneous tissue; and disseminated, adnexal structures infiltrated by inflammatory and intralesional injections, although the disease presenting with widespread cutaneous lesions lymphocytes is characteristic.11 tends to recur. Watchful observation is generally with and visceral involvement in acceptable for immunocompetent, asymptomatic The second stage is the plaque-stage, clinically Europeans.6 patients. If cryotherapy is used, treatment should appearing as small, palpable lesions that be given at three-week intervals with a mean of Endemic KS is a more aggressive variant mostly histologically represent the expansion of a spindle- three treatments for the best response. Endemic found in those of African descent, presenting cell vascular process throughout the dermis and African KS excluding lymphadenopathic disease with a high frequency of extracutaneous often into the subcutaneous fat. Spindle cells are responds favorably to systemic , while 7 found throughout the dermal bundles manifestation. There are four clinically distinct iatrogenic, immunosuppressive KS generally ways to describe endemic KS: benign nodular forming irregular, cleft-like, angulated vascular Page 16 AN UNUSUAL CASE OF NODULAR KAPOSI’S SARCOMA ON THE DORSAL HAND IN A NON-HIV LATINA FEMALE Table 1 - Kaposi’s Sarcoma Variants

Variant Epidemiology Variant Treatment

Classic KS - Elderly males - Erythematous, violaceous macules Local therapy - Mediterranean or - Progresses to purple-red-brown plaques/nodules - Induce a mild inflammatory East European - Lower extremities response - Jewish ancestry - Lymphedema/hyperkeratosis - Lead to tumor flattening, - Sixth decade of life disappearance - Rarely metastasizes Subtypes: 1. Cutaneous: long course; avg. survival 8-13 yrs. 2. Nodular: fungating, exophytic, ulcerating growths; diffuse, infiltrative; subcutaneous tissue 3. Disseminated: widespread cutaneous lesions; lymph node and visceral involvement

Endemic KS - African descent Subtypes: Systemic therapies - Children, 1. Benign nodular cutaneous: young adults adolescents, adults 2. Aggressive localized cutaneous: soft tissue, bone; avg. survival 5-7 - More aggressive yrs. course 3. Florid mucocutaneous, visceral 4. Fulminant lymphadenopathic: young children; lymph nodes, visceral organs; no cutaneous lesions

Iatrogenic KS Organ transplant Limited to skin involvement Regresses after reduction/cessation recipients on of immunosuppressive therapy immunosuppressive therapy

AIDS-KS HIV-positive patients - Multifocal and symmetric - Macules evolve to papules/tumors - Ocular adnexal structure involvement in up to 20% - Lymphatic obstruction or rapidly progressive pulmonary failure

Telangiectatic Translucent nodules w/ prominent telangiectasia KS

Ecchymotic KS - Periorbital ecchymoses - Extravasated red blood cells

Keloidal KS - Brown-violaceous nodules - Keloidal component

regresses after immunosuppressive therapy is such as interleukin-2, chorionic gonadotropin direct mechanism of action in this case is not stopped. For AIDS-KS, no curative therapy and .2 through its anti-estrogen-receptor activity (there 14 exists. Neither local nor systemic treatments for A study by Hong et al. demonstrated an are no estrogen receptors on KS cells), as seen in AIDS-KS have been shown to prolong survival. antiproliferative effect of toremifene on KS cells breast cancer, but instead is through TGF- ß1.15 is a well-tolerated treatment 15 However, the indirect effect of TGF- ß1 on the first detectable at 24 hours after use. Toremifene, down-regulation of estrogen suggests there may for large, localized lesions and has been used a selective estrogen-receptor modulator that be an agonistic relationship between estrogen for many years as they are highly radiosensitive. opposes estrogen activity, was found to be causing and KS that should be further investigated, Adverse effects of this therapy include residual the upregulation of growth-inhibitory factor particularly in women. This study also showed hypopigmentation, radiodermatitis, and TGF-ß1at the transcriptional level. TGF-ß1 is 2 that topical toremifene administration can be a ulceration of the skin. Recent studies have also known to be a down-regulator of estrogen and a experimented and shown some success with beneficial mode of localized treatment without potent inhibitor of KS cell growth. Toremifene’s 15 hormonal and immunomodulating therapies the risk of side effects. PATEL, CAMOUSE, SHITABATA Page 17 DeSouza YG, Greenspan JS, Greenspan D. Human Conclusion immunodeficiency virus-associated oral Kaposi’s Although there have been several reports in sarcoma. A heterogeneous cell population dominated the literature discussing atypical cases of KS, by spindle-shaped endothelial cells. Am J Pathol. there are very few reports of nodular Kaposi’s in 1993;143:240–249. non-HIV infected women. Since classic KS is 13. Cassoni P, et al. Oxytocin is a growth factor for Kaposi’s typically found in elderly, immunocompromised, sarcoma cells: evidence of endocrine-immunological cross- Eastern European and Mediterranean males, it talk. Cancer Res. 2002;62(8):2406-13. is important to note the rare case of an isolated, 14. Brenner B, Rakowsky E, Katz A, et al. Tailoring nodular Kaposi’s sarcoma on the upper extremity treatment for classical Kaposi’s sarcoma: comprehensive in an HIV-negative, immunocompetent Latina clinical guidelines. Int J Oncol. 1999;14:1097–1102. woman. Knowledge of atypical presentations of KS is important for proper assessment, biopsy, 15. Hong A, Leigh BR. Antiproliferative properties of diagnosis and treatment of this condition. toremifene on AIDS-related Kaposi’s sarcoma cells. Chemotherapy. 2002;48(5):238-43. References 1. Iscovich J, et al. Classic Kaposi Sarcoma Epidemiology Correspondence: Mayha Patel, DO, Pacific Hospital and Risk Factors. Cancer. 2000;88:500-517. of Long Beach, 4939 Kilburn Ct, Oak Park, CA 91377; 2. Jan RA, Koul PA, Ahmed M, Shah S, Mufti SA, et Ph: 818-571-8231; Fax: 818-889-2946; mkpatel@ al. Kaposi Sarcoma in a Non HIV Patient. Int J Health westernu.edu Sci. 2008;2(2). 3. Hengge U, Ruzicka, Tyring S, Stuschke M, Roggendorf M, Schwartz R, Seeber S. Update on Kaposi’s sarcoma and other HHV8 associated diseases. Part 1: Epidemiology, environmental predispositions, clinical manifestations, and therapy. The Lancet Infect Dis. 2002;2(5):281–292. 4. Hong A, Lee CS. The emerging role of the human herpesvirus 8 (HHV8) in human neoplasia. . 2001;33:460-467. 5. Prakash O, Tang Z Y, He Y, et al. Human Kaposi’s sarcoma cell-mediated tumorgenesis in human immunodeficiency type 1 Tat-expressing transgenic mice. J Natl Cancer Inst. 2000;92:721-728. 6. Hood AF, Farmer ER, Weiss RA. Clinical conferences at The Johns Hopkins Hospital: Kaposi’s sarcoma. Johns Hopkins Med J. 1982;151(5):222-30. 7. Rappersberger K, Tschachler E, Zonzits E, Gillitzer R, Hatzakis A, Kaloterakis A, Mann DL, Popow- Kraupp T, Biggar RJ, Berger R, Stratigos J, Wolff K, Stingl G. Endemic Kaposi’s sarcoma in human immunodeficiency virus type 1-seronegative persons: demonstration of retrovirus-like particles in cutaneous lesions. J Invest Dermatol. 1990;95:371–381. 8. Shuler JD, Holland GN, Miles SA, Miller BJ, Grossman I. Kaposi sarcoma of the conjunctiva and eyelids associated with the acquired immunodeficiency syndrome. Arch Ophthalmol. 1989;107:858–862 9. Hiatt K, Nelson A, Lichy J, Fanburg-Smith J. Classic Kaposi Sarcoma in the United States over the last two decades: A clinicopathologic and molecular study of 438 non-HIV-related Kaposi Sarcoma patients with comparison to HIV-related Kaposi Sarcoma. Mod Pathol. 2008;21:572–582. 10. Radu O, Pantanowitz L. Kaposi sarcoma. Arch Pathol Lab Med. 2013;137(2):289-94. 11. Ackerman AB. Subtle clues to diagnosis by conventional microscopy. The patch stage of Kaposi’s sarcoma. Am J Dermatopathol. 1979;1:165–172. 12. Regezi JA, MacPhail LA, Daniels TE, Page 18 AN UNUSUAL CASE OF NODULAR KAPOSI’S SARCOMA ON THE DORSAL HAND IN A NON-HIV LATINA FEMALE Asymptomatic Hyperpigmentation in an Elderly Male

Christopher Cook, DO,* Lacey Elwin, BS,** David Cleaver, DO,*** Lloyd Cleaver, DO****

*Dermatology Resident, 1st year, Northeast Regional Medical Center / KCOM, Kirksville, MO **Medical Student, 4th year, Chicago College of Osteopathic Medicine, Downers Grove, IL ***Dermatology Attending Physician, Northeast Regional Medical Center / KCOM, Kirksville, MO ****Dermatology Residency Program Director, Northeast Regional Medical Center / KCOM, Kirksville, MO

Abstract Silver dermatoses (argyria) have increased in incidence throughout the United States since the 1990s, when fears of antibiotics shortages became increasingly common. With a proven history of antiseptic properties, the ingestion of colloidal-silver solutions is a common treatment modality in many cultures that practice . We report a case of an 85-year-old male who presented to our clinic with an asymptomatic, slate-gray-blue hyperpigmentation distributed in sun-exposed areas.

Case Report An 85-year-old male presented to our office as a new patient for a full-body skin exam. The patient’s past medical history was significant for hypertension and atrial fibrillation, while his dermatological history included actinic keratoses. consisted of warfarin and lisinopril. Upon entering the room, it was immediately noted that the patient appeared cyanotic but was not in distress. A prompt vital-sign check yielded an oxygen saturation of 98% on room air and a blood pressure of 128/78 with a regular pulse of Figure 1 Figure 3 80. On physical exam, the patient was noted to have a strikingly slate-gray-blue hyperpigmentation Discussion that was most prominent in sun-exposed areas Argyria is a rare cutaneous caused including the head, neck, and upper extremities by chronic exposure to products containing (Figure 1). Non-sun-exposed areas, including silver. A slate-colored pigmentation develops the chest, back, and lower half of the body, were from silver-granule deposition in the skin that is uninvolved. Examination of the fingernails and most noticeable in sun-exposed parts of the body. toenails revealed a dark-gray hyperpigmentation However, hyperpigmentation can also develop in of the lunula on every digit (Figure 2). Both nails, mucous membranes, conjunctiva, and sclera. oral and nasal mucous membranes displayed a Hyperpigmentation occurs through several diffusely scattered hyperpigmentation, while the Figure 2 different mechanisms that yield a combined sclerae were normal. effect of reduction of the silver compound as well After several minutes of questioning, the patient patient would put a dose of silver water into a as an increase in production. Through admitted to drinking a homemade silver solution gallon of milk to extend the shelf life and prevent a process that is similar to the development of on a daily basis. Preparing this concoction curdling. a photo, sunlight acts as a catalyst in reducing 1 involved purchasing 99-percent pure silver from colorless silver compound to elemental silver. Our working differential diagnosis included a local jewelry store in sticks that measure 6 Metallic silver is then oxidized by the tissue argyria, warfarin-induced hyperpigmentation, inches long by 2 inches wide. The patient would and becomes bound as silver sulfide. Black silver amiodarone-induced hyperpigmentation, then connect the two silver sticks in series with sulfide is what makes up the granule deposition porphyria, hemochromatosis, , and a 14-gauge stainless steel wire and three 9-volt around eccrine glands. Finally, silver further dermal melanocytosis. Lab studies such as a batteries and submerge it in a bath of distilled increases dyschromia by stimulating serum iron level were considered, but the patient water and sea salt. The 9-volt batteries were activity with a resulting expansion of refused. A 4-0 punch biopsy was performed activated by an electrical charge, and the solution melanin synthesis.1 on a hyperpigmented area from the neck, cooked until the water became “foggy” and a which portrayed numerous fine, black granules Argyria can present as localized vapor of steam was emitted from the bath. surrounding the eccrine glands (Figure 3). hyperpigmentation or as diffuse, blue-gray The patient had been making “silver water” for The results were consistent with argyria both hyperpigmentation in sun-exposed areas. Cases more than 10 years for antiseptic purposes. For clinically and histologically. The patient was of localized argyria involve direct silver deposition example, the patient admitted to drinking a cup of advised against using his homemade tonic, and into the skin, while generalized argyria involves silver water when he started to feel an impending sunscreen use was recommended to prevent ingesting silver solution. The consumption of sore throat or food , and he sprayed further hyperpigmentation. colloidal silver has gained popularity worldwide the solution into his nose for sinus clearance secondary to evidence of its antiseptic properties. and upper respiratory infections. Moreover, the COOK, ELWIN, CLEAVER, CLEAVER Page 19 In alternative medicine, colloidal silver is widely the basement membrane of the glomerulus, embedding of needles. Eur J Dermatol. marketed as a dietary supplement with unfounded peritubular capillaries, and the elastic lamellae of 2002;12(6):609-11. claims of beneficial effects in diabetes mellitus, of the on autopsies.10 However, 5. Hristov AC, et al. Localized cutaneous argyria. J Am AIDS, arthritis, cancer and many other diseases.2 new research has concluded that silver is non- Acad Dermatol. 2011 Sep;65(3):660-61. Colloidal silver products in different forms as toxic to the kidneys after animal studies failed to 6. Garcias-Ladaria J, et al. Localized cutaneous well as generators are easily available through the reveal structural damage to the kidneys at massive argyria: A report of 2 cases. Actas Dermosifiliogr. 2013 Internet. exposure to silver nitrate in rats.11 Apr;104(3):253-4. Localized argyria can present up to 30 years Regarding the brain, Mirsattari et al. reported 7. Palamar M, et al. Black tears (melanodacryorrhea) from argyrosis. Arch Ophthalmol. 2010 Apr;128(4):503-5. after the permanent deposition of insoluble a 71-year-old man who developed myoclonic silver compound. The condition has been status epilepticus and coma after daily ingestion 8. Agency for Toxic Substances and Disease Registry illustrated in previous case reports secondary of colloidal silver for four months.12 The patient (ATSDR): Toxicological profile for silver. TP-90-24. to embedded acupuncture needles or topical remained in a persistent vegetative state until Atlanta, GA, ATSDR, 1990. application of silver nitrate.3 Most of the former his death five months later. This case leads to 9. Venugopal B, Luckey TP. Toxicology of non- cases occurred in Japan, where the embedment the hypothesis that silver products can cause radioactive heavy and their salts. Environ Qual of acupuncture needles was once a popular irreversible neurologic toxicity associated with a Saf Suppl. 1975;1:4-73,104-14. traditional Japanese therapy to control refractory poor outcome.12 10. Mayr M, et al. Kidney biopsy teaching case. 4 Argyria and decreased kidney function: Are silver back pain, arthralgias, neuralgias, and migraines. Treatment for argyria is limited. The first Although embedding acupuncture needles is no compounds toxic to the kidney. Am J Kidney Dis. 2009 recommendation is to eliminate exposure to May;53(5):890-4. longer a common treatment modality, accidental silver immediately. Beyond that, a standard of 11. Watanabe Y, et al. Case of membranous nephropathy breakage of acupuncture needles can still be an care does not currently exist, although laser etiology of localized argyria. Other reported cases associated with argyria. Nihon Jinzo Gakkai Shi. therapy with the quality-switched 1,064-nm 2005;47(5):547-51. of localized argyria involve the volar aspects of neodymium-doped yttrium aluminum garnet jewelers’ forearms, the mouths of patients with 12. Mirsattari SM, et al. Myoclonic status epilepticus (Nd:YAG) laser has been effective in a small following repeated oral ingestion of colloidal silver. amalgam fillings, and mirror shards embedded 13 5,6 number of case series. The 1,064-nm Nd:YAG . 2004 Apr 27;62(8):1408-10. during motor vehicle accidents. laser penetrates into the deep reticular dermis, 13. Hovenic W, et al. Treatment of argyria using the As aforementioned, the pathogenesis of argyria targeting dermal melanophages as well as silver quality-switched 1064 nm neodymium-doped yttrium is secondary to the deposition of insoluble silver granules that surround the eccrine glands. Saager aluminum garnet laser: efficacy and persistence of granules into the basal lamina of eccrine glands et al. reported the removal of pigment in a 3 results at 1-year follow-up. Dermatol Surg. 2012 and blood vessels. The histological features mm to 6 mm treatment area with a Q-switched Dec;38(12):2031-4. 14 can create a concerning clinical appearance of 1,064 Nd:YAG laser at 0.8-2 J/cm2 per area. In 14. Saager RB, et al. Quantitative near infrared melanocyte proliferation with a differential this study, there was an absence of discoloration spectroscopic analysis of Q-switched Nd:YAG diagnosis that includes metastatic melanoma, recurrence at one-year follow-up when the face, treatment of generalized argyria. Lasers Surg Med. blue , or traumatic . Moreover, neck, upper chest and arms were treated over 2013 Jan; 45(1) :15-21. melanodacryorrhea has been reported in a patient multiple sessions under general anesthesia.14 15. James WD, Berger TG, Elston DM. Andrews’ 7 with bilateral argyrosis of the conjunctiva. In this In addition to laser treatment, it is of utmost Diseases of the Skin, Clinical Dermatology. 9th ed. clinical portrait of black tears, it is imperative to importance to educate patients about eliminating Canada: Elsevier; 2006. question the history of topical use silver exposure and utilizing sunscreen due to its or silver ingestion, because it has also recently numerous potential systemic complications as Correspondence: Christopher Cook, 700 W. Jefferson been reported in a patient with necrotic uveal well as permanent discoloration of the skin. St., Kirksville, MO 63501; [email protected] 7 melanoma. With a fear of antibiotic shortage and a broadening Other cutaneous differential diagnoses of diffuse spectrum of alternative medical practices, a blue-gray hyperpigmentation in sun-exposed initiative should be undertaken to areas include drug-induced hyperpigmentation heighten awareness of the permanent sequelae (DIH), Addison’s disease, hemochromatosis, related to silver. From cutaneous manifestations Wilson’s disease, porphyria, , exogenous to internal involvement, it is best to counsel ochronosis, and pigmentosus (LPP). patients on the possible harmful outcomes and A thorough history and physical examination can encourage the termination of any silver exposure. help to elucidate each differential diagnosis and Public awareness of the potential toxicity of silver possibly avoid the need for a punch biopsy. The exposure is important to prevent the chronic definitive diagnosis of argyria is confirmed by a morbidity and incipient mortality seen in patients punch biopsy showing black granules surrounding with argyria. the eccrine glands. Adjunctive tests include a serum iron level, which should remain elevated months after discontinuation of silver intake. Other techniques such as scanning electron References microscopy with energy dispersive spectroscopy 1. Kim Y, Suh H, Cha H, et al. A case of generalized can aid in the diagnosis of chemical elements argyria after ingestion of colloidal silver solution. Am J within skin biopsies. of Ind Med. 2009;52(3):246-250. Although the Agency for Toxic Substances and 2. Kwon HB, Lee JH, Lee SH, et al. A case of argyria Disease Registry (ATSDR) considers silver following colloidal silver ingestion. Ann Dermatol. deposits in tissues to be relatively harmless and 2009;21(3):308-310. without serious health effects, a small number of 3. Tanita Y, Kato T, Hanada K, et al. Blue macules of case reports have stated otherwise, particularly localized argyria caused by implanted acupuncture 8,9 needles. Arch Dermatol. 1985;121:1550-2. regarding the brain and kidney. In previous literature, silver deposits were described in 4. Emiko T, et al. Localized argyria 20 years after

Page 20 ASYMPTOMATIC HYPERPIGMENTATION IN AN ELDERLY MALE Manual Dermabrasion: The Forgotten Tool for Perioral Rhytides

Adam J. Taylor, BS,* Derrick H. Adams, DO, FAOCD**

*Pre-Medical Student, California State University, Chico, CA **Medical Director, Vita Dermatology & Laser Institute, Red Bluff, CA

Abstract Manual dermabrasion is a cost-effective, safe, and efficient method of facial resurfacing that has been largely ignored in recent literature. We report a case of a highly successful manual dermabrasion of the perioral region. Manual dermabrasion has fared well in comparison to more expensive and high-tech methods of resurfacing. We would like to remind our profession of this simple and viable technique for perioral rhytide resurfacing.

Case Discussion A 65-year-old, healthy female with Fitzpatrick There are several effective and successful treatment encouraged to pursue non-ablative procedures.2,6 skin type II presented to the clinic seeking perioral options available for perioral rhytides. Depending For an experienced physician, complications rhytide treatment. She was a current smoker and on the underlying skin tone, medical history, and 2,6 associated with ablative resurfacing are rare. had only recently started wearing protective severity of rhytides, patients can seek rejuvenation Intraoperative risks are typically associated with sunscreen. She had previously undergone through methods such as dermabrasion, CO2 the modality used and an error in technique.2,6 fractional ablation CO2 laser treatment and lasers, permanent or absorbable fillers, and chemical On the contrary, postoperative complications such hyaluronic acid filler at another clinic about a year peels.1,2 Selected patients with advanced-to- as scarring, infection, hyperpigmentation and prior with mild improvement. severe rhytides are encouraged to pursue ablative 1,2 hypopigmentation, erythema, dyschromia, milia Upon examination, she was noted to have techniques for more dramatic results. Although a and acne flares can occur in any ablation technique advanced-to-severe (Glogau type III-IV), static variety of ablative techniques have proved successful, but can be largely avoided through respective recent studies show comparable results between 2,6 vertical rhytides periorally (Figure 1). Drywall preoperative precautions. Activation of the herpes manual dermabrasion and other ablative resurfacing sandpaper at 150-grit was obtained from a simplex virus is one of the more common and feared local hardware store and then autoclaved per modalities, each having specific advantages and 3,4 complications, and to avoid this and other infections, clinic protocol. Regional dental blocks using disadvantages. With similar cosmetic outcomes prophylactic antiviral and antibacterial medications and at a fraction of the cost, manual dermabrasion 1,2,6 bupivacaine achieved acceptable anesthesia to often are administered preoperatively. The should be considered an effective and resourceful the treatment area. Her face was cleaned with formations of scars are generally attributed to treatment option for ablative rhytide rejuvenation. chlorhexidine, and she was prophylaxed with ablation that occurs at the subcutaneous level, and if acyclovir and cephalexin before the procedure. Ablative resurfacing involves the removal of the identified early postoperatively, scars can be treated Using firm pressure, the sandpaper was worked 2,5 2,6 to the depth of the dermis. Following with serial intralesional triamcinolone injections. in a circular motion across the perioral region, ablation, support cells within the dermis facilitate Although most complications are considered and in straight lines perpendicular to the the growth of supplemental collagen parallel to universal, the rates of occurrence between ablative vermillion border rhytides, until papillary dermal the epidermis and deep to the dermal-epidermal modalities can vary, each having respective bleeding was achieved. The patient tolerated the 2 junction. Collagen formation continues advantages and disadvantages.2,6 procedure well, and there were no complications. postoperatively and is responsible for the desired Postoperative instructions included twice-daily This case exemplifies the seemingly forgotten cosmetic outcomes and rejuvenation.2 Generally, diluted vinegar soaks (1:4) with application of potential that manual dermabrasion has for patients with fairer complexions (Fitzpatrick petroleum jelly, as well as strict sun avoidance. She resurfacing perioral rhytides. Since ancient skin types I-III) and more severe photoaging and returned to the clinic 36 days post-operatively, Egypt, have been using sandpaper to rhytides (Glogau type III-IV) are considered 7 with pleasing results (Figures 2 and 3). Residual successfully resurface scars and rhytides. Despite its ideal candidates for ablative resurfacing.2,6 Patients erythema was noted but was of no concern to the proven efficacy, newer resurfacing techniques, such with darker skin types have greater risk for patient. as CO2 lasers and powered dermabraders, have hypopigmentation complications and are therefore 4 stolen the spotlight from manual dermabrasion.

Figure 1 Figure 2 Figure 3

TAYLOR, ADAMS, DO, FAOCD** PAGE 21 Perhaps a major influence in this transition has modalities, such as pulsed, fractional, or computer- associated with method-specific complications.3,4 been the industry promotions behind more modern scanned continuous wave CO2 lasers, can deliver Although these techniques are faster operatively in instruments. As sandpaper is the main apparatus fluencies in less than 1 ms with tissue vaporization comparison to manual dermabrasion, this difference for manual dermabrasion, there are no apparent range of 20-50 µM per pass and 30-150 µM of is insignificant when treating a small cosmetic marketing incentives associated with advertising its residual thermal damage.3,13 This improvement in unit such as the perioral and upper-lip region.3,4 use. On the contrary, newer modalities have been residual thermal damage and associated decreased Manual dermabrasion, therefore, should regain its advocated throughout the medical community, risk of scarring have increased the popularity of clinical recognition as a viable method of perioral which may contribute to their widespread use. CO2 lasers for perioral resurfacing.3,14 resurfacing, despite its current lack of industry support and prevalence in clinical literature. Today, the majority of dermabrasion cases are To those who promote fractional, pulsed, and performed using powered, hand-held dermabraders computer-scanned CO2 lasers, these methods with wire brushes, diamond fraise, and serrated are considered to be more reproducible, precise, References 8,9 wheel end pieces. These interchangeable end and operatively faster in comparison to manual 1. Gendler EC. Analysis and Treatment of the Aging pieces come in a variety of shapes and designs that dermabrasion.4,5,10,14 When compared to powered Face: Topical Treatment of the Aging Face. Dermatol allow the physician to quickly adjust to variations dermabraders, both manual dermabrasion and CO2 Clin. 1997;15(4):561-6. in tissue contour.8,9 With rotation speeds as high lasers reduce the risk of airborne infectious agents in 2. Deborshi R. Ablative Facial Resurfacing. Dermatol as 15,000 RPM to 30,000 RPM, however, these the operating room, but it should be noted that viral Clin. 2005;23(3):549-59. instruments pose risks for damaging loose tissue pathogens have still been discovered in the laser and exposing medical staff to potentially infectious plume.3,4 Additionally, laser equipment can result in 3. Gin I, Chew J, Kimberly R, Amos D, Bridenstine 3,8,9 3 J. Treatment of Upper Lip Wrinkles: A Comparison bloodborne pathogens and skin fragments. These ocular injury when used incorrectly. However, the of the 950 μsec Dwell Time Carbon Dioxide Laser infectious agents have also been noted to produce a primary disadvantage of CO2 lasers is the high cost to Manual Tumescent Dermabrasion. Dermatol Surg. bloody field which may impair the surgeon’s ability of purchasing and maintaining these instruments, 1999;25:468–74. to make an accurate assessment of the depth of especially when compared to the costs associated 3,9 ablation. Additionally, powered dermabrasion with manual dermabrasion. Although CO2 lasers 4. Holmkvist K, Rogers GS. Treatment of Perioral typically requires use of a cryogenic spray, are known to be faster operatively, when treating a Rhytides: A Comparison of Dermabrasion and particularly when using the wire brush end pieces, smaller cosmetic area, such as the perioral region, Superpulsed Carbon Dioxide Laser. Arch Dermatol. which can increase the risk of hypopigmentation the difference should be considered insignificant.3,4 2000;136:725-31. and hypertrophic scarring when used incorrectly.4,8,9 According to recent studies, dermabrasion and 5. Brightman LA, Brauer JA, Anolik R, et al. Ablative Alternatively, manual dermabrasion is a safer, more CO2 lasers have shown comparable results and Fractional Ablative Lasers. Dermatol Clin. affordable, and less technically difficult method for clinically.3,4 Holmkvist et al. conducted a study 2009;27(4):479-88. 3,4 perioral rhytide resurfacing. Perhaps the most comparing the clinical outcomes and adverse effects 6. Hirsch R, Stier M. Complications and Their obvious advantage of manual dermabrasion in of manual sandpaper dermabrasion and super- Management in Cosmetic Dermatology. Dermatol 4 comparison to other ablative resurfacing techniques pulsed CO2 laser treatment on the perioral region. Clin. 2001;19(3):507-12. is the cost of purchasing and maintaining equipment. It was found that both methods significantly 7. Lawrence N, Mandy S, Yarborough J, Alt T. History There are also a wide range of sandpaper coarseness improved the rhytide scores, with no statistically of Dermabrasion. Dermatol Surg. 2000;26(2):95–101. options that can be utilized for more conservative significant difference between them.4 Similarly, or aggressive approaches and adjusted depending Gin et al. compared the clinical results of manual 8. Harmon CB. Dermabrasion. Dermatol Clin. 4 on the physician’s experience. Manual use of dermabrasion to a computer scanned 950 µsec 2001;19(3):439-42. 3 sandpaper also minimizes the airborne pathogens dwell time CO2 laser for upper lip rhytides. This 9. Gold MH. Dermabrasion in Dermatology. Am J and tissue fragments, and thus provides the surgeon study also showed comparable cosmetic results, Clin Dermatol. 2003;4(7):467-71. with a clear field for a more thorough intraoperative along with similar respective disadvantages for each 3,4 10. Fitzpatrick RE. CO2 Laser Resurfacing. Dermatol assessment. Additionally, firm pressure applied method.3 The associated disadvantages of the CO2 Clin. 2001;19(3):443-51. on the sandpaper can provide sufficient skin treatment included more extensive postoperative 3,4 turgor, so cryogenic instruments are not required. crusting, more pronounced erythema, and slower 11. Alster TS, Lupton JR. Lasers in Dermatology. Am J Despite these advantages, the clinical use of manual re-epithelialization.3,4 Disadvantages for manual Clin Dermatol. 2001;2(5):291-303. dermabrasion has been overshadowed by newer dermabrasion were noted to include decreased acute 12. Goldberg DJ. Lasers for Facial Rejuvenation. Am J techniques, most notably CO2 laser resurfacing hemostasis, longer operating time, and variability Clin Dermatol. 2003;4(4):225-34. instruments. in the depth of tissue abrasion.3,4 There was no 13. Ayram M, Tsao S, Tannous Z, Ayram M. reported difference between the two when it came CO2 laser resurfacing techniques are based Photoaging. Color Atlas of Cosmetic Dermatology: A to common complications such as postoperative on selective photothermolysis, where a 10,600 Medical and Surgical Reference. 2006; pp.31-33. nm wavelength of light targets water as the herpes infections, scarring, hyperpigmentation, chromophore.5,10-12 When this light energy interacts hypopigmentation, milia formation, and acne 14. Gross EA, Rogers GS. A side-by-side comparison with intracellular water, it immediately vaporizes flares.3,4 of carbon dioxide resurfacing lasers for the treatment 10 of rhytides. J Am Acad Dermatol. 1998;39(4):547-53. and thermally ablates superficial tissue layers. As thermal energy is the method for ablation, CO2 Conclusion lasers also cauterize, via the photocoagulative Of the various treatment options available for Correspondence: Derrick Adams, DO, 2450 Sister effect, which results in a virtually bloodless Mary Columba Dr., Red Bluff, CA 96080; (530) 528- 5,10 ablative facial resurfacing, manual dermabrasion procedure. Residual thermal energy, however, is a safe, resourceful, and comparably effective 8482; [email protected] can damage surrounding tissue, in particular the method. Alternative treatment modalities, such older continuous-wave models, and therefore as powered dermabraders and CO2 lasers, show is considered a primary limitation that is not similar cosmetic results to manual dermabrasion 3-5 encountered in dermabrasion. However, newer but are more expensive to maintain and are

Page 22 MANUAL DERMABRASION: THE FORGOTTEN TOOL FOR PERIORAL RHYTIDES A Novel Case of Scrotal Angiolymphoid Hyperplasia

Renee N. Lucero, BS,* Derrick H. Adams, DO, FAOCD**

*Pre-Medical Student, California Polytechnic State University, San Luis Obispo, CA **Medical Director, Vita Dermatology & Laser Institute, Red Bluff, CA

Abstract Angiolymphoid hyperplasia with (ALHE) is a rare, cutaneous vascular proliferation classically observed on the head and neck areas. We are reporting only the second known case of ALHE appearing on the scrotum.

Case Report A 17-year-old male with a history of refractory verrucous vulgaris presented for asymptomatic nodules on the scrotum, increasing in size and number over the last three years (Figure 1). The patient denied any sexual history, pain, discharge, or trauma to the area. A biopsy was taken to rule out scrotal syringomas or steatocystoma multiplex. Dense collections of lymphocytes with scattered histiocytes and eosinophils were appreciated against a background of increased vasculature (Figure 2). Microbial stains to Figure 2. Histopathology revealed dense collections of lymphocytes with scattered histiocytes and rule out an infectious trigger were negative. Figure 1. Clinical presentation of asymptomatic eosinophils and a background of increased Angiolymphoid hyperplasia with eosinophilia nodules of angiolymphoid hyperplasia with vasculature with a diagnosis of angiolymphoid was diagnosed. Treatment options were discussed eosinophilia on the scrotum. hyperplasia with eosinophilia. (H&E; original with the patient, but he has yet to decide upon a course of action. Molecular clonality was not result from trauma to an or vein; infection; eosinophil infiltrate.2,7 ALHE is a benign, investigated due to cost constraints. or uncontrolled vascular factors.2,3,7 A study by primary vascular proliferation, while KD is due to Olsen and Helwig suggested that ALHE may be chronic and is either an allergic or caused by arteriovenous shunts, which affected 53 autoimmune disorder.7 Discussion 5,7,8 Angiolymphoid hyperplasia with eosinophilia out of 116 patients. Kempf et al. showed that Many treatment modalities have been used ALHE may be a benign or low-grade malignant in attempts to clear ALHE lesions, but it is (ALHE) is an uncommon vascular proliferation. 3,9 The wide histologic variations in presentation have CD4+ T-cell lymphoproliferation. notoriously refractory to treatment. Surgical spawned an equally wide variety of nomenclature Clinically, ALHE presents as pink to red-brown excision is often used after other non-invasive for the condition. Epithelioid , papules or nodules on the face or neck with a options have failed. Other commonly used pseudopyogenic granuloma, inflammatorytendency to form in the preauricular area.1-3,7 treatments include intralesional angiomatous nodule, popular angioplasia, Involvement of the oral mucosa, bone, muscle, and laser therapy. Lesions after surgical excision subcutaneous angioblastic lymphoid hyperplasia parapharyngeal space, tongue, colon, and salivary have a 33 percent to 50 percent recurrence rate. 2,3,10 Mohs micrographic has also been used with eosinophilia and lymphofolliculosis, glands is rare. There are fewer than 30 for treatment, with results showing promise of intravenous atypical vascular proliferation, and reported cases of male urogenital involvement. completely resolving lesions with no recurrence histiocytoid hemangioma have all been utilized Our patient is only the second reported case and minimal destruction of healthy tissue.3 by various authors over the decades. of scrotal involvement.11 ALHE lesions often The high cost and exclusion criteria, however, The lesions of ALHE are benign and typically bleed easily and present either as asymptomatic preclude most patients from considering present as papules or nodules on the face or or with pain, pruritus, or pulsation.3,10 1-3 this option. Other treatment modalities have neck. There is a slight predilection for females Case reports of angiolymphoid hyperplasia included topical tacrolimus, electrocoagulation, over males in ALHE, and most cases occur with eosinophilia have been inconsistent and corticosteroids, sclerotherapy, indomethacin, 4 between the ages of 20 and 50 years. ALHE underreported due to the condition being retinoids, cryotherapy, pentoxifylline, intravenous more commonly affects patients of Asian and incorrectly diagnosed as Kimura’s disease vinblastine sulfate, radiotherapy, interferon 5 Caucasian decent. ALHE is rare in black (KD).2 While ALHE and KD have similar α-2b therapy, intralesional bleomycin, and populations. It is likely an underreported characteristics, they are now characterized as radiofrequency excision.1,5,10 condition, however, so accurate demographic different disorders.1,7,10 Histologically, the main information may be lacking. characteristic of ALHE is vascular proliferation Conclusion The first description of ALHE was by Wells sometimes demonstrating cobblestoning with We have reported only the second known case and Whimster in 1969.6 The pathogenesis is an eosinophil infiltrate. KD is generally deeper, of scrotal angiolymphoid hyperplasia with unknown, but there is speculation that the lesions with lymphoid follicles, dense fibrosis, and an eosinophilia. It is a rare but benign vascular LUCERO, ADAMS Page 23 proliferation that typically presents on the head or neck area. Due to the high rates of recurrence, many treatment modalities have been used in Verrucous Intertriginous Plaques in a Young attempts to clear lesions. Female

References Joseph Dyer, DO,* Kathleen P. Soe, DO, FAOCD,** George Gibbons, MD*** 1. Padilla-España L, et al. Angiolymphoid Hyperplasia *Traditional Rotating Intern, Delaware County Memorial Hospital, Drexel Hill, PA with Eosinophilia: Analysis of 7 Cases. Actas **Dermatologist, Virginia Street Dermatology, Dunedin, FL Dermosifiliogr. 2013;104:353-5. ***Dermatopathologist, Dermpath Diagnostics, Tampa, FL 2. Mariatos G, Gorgoulis VG, Laskaris G, Kittas C. Epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia) in the oral mucosa: A case report and review of the literature. Oral Oncol. 1995;35:435-8. Abstract We report on a woman who presents with chronic fungating plaques in intertriginous areas and discuss 3. Miller CJ, Ioffreda MD, Ammirati CT. Mohs salient features of her history, physical examination, and histopathology. After a diagnosis of keratitis- Micrographic Surgery for Angiolymphoid Hyperplasia -deafness syndrome is made, we provide commentary on the condition and elaborate on its history, with Eosinophilia. Dermatol Surg. 2004;30:1169-73. pathophysiology, and prognosis. 4. Kobraei KB, Church AB, Judge KW, Shigo AL, Vincek V. What Is Your Diagnosis? Angiolymphoid Hyperplasia with Eosinophilia. Cutis. 2013;92:8, 15-16. Case Report A 25-year-old black female presented with 5. Damle DK, Raotole SS, Belgaumkar VA, Mhaske history of malodorous intertriginous plaques for CB. Angiolymphoid hyperplasia with eosinophilia on one year. The patient was unable to hear and penis in HIV-positive patient: An unusual presentation. communicated through sign language with the Indian J Dermatol Venereol. 2013;79:109-11. help of her husband. The patient was visually 6. Gutte R, Doshi B, Khopkar U. Angiolymphoid impaired. Limited finances precluded previous hyperplasia with eosinophilia with follicular mucinosis. treatment. Indian J Dermatol Venereol Leprol. 2013;58:159. Physical exam revealed verrucous plaques and 7. Acocella A, Catelani C, Nardi P. Angiolymphoid erythematous nodules in the pubic, inguinal, and Hyperplasia with Eosinophilia: A Case Report of Orbital inframammary areas (Figure 1). Conjunctival Involvement. J Oral Maxillofac Surg. 2005;63:144-7. injection was observed in both eyes, and the patient appeared to be squinting due to ocular Figure 1. Verrucous and malodorous plaques of the 8. Olsen TG, Helwig EB. Angiolymphoid hyperplasia discomfort (Figure 2). Rugated skin surrounded pubic region. Biopsy site on left groin. with eosinophilia. A clinicopathologic study of 116 her mouth. Thickened palmar skin showed patients. J Am Acad Dermatol. 1985;12:781-96. hyperlinear creases and a stippled appearance. 9. Kempf W, Haeffner AC, Zepter K, et al. Her fingernails and toenails were dystrophic Angiolymphoid hyperplasia with eosinophilia: evidence and yellowed. Eyelashes and eyebrows were for a T-cell lymphoproliferative origin. Hum Pathol. scant. Routine hematological parameters were 2002;33:1023–9. unremarkable. 10. Stewart N, Zagarella S, Mann S. Angiolymphoid A biopsy was obtained from the left groin. hyperplasia with eosinophilia after venipuncture trauma. Hematoxylin and eosin (H&E) stains showed J Dermatol. 2013;40:393-5. digitated acanthosis and hyperkeratosis with 11. Chen J, Gao H, Wu B, Tsai W, Chiang C. numerous melanophages, lymphocytes, and Angiolymphoid Hyperplasia with Eosinophilia plasma cells in the dermis (Figure 3). Periodic Affecting the Scrotum: A Rare Case Report with acid-Schiff stain demonstrated the presence of Molecular Evidence of T-cell Clonality. J Dermatol. numerous septate fungal hyphae in the thickened Figure 2. Corneal inflammation and hyperkeratotic facial skin. 2010;37(4):355. cornified layer (Figure 4), and subsequent cultures grew Trichophyton rubrum. A diagnosis of dermatophytosis in the setting of Correspondence: Derrick Adams, DO, Vita keratitis-ichthyosis-deafness (KID) syndrome Dermatology & Laser Institute, 2450 Sister Mary was made. The patient had a daughter, age 6, Columba Dr., Red Bluff, CA 96080; 530-528-8482; and a son, age 2, who displayed similar ocular, [email protected] dermatologic, and audiologic stigmata. Notably, the daughter was prone to abscess and kerion formation and had been hospitalized for surgical debridement of pyoderma of the scalp. Subsequent to the birth of her son, our patient underwent a bilateral tubal ligation. In this case, management was multifaceted. The patient was started on terbinafine 250 mg daily for three months, monitoring periodically Figure 3. H&E, 40x. Digitated acanthosis and for transaminitis and neutropenia. In hyperkeratosis.

Page 24 VERRUCOUS INTERTRIGINOUS PLAQUES IN A YOUNG FEMALE stated age.1,2 6. Mazereeuw-Hautier J, Bitoun E, Chevrant-Breton J, Man SYK, Bodemer C, Prins C, et al. Keratitis- Beyond the acronymic triad, patients with ichthyosis-deafness syndrome: disease expression and KID syndrome are prone to repeated bacterial spectrum of 26 (GJB2) mutations in 14 and fungal infections. No clear immune patients. Br J Dermatol. 2007;156:1015-9. deficit has been identified in KID syndrome, but defects in chemotaxis and absence of 7. Koppelhus U, Tranebjærg L, Esberg G, Ramsing M, lymphocyte stimulation have been noted.4,5 Lodahl M, Rendtorff ND, Olesen HV, Sommerlund The phenotype of KID syndrome stems from M. A novel mutation in the connexin 26 gene (GJB2) an autosomal-dominant mutation in connexin in a child with clinical and histological features of 26 or connexin 30 genes.1 These genes code for keratitis-ichthyosis-deafness (KID) syndrome. Clin gap junction proteins that allow for intercellular Exp Dermatol. 2010;36:142-8. communication and transportation of small molecules. To date, six heterozygous missense Correspondence: Joseph Dyer, DO, 15 Thomas mutations have been identified: p.Asp50Asn, Eakins Way, Marlton, NJ 08053; Ph: (770) 235-7028; p.Ser17Phe, p.Asp50Tyr, p.Gly45Glu, [email protected] p.Gly12Arg, and p.Ala88Val.6,7 The majority of patients harbor the p.Asp50Asn mutation. Although limited by rarity and scant clinical descriptions in some reports, genotype may relate to prognosis. There is some evidence that Figure 4. PAS, 400x. Numerous septate hyphae in the p.Ser17Phe mutation is associated with more the thickened cornified layer. severe skin involvement and a fatal squamous- cell carcinoma of the tongue. The p.Gly45Glu addition, she was directed to soak in therapeutic and p.Ala88Val mutations may portend poor baths, alternating between 1 cup of vinegar per prognosis, as the patients in whom these were bath and 1 cup of bleach per bath, to prevent identified died in infancy. Although most cases superinfections. Ammonium lactate emollients of KID syndrome arise de novo, approximately were recommended for liberal application to 10 percent to 36 percent show a familial thickened, dry skin, and tretinoin 0.05% cream inheritance.1,6 was prescribed for facial hyperkeratosis. Finally, the patient was referred to an ophthalmologist and audiologist for further evaluation. Conclusion KID syndrome is a rare with a devastating constellation of manifestations. Our Discussion case affirms that an exuberant fungal infection Keratitis-ichthyosis-deafness syndrome is a may be the presenting feature of KID syndrome. rare with about 100 cases Further, it is noted that specific genotyping may 1,2 in English literature. Most are reported render important prognostic information in this to occur sporadically, although a minority case and should be advised as financial resources show documented transmission from one dictate. generation to the next.3 The name KID syndrome emphasizes the three principle features of the condition: keratitis, ichthyosis, References and deafness. Some authors contend that 1. Bolognia JL, Jorizzo JL, Rapini RP. Dermatology, the cutaneous findings do not represent true 2nd ed. Spain: Elsevier, 2008;769-71. ichthyosis, but rather erythrokeratoderma and 2. Caceres-Rios H, Tamayo-Sanchez L, Duran- hyperkeratosis.2 However they are categorized, Mckinster C, de la Luz Orozco M, Ruiz-Maldonado typical skin manifestations include symmetric, R. Keratitis, ichthyosis, and deafness (KID syndrome): coalescent plaques of the face and occasionally review of the literature and proposal of new terminology. the knees, elbows, and buttocks, along with Ped Dermatol. 1996;13(2):105-13. 1 . The skin may 3. Kelly B, Lozano A, Altenberg G, Makishima become diffusely thickened, leathery, and T. Connexin 26 mutation in keratitis-ichthyosis- xerotic. Ophthalmologic problems develop over deafness (KID) syndrome in mother and daughter with time, beginning in childhood with photophobia combined conductive and sensorineural hearing loss. 1 and blepharitis. Eventually, a vascularizing Int J Dermatol. 2008;47:443-7. keratitis with subsequent scarring may obstruct vision. In contrast, hearing deficits are non- 4. Alli N, Gungor E. Keratitis, ichthyosis, and deafness (KID) syndrome. Int J Dermatol. 1997;36:37-40. progressive and present from birth.1 Auditory disability is generally profound, affecting both 5. Mansur AT, Aydingoz IE, Uygur T, Gunduz S. ears.1 Other distinguishing symptoms include Long-term use of fluconazole for verrucous plaques ungual dysplasia, varying degrees of alopecia, of cutaneous in KID syndrome. Eur J and a characteristic facies with perioral furrows Dermatol. 2008;18(4):469-7. that make the patient appear older than the

DYER, SOE, GIBBONS Page 25 Lupus Pernio: A Case Presentation and Review of Treatment Options

Teresa Ishak, DO,* Mayha Patel, DO,** David Horowitz, DO, FAOCD***

*Dermatology Resident, 2nd year, Pacific Hospital of Long Beach/Western University, Long Beach, CA **Intern, 1st year, Pacific Hospital of Long Beach/Western University, Long Beach, CA ***Dermatology Residency Program Director, Pacific Hospital of Long Beach/Western University, Long Beach, CA

Abstract Sarcoidosis is a systemic disease characterized by the formation of non-caseating granulomas in various tissues. Lupus pernio is the most characteristic cutaneous involvement, occurring in 25 percent to 35 percent of patients, and most often is the initial manifestation of the disease. It is a disfiguring sarcoidosis that is difficult to treat, often causing psychosocial effects that may adversely affect the patient’s quality of life. We present the case of a 57-year-old female with biopsy-proven lupus pernio and the various treatment options available.

Introduction Lupus pernio is the most characteristic cutaneous manifestation of chronic sarcoidosis. It is most commonly seen in black women and is a distinctive feature of chronic fibrotic disease. It presents as an indolent, red-purple or violaceous, indurated skin lesion that most commonly occurs on the nose, cheeks, ears, lips, and forehead. A granulomatous infiltration of the nasal mucosa and bone with ulceration and septal perforation can occur with involvement of the nose in Figure 2 Figure 3 lupus pernio. In addition, lupus pernio is often associated with concomitant involvement of the improve her cutaneous symptoms. Methotrexate become confluent to form nodular plaques on the upper respiratory tract in sarcoidosis. Typically, was also attempted but quickly discontinued, face.1 LP is the most characteristic skin feature it is associated with pulmonary fibrosis, chronic as the patient did not tolerate the side effects. of chronic sarcoidosis and is found in patients uveitis, and bone cysts. Treatment options include She also had evidence of sinus involvement of with chronic progressive systemic sarcoidosis the use of steroids, THF-alpha inhibitors, and sarcoidosis. When she presented she was on with both severe pulmonary and extrathoracic laser treatments. We present the case of a 57-year- prednisone 10 mg daily. In our office, the patient involvement.3 LP was named in 1889 by Besnier, old African American female with lupus pernio, was placed on prednisone 20 mg orally every other who reported an association between reddish-blue and we discuss several treatment options. day and started on hydroxychloroquine 200 mg lesions of the face and nose and swellings of the twice daily. This combination in conjunction with fingers.4 It is these fibrotic lesions that typically Case Report monthly intralesional triamcinolone injections scar and distort facial structures. In addition, the A 57-year-old African American female at 10 mg/cc over 10 months produced favorable lesions can involve the upper respiratory tract presented to the clinic with several flesh-colored results (Figure 3). and cause nasal ulceration and obstruction and to slightly violaceous, pedunculated papules perforation of the nasal septum.1 Some patients and nodules of the bilateral nasal ala (Figure 1). Discussion have developed plaques on the arms, thighs, and Lesions had been present for four years prior to Sarcoidosis is a multi-organ, granulomatous buttocks.1 Lupus pernio plaques can also affect the initial visit to our office. Biopsy showed naked disease most commonly involving the lungs, the bones of the fingers and present with cystic granuloma, confirming the diagnosis of sarcoidosis lymph nodes, and skin. Cutaneous involvement bone lesions on radiographic examination.5 (Figure 2). The patient had tried mycophenolate is present in more than 25% of sarcoidosis The ear lobes can also become infiltrated. In a mofetil with a previous physician, which failed to cases and is the initial disease manifestation series of 35 lupus pernio cases by Mana et al. in in approximately one-third of patients.1 The 1997, intrathoracic involvement was present in incidence of sarcoidosis varies among different 74 percent of patients, sarcoidosis of the upper ethnicities, with high prevalence in Sweden and respiratory tract in 54 percent, bone cysts in 43 the United States. There is a racial distinction in percent, and ocular involvement in 37 percent.3 sarcoidosis incidence in the United States, with The histological findings of sarcoidosis are the Caucasians accounting for 10 to 14 per 100,000 classic non-caseating granulomas with collections cases and African Americans accounting for 35.5 of macrophages and epithelioid cells centrally, to 64 per 100,000.2 encircled by lymphocytes. These granulomas are Lupus pernio (LP) is characterized by chronic, formed by the stimulation of an uncontrolled type indolent, violaceous and indurated, small papules 1 helper T-cell immune response triggered by to large plaques predominantly affecting the foreign antigens.1 The extrinsic antigen or antigens Figure 1 nose and cheeks. The lesions can enlarge and causing this reaction are thought to originate

Page 26 LUPUS PERNIO: A CASE PRESENTATION AND REVIEW OF TREATMENT OPTIONS from a persistent infectious organism or agent infliximab and adalimumab.1 patients with moderate success. The first type of associated with environmental or occupational laser used to treat lupus pernio was the flashlamp 1 Methotrexate has been used successfully in the exposure. Mycobacteria have long been treatment of sarcoidosis, showing a response pulsed dye laser in 1992, which produced good implicated in the etiology of sarcoidosis. Other 15 results although relapses occurred after six to 10 rate of greater than 80 percent. One clinical 19 The VersaPulse system (532 nm) was infectious agents with speculated associations are trial of 15 patients showed clinical resolution in months. used for the first time in 2005 with significant propionibacterium acnes, Epstein Barr virus, and 12 patients at a dose of 25 mg of methotrexate herpes virus.6 Genetic involvement is evident clearance of erythema and a three-year remission weekly.16 Hydroxychloroquine or chloroquine 21 through familial case reports, increased incidence has been used successfully in the treatment of seen in patients. A carbon dioxide laser was in monozygotic twins, and human leukocyte also used on three patients by O’Donoghue 7-10 sarcoidosis as monotherapy. In one literature antigen association. Granuloma resolution review, 57 of 78 patients showed improvement and Barlow, but relapse occurred at nine and 14 21 within two years to five years, sans sequelae, is of skin lesions with hydroxychloroquine or months. 1,11 evident in 60 percent of cases. chloroquine alone.17 Cutaneous sarcoidosis is classified into two Tumor necrosis factor-alpha inhibitors such as Conclusion Lupus pernio is the most characteristic skin categories: specific and nonspecific. Specific infliximab and adalimumab have been shown feature of chronic sarcoidosis and a more frequent eruptions indicate the presence of non-caseating to be beneficial in recalcitrant, disfiguring lupus skin lesion in middle-aged females, advanced- granulomas on biopsy, and nonspecific eruptions pernio.1 A retrospective study by Stagaki et al. in stage patients, and patients with extrapulmonary indicate the development of lesions through 2009 looked at 54 patients treated in a sarcoidosis involvement. In most patients, LP will be the initial a reactive process and not through granuloma clinic for lupus pernio and found that drug 1 presenting sign of sarcoidosis. Corticosteroids formation. Specific lesions are more often regimens containing infliximab were superior remain the mainstay of therapy, although many associated with a chronic disease course, whereas to corticosteroids plus non-corticosteroids, other treatments have been found effective. nonspecific lesions are more common with corticosteroids alone, and non-corticosteroids in 4 Given the lack of level I evidence, therapy the acute presentation of sarcoidosis. Specific achieving resolution of disease.18 The results also remains at the discretion of the dermatologist lesions include lupus pernio, infiltrated plaques, showed that systemic corticosteroids are effective based on clinical experience. Infliximab appears maculopapular eruptions, subcutaneous nodules, in improving, but rarely resolving, lupus pernio superior to systemic corticosteroids with or and infiltration of old scars. An example of lesions. More than 70 percent of the patients on without additional agents for the treatment of the most common non-specific skin lesion is infliximab had improvement of their lupus pernio, 3 lupus pernio. In cases of an allergic reaction to (EN). It has been reported and 25 percent had resolution or near-resolution. infliximab, adalimumab can be used. that specific lesions develop in 3% to 15% of all This is compared to a 29-percent improvement sarcoidosis patients. In a case series by Haimovic seen in patients on the corticosteroids plus et al. in 2012, of the 330 patients diagnosed with non-corticosteroid regimen.18 Treatment with References sarcoidosis, 37 patients (11%) showed the typical an anti-TNF-a antibody such as infliximab 1. Haimovic A, Sanchez M, Judson M, Prystowsky S. sarcoid granulomas on biopsy. Another study by was recommended as second-line therapy for Sarcoidosis: A comprehensive review and update for the Yanardag et al. in 2003 found that out of 516 corticosteroid-unresponsive lupus pernio. In cases dermatologist. J Am Acad Dermatol. 2012;66(5):699. sarcoidosis patients diagnosed within a 36-year of an to infliximab, adalimumab can be 2. Reich JM, Johnson R. Incidence of clinically identified period, 14 (2.7%) had skin lesions that were used. In a case report by Judson in 2011 involving sarcoidosis in a northwest United States population. pathologically and clinically diagnosed as LP, and a 37-year-old African American woman with Sarcoidosis Vasc Diffuse Lung Dis. 1996;13:173–177 of those, nine patients (63.4%) were identified as a history of lupus pernio, an infusion of 5 mg/ 12 having pulmonary involvement. kg infliximab caused a severe allergic reaction. 3. Mana J. Marcoval J, Graells J, Salazar A, Peyri J, Pujol The patient was subsequently treated with R. Cutaneous Involvement in Sarcoidosis Relationship subcutaneous adalimumab at 40 mg per week. to Systemic Disease. Arch Dermatol. 1997;133:882- Treatment 888. Treatment for cutaneous sarcoidosis is The cutaneous lesions improved noticeably after often guided by the extent of disfigurement one month of therapy, and after nine months 4. Marchell R, Judson M.A. Cutaneous Sarcoidosis. and symptomatic disease, and is limited by they had resolved with post-inflammatory Semin Respir Crit Care Med. 2010;31(4):442-51. 19 comorbidities that increase the risk of drug hyperpigmentation remaining. 5. Fernandez-Faith E, McDonnell J. Cutaneous toxicity. Thalidomide has also been tried as a treatment for sarcoidosis: differential diagnosis. Clin Dermatol. LP is often recalcitrant to most therapeutic lupus pernio. It was administered in an open-label 2007:25,276–287. modalities and may be an indicator of current trial to 15 patients with lupus pernio and systemic 6. Chen ES, Moller DR. Etiology of sarcoidosis. Clin 13 or impending systemic involvement. Topical sarcoidosis in doses ranging from 50 mg to 200 Chest Med. 2008;29:365–377. or intralesional corticosteroids are the first-line mg daily. Fourteen patients showed improvement therapy for localized and mild disease limited to of their cutaneous lesions. In another case series, 7. Familial associations in sarcoidosis. A report to the skin. the biopsy specimens of eight patients treated the Research Committee of the British Thoracic and with thalidomide revealed a reduction in the Tuberculosis Association. Tubercle. 1973;54:87–98. Oral corticosteroids are the drug of choice for 14 size of granulomas and in epidermal thickness. 8. Smith G, Brownell I, Sanchez M, Prystowsky S. rapidly progressive or unresponsive lesions. However, because of its teratogenicity and Advances in the genetics of sarcoidosis. Clin Genet. Corticosteroid-sparing agents are often added high risk of peripheral neuropathy, this study 2008;73:401–412. to the oral corticosteroid taper, as it is believed recommended that other agents be evaluated as they accelerate the taper without recurrence of 9. Grunewald J. Review: role of genetics in susceptibility first-line treatment.1 Mycophenolate mofetil was disease. It is generally accepted that these agents and outcome of sarcoidosis. Semin Respir Crit Care reported to improve cutaneous symptoms in five are indicated in patients requiring 10 mg of Med. 2010;31:380–389. 14 patients with systemic and cutaneous sarcoidosis prednisone daily. The treatment options include: whose conditions were recalcitrant to other 10. Grunewald J, Brynedal B, Darlington P, Nisell M, methotrexate, hydroxychloroquine, chloroquine, 20 treatment modalities. Cederlund K, Hillert J, et al. Different HLA-DRB1 tetracyclines, and TNF alpha inhibitors such as allele distributions in distinct clinical subgroups of Laser therapy has also been used in a handful of ISHAK, PATEL, HOROWITZ, Page 27 sarcoidosis patients. Respir Res. 2010;11:25. 11. Baughman RP, Lower EE, du Bois RM. Sarcoidosis. Cutaneous Rosai-Dorfman Disease: A Case Lancet. 2003;361:1111–1118. 12. Yanardag H, Pamuk O.M, Pamuk G.E. Lupus Report and Review Pernio in Sarcoidosis Clinical Features and Treatment Outcomes of 14 Patients. J Clin Rheumatol. Khasha Touloei, DO,* Adam Wiener, DO,** Angela Macri, DO,*** Bradley P. Glick, DO, MPH, FAOCD**** 2003;9(2):72-6. *First-year Dermatology Resident, Broward Health Medical Center, Ft. Lauderdale, FL 13. James DG. Lupus pernio. Lupus. 1992;1:129–131. **Attending Physician, Melbourne Dermatology Center, Melbourne, FL ***Intern, Broward Health Medical Center, Ft. Lauderdale, FL 14. Badgwell C, Rosen T. Cutaneous sarcoidosis therapy ****Program Director, Wellington Regional Medical Center Dermatology Residency Program, Wellington, FL updated. J Am Acad Dermatol. 2007;56:69–83. ******Professor and Vice Chairman, Department of Dermatology, University of California, San Francisco, San Francisco, CA 15. Baughman RP, Lower EE. Evidence-based therapy for cutaneous sarcoidosis. Clin Dermatol. 2007;25:334– 340. 16. Veien NK, Brodthagen H. Cutaneous sarcoidosis Abstract treated with methotrexate. Br J Dermatol. 1977;97:213– Rosai-Dorfman disease (RDD) is a rare, benign, proliferative disorder of histiocytes in the lymph nodes that 216. may have extranodal involvement. RDD limited to the skin without nodal involvement, known as cutaneous Rosai-Dorfman disease, is even rarer. We describe a 29-year-old male with RDD of the skin over the abdomen. 17. Hawk A, English J. Cutaneous manifestations of Histopathology showed many large histiocytes (Rosai-Dorfman cells) exhibiting emperipolesis, among many sarcoidosis. Evidence-based dermatology. London: BMJ plasma cells, lymphocytes and neutrophils throughout the dermis and subcutaneous tissue. The histiocytes were Books; 2003. p. 659–672. immunohistochemically positive for S-100 protein but negative for CD1a. Physical examination showed no 18. Stagaki E, Mountford WK, Lackland DT, Judson lymphadenopathy or any extra-cutaneous lesions. The diagnosis of cutaneous RDD may be difficult in the MA. The Treatment of Lupus Pernio Results of 116 absence of associated lymphadenopathy. Hence, not only is histopathological examination required for definitive Treatment Courses in 54 Patients. Chest. 2009;135:468– diagnosis, but a high index of suspicion is essential to help diagnose this very . 476. 19. Judson MA. Successful treatment of lupus pernio Introduction with adalimumab. Arch Dermatol. 2011;147(11):1332- Sinus with massive 3. lymphadenopathy (SHML) was first described by 1 20. Kouba DJ, Mimouni D, Rencic A, Nousari HC. Destombes in 1965. However, it was introduced Mycophenolate mofetil may serve as a steroid-sparing by Rosai and Dorfman in 1969 as a well-defined agent for sarcoidosis. Br J Dermatol. 2003;148:147–148. clinicopathologic entity that is now widely known as Rosai-Dorfman disease (RDD).2 RDD is a 21. Rosende L, del Pozo J, de Andrés A, Pérez Varela rare, non-malignant, histiocytic proliferative L. Intense pulsed light therapy for lupus pernio. Actas disorder that typically presents in male children Dermosifiliogr. 2012;103(1):71-3. and young adults.3 Classic presentation includes painless, bilateral lymphadenopathy, fever, Figure 1. Erythematous, scattered annular papules. Correspondence: Mayha Patel, 4939 Kilburn Ct., Oak leukocytosis, elevated sedimentation rate, and 3 Park, CA 91377; phone: 818-571-8231; fax: 818-889- polyclonal hyper-gammaglobulinemia. Forty 2946; [email protected] percent of patients have extranodal involvement, most commonly presenting on the skin.3 RDD without lymph-node involvement that is limited to the skin is called cutaneous Rosai Dorfman disease (C-RDD). The etiology of RDD is uncertain but may be immune-mediated.4 Associations with HHV6 and parvovirus B19 have been found.5,6 The disease typically runs a self-limiting course, and only a small number of patients will have extensive systemic disease that Figure 2a. Monomorphic proliferation of large histiocytes leads to death.4 exhibiting inflammatory cells within their cytoplasm.

Case Report A 29-year-old Caucasian male presented to the clinic with a persistent rash. He had several lesions on his trunk, present for months, without any associated symptoms. The lesions were erythematous, ovular papules, 3 mm to 4 mm in diameter, scattered on the trunk (Figure 1). Multiple biopsies revealed a perivascular and interstitial infiltrate throughout the dermis, composed of plump cells with ample, somewhat foamy cytoplasm (Figures 2a, 2b). Significant Figure 2b. 400x magnification

Page 28 CUTANEOUS ROSAI-DORFMAN DISEASE: A CASE REPORT AND REVIEW CD1a, which confirms the diagnosis.12,14,15 Immunohistologic findings and adhesion molecule pattern in primary pure cutaneous Rosai-Dorfman C-RDD has a good prognosis and tends to disease with xanthomatous features. Am J resolve over months to years.16 Cutaneous Dermatopathol. 1998;20:393–8. lesions do not require treatment, but surgical excision may be indicated for cosmetic reasons or 15. Kang JM, Yang WI, Kim SM, Lee MG. Sinus symptomatic relief. Cutaneous lesions have also histiocytosis (Rosai-Dorfman disease) clinically limited responded to radiotherapy and thalidomide.17 to the skin. Acta Derm Venereol. 1999;79:363–5. Other treatment methods that have been used 16. Ang P, Tan SH, Ong BH. Cutaneous Rosai- include radiotherapy, cryotherapy, chemotherapy, Dorfman disease presenting as pustular and acneiform 8,18 isotretinoin, hydroxychloroquine, and dapsone. lesions. J Am Acad Dermatol. 1999;41:335–7. 17. Komp DM. The treatment of sinus histiocytosis Figure 3. S-100 staining References with massive lymphadenopathy (Rosai-Dorfman 1. Destombes P. Adenitis with lipid excess, in child or disease). Semin Diagn Pathol. 1990;7:83–6. nuclear atypia was not identified within the young adults, seen in the Antilles and in Mali (4 cases). 18. Chan CC, Chu CY. Dapsone as a potential treatment cells of the infiltrate. Immunohistochemical Bull Soc Pathol Exot Filiates. 1965;58:1169–75. for cutaneous Rosai-Dorfman disease with neutrophilic studies revealed no labeling within these cells 2. Rosai J, Dorfman RF. Sinus histiocytosis with massive predominance. Arch Dermatol. 2006;142:428-430. for melan-A, CD34, or CD1a. These cells lymphadenopathy. Arch Pathol. 1969;87:63–70. expressed CD68, Factor XIII and S-100 protein (Figure 3). The patient is being followed by 3. Merola JF, Pulitzer M, Rosenman K, Brownell I. Correspondence: Angela Macri, DO; Broward Health oncology. As of this paper’s submission, he Cutaneous Rosai-Dorfman disease. Dermatol Online J. Medical Center, 1600 S. Andrews Ave., Ft. Lauderdale, has no signs of lymphadenopathy and has had 2008 May 15;14(5):8. FL 33316; 561-601-7856; [email protected]. multiple laboratory and imaging studies. With 4. Gaitonde S. Multifocal, extranodal sinus histiocytosis no identifiable association of systemic disease, a with massive lymphadenopathy: an overview. Arch diagnosis of C-RDD is suggested. Pathol Lab Med. 2007;131:1117-1121. 5. Levine PH, et al. Detection of human herpesvirus 6 Discussion in tissues involved by sinus histiocytosis with massive The first report of C-RDD was in 1978 by 7 lymphadenopathy (Rosai-Dorfman disease). J Infect Thawerani et al. Thus far, roughly 80 cases Dis. 1992;166:291 have been reported.8 The gross presentation of the skin lesions in C-RDD and RDD are the 6. Mehraein Y, et al. Parvovirus B19 detected in 9 Rosai-Dorfman disease in nodal and extranodal same. C-RDD is not associated with any other manifestations. J Clin Pathol. 2006;59:1320 symptoms or abnormal lab values and is more commonly seen in adults and females.9,10 Skin 7. Thawerani H, Sanchez RL, Rosai J, et al. The lesions may be solitary or multiple and range from cutaneous manifestations of sinus histiocytosis papulonodular (79.5%), indurated plaque (12.8%), with massive lymphadenopathy. Arch Dermatol. and tumor (7.7%), with the extremities most 1978;114(2):191-197. 8 frequently involved. The characteristic histiocyte, 8. Kong YY, et al. Cutaneous Rosai-Dorfman Disease: a the “Rosai-Dorfman cell” (RD cell), is the clinical and histopathologic study of 25 cases in China. diagnostic hallmark for RDD. It is histologically Am J Surg Pathol. 2007;31:341 recognized by abundant amorphous cytoplasm, 9. Brenn T, Calonje E, Granter SR, et al. Cutaneous indistinct borders, and a large, vesicular nucleus Rosai-Dorfman disease is a distinct clinical entity. Am with prominent nucleoli.11 Phenotypically, RD J Dermatopathol. 2002;24:385-391. cells uniquely express /macrophage markers such as lysozyme, Mac-387 and CD68, 10. Middel P, Hemmerlein B, Fayyazi A, et al. Sinus as well as the dendritic/Langerhans cell marker histiocytosis with massive lymphadenopathy: evidence S-100. Owing to the rarity of the disease, while for its relationship to macrophages and for a cytokine- there have been multiple studies of C-RDD, related disorder. Histopathology. 1999;35:525–33. a systematic and quantitative documentation 11. Ng SB, Tan LHC, Tan PH. Rosai-Dorfman disease of its histological spectrum and evolution is of the breast: a mimic of breast malignancy. Pathology. 10 still lacking. Histologic findings in RDD are 2000;32:10–5. characteristic and essentially similar in all sites. 12. Foucar E, Rosai J, Dorfman RF. Sinus histiocytosis A dense histiocytic infiltrate is accompanied by a with massive lymphadenopathy (Rosai-Dorfman background infiltrate of lymphocytes and plasma disease): review of the entity. Semin Diagn Pathol. cells, and lymphoid follicles with germinal centers 1990;7:19–73. may occur.11 The large histiocytic cells (RD cells) have indistinct, “feathery” borders, abundant pale 13. Carbone A, Passannante A, Gloghini A, et al. Review eosinophilic cytoplasm and large vesicular nuclei, of sinus histiocytosis with massive lymphadenopathy and they exhibit emperipolesis (cytophagocytosis (Rosai-Dorfman disease) of head and neck. Ann Otol of lymphocytes and plasma cells).12,13 Less often, Rhinol the cytoplasm may contain neutrophils and red Laryngol. 1999;108:1095–104. blood cells. These histiocytes stain positively for S-100 protein and CD68 but negatively for 14. Quaglino P, Tomasini C, Novelli M, et al.

TOULOEI, WIENER, MACRI, GLICK Page 29 A Case of Punctate Porokeratotic Keratoderma: Manifestation of Uncontrolled Hyperlipidemia or Delayed Paraneoplastic Syndrome?

Charisse McCall, DO,* Sanjosh Singh, DO,** Michael Berry, MD***

*Third-year Resident, Department of Dermatology, St John’s Episcopal Hospital, Far Rockaway, NY **Dermatologist, Private Practice, Tenafly, NJ ***Clinical Preceptor, Department of Dermatology, St John’s Episcopal Hospital, Far Rockaway, NY

Abstract Punctate porokeratotic keratoderma is a rare dermatologic condition characterized by numerous pinpoint projections on the palms and soles. Although the cause is unknown, sporadic cases have been associated with dyslipidemia, renal cysts, chronic renal failure, myelofibrosis, spondylolisthesis and asthma. Of most concern, this condition has been reported in association with malignancy, not necessarily running parallel courses. We report a case of punctate porokeratotic keratoderma in a patient with uncontrolled hyperlipidemia and a history of endometrial cancer. Our case presentation promotes awareness of a rare dermatologic condition and supports the need to perform age-related cancer screenings upon diagnosis. Multiple treatment modalities have been reported in the past, such as topical urea, salicylic acid, retinoids and 5-fluorouracil, with variable efficacy. We report successful treatment with imiquimod cream and propose it as a new treatment modality.

Introduction Punctate porokeratotic keratoderma is an uncommon disorder. It presents as numerous pinpoint projections resembling the spines of an old-fashioned music box cylinder, appearing on the palms and soles.1-3 In 1971, Brown reported the first case of a keratoderma marked by numerous tiny spicules on the palmoplantar Figures 1 and 2: Multiple spiny, hyperkeratotic papules on the palms and soles. surfaces.4 The condition has since been described before the onset of the lesions and caused her in the literature under the names filiform primary care doctor to increase her simvastatin Discussion hyperkeratosis, minute digitate hyperkeratosis, dose. Differential Diagnosis punctate keratoderma, punctata There are several skin conditions that clinically palmaris et plantaris, and spiny keratoderma.5-7 Physical exam revealed multiple 1 mm, flesh- resemble punctate porokeratotic keratoderma. The disorder has been reported in all races, with colored, spine-like hyperkeratotic papules on the Many are associated with systemic 8 palms and soles (Figures 1 and 2). the age of onset ranging from 12 to 50 years. syndromes and can be differentiated by the Woods light examination may be a helpful Shave biopsy revealed cornoid lamellae, consistent presence of other classic physical findings. If diagnostic tool, revealing a white fluorescence with a diagnosis of punctate porokeratotic the etiology is still uncertain, a skin biopsy 9 likened to stars under the moonlight. Although keratoderma (Figure 3). She was treated with is indicated. The lesions of multiple filiform most cases are sporadic, inherited forms have imiquimod 5% cream nightly, and her condition verrucae are similar in appearance to punctate been described. The exact etiology is unknown, was nearly resolved at two-week follow-up, porokeratotic keratoderma but are usually seen but there have been cases associated with systemic considered to be 90% better by both patient and on the face around the lips, nares or eyelids. disease. Of most concern, this condition has physician. The patient had a few scattered spiny Acrokeratoelastoidosis lichenoides are 1 mm to been linked to malignancy. We report a case of papules remaining, so we added a salicylic acid 4 mm, round-to-oval, sometimes umbilicated punctate porokeratotic keratoderma in a patient plus urea compounded cream in the morning. papules on the borders of hands, feet and wrists, with uncontrolled hyperlipidemia and a history The combination of this compound once daily and they can become confluent. These lesions of endometrial cancer. and the imiquimod cream once daily maintained may be associated with Cowden’s disease or patient satisfaction without adverse effects at Darier’s disease. Palmar keratoses may also be Case Presentation three-month follow-up. seen in Cowden’s syndrome. Nevoid basal cell A 48-year-old white female presented to the office carcinoma is associated with palmar pits but complaining of rough palms with asymptomatic, not spiny lesions. Arsenical keratoses are round, tiny bumps for about four months duration. She verrucous or acuminate. It is important to inquire had never been treated by a physician for this about history of arsenic exposure via drinking condition but admitted to using files and water or occupation. Clinicians should be aware pumice stones to file the bumps down, only for of the risk of these lesions progressing to SCC. them to return in a matter of days. She reported Punctate keratoses of the palmar creases are 1 mm a past medical history of endometrial cancer to 5 mm depressions confined to flexural creases treated by hysterectomy and bilateral salpingo- and are commonly seen in patients of Afro- oophorectomy 16 months prior. She also had Caribbean descent. These lesions are benign but 5 a course of radiation, which was completed one can sometimes cause discomfort. year prior. In addition, the patient reported a Figure 3: Histologic specimen showing classic Associated Conditions history of hyperlipidemia, which worsened just findings of punctate porokeratotic keratoderma. Punctate porokeratotic keratoderma has been Page 30 A CASE OF PUNCTATE POROKERATOTIC KERATODERMA: MANIFESTATION OF UNCONTROLLED HYPERLIPIDEMIA OR DELAYED PARANEOPLASTIC SYNDROME? reported in association with various lymphoproliferative disorder. This shows that palms and soles. J Am Acad Dermatol. 1992;26:879-81. such as bronchial carcinoma, renal cancer, rectal the dermatosis and the underlying malignancy 8. Sakas EL, Gentry RH. Porokeratosis punctata carcinoma, esophageal carcinoma, chronic do not necessarily run parallel courses and leads palmaris et plantaris (punctate porokeratosis). Case lymphocytic , breast cancer, melanoma us to wonder whether the lesions can manifest report and literature review. J Am Acad Dermatol. 1,10-15 and ovarian carcinoma. Most studies report after the eradication of a cancer. Our patient 1985;13:908-12. that spiny keratoderma arises just before the was treated for endometrial cancer with surgery 9. Asawanonda P, Taylor CR. Wood’s light in internal malignancy is diagnosed. However, one and radiation, which completed one year prior to dermatology. Int J Dermatol. 1999;38:801-7. researcher reported a 30-year discrepancy between the onset of the palm and sole lesions. She has the onset of spiny keratoderma and diagnosis of maintained close follow-up with her oncologist, 10. Beylot C, Taieb A, Bioulac P, Doutre MS, Houdee a lymphoproliferative disease.12 It is of note that who reports no recurrence. She is also up to date G. Hyperkeratose palmoplantaire filiforme et neoplasie although punctate porokeratotic keratoderma on all of her age-appropriate cancer screenings, viscerale. Ann Dermatol Venereol. 1982;109:747-8. including colonoscopy and mammography. has been linked to various underlying cancers, 11. Fegueux S, Bilet S, Crickx B, Perron J, Grossin malignant transformation of the spiny lesions Punctate porokeratotic keratoderma has also M, Belaich S.Hyperkeratose palmoplantaire filiforme 5 themselves has not been reported. Other been linked with several other systemic diseases, et cancer recto-sigmoidien. Ann Dermatol Venereol. than malignancy, this dermatosis has been including hyperlipidemia, and our patient 1988;115:1145-6. reported in association with chronic renal reported a spike in her cholesterol levels that 12. Bernal AI, Gonzalez A, Aragoneses H, Martinez failure, myelofibrosis, Darier’s disease, type IV prompted her primary medical doctor to increase G, Garcia M. A patient with spiny keratoderma of the hyperlipoproteinemia, adult polycystic kidney the dose of her statin medication. The lesions palms and lymphoproliferative syndrome: An unrelated disease with liver cysts, spondylolisthesis and appeared two weeks after this increased dose, so paraneoplastic condition. Dermatology. 2000;201:379- asthma.16-21 the patient had initially viewed the lesions as a 80 Histopathology type of medication reaction. From what we have learned in previous studies, it is more likely that 13. Hillion B, Le Bozec P, Moulonguet-Michau Histopathology typically reveals lack of granular the worsening hyperlipidemia contributed to the I, Blanchet-Bardon C, Petit A, Stefan J, et al. layer and enhanced epidermal proliferation of the onset of the keratoderma. Data to explain the Hyperkeratose palmo-plantaire filiforme et cancer du 1,2 basal layer under columnar parakeratoses. The pathophysiology behind an underlying neoplasm sein. Ann Dermatol Venereol. 1990;117:834-6. spines seen on clinical presentation correspond to or systemic disease leading to the development 14. Kaddu S, Soyer P, Kerl H. Palmar filiform parakeratotic columns, located over the eccrine of PPK is currently lacking. Further studies are hyperkeratosis: a new paraneoplastic syndrome? J Am ducts, follicles, or interadnexal epidermis.1 The warranted to help make this connection and Acad Dermatol 1995;33:337-40. lesions have been shown to stain with AE13, classify the timing of the two events. Multiple an immunohistochemical stain for a hair-type treatment modalities have been reported to 15. Valverde R, Sanchez-Caminero MP, Calzado 6 keratin, suggesting ectopic hair formation. improve cosmesis. However, it is most important L, Frutos O, Rodriguez-Peralto J, Vanaclocha F. Dermatomyositis and Punctate Porokeratotic Treatment to emphasize age-related cancer screenings upon diagnosis. In the past, topical urea, salicylic acid, Keratoderma as Paraneoplastic Syndrome of Ovarian Spiny keratoderma is difficult to manage, with retinoids and 5-fluorouracil have shown variable Cancer. Actas Dermosifiliogr. 2007; 98:358-60 available treatment options showing minimal efficacy. To our knowledge, we are the first to 16. Feldman R, Harms M. Multiple filiforme success. The spines tend to be a nuisance, and report imiquimod 5% cream as a successful hyperkeratosis. Hautarzt. 1993;44:658-61. patients often seek treatment for cosmetic treatment modality. reasons. Reported management involves various 17. Mehta RK, Mallet RB, Green C, Rytine E. Palmar modalities such as paring, dermabrasion and filiform hyperkeratosis (FH) associated with underlying mechanical debridement. Topical therapies such References pathology? Clin Exp Dermatol. 2002;27:216-9. as urea, salicylic acid and retinoids have also 1. Bianchi L, Orlandi A, Iraci S, Spagnoli LG, Nini G. 18. Zarour H, Grob J, Andrac L, Bonerandi J. been reported as successful treatment options. Punctate porokeratotic keratoderma—its occurrence Palmoplantar orthokeratotic filiform hyperkeratosis in Recently, 5-fluorouracil has been reported to with internal neoplasia. Clin Exp Dermatol. a patient with associated Darier disease. Dermatology. alleviate symptoms. Besides aesthetic treatments, 1994;19:139-41. 1992;185:205-9. of more importance is the awareness of a possible 2. Kondo S, Shimoura T, Hozumi Y, Aso K. Punctate 19. Urbani C, Moneghini L. Palmar spiny keratoderma underlying malignancy. A thorough history and porokeratotic keratoderma: some pathogenetic analyses assocciated with type IV hyperlipoproteinemia. J Eur physical and age-appropriate cancer screenings of hyperproliferation and parakeratosis. Acta Derm Acad Dermatol Venereol. 1198;10:262-6. are essential to early detection of associated Venereol. 1990;70:478-82. disease.5 20. Anderson D, Cohen D, Lee H, Thellman C. Spiny 3. Friedman SJ, Herman PS, Pittelkow MR, Su WP. keratoderma in association with autosomal dominant Punctate porokeratotic keratoderma. Arch Dermatol. polycystic kidney disease with liver cysts. J Am Acad Conclusion 1988;124:1678-82. Dermatol. 1196;34:935-6 We have described an interesting case of punctate porokeratotic keratoderma of the palms 4. Brown F. Punctate keratoderma. Arch Dermatol. 21. Perez-Perez L, Peteiro C, Sanchez-Aguilar D, and soles. The etiology of these lesions in our 1971;104:682-3. Toribio J. Palmar filiform parakeratotic hyperkeratosis patient may be idiopathic or related to one of her 5. Torres G, Beshad R, Han A, Castrovinici A, Gilliam without underlying malignancy. Actas Dermosifiliogr. underlying medical problems. The association A. “I Forgot To Shave My Hands”: A Case Of Spiny 2007;98(6):420-4 between punctate porokeratotic keratoderma and Keratoderma. J Am Acad Dermatol. 2008;58:344-348. internal malignancy has been well documented 6. Caccetta T, Dessauvagie B, McCallum D, in the literature. Most studies describe the onset Correspondence: Charisse McCall, DO, St John’s Kumarasinghe S. Multiple minute digitate of the spiny lesions just before the diagnosis Episcopal Hospital, 327 Beach 19th St., Far Rockaway, hyperkeratosis: A proposed algorithm for digitate of internal malignancy; however, one case NY 11691; Ph: 718-869-7815; Fax: 718-869-7834; keratoses. J Am Acad Dermatol. 2012;67:e49-55. described a patient with punctate porokeratotic [email protected]. keratoderma for 30 years prior to diagnosis of a 7. Osman Y, Daly TJ, Don PC. Spiny keratoderma of the

MCCALL, SINGH, BERRY Page 31 Multiple Eruptive Dermatofibromas Following Immunosuppressive Therapy in a Patient with Systemic Lupus Erythematosus

Maria Tempera, BS,* Peter Saitta, DO, FAOCD,** Cherise Khani, DO,*** Cindy Hoffman, DO, FAOCD,**** Ronald Brancaccio, MD, FAAD*****

*Medical Student, Rowan School of Osteopathic Medicine, Stratford, NJ **Academic Professor of Dermatology, Department of Dermatology, St. Barnabas Hospital, Bronx, NY ***Department of Dermatology, St. Barnabas Hospital, Bronx, NY ****Director, Department of Dermatology, St. Barnabas Hospital, Bronx, NY *****Clinical Professor of Dermatology, Ronald O. Perelman Department of Dermatology, New York University, New York, NY

Abstract Dermatofibromas (DF) are common, benign dermal tumors typically occurring as single lesions located on the lower extremities of young women.1 In contrast, multiple eruptive dermatofibromas (MEDF) are rare and commonly associated with autoimmune diseases and immunosuppressive therapy.2 We present a case of a patient with systemic lupus erythematosus (SLE) and MEDF of her lower extremities. Our patient demonstrated a significant increase in dermatofibromas with corticosteroid treatment, supporting the association between MEDF and immunosuppressive therapy.

Report of a Case A 53-year-old woman initially presented to our clinic with a history of numerous, pruritic lesions covering her body, the majority of which involved her lower extremities. The patient was first diagnosed with SLE in 1977. At that time, she was started on oral corticosteroids, and has received continuous corticosteroid therapy ever since. In 1994, she experienced an initial episode of MEDF, with an eruption of Figure 2 approximately 30 lesions. Fifteen years later, she developed end-stage renal disease, requiring a kidney transplantation. Her subsequent immunosuppressive regimen consisted of a significantly increased prednisone dose, as well as initiation of tacrolimus 0.5 mg twice daily. In 2010, following organ transplantation and an alteration of daily medications, the patient Figure 1 experienced a second episode of MEDF, this time with roughly 90 lesions. Family history that usually develop on the lower extremities was significant for , but not MEDF. and are frequently asymptomatic, although there No significant social history was reported, and have been reports of pruritus as a symptom.3 Figure 3 her only drug allergy was to penicillin. Her Dermatofibromas affect females more commonly included long-term use of systemic than males, at a ratio of 4:1.4 The mean age of corticosteroids. Physical examination revealed onset is typically in young adulthood. Classically, 90 non-tender, brown papules ranging from dermatofibromas are solitary, flesh-colored-to- 3 mm to 8 mm (Figures 1 and 2). The lesions brown, 0.5 cm to 1 cm, firm nodules.3 A useful demonstrated the characteristic clinical sign for diagnosis is the tethering of “.” the overlying epidermis to the underlying Punch biopsy of two upper-extremity lesions lesion with lateral compression, known as the 5 revealed epidermal hyperplasia and basal-cell- “dimple sign.” Some dermatofibromas arise as layer hyperpigmentation overlying a spindle-cell a reactive process after insult to the skin, such as arrangement of and histiocytes, with trauma or assault, while others appear Figure 4 associated thickened collagen bundles (Figures 3 spontaneously.6 [40x] and 4 [100x]). In contrast to the classic, solitary dermatofibroma, definition of multiple eruptive dermatofibromas The results of the pathologic and clinical multiple dermatofibromas (MDF) are rare. This (MEDF) is subjective but has been acknowledged examinations supported a diagnosis of MEDF. infrequency was first described by Baraf and as the presence of five to eight dermatofibromas 8 Shapiro in 1970 when they noted patients with developing in a period of less than four months. Discussion three or more dermatofibromas as occasionally The literature has shown that the onset of observed but those with more than 15 Solitary dermatofibromas (or superficial, benign, MEDF is usually in conjunction with an dermatofibromas (MDF) as rarely observed.7 The fibrous histiocytomas) are common skin tumors underlying immunosuppressive disease and/

Page 32 MULTIPLE ERUPTIVE DERMATOFIBROMAS FOLLOWING IMMUNOSUPPRESSIVE THERAPY IN A PATIENT WITH SYSTEMIC LUPUS ERYTHEMATOSUST or immunosuppressive therapy. MEDF can be 4. Zaccaria E. Multiple eruptive dermatofibromas and associated with SLE, human immunodeficiency immunosuppression report of two cases and review of virus, myasthenia gravis and Hashimoto’s the literature. Int J Dermatol. 2008;47:723-727. thyroiditis, implicating the condition as a 5. Fitzpatrick TB, Gilchrest BA. Dimple sign to 9 manifestation of immune-mediated disease. differentiate benign from malignant pigmented The pathogenesis of MEDF is not fully cutaneous lesions. N Engl J Med. 1977 Jun understood. The serum of SLE patients expresses 30;296(26):1518. a greater-than-normal growth-stimulatory 6. Gualandri L. Eruptive dermatofibromas and activity on both normal and derived fibroblasts. immunosuppression. Eur J Dermatol. 1999 Jan- The serum from SLE patients with MDF has Feb;9(1):45-7. been found to contain basic growth 7. Baraf CS, Shapiro L. Multiple histiocytomas, report factor (bFGF) as well as antiplatelet-derived of a case. Arch Dermatol. 1970;101:588-590. growth factor (PDGF), which stimulates fibroblast proliferation.10 One postulation is that 8. Ammirati CT, Mann C, Hornstra IK. Multiple the growth effects are inhibited by antibodies eruptive dermatofibromas in three men with HIV to antiplatelet-derived growth factor and basic infection. Dermatology. 1997;195:344-348. 11 fibroblast growth factor. 9. Kimura Y. Multiple eruptive dermatofibromas Some patients with immune-mediated associated with Hashimoto’s thyroiditis and myasthenia diseases developed MEDF after intake of gravis. Eur J Dermatol. 2010 Jul-Aug;20(4):538-9. immunosuppressive drugs or after an increase 10. Kubo M, et al. The expression levels and the in the dose of immunosuppressive medication. differential expression of transforming growth Our patient’s number of DF increased from factor-beta receptors in dermatofibroma and 30 to 40 lesions to 90 lesions after taking an dermatofibrosarcoma protuberans. Br J Dermatol. 2006 increased dose of corticosteroids. It is proposed May;154(5):919-25. that immunosuppressants impede the function of 11. Yamamoto T, Katayama I, et al. Involvement of basic down-regulatory T-cells, causing an immunologic fibroblast growth factor in fibroblast-stimulatory serum upregulation.12 activity of a patient with systemic lupus erythematosus Treatment of DF is not obligatory, as they are and multiple dermatofibromas. Dermatology. solely treated for cosmesis. The lesions may 1995;191(4):281-5. be shaved with a surgical blade or completely 12. Ou DM. Clinical and pathologic characteristics and excised. may instead be employed to surgical management of benign fibrous histiocytoma eliminate unwanted dyspigmentation.12 of the mandible; a case report. J Oral Maxillofac Surg. 2012 Nov;70(11):2719-23. Conclusion Solitary dermatofibromas represent a benign reactive process due to various insults to the skin. Correspondence: Cherise Khani, DO, Department They are commonly encountered in the clinical of Dermatology, St. Barnabas Hospital, 4422 3rd Ave., setting and do not require treatment. Multiple Bronx, NY 10475; [email protected] eruptive dermatofibromas, however, are rare occurrences that are strongly associated with both autoimmune disease and immunosuppressive therapy. Our patient demonstrated both of these associations, as she had systemic lupus erythematous and developed MEDF after starting oral corticosteroid therapy.

References 1. Yamamoto T. Multiple cutaneous fibrous histiocytomas in association with systemic lupus erythematosus. J Dermatol. 2005 Aug;32(8):645-9. 2. Huang PY. Multiple eruptive dermatofibromas in a patient with dermatomyositis taking prednisolone and methotrexate. J Am Acad Dermatol. 2007 Nov;57(5 Suppl):S81-4. 3. Massone C, Parodi A. Multiple eruptive dermatofibromas in patients with systemic lupus erythematosus treated with prednisone. Int J Dermatol. May 2002;41:279-281.

TEMPERA, SAITTA, KHANI, HOFFMAN, BRANCACCIO Page 33 Darier’s Disease: A Case Study and Review of the Literature

Jeffrey Kushner, BA,* David A. Kasper, DO, FAOCD, MBA**

*Medical Student, 4th year, Philadelphia College of Osteopathic Medicine, Philadelphia, PA **Dermatologist, Dermatology and Institute, Lansdale, PA

Abstract Darier’s disease is an autosomal-dominant disorder caused by a mutation on the ATP2A2 gene, which encodes a calcium pump. We present a case of an 81-year-old Caucasian female who presented to the clinic complaining of a blistering rash that was described as both itchy and painful. The pathogenesis, histology and clinical manifestations of Darier’s disease are reviewed. We also discuss some of the treatment modalities available and the challenge of managing a genetic disease.

Introduction Darier’s disease, also known as Darier-White disease or keratosis follicularis, was independently identified in 1889 by both Jean Darier of Hospital Saint-Louis in Paris and James White of Harvard University.1 It is an autosomal-dominant disorder altering the ATP2A2 gene, which encodes for a calcium pump. Patients often present with greasy, yellow-brown, hyperkeratotic lesions in Figure 1 Figure 2 the seborrheic areas with accompanying nail changes. Due to the chronicity of the disease, diagnosis and treatment can sometimes be challenging. We present a case of an 81-year-old Caucasian female with an extensive history of an unremitting rash that was still symptomatic despite prior treatment. A punch-biopsy revealed Darier’s disease, and the patient was subsequently treated with clobetasol 0.05% cream, amlactin 12% cream, and amoxicillin. Figure 3 Figure 4

Case Report differential diagnoses included , 12% creams very well and became asymptomatic. Darier’s disease and Grover’s disease. Final Her impetiginized lesions cleared, and post- An 81-year-old Caucasian female presented histological diagnosis demonstrated acantholysis inflammatory erythema was noted (Figure 6). to our office with a rash located on her trunk in the lower epidermis as well as the presence of She was instructed to continue the lactic-acid that had been present since childhood and corps ronds and grains (Figure 5). No specific 12% cream daily but to stop the clobetasol 0.05% had waxed and waned for several years. At immunoreactants (IgM, IgG, IgA, C3, fibrin and cream to minimize adverse side effects. She was presentation, she described her rash as blistering, albumin) were detected. Based on the history, then advised to use triamcinolone 0.1% cream burning, itchy and painful. The patient was clinical appearance and histologic findings, a when her lesions flared up again. At the three- currently being treated with topical econazole, diagnosis of Darier’s disease was made. month follow-up visit, the patient continued to hydrocortisone and triamcinolone creams. The be asymptomatic, and her erythema was clearing. patient mentioned that her two sons also have the The patient was first instructed to discontinue same rash. Her past medical and surgical history the current antifungal and low-mid potency included hypertension, hypercholesterolemia, and corticosteroid creams since she had minimal Discussion hysterectomy secondary to uterine cancer. response to this treatment. After a thorough Darier’s disease, an autosomal-dominant genetic discussion with our patient regarding treatment condition, is linked to a mutation in the ATP2A2 Physical exam revealed palmar hyperkeratotic options, she refused to take any oral medication gene on 12q23-24 encoding for the sarco/ pits and yellowish-to-brown, greasy papules such as acitretin or isotretinoin given their side- endoplasmic reticulum Ca2+ ATPase (SERCA2), that coalesced into erythematous plaques along effect profiles. To better control her symptoms which normally acts as a pump to maintain a low the abdomen, trunk and inframammary creases while simultaneously avoiding systemic agents, 2 (Figures 1 and 2). Additionally, some of her calcium level in the cytoplasm. The mutation she was switched to clobetasol 0.05% cream twice plaques were impetiginized. Her nails were causes distortions in the proteins responsible daily with lactic-acid 12% cream applied nightly dystrophic with V-nicking and longitudinal red for normal cell-to-cell-adhesion, resulting in to the affected areas. Additionally, the patient was bands (Figures 3 and 4). desmosome breakdown. This ultimately causes given amoxicillin 500 mg tablets twice daily for acantholysis while also promoting caspase-driven Two 3 mm punch biopsies were performed from 15 days for secondary infection. apoptosis and dyskeratosis.3 Darier’s disease has the abdomen and sent for routine On follow-up at two weeks, our patient tolerated complete inheritance with variable expressivity, H&E and direct immunofluorescence. The the amoxicillin, clobetasol 0.05% and lactic-acid and thus rarely skips generations. Affecting

Page 34 DARIER’S DISEASE: A CASE STUDY AND REVIEW OF THE LITERATURE and concerns over their appearance. Secondary and smooth papules. However, significant infection with bacteria, yeast or is adverse side effects are possible and can include a possible complication to the primary lesions.1 mucosal dryness, photosensitivity, hair loss, Staphylococcus aureus and are hyperlipidemia, elevated liver transaminases, and particularly common in patients with Darier’s depression. As a result, baseline lipid and enzyme disease.2 Other less frequent complications levels should be taken and periodically monitored include salivary gland obstruction, parotid throughout treatment. The decision whether swelling secondary to hyperplasia, mental to use isotretinoin vs. acitretin depends upon retardation, epilepsy, schizoaffective disease, multiple factors such as length of treatment, age depression leading to suicide, and cutaneous of patient, and gender. For instance, both acitretin squamous cell carcinoma. Additionally, there and isotretinoin are teratogenic, pregnancy Figure 5 are several clinical variants of Darier’s disease category X. For women of childbearing age including vesiculobullous, cornifying, comedonal, with Darier’s disease, isotretinoin may be a more acral, hemorrhagic and linear.2 attractive option since iPledge helps regulate the medication, and patients only need to avoid Diagnosis is made by a combination of clinical pregnancy for one month after discontinuation as suspicion and histological examination of a opposed to three years with acitretin. skin biopsy. A differential diagnosis includes acrokeratosis verruciformis of Hopf, Hailey- Additionally, Kontochristopoulos et al. report Hailey disease, seborrheic dermatitis, and Grover that botulinum type A is a possible adjuvant disease. Acrokeratosis verruciformis of Hopf is an treatment to acitretin for challenging patients 6 autosomal-dominant disease presenting at birth who remain symptomatic despite therapy. with clinically indistinguishable involvement of Their patient was treated with a single injection the hands and feet compared to Darier’s disease. of botulinum toxin to the left inframammary Figure 6 Some clinicians even consider this to be an area and showed significant improvement for extension of Darier’s disease rather than a separate four months, at which point injections were males and females equally, this condition has a entity. Differentiating the two diseases is the lack done bilaterally. Cyclosporine has also been prevalence of 1 in 100,000 in Scandinavia, 1 in of acantholytic and dyskeratotic keratinocytes used to treat rebound or flared disease states. 55,000 in central England, and 1 in 36,000 in seen with acrokeratosis verruciformis. Hailey- Skin improvement is evident in 90% of cases, 2 Hailey disease also affects the intertriginous most noticeably with reduced hyperkeratosis northeast England. 2 areas but frequently lacks the nail changes. and flattening of papules. Patients should be The histopathological hallmark of Darier’s Seborrheic dermatitis and Grover disease both aware of the adverse effects of oral retinoids, disease is suprabasal acantholytic dyskeratosis lack the palmoplantar and mucosal changes seen which include: teratogenic effects if taken during 4 with an overlying hyperkeratosis. Dyskeratosis in Darier’s disease, and also appear different pregnancy, cheilitis, mucosal and skin xerosis, is apparent in two types of cells, “corps rods” and histologically.1-3 elevated transaminases, hypercholesterolemia, “grains.” Corps rods are abnormal keratinocytes and photosensitivity. In the case of recalcitrant Since Darier’s disease is a genetic condition, there found in the stratum spinosum and stratum lesions in flexural areas, surgical excision, is no cure. The overall goals are to improve quality granulosum with a pale halo surrounding the debridement, or laser removal are treatment of life through symptomatic management and eosinophilic nucleus. Grains are flat, basophilic considerations. Topical antibiotics, antifungals, minimize secondary infections. Initial treatment cells found in the stratum corneum with cigar- and chlorhexidine washes are used concomitantly 3,4 guidelines include minimizing sun exposure and shaped nuclei. to manage secondary infections. Patients sweating with appropriate sunscreen and cotton with Darier’s disease can expect a normal life Onset usually begins during puberty, most clothing.5 Patients on lithium should consider frequently appearing as greasy, yellow-brown, expectancy. However, due to the chronic nature altering medications, as the drug is known of this disease, relapses occur frequently when keratotic papules involving the seborrheic areas 2 to exacerbate Darier’s disease. Keratolytic (scalp, face, trunk, and neck). Hypomelanotic treatment is discontinued. Lifelong treatment is moisturizers are recommended to reduce scaling macules are also common, while intertriginous usually necessary to prevent these relapses. and improve appearance, while antiseptic washes lesions (groin, axillae and submammary fold) decrease malodorous skin bacteria. Topical occasionally appear as malodorous fungating options include corticosteroids (class four to six) Conclusion masses. Palmoplantar papules with red and to decrease inflammation as well as retinoids Darier’s disease is an intriguing dermatologic white nail changes are often evident upon such as tretinoin 0.1%, adapalene 0.1%, and condition due to its genetic basis and inspection. Nail involvement is characteristic of tazarotene 0.05% to reduce hyperkeratosis. characteristic findings on exam. The disorder the disease. Red and white longitudinal banding Alternating these topical treatments is common can be diagnosed based upon its unique clinical and V-shaped notches are pathognomonic, presentation and classic histological findings. The 2 to help alleviate irritation. Second-line topical while subungual hyperkeratosis is also evident. therapies include 5-fluorouracil, tacrolimus, and chronicity of the disorder can present challenges Prevalence of oral involvement ranges from 15 pimecrolimus. Oral retinoids such as isotretinoin in long-term treatment. After confirmation percent to 50 percent, and the palate may appear and acitretin are the treatment of choice for of the diagnosis, our patient was being treated 2 as fine, granular-to-coarse, “pebbly” textured. generalized disease and instances refractory to effectively and reported significant improvement Often asymptomatic, treatment is usually not topical therapy. However, oral retinoids typically of her symptoms. required for oral involvement. do not result in prolonged remission, so long- Darier’s disease is a chronic condition with term treatment with these agents is often frequent exacerbations precipitated by heat, sweat, required to prevent relapse. Therapy should be infection, sunshine or friction.3 Patients often continued for at least three months to achieve complain of moderate itching, malodorous skin, reduction in malodor, decrease hyperkeratosis,

KUSHNER, KASPER Page 35 References 1. Bolognia J, Jorizzo JL, Rapini RP. Dermatology. Erythrodermic Psoriasis: A Case Report and London: Mosby, 2003. Chapter 59, Darier’s Disease and Hailey-Hailey Disease; p. 823-29. Print. Literature Review 2. Cooper SM, Burge SM. Darier’s Disease: Jacqueline Fisher, DO,* Nanda Channaiah, DO, FAOCD** Epidemiology, Pathophysiology, and Management. Am J Clin Dermatol. 2003;4(2):97-105. *Traditional Intern, OU-HCOM/O’Bleness Memorial Hospital, Athens, OH **General Dermatologist, Center for Surgical Dermatology & Dermatology Associates, Westerville, OH 3. Kwok, PY. Darier disease. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2013. 4. James WD, Elston DM, Berger TG, Andrews GC. Andrews’ Diseases of the Skin: Clinical Dermatology. Abstract [London]: Saunders/ Elsevier, 2011. Chapter 27, Erythrodermic psoriasis is a rare clinical phenotype of psoriasis. The condition is characterized by generalized Genodermatoses and Congenital Anomalies; p. 560. erythema and scaling covering the majority of the body surface. The diagnosis of erythrodermic psoriasis is Print. primarily through clinical presentation while excluding other etiologies of erythroderma. Treatment is often difficult due to the combination of cutaneous and systemic symptoms that contribute to an increased risk for 5. Lebwohl M, Heymann W, Berth-Jones J, Coulson I. morbidity and mortality. Current treatment requires the use of systemic agents, but the specific regimen is based Treatment of Skin Disease: Comprehensive Therapeutic on the patient’s level of clinical severity and comorbidities. We present the case of a 31-year-old male diagnosed Strategies. 2nd ed. Philadelphia, Pa.: Mosby/Elsevier, with erythrodermic psoriasis and review the current literature on the disease. The clinical findings, differential 2006. Darier’s Disease; p.143-45. Print. diagnosis, and treatment options will be discussed. 6. Kontochristopoulos G, Katsavou AN, Kalogirou O, Agelidis S, Zakopoulou N. Letter: Botulinum toxin type A: an alternative symptomatic management of Darier’s Introduction disease. Dermatol Surg. Jul 2007;33(7):882-3. Erythrodermic psoriasis is the most severe variant of psoriasis, and it is often challenging to treat. Of the 2 percent of the world population affected by Correspondence: Jeffrey Kushner, Philadelphia College psoriasis, the erythrodermic subtype is estimated of Osteopathic Medicine, 409 Alexander Ave., Drexel to affect only 1 percent to 2.25 percent.1,2 It most Hill, PA 19026; 484-919-7367; [email protected]. commonly arises in a patient experiencing an extensive exacerbation of plaque psoriasis but can occur during periods of psoriatic inactivity. Other etiologies of erythroderma should be considered and excluded when diagnosing a patient with erythrodermic psoriasis. Currently, first-line treatment requires systemic therapies, including the conventional medications methotrexate, cyclosporine, and acitretin, or biological therapies targeting specific pathogenic mechanisms of psoriasis. Identification and prompt treatment of erythrodermic psoriasis is necessary due to the risk of severe complications. We report the case 1A of a 31-year-old male with a history of plaque psoriasis presenting with diffuse erythroderma after abrupt discontinuation of acitretin.

Case Report A 31-year-old Caucasian male presented with generalized scaling erythema covering greater than 90 percent of his body following abrupt discontinuation of acitretin. The patient’s past medical history included plaque psoriasis. Two months prior, he was treated for an acute exacerbation of severe plaque psoriasis triggered by tanning-bed use. At that time, he was treated with a medium-potency topical steroid for his face and groin psoriasis and a high-potency topical steroid for the remaining body psoriasis. For increased efficacy, he was advised to wrap affected areas in wet towels for ten minutes per 1B day for one week. At the patient’s four-day follow-up visit, acitretin 10 mg was started due to Figure 1. (A and B) Thin, confluent, scaling persistence of generalized erythema, mild chills, erythematous plaques covering >95% of patient’s body. and palmoplantar . One month Page 36 ERYTHRODERMIC PSORIASIS: A CASE REPORT AND LITERATURE REVIEW 2A 2B

Figure 2. (A and B) Thick, confluent, scaling erythematous plaques to the patient’s bilateral lower extremities. 3A 3B follow-up showed the patient doing remarkably Figure 3. Erythematous, confluent scaling patches to the dorsal hands, feet, and periungual areas. Psoriasis- well on a combination of acitretin and topical associated onycholysis and onychodystrophy to the patient’s (A) fingernails and (B) toenails. steroids. Considerable improvement of his systemic symptoms and extent of scaling was Erythrodermic psoriasis may develop gradually diagnose the disease.7 Erythrodermic psoriasis noted on exam. An attempt was made to increase or acutely during the course of chronic plaque classically presents with generalized erythema the patient’s acitretin dosage, but the patient was psoriasis, but it may also be the first manifestation and confluent scaling patches and plaques non-compliant with laboratory requests and then of psoriasis, even in children. encompassing greater than 90 percent of the lost to follow-up for several weeks. 4,9,11 Pathogenesis total body surface area. The scaling in The patient returned one month later with erythrodermic psoriasis is thinner, flakier, and The specific pathogenesis of erythrodermic acute erythroderma after abruptly discontinuing more desquamative compared to the thick, silvery, psoriasis has yet to be determined, although it’s 9 acitretin early in his treatment course. Review rough scales of chronic plaque psoriasis. Pruritus likely similar to the underlying pathogenesis of systems was positive for severe generalized of varying intensity often accompanies these of psoriasis. The mechanism for psoriatic 9 pruritus, mild tenderness to palpation, and stiff, cutaneous findings. In one clinical study, 78 keratinocyte proliferation was once thought to painful joints. On physical examination, the percent of patients with erythrodermic psoriasis be regulated by the keratinocyte itself. However, patient’s skin was malodorous, diffusely bright had nail abnormalities ranging from mild pitting the current focus in psoriasis pathogenesis has red, and warm, with scaling inflammatory patches to complete dystrophy.1 Patients who present shifted to helper-T (Th) cell subsets and secreted and plaques covering at least 95 percent of his with nail involvement have a higher propensity cytokines that are well documented to reside total body surface area (Figures 1 and 2). Only 10 within the epidermis and dermis of lesional for scalp psoriasis and psoriatic arthritis. his cheeks, forehead, lower lip, and genitalia skin.5,6 Th17 cells produce interleukin-22 (IL- Erythrodermic psoriasis has been associated were spared. Significant onychodystrophy and 22), and its receptor is expressed on epidermal with a variety of systemic complications.3,4,12 onycholysis to all digits were noted (Figure keratinocytes. IL-22 is the strongest cytokine in Lymphadenopathy and feelings of fatigue are 3). Lymphadenopathy and joint effusions were keratinocyte-proliferative ability and correlates 3,4,9 absent. The patient was instructed to resume fairly common accompanying symptoms. with disease severity.2,5 Th1 cells release tumor his topical steroid regimen with 10 mg of oral Hyperthermia can result from an increased necrosis factor-α (TNF-α) and interferon gamma acitretin. In addition, he was placed on an oral basal metabolic rate and generalized cutaneous (IFN-γ), which amplify the inflammatory cascade, antibiotic and an antibacterial wash due to vasodilation causing increased blood perfusion acting on keratinocytes. IL-23 is released by 3,9 malodorous skin and concern for a secondary and transepithelial water loss. Hypothermia TNF-α and is required to maintain Th17 cells. bacterial infection. He was then lost to follow- can also occur because of excessive heat loss due Some of the phenotypic variations of psoriasis, up again. Given the patient’s personal history to the generalized vasodilation, causing patients such as vasodilation-induced by inducible nitric- of plaque psoriasis along with classic and to experience chills to increase their core body oxide synthase (iNOS) and accumulation of T 13 significant psoriatic nail and cutaneous findings, temperature. The vasodilation contributes to cells in the epidermis, are thought to be explained erythrodermic psoriasis was diagnosed over other loss of fluid, electrolytes, and protein out of γ 2,5 etiologies of erythroderma. by the IFN- pathway. Erythrodermic psoriasis capillaries and into the interstitial space. This may occur from the interactions between these phenomenon has the potential for development of immunologic modulators, causing an increase , hypoalbuminemia, electrolyte Discussion of the epidermal turnover rate while decreasing imbalance, and high-output cardiac failure due Erythrodermic psoriasis is a rare and severe the time required for cells to mature and travel to shunting of blood through inflamed skin.3,4,9 9 morphologic variant of psoriasis, and onset may be through the epidermis. This may manifest One study reported the mortality rate directly acute or gradual. It is characterized by erythema as increased loss of epidermis, giving the related to erythrodermic psoriasis to be as high with confluent scaling plaques covering at least 1 characteristic superficial scaling and exfoliation as 15%. Laboratory abnormalities can include 1,3,4 9 90 percent of a person’s total body surface. seen in erythrodermic psoriasis. an elevated erythrocyte sedimentation rate Associated include edema, (ESR) or leukocytosis due to the body’s increased 5 Diagnosis nail dystrophy, alopecia, pruritus, and/or pain. inflammatory response.4,12 Occasionally, The diagnosis of erythrodermic psoriasis is Systemic manifestations can include fever, elevated liver transaminases can result from chills, fatigue, , arthralgias, high-output based largely on a thorough history and physical 4,12 erythroderma. cardiac failure, and increased risk for sepsis from examination at the time of clinical presentation. bacterial colonization by cutaneous pathogens.5 There is currently no laboratory test to specifically Contrary to typical psoriasis patients, those

FISHER, CHANNAIAH Page 37 with erythrodermic psoriasis appear to be at Table 1 - Differential Diagnosis an increased risk for bacterial colonization and overgrowth, especially by Staphylococcus Underlying Disease Clinical Clues aureus.3,7,14-16 Typically, patients diagnosed with plaque psoriasis are believed to be at decreased Erythrodermic psoriasis • Pre-existing psoriatic plaques on extensor surfaces risk for cutaneous infections due to the increased • Personal or family history of plaque psoriasis antimicrobial peptides released by Th1/Th17 subclasses. Erythroderma, however, regardless of • Nail changes (onycholysis, onychodystrophy, pitting, oil its underlying etiology, seems to correlate with spots) 17 increased likelihood of S. aureus colonization. • Sparing of the face (common) One case-control study found 100 percent of • Asymmetric arthritis (possible) erythrodermic patients were colonized by S. aureus compared to only 60 percent of patients • Abrupt withdrawal from medications (including with psoriasis and 88% of patients with atopic corticosteroids, methotrexate, etc.) dermatitis.17 This study also suggests the more severe the disease process of psoriasis, the more Generalized atopic dermatitis • Pre-existing lesions in flexure surfaces likely the patient is to be colonized by S. aureus. • Lichenification The exact etiology of this difference is unknown. Colonization with S. aureus might play a role in • Severe pruritus the development of erythroderma or propagation of disease possibly from staphylococcal antigens, • Salmon-colored erythema such as toxic syndrome toxin-1 (TSST- • “Skip spots” or “islands of sparing” 1).7,18-20 Erythrodermic patients seem to be at an • Flare after sun exposure increased risk for Staphylococcus aureus septicemia, possibly as a result of the compromised cutaneous • Waxy keratoderma barrier being perpetuated by exotoxins acting as superantigens, allowing S. aureus to gain access Cutaneous T-cell lymphoma • Severe pruritus to systemic circulation through excoriations • Lymphadenopathy (common) and fissures.1,19,20A series of case studies looked at five patients presenting with fever, chills, and • Deep purple-red hue erythrodermic psoriasis and found all five also • Alopecia had staphylococcal septicemia.18 • Elevated CD4+:CD8+ ratio (blood), with ≥10:1 ratio seen Even though an astute physician can diagnose in Sézary syndrome erythrodermic psoriasis based on history and • Sézary syndrome, ≥1,000 Sézary cells/mm3 physical examination, a skin biopsy can help support the diagnosis. Erythrodermic psoriasis histopathology includes confluent parakeratosis Drug reactions • History of starting a new medication within 2 weeks of where the keratinocytes of the stratum corneum erythroderma onset retain their nuclei, which is seen in scaling of • Resolution within 2-6 weeks after withdrawal of psoriasis.12 Collection of neutrophils, known as provoking drug (usual) Munro microabscesses, would also be expected • Preliminary morbilliform or scarlatiniform exanthema within the stratum corneum due to the body’s underlying inflammatory response.12 • Facial edema Other etiologies of erythroderma that could • Generalized pruritus (common) present clinically similar to erythrodermic psoriasis include generalized atopic dermatitis, pityriasis rubra pilaris, cutaneous T-cell Erythrodermic • Doughy and/or leathery appearance lymphoma, drug reactions, and a rare presentation 3,13,21 • Urticaria after light stroking to skin of cutaneous mastocytosis (Table 1). Generalized atopic dermatitis can present with • Pediatric patient (common) lesions of erythema, excoriations, and scaling • Symptoms controlled by with associated pruritus.22 In atopic dermatitis, however, unlike in erythrodermic psoriasis, it is pityriasis rubra pilaris, although onycholysis is psoriasis.24 A skin biopsy showing atypical the patient’s habitual scratching of dry, pruritic often present.23 Cutaneous T-cell lymphoma lymphocytes would suggest a diagnosis more skin that creates the rash of red scales, papules, 13 22 and the leukemic form, Sézary syndrome, have consistent with a cutaneous T-cell lymphoma. and/or lichenification. Pityriasis rubra pilaris been associated with a clinical presentation of A Sézary-cell/immature-neutrophil count from generally begins as a small, red-orange, scaling erythroderma, although lymphomas may not a blood sample can rule out Sézary syndrome.13 plaque on the face or upper body that expands respond to corticosteroid therapy as erythrodermic Numerous topical and systemic medications have and progresses into erythroderma with areas of 8,13 22 psoriasis would. Lymphadenopathy is usually been known to cause erythroderma/exfoliative uninvolved skin or “skip spots.” The face, palms present in cutaneous T-cell lymphoma but dermatitis.6,14 These include, but are not limited and soles are usually covered in thick, tight red 22 may or may not be present in erythrodermic to, antiepileptic medications, antihypertensive scales. Pruritus is not usually associated with

Page 38 ERYTHRODERMIC PSORIASIS: A CASE REPORT AND LITERATURE REVIEW medications, antibiotics, and calcium-channel immunosuppressive.28 The efficacy and toxicity medications with long-term efficacy for improving blockers.8,23 “Drug-induced rash” should always of acitretin both increase in a dose-dependent the underlying psoriasis and preventing future be considered on a differential diagnosis list if fashion. Berbis et al. found that initiating therapy episodes of erythrodermic psoriasis.21 a new medication was started within two weeks of acitretin at a low dose of 10 mg and then of an appearance of a dermatologic condition.23 increasing the dose as necessary, to an optimal References The most frequent patterns of cutaneous drug- dose of 25 to 50 mg/day, retained its efficacy 29 1. Boyd AS, Menter A. Erythrodermic psoriasis. induced are morbilliform, urticarial, and/ but minimized the adverse effects. Acitretin Precipitating factors, course, and prognosis in 50 or generalized pruritus possibly progressing may not be the best initial treatment choice patients. J Am Acad Dermatol. 1989;21(5 Pt 1):985-91. to generalized, exfoliative dermatitis.8,23 for erythrodermic psoriatic patients acutely ill A rare variant of cutaneous mastocytosis, with systemic symptoms because it has a slower 2. Bolognia J, Jorizzo J, Schaffer J. Dermatology. 3rd ed. erythrodermic diffuse cutaneous mastocytosis onset of action compared to methotrexate and Philadelphia, PA: Saunders; 2012:135-173. Print. 3,9,28 should be considered as a cause of generalized cyclosporine. Studies indicate that it can take 3. Ferrándiz C, Carrascosa JM. Current strategies for erythroderma, especially if seen in a pediatric as long as three to six months for acitretin to treating erythrodermic and flaring psoriasis. Int J Clin 3,30 patient. In contrast to erythrodermic psoriasis, reach its peak efficacy. Rev. 2011;10:10. the cutaneous manifestations of erythrodermic Cyclosporine has a very rapid onset of action, 4. Meier M, Sheth PB. Clinical spectrum and severity mastocytosis have been described as having a 22 making it an ideal first-line traditional medication of psoriasis. Curr Probl Dermatol. 2009;38:1-20. doughy consistency and a leathery appearance. for treating erythrodermic psoriasis in acutely ill Another important distinguishing feature of 3,27 5. Griffiths CE, Powles AV, Leonard JN, et al. Clearance patients suffering from systemic symptoms. of psoriasis with low dose cyclosporine. Br Med J (Clin erythrodermic mastocytosis is the tendency to However, cyclosporine does have significant develop pruritic and raised wheals after light Res Ed). 1986;293:731-732. 22 safety issues and should be discontinued and stroking to the skin. This urticarial reaction is due switched to a less toxic alternative once the acute 6. Tokura Y, Mori M, Hino R. Psoriasis and other to the large release of from cutaneous 3,5,21 erythrodermic episode is under control. The Th17-mediated skin diseases. J UOEH. 2010 Dec mast-cell invasion, which is believed to be the onset of action for methotrexate is faster than 1;32(4):317-328. underlying cause of the diffuse erythroderma 3,5,21 for acitretin but slower than cyclosporine. 7. Rosenbach M, Hsu S, et al. Treatment of seen in erythrodermic mastocytosis.22 Methotrexate use is somewhat limited because erythrodermic psoriasis: from the medical board of the Erythrodermic psoriasis usually arises in a often an initial test dose is administered to National Psoriasis Foundation. J Am Acad Dermatol. patient who is currently experiencing an active assess drug tolerability, which can delay the full- 2010;62(4):655-62. exacerbation of extensive plaque psoriasis, 3,5,21 dose treatment by one week. Because of this 8. Mrowietz U, Reich K. Psoriasis-new insights into although it is possible for it to occur during a built-in delay, methotrexate is not generally used 1,23 pathogenesis and treatment. Dtsch Arztebl Int. period of psoriasis inactivity. Even plaque in erythrodermic psoriatic patients with severe 2009;106(1-2):11-18. psoriasis that is fairly controlled can evolve into systemic symptoms, as more urgent treatment is erythrodermic psoriasis if treatment is abruptly needed.3 9. Virenda SN, Srivastava G, Sardana K. Erythroderma/ stopped.12 Other precipitating factors that can exfoliative dermatitis: a synopsis. Int J Dermatol. Biologics is the most recent class of medications 2004;43:39-47. trigger erythrodermic psoriasis include abrupt introduced for the treatment of plaque psoriasis withdrawal of topical ultrapotent or systemic that may be beneficial for treating erythrodermic 10. Naldi L, Gambini D. The clinical spectrum of steroids; excessive use of topical steroids; psoriasis. There are few studies directly comparing psoriasis. Clin Dermatol. 2007;25(6):510-18. discontinuation of methotrexate; sunburn; the outcomes of different biologics when used on 11. Griffiths CE, Christophers E, et al. A classification systemic illness; emotional stress; or colonization 4,12 erythrodermic patients. The biologics that have of psoriasis vulgaris according to phenotype. Br J of psoriatic plaques with Staphylococcus aureus. received the most focus thus far in the treatment Dermatol. 2007;156(2):258-262. Traumatic injury to the dermis of a psoriasis of erythrodermic psoriasis are tumor necrosis 12. Prystowsky JH, Cohen PR. Pustular patient, such as that produced by a sunburn, can factor-alpha (TNF-α) antagonists and include and erythrodermic psoriasis. Dermatol Clin. cause plaque psoriasis lesions to develop at the 31 infliximab, etanercept, and adalimumab. The 1,4,12 1995;13(4):757-70. site of injury and even lead to erythroderma. available research suggests that infliximab is Treatment a reasonable option for first-line treatment of 13. Geiger J-M, Czarnetzki BM. Acitretin (Ro 10- erythrodermic psoriasis because of its rapid onset 1670, Acitretin): overall evaluation of clinical studies. Erythrodermic psoriasis is a potentially severe of action and the significant improvements seen in Dermatologica. 1988;176(4):182-90. disease that requires prompt initiation of 5,21,32 Ultimately, treatment upon clinical presentation. The first patients over a short time period. 14. Guttman-Yassky E, Nograles KE, Krueger JG. further research with prospective clinical trials is Contrasting pathogenesis of atopic and psoriasis-Part step in management is to discontinue the use of needed to determine the place of biologics in the 1: Clinical and pathologic concepts. J Allergy Clin any potentially offending agents or provocative 3 treatment of erythrodermic psoriasis. Immunol. 2011;127(5): 1110-1118. factors. Systemic treatment that focuses on short-term efficacy with a quick onset of action Regardless of what first-line systemic therapy is 15. Mrowietz U, Reich K. Psoriasis-New insights should be initiated in patients suffering from chosen, it is generally recommended to initiate into pathogenesis and treatment. Dtsch Arztebl Int. erythrodermic psoriasis.21 The three first-line adjuvant treatments such as medium-potency 2009;106(1-2):11-19. topical steroids, calcipotriene/betamethasone, traditional medications with proven efficacy in 16. Olesen AB. Chronic Skin Disease and Risk of treating erythrodermic psoriasis are acitretin, moisturizers, wet dressings, oatmeal baths, 5 Infection. Open Infect Dis J. 2012;6:60-64. methotrexate, and cyclosporine.3,5,21,27 Acitretin is and continued supportive care. Combination 17. Tomi NS, Kranke B, Aberer E. Staphylococcal known to have a reasonable safety profile while treatments may provide greater efficacy than the in patients with psoriasis, atopic dermatitis, and effectively treating erythrodermic psoriasis.3,5,27 use of monotherapy and reduce the incidences of erythroderma, and in healthy control subjects. J Am It is the drug of choice in immunocompromised adverse effects as lower doses of each individual 33 Acad Dermatol. 2005 Jul;53(1):67-72. patients because it is one of the few systemic agent are used. Once the acute erythrodermic therapies for erythrodermic psoriasis that is not episode is well controlled, therapy can focus on 18. Green MS, Prystowsky JH, Cohen SR, Cohen

FISHER, CHANNAIAH Page 39 JI, Lebwohl MG. Infectious complications of autoimmunity. Br J Dermatol. 2007;156:329-36. erythrodermic psoriasis. J Am Acad Dermatol. 33. Ghasri P, Yentzer BA, Dabade TS, Feldman SR. 1996;34(5 Pt 2):911-14. Acitretin for the treatment of psoriasis: an assessment of 19. McFadden JP, Noble WC, Camp RD. national trends. J Drugs Dermatol. 2011;10(8):873-7. Superantigenic exotoxin-secreting potential of staphylococci isolated from atopic eczematous skin. Br J Dermatol. 1993;128:631-2. Correspondence: Jacqueline Fisher, DO, O’Bleness Memorial Hospital, 55 Hospital Drive, Athens, OH 20. Tomi NS, Kranke B, Aberer E. Staphylococcal 45701; 937-681-0104; [email protected]. toxins in patients with psoriasis, atopic dermatitis, and erythroderma, and in healthy control subjects. J Am Acad Dermatol. 2005;53:67-72. 21. American Academy of Dermatology Work Group, Menter A, Korman NJ, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 6. Guidelines of care for the treatment of psoriasis and psoriatic arthritis: Case-based presentations and evidence-based conclusions. J Am Acad Dermatol. 2011; 65(1):137-74. 22. Requana L. Erythrodermic mastocytosis. Servicio de Dermatología. 1992; 49(3):189-92. 23. Habif TP. Clinical dermatology: a color guide to diagnosis and therapy. Mosby Elsevier Inc., 2010:156,269,309-11,568. Print. 24. Karakayli G, Beckham G, Oregano T, et al. Exfoliative dermatitis. Am Fam Physician. 1999;59:625-30. 25. DermNetNZ [Internet]. Palmerston North (New Zealand): New Zealand Dermatologic Society, Inc. ©2013. Cutaneous T-cell Lymphoma; [last updated 2012 Nov 23; cited 2013 May 30]. Available from: http://www.dermnetnz.org. 26. Green MS, Prystowsky JH, Cohen SR, Cohen JI, Lebwohl MG. Infectious complications of erythrodermic psoriasis. J Am Acad Dermatol. 1996;34(5 Pt 2):911-14. 27. Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents. J Am Acad Dermatol. 2009;61(3):451- 85. 28. Booij MT, Van De Kerkhof PC. Acitretin revisited in the era of biologics. J Dermatolog Treat. 2011;22(2):86- 9. 29. Berbis P, Geiger JM, Vaisse C, et al. Benefit of progressively increasing doses during the initial treatment with acitretin in psoriasis. Dermatologica. 1989;178:88-92. 30. Ling MR. Acitretin: optimal dosing strategies. J Am Acad. 1999;41(3 Pt 2):S13-7. 31. Viguier M, Pagès C, Aubin F, Delaporte E, et al. Efficacy and safety of biologics in erythrodermic psoriasis: a multicentre, retrospective study. Br J Dermatol. 2012;167(2):417-423. 32. Poulalhoun N, Begon E, Lebbe C, Liote F, Lahfa M, Bengofa D, et al. A follow-up study in 28 patients treated with infliximab for severe recalcitrant psoriasis: evidence for the efficacy and high incidence of biological

Page 40 ERYTHRODERMIC PSORIASIS: A CASE REPORT AND LITERATURE REVIEW Iatrogenic Kaposi’s Sarcoma Arising After Renal Transplant Immunosuppression

Katherine Johnson, DO,* Jessica Garelik, DO,** Howard D. Lipkin, DO***

*Dermatology Resident, PGY-II, Botsford Hospital, Farmington Hills, MI **Intern, PGY-I, Botsford Hospital, Farmington Hills, MI

Abstract Kaposi’s sarcoma (KS) is a spindle-shaped, vascular-cell tumor associated with human herpes virus 8 (HHV-8). It most commonly presents as multiple, bilateral, violaceous-to-brown papules, plaques or patches distributed on the lower extremities. Of the four clinically defined types of KS, iatrogenic KS most often occurs in organ transplant recipients who are immunosuppressed after receiving post-transplant chemotherapeutic agents to prevent allograft rejection. We present a case of a 67-year- old, post-renal-transplant Caucasian male with a chief complaint of pruritic, purple plaques on his legs and axillae.

there were violaceous plaques on the bilateral tacrolimus was maintained at the same dose. The Case Report plantar surfaces and 2 mm to 4 mm erythematous patient began showing regression of his lesions History macules on the bilateral dorsal feet and anterior shortly after discontinuing the mycophenolate A 67-year-old Caucasian male presented to the lower legs (Figures 1-3). The right lower extremity mofetil. He was also scheduled to initiate clinic with a chief complaint of lower extremity had pitting edema and pain upon palpation. treatment with sirolimus. swelling, pruritus, pain and discoloration of one-month duration. He also complained of Laboratory Discussion dark patches on his right arm and axillae. He An HIV screen was negative. Kaposi’s sarcoma (KS) is an angioproliferative had recently visited his podiatrist, an emergency disorder, characterized by a spindle-shaped room, and an urgent care over the concern that Histopathology vascular-cell tumor. It can occur in the skin and one of his feet was “turning black.” Laboratory Punch biopsies of the right upper extremity visceral tissues and is associated with human studies, radiographs, and an EKG were all found and right plantar foot were performed, which herpes virus 8 (HHV-8) infection.1 There are to be normal. The patient’s past medical history demonstrated a proliferation of endothelial cells four clinically defined types of KS, which include included a renal transplantation in October forming bizarre-shaped, thin-walled vessels the classic form, endemic (African) form, HIV- 2010, and he was maintained on mycophenolate that followed pre-existing vascular plexuses associated form, and iatrogenic form. Iatrogenic mofetil 1 g PO BID, tacrolimus 3 mg PO BID, (Figures 4 and 5). A CD31 stain was performed, Kaposi’s sarcoma most commonly occurs in organ and prednisone 10 mg PO daily. Pertinent family highlighting the vascular proliferative changes, transplant recipients secondary to post-transplant medical history included a brother who was and an HHV-8 stain decorated many spindle treatment with chemotherapeutic agents, which deceased due to malignant melanoma found in cells that were associated with the vessels (Figure are used to suppress the and thus the axillae. 6). prevent allograft rejection. Examination Course and Therapy The incidence of Kaposi’s sarcoma among Physical examination revealed violaceous papules In light of the histopathology results and solid organ transplant recipients has been and plaques over the extensor surfaces of the with approval of his renal transplant team, found to be 500-fold higher than the general right upper and lower extremities. In addition, mycophenolate mofetil was discontinued, and population, and renal transplant patients are 10

Figure 1. KS lesions on toes. Figure 2. KS lesions on plantar Figure 3. KS lesions on toes. surface of right foot.

JOHNSON, GARELIK, LIPKIN Page 41 strictly cutaneous involvement.5 The remaining replication, especially in genetically predisposed eight patients developed a combination of individuals. visceral, mucosal and cutaneous lesions, and two Studies have shown that sirolimus, a rapamycin of the patients succumbed to the disease. In cases inhibitor, which acts by inhibiting mTOR, where there is involvement of visceral structures prevents acute graft rejection and blocks such as the lungs, KS is considered aggressive and cytokine signal transductions.6 This provides carries a poor prognosis. both anti-neoplastic and immunosuppressive The exact etiology of KS is unknown, although effects. It may also restore functional balance HHV-8 is highly implicated in its pathogenesis. of cell growth and reduce HHV-8 activity, The relationship between HHV-8 and KS was leading to both regression of KS in kidney identified in 1994, but it was determined that transplant recipients and a decreased risk of Figure 4. Low-power magnification of KS. HHV-8 is necessary but not sufficient for the malignancy.4 The immunosuppressant effects development of the malignancy. HHV-8 virus of sirolimus are also useful in maintaining an is transmitted via sexual contact and saliva. As anti-rejection environment on organ allografts. with other herpes viruses, once contracted, an Monotherapy with sirolimus in the treatment individual will have it for the duration of his/ of KS may not be adequate when high dosage her life. HHV-8 can remain latent for decades of immunosuppression is required, in which case and become reactivated given the proper other topical or systemic therapies may need to immunosuppressed environment. HHV-8 is be added.7 able to target tumor suppressor pathways such Many studies compare both individual as the p53 pathway and the retinoblastoma medications and combination therapies. A protein, thereby producing tumorigenesis in 2012 study evaluating sirolimus/tacrolimus vs. susceptible immunocompromised individuals.6 mycophenolate mofetil/tacrolimus found the More specifically, a G-protein-coupled receptor combination of sirolimus/tacrolimus to be better Figure 5. HHV-8 stain (vGPCR), which is an HHV8-specific gene tolerated and overall more effective in renal and product, promotes activation of a kinase known as pancreatic transplants, resulting in fewer rejections mammalian target of rapamycin (mTOR), which within the first year after transplantation.8 enhances vascular endothelial growth factor (VEGF) secretion and its receptor’s binding Other studies have shown that when compared affinity on endothelial cell surfaces.4 This leads to cyclosporine, tacrolimus has a significantly to IL-2 production and lymphocytic activation. lower incidence of acute rejection without an While mTOR plays a key role in controlling increase in adverse side effects associated with cell growth and division, hyperactivation of its long-term immunosuppression. It has also been signaling pathway has been implicated in many shown that tacrolimus results in patients needing human cancers, like Kaposi’s sarcoma. less medication to control hyperlipidemia and hypertension, comorbidities which worsen the The approach to treating iatrogenic KS involves a long-term prognosis of transplant patients.9,10 complex set of targets including IL-2 production Despite cyclosporine and tacrolimus having Figure 6. Vascular proliferation of KS and mTOR inhibition, while maintaining similar mechanisms of action, data indicates that adequate immunosuppression to avoid graft they are not equally efficacious and do not have to 20 times more likely to suffer a malignancy rejection. When this balance can be accomplished, 2 similar adverse-effect profiles in renal transplant after transplantation. This is significant when it often leads to spontaneous regression of the KS. patients. compared to the incidence of other skin cancers Conversely, an increase of immunosuppression in transplant recipients: Squamous cell cancer has can cause recurrence of KS. Immunosuppressive Treatment modalities involving the use of been described as being increased 65-fold; basal regimens can include a variety of medication sirolimus in transplant recipients, combination cell carcinoma as 10-fold; and melanoma three- combinations. Commonly used medications in therapies of sirolimus/tacrolimus, as well as to four-fold.3 The incidence of skin cancer in this renal transplant patients include prednisone, potentially effective anti-herpes virus therapies population is related to the type, intensity and cyclosporine, mycophenolate mofetil, tacrolimus have added new opportunities for preventing duration of immunosuppression. and sirolimus. Kaposi’s sarcoma in transplant recipients. KS has a heterogeneous clinical presentation. It Cyclosporine is a calcineurin inhibitor commonly can present solely as cutaneous lesions, involve used post-organ transplant to prevent allograft Conclusion mucosal membranes, attack visceral structures, rejection.4 Cyclosporine binds to cyclophillin Iatrogenic Kaposi’s sarcoma most commonly or have any combination of cutaneous and to induce inhibition of calcineurin. Similarly, occurs in solid-organ transplant recipients due systemic involvement. Clinically, KS lesions are tacrolimus inhibits calcineurin, but by binding to to post-transplant immunosuppressive treatment found to be multicentric and widely dispersed at FK-506 binding protein. The complex then exerts with chemotherapeutic agents. HHV-8 is involved the onset of disease. The lesions can present as its inhibition on calcineurin. Both medications act in its pathogenesis; the immunosuppressive a variety of violaceous-to-brown/black papules, as immunosuppressants by blocking production agents that are used to prevent organ rejection plaques or patches. The lesions are often bilateral of IL-2 via calcineurin inhibition, thus reducing can enhance the virus’s replication. Treatment and affect the skin of the lower extremities, but lymphocyte activation and decreasing T-cell- is aimed at decreasing immunosuppressive they can be present in visceral tissues such as the mediated rejection of the transplanted organ. medications when possible. In addition, sirolimus gastrointestinal and respiratory tracts.4 In one However, the immunosuppressive actions of may be useful due to its antineoplastic and study of 820 kidney transplant patients, 13 people these drugs pose risks of development of KS immunosuppressive properties, reducing HHV-8 developed KS, and only five of those 13 had in transplant patients by allowing HHV-8 activity, which frequently results in improvement

Page 42 PAGETOID RETICULOSIS (WORINGER-KOLOPP DISEASE) IN A 43-YEAR-OLD WOMAN of KS. These broadened treatment modalities have allowed for better treatment of Kaposi’s sarcoma in post-transplant individuals. Pagetoid Reticulosis (Woringer-Kolopp Disease) in a 43-Year-Old Woman References 1. Jan MM, Laskas JW, Griffin TD. Eruptive Kaposi Helia Eragi, DO,* Matthew Koehler, DO,* Paul Shitabata, MD,** David Horowitz, DO, FAOCD*** sarcoma: an unusual presentation in an HIV-negative patient. Cutis. 2011;87:34-38. *Dermatology Resident, Western University - Pacific Hospital, Long Beach, CA **Director of Dermatopathology, Harbor-UCLA Dermatology, Torrance, CA; Clinical Professor of Medicine, 2. Johari Y, Nicholson ML. Complete resolution David Geffen School of Medicine at UCLA; Los Angeles, CA of oral Kaposi’s sarcoma achieved by changing ***Dermatology Residency Program Director, Western University - Pacific Hospital, Long Beach, CA immunosuppression: a case report. Ann R Coll Surg Engl. 2010;92. 3. Schwartz R, et al. Kaposi Sarcoma: A Continuing Abstract Conundrum. J Am Acad Dermatol. 2008;(59)2:179- Pagetoid reticulosis (PR), or Woringer-Kolopp disease (WKD), is a rare variant of with 206. a generally benign and indolent course. Woringer-Kolopp disease classically presents as a slowly growing, 4. Jakob L, et al. Non-AIDS associated Kaposi’s solitary hyperkeratotic plaque on a distal extremity. Histology shows marked acanthosis and epidermotropic sarcoma: clinical features and treatment outcome. PLoS. neoplastic cells. The immunophenotypes CD4-/CD8-, CD4+/CD8, and CD4-/CD8+ have been reported, 2011;6(4):e18397. and all phenotypes carry an excellent prognosis. While mortality has never been reported in Woringer-Kolopp disease, morbidity and disease progression in spite of treatment can occur. Accurate diagnosis requires careful 5. Montagnino G, et al. Clinical features and course of analysis of both clinical and histopathological features. Treatment of choice is radiation therapy, but skin- Kaposi’s sarcoma in kidney transplant patients: report of directed therapies, systemic therapies and surgical excision are also effective options. We present a case of 13 cases. Am J Nephrol. 1994;14(2):121-6. pagetoid reticulosis expressing CD8+ cells in a 43-year-old female, and we review diagnostic features of and 6. Zwald FO, Brown M. Skin Cancer in solid organ current treatment options for this uncommon disease. transplant recipients: Advances in therapy and management. J Am Acad Dermatol. 2011;65:253-261. Case Report 7. Pranteda G, et al. Sirolimus and regression of Kaposi’s A 43-year-old woman presented with a lesion on sarcoma in immunosuppressed transplant patient. J Eur her left heel that she first noticed a few months Acad Dermatol Venereol. 2008;22:1003-1030. prior. The lesion was asymptomatic and had 8. Ciancio G, et al. Advantage of rapamycin over slowly grown to its current size and thickness. mycophenolate mofetil when used with tacrolimus for She denied any other similar lesions present at simultaneous pancreas kidney transplants: randomized, that time or in the past. No treatments had been single center trial at 10 years. Am J Transplant. attempted prior to presentation. Dermatologic Figure 1 Figure 2 2012;12(12):3363-76. history was significant for malignant melanoma on her right forearm that was successfully 9. Pirsch JD, et al. A comparison of tacrolimus (FK506) removed 25 years earlier. Physical exam showed a and cyclosporine for immunosuppression after cadaveric 1 cm, sharply demarcated, hyperkeratotic plaque renal transplantation. FK506 Kidney Transplant Study with irregular pigmentation adjacent to the left Group. Transplantation. 1997;63:977-983. lateral heel (Figures 1 and 2). Clinical differential 10. Vincenti F, et al. Jensik SC, Filo RS, Miller J, Pirsch diagnosis was broad and included verruca vulgaris, J. A long-term comparison of tacrolimus (FK506) and dysplastic nevus, inflammatory dermatosis cyclosporine in kidney transplantation: evidence for pigmented squamous cell carcinoma. There was improved allograft survival at five years. Transplantation. no lymphadenopathy, and the remainder of the 2002;73:775-782. physical exam was benign. Blood work was not obtained, but a punch biopsy was performed.

Correspondence: Katherine Johnson, DO, Botsford The histopathological sections revealed acral skin Hospital, 28050 Grand River Ave., Farmington Hills, showing an extensive atypical lymphoid infiltrate MI 48336; [email protected]. with extensive epidermotropism by the lymphocytes Figure 3 (Figures 3 and 4). The intraepidermal lymphocytes showed enlarged and hyperchromatic nuclei with extensive intercalation with the basal keratinocytes, focally forming Pautrier-like microabscesses in the stratum malpighii. Immunohistochemical analyses revealed primarily CD8+ T cells, with a background of CD4-highlighted, small, reactive T-lymphocytes (Figures 5 and 6). CD30 was negative. Based on the clinical and histopathologic examination, the diagnosis of pagetoid reticulosis, or Woringer- Kolopp disease, was established. The patient was referred to radiation oncology for treatment. As of this article’s writing, the patient has not returned for follow-up. Figure 4

ERAGI, KOEHLER, SHITABATA, HOROWITZ Page 43 prognosis. Because the histopathology and immunophenotypes of Woringer-Kolopp disease and KGD are indistinguishable, they were previously described as localized and disseminated pagetoid reticulosis, respectively. However, because of their drastically different clinical courses, the term “pagetoid reticulosis” should be used exclusively for Woringer-Kolopp disease.1 One reason for their clinical differences could be related to the complete loss of CD45 in WKD compared to a partial loss in KGD. As CD45 is an important component in lymphocyte growth and transformation, this could explain the relatively benign nature of WKD.13 There is some Figure 5 Figure 6 controversy regarding the classification of KGD, with some papers suggesting it is a variant of not usually aid in an absolute distinction since cytotoxic CD8 lymphomas and others a variant Discussion the majority of cases of pagetoid reticulosis of mycosis fungoides. Since nearly all cases of Pagetoid reticulosis is a rare form of cutaneous exhibit a preponderance of CD4+ intraepidermal KGD have a more aggressive clinical course T-cell lymphoma (CTCL) defined as “a variant lymphocytes with loss of CD7 and CD62L, which compared to WKD, it may be prudent to consider of mycosis fungoides characterized by the is also the most common immunohistochemical KGD as an epidermotropic variant of mycosis presence of localized patches or plaques with staining pattern with mycosis fungoides and one fungoides, distinct from Worringer-Kolopp.14-16 an intraepidermal proliferation of neoplastic basis for categorizing pagetoid reticulosis as a 1 Our patient’s stable and benign clinical course is T cells.” Classic presentation is of a solitary histopathological variant of mycosis fungoides. In consistent with the diagnosis of WKD, not KGD. hyperkeratotic or psoriasiform plaque or plaques both diseases, there may be heterogeneity with the on the extremities with a slowly progressing immunophenotype, with CD8 variants and co- The dermoascopic findings of pagetoid reticulosis, course. Lesions generally start as patches and expression of CD4 and CD8. Epidermotropism is described by Suzaki et al. as a “homogenous progress to plaques, but papules, tumors and found in both early MF and pagetoid reticulosis. pinkish area in the central area of the lesion ulcerating lesions have been reported. Lesions In pagetoid reticulosis, though, as lesions mature, and a whitish network in the marginal area with are most commonly on distal extremities but epidermotropism remains, with progression of dotted and glomerular vessels,” are similar to may occur more centrally or even on the perioral hyperkeratosis and acanthosis; but as MF lesions the pattern found in Bowen’s disease. However, 2,3 region and tongue. Because of its rarity and mature, they may lose their epidermotropism and those authors state that pagetoid reticulosis indolent nature, diagnosis is often delayed for diffusely infiltrate the dermis, particularly in the can be differentiated from Bowen’s by the less- 3,4 years or decades. Middle-aged men are most tumor stage. Mycosis fungoides can progress to prominent glomerular vessels, corresponding to commonly affected, but the disease has been extracutaneous dissemination, and possibly death, an absence of glomerular vessels in the dermal reported in patients of all ages, including children which has never been reported in WKD. papillae and papillary dermis.17 only a few months old.5-7 Considering the location of this lesion -- Initial workup of pagetoid reticulosis should Histopathologic features universally demonstrate adjacent to the heel – the differential could also include a complete physical exam including a hyperplastic epidermis with an epidermotropic include mycosis fungoides palmaris et plantaris lymph node assessment, complete blood count, infiltrate of atypical pagetoid cells, singly (MFPP), a rare form of MF presenting as slowly a comprehensive metabolic panel, chest X-ray, or in aggregates. As lesions mature, marked growing, thin, acral plaques confined to the palms and flow cytometry to screen for Sezary cells. hyperkeratosis and acanthosis may occur. Dermal and soles. MFPP has an indolent course and is The clinical differential diagnosis is broad and infiltrates contain mostly histiocytes and reactive often confused with recalcitrant hand dermatitis. can include , psoriasis, atrophic lymphocytes, but not neoplastic T cells. Atypical Tumor progression and spread of MFPP is porokeratosis, Bowen’s disease, bacterial infection, cells contain abundant cytoplasm and may usually limited to palms and soles, and maturing fungal infection, verruca vulgaris, and other forms have hyperchromatic and cerebriform nuclei. lesions do not have the progressive thickening and of CTCL. See Table 1 for a more thorough Clonality is frequently seen in WKD, but it may hyperkeratosis that pagetoid reticulosis lesions differential diagnosis. be absent and is not a requisite for the diagnosis.1 3 Atypical cells in MFPP also can demonstrate. Treatment of choice for PR, especially extensive Eosinophils are usually not present in pagetoid show CD4+ staining, but there have been reports or refractory cases, is localized radiation reticulosis.3 The immunophenotype of pagetoid of MFPP lesions expressing primarily CD8+ 4,18 therapy. Localized electron beam therapy reticulosis is variable and includes CD4+/CD8, 12 Histologically, epidermotropic lymphocytes. (EBT) is useful, as radiation is localized to CD4-/CD8+, and CD4-/CD8- patterns, but MFPP resembles mycosis fungoides. Our case, the dermis and epidermis. Studies with MF there is no prognostic implication in these containing strongly positive CD8+ tumor cells in 2,4,8-11 patients show a near 100 percent response rate subsets. a verrucous and hyperkeratotic plaque, leads to a to EBT, with full response rates ranging from diagnosis of PR rather than MFPP. Differentiating pagetoid reticulosis from other 40 percent to 98 percent depending on extent similar diseases requires a combination of Ketron-Goodman Disease (KGD) has similar of skin involvement.19 Maintenance PUVA careful clinical and microscopic examination histopathologic findings to pagetoid reticulosis or other localized treatments may be used to make an accurate diagnosis. Clinically, early but a markedly different clinical presentation. after EBT as maintenance therapy, but formal mycosis fungoides (MF) and pagetoid reticulosis KGD has widespread, disseminated cutaneous recommendations are lacking. can be indistinguishable; MF, however, has a involvement, can have extracutaneous Due to the localized nature of PR, topical propensity for the buttocks, trunk and proximal involvement, is more likely to present with strategies are an attractive alternative to radiation extremities, while pagetoid reticulosis prefers ulcerative and eroded lesions, and has a more therapy, offering patients the convenience of at- distal extremities. Immunohistochemistry does aggressive clinical course with a guarded home use. Topical bexarotene targets retinoid Page 44 IATROGENIC KAPOSI’S SARCOMA ARISING AFTER RENAL TRANSPLANT IMMUNOSUPPRESSION Table 1 - Differential Diagnosis

Condition Clinical Features Histopathology

Dermatitis – Contact/Allergic Acute vesicular reaction common. Pruritic plaques may Acute lesions show marked spongiosis and progress to become chronic with continued irritation. Inflamed skin acanthosis in chronic lesions. Perivascular lymphocytes in thickens, and skin markings become accentuated. dermis and epidermis.

Fungal Infection Nummular or annular lesion with hyperkeratotic scaling Fungi noted in stratum corneum with staining. border. Lesions classically have expanding mobile Orthokeratosis is observed with parakeratosis. Spongiosis borders. May occur anywhere on the body in any age and perivascular inflammation often present group.

Verruca Vulgaris HPV infection of keratinocytes that produces cylindrical Immunoperoxidase staining can confirm HPV capsid projections and evolve into dome-shaped hyperkeratotic antigen. Hyperkeratosis, parakeratosis, and acanthosis growths. Hands and feet are most common, but may present. Vacuolized basophilic and irregular nuclei. occur anywhere.

Porokeratosis (Mibelli) Autosomal-dominant clonal disorder of keratinization Hyperkeratosis, acanthosis and parakeratosis present in with malignant potential. Annular atrophic and epidermis. Cornoid lamella lacks a granular cell layer, and hypopigmented plaque surrounded by hyperkeratotic central portion displays atrophy. border known as cornoid lamella.

Bowen’s Disease (squamous cell Slow-growing, asymptomatic, solitary, erythematous Atypical keratinocytes and full-thickness anaplasia carcinoma in situ) scaly plaque with distinct borders. Lesion may become of epidermis. Acanthosis and hyperkeratosis present. hyperkeratotic, crusted or ulcerated, and foci of Dermis shows chronic inflammation. Bowen’s disease is pigmentation may be present. Common in sun-exposed positive for CK 5/6 and 7. areas and with arsenic exposure.

Mycosis Fungoides Slow-growing, progressive cutaneous T-cell lymphoma. T-cell subtype always CD3+, CD4+, CD7-, and CD8-. Lesions typically centrally located patches or plaques. CD30 neg. or weakly pos. Proliferation rate (Ki-67) Older adults most commonly affected. Widespread neg. or weakly pos. Epidermotropism may be present in involvement and death possible. early MF; tumor cells present in dermis and epidermis as disease progresses. Microabscesses with lymphocytes (Pautrier’s microabscesses).

Mycosis Fungoides Palmaris et Rare variant of MF. Presents as palmar or solar plaques, Identical to MF. Acanthosis and hyperkeratosis less Plantaris often confused with recalcitrant hand or foot dermatitis. prominent than in WKD. Plaques remain thin but may spread to other acral sites.

Woringer-Kolopp Disease Solitary hyperkeratotic or psoriasiform plaque or plaques T-cell subtypes are variable. CD30 is variable and often on the extremities with a slowly progressing course. exceeds 50%. Proliferation rate (Ki-67) usually more than Plaques may thicken, but advancement is localized. 30%. Tumor cells restricted to epidermis. Widespread involvement or death not reported.

Psoriasis Chronic inflammatory disease with recurrent, round Epidermal hyperplasia with test-tube-shaped rete plaques with distinct borders and thick silvery scale. ridges. Prominent dermal papillae with thin overlying Lesions may remain for months or years. skin. Tortuous capillary loops. Microabscesses may be present containing polymorphonuclear leukocytes (microabscesses of Munro).

X-receptors and is approved for use in early- will develop an allergy to mechlorethamine, it limit its use to lesions <3% of total body surface and late-stage cutaneous T-cell lymphomas in is usually compounded as an ointment to reduce area. Bone marrow suppression is possible, and patients who have failed or do not tolerate other sensitization, even though this may diminish routine blood work is required. Telengectasias, therapies. Specifically, bexarotene has been used effectiveness.23 It is applied daily until remission hyperpigmentation, atrophy and burning are with good results in pagetoid reticulosis.20,21 The and then continued for months to years afterward reported, but these effects are usually self-limited most common adverse effects are local irritation, depending on treating institution. Concentrations and short-lasting. Topical steroids can be used as pain and pruritus, which can be controlled with may be titrated until response is achieved. Topical the sole agent, and often with excellent results, the addition of topical steroids.22 The carmustine (BCNU) is another alkylating agent but are frequently used in combination with mustard mechlorethamine is an alkylating agent that is used on patch- and plaque-stage cutaneous other therapies to mitigate irritation and enhance that has also proven beneficial in the treatment lymphomas. Efficacy is excellent in localized overall efficacy of treatment. of localized CTCLs. Because 10% of patients CTCL, but side effects and systemic absorption Psoralen plus A (PUVA) and UVB

ERAGI, KOEHLER, SHITABATA, HOROWITZ Page 45 have shown success and are considered an 5. Mandojana RM, Helwig EB. Localized 20. Yao Y, Mark LA. Woringer-Kolopp disease acceptable alternative treatment for pagetoid epidermotropic reticulosis (Woringer-Kolopp disease). mimicking foot dermatitis. Cutis. 2012 Dec;90(6):307- reticulosis. Further, additional topical therapies J Am Acad Dermatol. 1983;8:813–829. 9,16. can be added to PUVA to enhance response. 6. Matsuzaki Y, Kimura K, Nakano H, Hanada 21. Breneman D, Duvic M, Kuzel T, Yocum R, Truglia Case reports have shown photodynamic therapy K, Sawamura D. Localized pagetoid reticulosis J, Stevens VJ. Phase 1 and 2 Trial of Bexarotene Gel for and excimer lasers to be useful in curing or (Woringer-Kolopp disease) in early childhood. J Am Skin-Directed Treatment of Patients With Cutaneous 24-26 inducing remission, as well. Surgical excision Acad Dermatol. 2009;61:120–3. T-Cell Lymphoma. Arch Dermatol. 2002;138:325-32. is usually unnecessary, since non-surgical options 22. Zackheim, HS. Bexarotene in the Treatment of are so efficacious. Systemic therapies using 7. Miedler J, Gould J, Tamburro J, Gilliam AC. Pagetoid reticulosis in a 5 year old boy. J Am Acad Dermatol. Cutaneous T-Cell Lymphoma (CTCL) [Internet]. , retinoids and chemotherapeutics can 2008 April;58(4):679–81. Birmingham (MI): Cutaneous Lymphoma Foundation; be considered with extensive disease burden or [updated 2010 Aug; cited 2013 Feb 22]. Available from: failure of localized therapies, but this is rare with 8. Mourtzinos N, Puri P, Wang G, Liu M. CD4/CD8 http://www.clfoundation.org/treatment/bexarotene- pagetoid reticulosis. double negative pagetoid reticulosis: a case report and the-treatment-of-cutaneous-t-cell-lymphoma-ctcl. literature review. J Cutan Pathol. 2010;37:491–6. With no known fatalities from PR, prognosis 23. Odom RB, James WD, Berger TG. Andrews’ is excellent. However, significant morbidity in 9. Gorpelioglu C, Sarifakioglu E, Haltas H. Spider Diseases of the Skin: Clinical Dermatology. 9th ed. the form of aesthetically distressing lesions, bite-induced pagetoid reticulosis. J Eur Acad Dermatol Philadelphia: W.B. Saunders Company; c2000. Chapter superinfection, loss of function and pain can Venereol. 2009;23:446–7. 32, Cutaneous Lymphoid Hyperplasia, Cutaneous occur. Reports of recalcitrant cases of pagetoid 10. Burns MK, Chan LS, Cooper KD. Woringer- T-Cell Lymphoma, Other Malignant Lymphomas, and reticulosis with many bouts of recurrence, growth Kolopp disease (localized pagetoid reticulosis) or Allied Diseases; p. 918-42. in spite of treatment and dissemination have unilesional mycosis fungoides? An analysis of eight cases 24. Mendese GW, Beckford A, Krejci N, Mahalingam caused some to question the benign nature of with benign disease. Arch Dermatol. 1995;131:325–9. PR.3,27-30 Because of this, it is prudent to deliver M, Goldberg L, Gilchrest BA. Pagetoid reticulosis focused treatment with careful and regular 11. Martin SJ, Cohen PR, Cho-Vega JH, Tschen JA. in a prepubescent boy successfully treated with follow-up for all patients. Most cases appear to be CD8+ Pagetoid Reticulosis Presenting as a Solitary photodynamic therapy. Clin Exp Dermatol. 2012 quite manageable, however, with many effective Foot Plaque in a Young Woman. J Clin Aesthet Oct;37(7):759-61. Dermatol. 2010 Oct;3(10):46-9. treatment options available. Radiation therapy is 25. Berroeta L, Lewis-Jones MS, Evans AT, Ibbotson the recommended initial treatment, but clinician 12. McNiff JM, Schechner JS, Crotty PL, Glusac EJ. SH. Woringer-Kolopp (localized pagetoid reticulosis) experience, regional access to therapies and Mycosis fungoides palmaris et plantaris or acral pagetoid treated with topical photodynamic therapy (PDT). patient preference should be considered when reticulosis? Am J Dermatopathol. 1998;20(3):271–5. Clin Exp Dermatol. 2005 Jul;30(4):446-7. making individual treatment recommendations. 13. Sterry W, Hauschild A. Loss of leukocyte common More studies are needed to guide future treatment 26. Jin SP, Jeon YK, Cho KH, Chung JH. Excimer antigen (CD45) on atypical lymphocytes in the localized recommendations. laser therapy (308 nm) for mycosis fungoides palmaris but not disseminated type of Pagetoid reticulosis. Br J et plantaris: a skin directed and anatomically feasible Dermatol. 1991;125:238–42. treatment. Br J Dermatol. 2010;163:641–66. Conclusion 14. Willemze R, Kerl H, Sterry W, et al. EORTC 27. Tan RS, MacLeod TI, Dean SG. Pagetoid Pagetoid reticulosis, or Woringer-Kolopp disease, classification for primary cutaneous lymphomas: reticulosis, epidermotropic mycosis fungoides and is a rare and indolent variant of mycosis fungoides a proposal from the Cutaneous Lymphoma Study mycosis fungoides: a disease spectrum. Br J Dermatol with an excellent prognosis. Practitioners should Group of the European Organization for Research and 1987;116(1):67–77. consider pagetoid reticulosis when presented Treatment of Cancer (EORTC). Blood. 1997;90:354- 28. Ioannides G, Engel MF, Rywlin AM. Woringer- with a solitary, slow-growing, unremitting 71. hyperkeratotic lesion on the distal extremities. Kolopp disease (pagetoid reticulosis). Am J A combination of clinical characteristics in 15. Berti E, Tomasini D, Vermeer MH, Meijer Dermatopathol. 1983;5:153–8. CJLM,Alessi E, Willemze R. Primary cutaneous CD8- conjunction with microscopic findings will lead 29. Yagi H, Hagiwara T, Shirahama S, Tokura Y, positive epidermotropic cytotoxic T-cell lymphoma: a the diligent practitioner to the correct diagnosis, Takigawa M. Disseminated pagetoid reticulosis: distinct clinicopathologic entity with an aggressive ensuring the best outcome for patients. need for long-term follow-up. J Am Acad Dermatol. clinical behavior. Am J Pathol. 1999;155:483-92. 1994;30:345–9. 16. Mielke V, Wolff HH, Winzer M, Sterry W. References 30. Zackheim HS. Is ‘‘localized epidermotropic Localized and disseminated pagetoid reticulosis: 1. Willemze R, et al. WHO-EORTC classification for reticulosis’’ (Woringer-Kolopp disease) benign? J Am diagnostic immunophenotypical findings. Arch cutaneous lymphomas. Blood. 2005;105:3768–85. Acad Dermatol. 1984;11:276–83. Dermatol. 1989;125:402-6. 2. Sedghizadeh PP, Allen CM, Kalmar JR, Magro CM. 17. Suzaki R, Kobayashi K, Ishizaki S, Fujibayashi Pagetoid reticulosis: a case report and review of the M, Tanaka M. Dermoscopic features of CD8- Correspondence: Helia Eragi, DO, Western University literature. Oral Surg Oral Med Oral Pathol Oral Radiol positive solitary pagetoid reticulosis on the left leg. – Pacific Hospital, 23550 Hawthorne Blvd., Ste. 200, Endod. 2003;95:318–23. Dermatol Res Prac. 2010;2010. pii: 850416. doi: Torrance, CA 90505; Ph: 310-373-2636; Fax: 310-373- 3. Haghighi B, et al. Pagetoid Reticulosis (Woringer- 10.1155/2010/850416. Epub 2010 Jul 26. 2633; [email protected]. Kolopp Disease): An immunophenotypic, molecular, 18. Drummer R, Dreyling M. Primary cutaneous and clinicopathologic study. Mod Pathol. 2000;95:318– lymphoma: ESMO Clinical Recommendations for 23. diagnosis, treatment and follow-up. Ann Oncol. 2008 4. Lee J, Viakhireva N, Cesca C, Lee P, Kohler S, Hoppe May;19 (Suppl 2):ii72–ii76. TR, Kim YH. Clinicopathologic features and treatment 19. Jones GW, Hoppe RT, Glatstein E. Electron beam outcomes in Woringer--Kolopp disease. J Am Acad treatment for cutaneous T-cell lymphoma. Hematol Oncol Dermatol. 2008;59:706–12. Clin North Am. 1995 Oct;9(5):1057-76.

Page 46 PAGETOID RETICULOSIS (WORINGER-KOLOPP DISEASE) IN A 43-YEAR-OLD WOMAN Blue Vein at the Nasal Root: A Case Presentation and Discussion A Case Report and Review of the Literature

Adam Sorensen, DO,* Harper Price, MD,** Stephen Kessler, DO,*** Rebecca E. Fisher, PhD****

*Dermatology Resident, 1st year, Alta Dermatology / LECOMT, Mesa, AZ; Scottsdale Healthcare System – Osborne Campus, Scottsdale, AZ **Pediatric Dermatologist, Phoenix Children’s Hospital, Phoenix, AZ ***Program Director, Alta Dermatology / LECOMT, Mesa, AZ; Scottsdale Healthcare System – Osborne Campus, Scottsdale, AZ ****Associate Professor, Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, AZ

Abstract A blue vein at the root of the nose in lighter-skinned children is a not-uncommon finding, but it may nonetheless concern parents. It usually represents the nasal arch, a communicating vein between the right and left frontal veins that can be transiently visible in early childhood. Its appearance may be due to a mild translucency of developing skin with a relative lack of subcutaneous fat in this location. Correct identification is important, as the vein is often mistaken for a hemangioma, vascular malformation, or tumor, and it has a variety of interpretations in Folk and Chinese medicine. The prognosis is completely benign, and the vein is usually no longer visible by 1 to 2 years of age. We present here several cases of a visible nasal arch, a brief discussion of the differential diagnosis, and several non-medical interpretations of this finding that a practitioner may encounter.

Introduction Discussion Differential Diagnosis The nasal arch is a transverse vein usually The significance of a visible nasal arch in children The important differential diagnostic spanning the root of the nose. It receives venous has been considered in Western and Chinese considerations for a visible nasal arch include a return from the two frontal veins and then joins medicine for at least a century, with several deep hemangioma and a venous malformation. the supraorbital veins at either angle of the colorful interpretations. An article in the British Hemangiomas are benign vascular tumors orbit, forming the angular veins.1 This normally Medical Journal from August 1887 discusses an of infancy. Since they usually begin with a inconspicuous vessel can cause concern to parents association with what might be chronic rhinitis precursor lesion that may be blue or bruise-like, and practitioners when it becomes visible in a affecting the more “feeble offspring of the poorer confusion with the nasal arch is possible. Unlike young child or infant. In our experience, the typical classes.” It describes a “black distended vein at the a hemangioma, however, the nasal arch does not presentation is that of a healthy infant or toddler root of the nose” and predicts: grow or evolve over time and should not deform brought to dermatologic attention for concerns of “On investigation, these children will be found the skin contours or have any nodular component. a hemangioma, vascular malformation, or tumor. to have a neglected or intractable chronic Venous malformations tend to have a soft and catarrh (inflammation) of the nose and compressible quality and often swell with Valsalva, Case Report pharynx, often with swollen middle turbinated exercise, or crying; also, unlike with a visible nasal arch, pain is fairly common.5 An 8-month-old female was referred to the bodies and rhinorrhea, and are generally in a Phoenix Children’s Hospital dermatology clinic low state of health; and on further examination with a history of an asymptomatic, blue macule chronic congestion or hypertrophy of post- Conclusion on the bridge of her nose (Figure 1); there were nasal mucosa, or post-nasal vegetations will be Despite the variety of interpretations of a visible concerns for a vascular anomaly or malformation. found.” nasal arch, there is likely little significance to the The macule appeared shortly after birth but had Proposed treatment of the condition involves finding. In our experience, it seems to disappear not grown in size since its initial appearance and local blood-letting, applications of astringents, around age 2 or 3, without sequelae. The did not swell with crying or straining. On physical and removal of nasal “vegetations.”2 appearance of the vein may be due to the relative exam, there was a somewhat linear, deep blue, thinness of the skin in young children in an area non-tender, smooth, blanchable macule on the Chinese medicine offers an alternativewith relatively low levels of both subcutaneous bridge of the patient’s nose that was compressible interpretation, stating that when examining a fat and pigmentation, which results in some and soft. The patient’s family was reassured that child’s facial complexion one should specifically translucency; however, this phenomenon might this was a normal variant found in many infants “look at the vein at the root of the bridge of the also be due to a simple anatomical variant, and a and young children and that no intervention was nose between the two eyes.” This area is known definite etiology is not clear. warranted. as shan gen in Chinese, or “the root of the mountain.” A visible blue vein in this location is seen as a “very reliable diagnostic sign” that the References baby’s (i.e., digestion) is weak.3 1. Grey, H. Anatomy of the Human Body, 20th Ed [Internet]. Philadelphia (PA): Lea & Febiger, 1918; In Japanese pediatric acupuncture, the visible Bartleby.com, 2000 [cited 2013 July 10]. Available from: blue vein has been referred to as a “sugar bug” www.bartleby.com/107/. associated with a syndrome of “Kanmushi,” which according to varying explanations may involve 2. Spicer, S. On Distention of the Nasal Arch (Transverse hyperactivity, poor sleep, a proclivity for sweets, Nasal Vein) in Children; Its Pathology and Treatment. and/or food sensitivity. Of note, Kanmushi Br Med J. 1887 Aug 27;2(1391):459-71. is also one of many mythical illness-causing 3. Flaws, B. A Handbook of TCM : A 4 parasites in Japanese . Practitioner’s Guide to the Care and Treatment of Figure 1

SORENSEN, PRICE, KESSLER, FISHER Page 47 Common Childhood Diseases. Denver (US): Blue Poppy Press, 2006. Chapter 4, Key points in diagnosing children; p. 18-19. Combination of Photodynamic Therapy with 4. Holistic Squid. Is your baby’s blue vein a sugar bug? [Internet]. c2011 [cited 2013 July 10]. Available from: Blue Light for Treating Pyoderma Faciale in a http://holisticsquid.com/is-your-babys-blue-vein-a- Post-partum, Breast-feeding Patient: A Case sugar-bug 5. Schachner LA, Hansen RC. Pediatric Dermatology, Report and Literature Review 4th Ed [Internet]. Philadelphia (PA): Elsevier; 2011 [cited 2013 July 10]. Available from: www. Dorene Niv, BS,* Patrick Keehan, DO** expertconsultbook.com *Medical Student, 3rd year, University of North Texas Health Science Center, Fort Worth, TX **Board-certified Dermatologist, Premier Dermatology, Fort Worth, TX

Correspondence: Adam Sorenson, DO, Alta Dermatology, 130 S. 63rd St. #114, Mesa, AZ 85206; 480-981-2888; [email protected]. Abstract Pyoderma faciale is a rare skin disease that can present suddenly in young women in their 20s. It is characterized by coalescent nodules and draining sinuses with severe facial erythema. The condition is often localized to the face. The standard treatment is either the retinoid drug isotretinoin in combination with systemic corticosteroids or else high-dose oral tetracycline antibiotics alone. Due to the negative consequences of isotretinoin during pregnancy, alternatives are needed for pregnant patients who present with pyoderma faciale. This case report describes the efficacy and safety of photodynamic therapy (PDT) with blue light in treating a 29-year-old, post-partum, breast-feeding woman. To the best of our knowledge, this is the first reported case of pyoderma faciale treated with PDT with aminolevulinic acid (ALA). The results were considered excellent by both investigators and the patient.

Introduction In 1940, O’Leary and Kierland of the Mayo Clinic reported an unusually severe disease that presented unlike the commonly encountered acne vulgaris.1 Thirteen cases out of 1,600 were characterized as a “sudden, fulminating onset of pyoderma in young women.” In 1992, Plewig et al. reported an additional 20 cases concluded to be an extreme form of rosacea and not of acne, establishing the term “rosacea fulminans.”2 Figure 1 The onset of the disease is sudden, without prodromes. Lesions consist of often-painful pustules, papules, nodules, cysts and draining sinuses over a surface of erythematous skin. Current treatments function to counteract the inflammation present with nodular acne and provide rapid control to prevent scarring. However, issues with long-term risks of retinoid and antibiotic use in pregnant patients has generated interest in alternative therapies.3 This report describes the use of PDT with blue light to Figure 2 treat pyoderma faciale in a post-partum, breast- feeding, 29-year-old woman. A clinical diagnosis of pyoderma faciale was made. Because the patient chose to continue breast-feeding, isotretinoin was disregarded as a Case Report treatment option. An initial trial of prednisone A 29-year-old, post-partum woman presented for two weeks and alendronate sodium for one with erythematous papules, pustules, and severe month resulted in mild benefit. One month after scarring localized to her face (Figures 1 & 2). A initial consultation, PDT treatment was initiated. trial of oral and topical clindamycin prescribed by An cleanse was first applied, followed her primary care provider offered minimal relief. by 20% ALA of a single unit dosage form (354 Upon further questioning, the patient described a mg). ALA was allowed to incubate for one hour. similar episode that occurred after a miscarriage Blue-light therapy followed, with application more than one year prior. The patient reported totaling 16 minutes and 40 seconds. After little improvement with triamcinolone injections completion of blue-light therapy, the face was administered at that time.

Page 48 COMBINATION OF PHOTODYNAMIC THERAPY WITH BLUE LIGHT FOR TREATING PYODERMA FACIALE IN A POST-PARTUM, BREAST-FEEDING PATIENT: A CASE REPORT AND LITERATURE REVIEW cleansed and sunblock applied. The patient was of photosensitizer and light, as photodynamic faciale. Further study is necessary to determine advised to avoid the sun for 48 hours following therapy, has not yet been approved. This new if such treatment provides positive long-term PDT treatment. After one month, the patient treatment involves PDT, in which a topical results without pregnancy complications. To returned with improvement, and no new lesions application of ALA is followed by light therapy.4 the best of our knowledge, this is the first report were noted (Figure 3). ALA is absorbed by the sebaceous gland and describing PDT-ALA as a successful treatment The patient continued with PDT therapy for then metabolized to protoporphyrins, primarily for pyoderma faciale. a total of seven treatments, with applications protoporphyrin IX (PpIX). These protoporphyrins one month apart. Figure 4 reveals the patient’s absorb light, with maximum absorption at References 410 nm. Following application of ALA, blue condition after the fifth treatment. Over the 1. Firooz A, Mehdi RF, Dowlati Y. Rosacea fulminans light is administered to the skin, resulting in course of treatment, the patient experienced (pyoderma faciale): successful treatment of a 3-year- post-inflammatory hyperpigmentation and one photodestruction of Propionibacterium acnes (P. 4 old girl with oral isotretinoin: Int J Dermatol. episode of reappearance of new lesions over her acnes) with shrinkage of sebaceous glands. 2001;40:191-209. forehead and cheeks. PDT using ALA induces transient antimicrobial 2. Plewig G, Jansen T, Kligman AM. Pyoderma Faciale. and anti-inflammatory effects. Studies have A Review and Report of 20 Additional Cases: Is It shown narrowband blue light may have Rosacea? Arch Dermatol.1992;128:1611-17. anti-inflammatory effects, enhancing the therapeutic benefits.5 When exposed to blue 3. Jarrett R, Gonsalves R, Anstey AV. Differing light, keratinocytes decrease cytokine-induced obstetric outcomes of rosacea fulminans in pregnancy: production of IL-1a and intracellular adhesion report of three cases with review of pathogenesis and management: Clin Exp Dermatol. 2010;35:888-891. molecule-1 (ICAM-1).5 High-intensity blue light provided a 59 percent to 67 percent reduction 4. Taub AF. Photodynamic Therapy for the of inflammatory acne lesions in patients for up to Treatment of Acne: A Pilot Study. J Drugs Dermatol. eight weeks after treatment.5 2004;3(6):S10-S14. Figure 3 Blue light also may function to decrease sebum 5. Sakamoto FH, Lopes JD, Anderson RR. production. Light sources with long wavelengths Photodynamic therapy for acne vulgaris: A critical are required to reach facial sebaceous glands, review from basics to clinical practice. Part I. Acne as they are located deep beneath the cutaneous vulgaris: When and why consider photodynamic surface.6 In studies evaluating the quantity of P. therapy? J Am Acad Dermatol. 2010;63:183-93. acnes after PDT, a decrease in sebum production 6. Sakamoto FH, Lopes JD, Anderson RR. was observed. It has been proposed that toll-like Photodynamic therapy for acne vulgaris: A critical receptor 2 (TLR-2) is involved in inflammatory review from basics to clinical practice. Part II. responses in sebocytes. PDT is thought to Understanding parameters for acne treatment moderate the increased expression of TLR-2 that with photodynamic therapy. J Am Acad Dermatol. 5 is observed in acne. 2010;63:195-211. Figure 4 ALA-PDT with blue-light therapy has been 7. Braun M. Case Reports: Combination of a New shown to achieve successful results. In patients Radiofrequency Device and Blue Light for the with moderate to severe acne, Goldman and Treatment of Acne Vulgaris. J Drugs Dermatol. Discussion Boyce found a 32 percent improvement with 2007;6(8);838-40. 4 Traditional systemic medications for nodular ALA-PDT followed by blue-light therapy. A 68 8. Yang YG, Zou XB, Zhao H, Zhang YJ, Li HJ. inflammatory acne include isotretinoin, systemic percent reduction in counts also occurred. Photodynamic Therapy of Condyloma Acuminata corticosteroids, and high-dose oral tetracycline. The concern for high risk of fetal defects in Pregnant Women. Chin Med J (Engl). When treating patients who present in pregnancy, in pregnant patients was tested by use of 2012;125(16):2925-8. isotretinoin and tetracyclines are contraindicated photodynamic therapy for condyloma acuminata. 9. Soltes B. Intense Pulsed Light Therapy: Obstet due to the risks of congenital anomalies and The study treated five pregnant patients with Gynecol Clin North Am. 2010;37(4);489:99. impaired bone growth. three to four treatments of ALA-PDT. Follow- Alternatives have been attempted, including a up occurred for six months to 23 months after trial of oral erythromycin and prednisolone in treatment. All pregnancies resulted in healthy Correspondence: Dorene Niv, BS, University of North a pregnant female during her first trimester.3 live births without delivery complications, and Texas Health Science Center, 855 Montgomery St., Rapid improvement occurred, and the patient treatment was reported as well-tolerated by the Fort Worth, TX 76107; [email protected] 8 was placed on a maintenance treatment of patients. Further studies are needed to continue prednisolone. At 30 weeks, fetal arrhythmia testing the safety and efficacy of photodynamic occurred, and elective admission for steroids was therapy use in pregnant patients with various planned. However, severe oligohydramnios soon conditions. followed. The patient subsequently presented with an intrauterine death. Conclusion Alternative effective treatments are needed for Despite the current off-label indication of PDT pregnant patients presenting with such severe for acne in the United States, success has been conditions. Several light and laser therapies shown in patients who are unable to receive have been cleared by the FDA for acne vulgaris, currently approved treatments like isotretinoin.6 including intense pulsed light therapy (IPL) and Use of ALA followed by blue light appears to be blue-light therapy.5,9 However, the combination an effective alternate modality to treat pyoderma

Niv, Keehan Page 49 A Case of Pseudoxanthoma Elasticum (PXE) in a 14-year-old Female: A Case Report and Review of the Literature

D. Ryan Skinner, DO,* Samuel Ecker, BS,** Daniel Hurd, DO, FAOCD***

*Dermatology Resident, 1st year, LewisGale Montgomery Hospital/VCOM, Blacksburg, VA **Medical Student, 4th year, Midwestern University, Glendale, AZ ***Program Director, Dermatology Residency, LewisGale Montgomery/VCOM, Blacksburg, VA

Abstract Pseudoxanthoma elasticum (PXE) is an inherited disorder characterized by calcified elastic fibers found in the skin, eyes, and cardiovascular system. Although the pathomechanics of PXE are poorly understood, the discovery of an inactivating gene mutation encoding a hepatic efflux pump suggests PXE is a metabolic disorder with secondary tissue mineralization due to decreased circulation of hepatic enzymes. As more is understood about this process, effective therapeutic options can be developed to restore mineral homeostasis within affected tissues. We present a case of PXE in a 14-year-old female who presented with a four-year history of asymptomatic white papules on her neck. We also discuss recent advances that have been made in understanding the pathogenesis of this currently untreatable disorder.

Case Report A 14-year-old female presented to the dermatology clinic with asymptomatic white papules on her neck that appeared four years prior. The patient denied any family history of similar symptoms. On physical exam, multiple yellow-to-flesh-colored papules were present on the lateral aspects of her neck (Figure 1). Her oral mucosa and gingiva appeared uninvolved. Figure 3 Figure 4 The affected total body surface area was less than 5 percent, and there was no palpable profile were within normal limits. as an efflux pump in the liver that facilitates lymphadenopathy. transport of molecules from hepatocytes to The clinical and laboratory findings were the general circulation.5 Consequently, many A cutaneous biopsy of the lateral neck was consistent with a diagnosis of pseudoxanthoma experts believe PXE is the result of a metabolic performed (Figure 2), which demonstrated elasticum (PXE). The patient was counseled disease in which decreased levels of circulating abnormal, thickened basophilic elastic fibers in regarding the cardiovascular and ophthalmologic hepatic enzymes leads to increased calcium and the reticular dermis (Figure 3). Orcein elastic manifestations seen in this disorder. She was phosphate mineralization in the skin, eyes and stain revealed numerous black fragmented referred to a cardiologist and ophthalmologist for systemic vasculature in the setting of normal and irregularly shaped fibers (Figure 4). Her further cardiac and fundoscopic evaluation. complete blood count with differential and lipid serum calcium and phosphate levels.2,5,6 Matrix gla protein, which prevents tissue mineralization Discussion when fully carboxylated, may also play a role in PXE, also known as Grönblad-Strandberg the pathogenesis of PXE.1,2,7 syndrome, is an inherited disorder characterized by calcification of elastic fibers affecting the Cutaneous features of PXE are characterized skin, eyes and vasculature. PXE demonstrates by yellow papules coalescing into plaques with autosomal-recessive inheritance with extreme an appearance that is commonly described as variability in phenotypic expression. The “plucked chicken skin.” Redundant and lax skin incidence rate is estimated to be in the range of folds may also be present. Affected areas include 1:50,000 to 1:70,000. It occurs in all races and the neck, axillae, antecubital fossae, umbilicus, groin, and thighs as well as oral, rectal and vaginal appears to have a slight female preponderance. 8 Figure 1 The average age at diagnosis is 8 to 12 years; mucosa. however, diagnosis may be delayed until the third The hallmark retinal finding seen in PXE is or fourth decade after gastrointestinal or ocular , which represent breaks in the complications develop.1,2 calcified elastic lamina of Bruch’s membrane. The pathogenesis of PXE is not completely They appear as lightly colored gray, brown or understood. A loss-of-function mutation in the red streaks extending from the optic disc. The ABCC6 gene on the short arm of chromosome majority of patients with PXE will have angioid streaks on fundoscopic exam; after age 30, nearly 16 is identified in the majority of patients with 9,10 PXE. This gene encodes multidrug-resistance 100% of patients have this finding. These protein 6 (MRP6), which is primarily expressed lesions may result in progressive loss of visual 1 in the liver and kidneys but rarely found in tissues acuity, but rarely lead to legal blindness. 3,4 Figure 2 affected by PXE. MRP6 is thought to function The major life-threatening complications of

Page 50 A CASE OF PSEUDOXANTHOMA ELASTICUM (PXE) IN A 14-YEAR-OLD FEMALE: A CASE REPORT AND REVIEW OF THE LITERATURE PXE are , gastrointestinal requires surgical intervention.4 Information 11. Martin L, Maître F, Bonicel P, et al. Heterozygosity hemorrhage and stroke, which result from about patient support groups can be found for a single mutation in the ABCC6 gene may closely calcification of the elastic media and intima of online through the National Association for mimic PXE. Arch Dermatol. 2008;144(3):301-306. 1,7 mid-sized arteries. Additional cardiovascular Pseudoxanthoma Elasticum (www.napxe.org) and 12. Lewis K, Bercovitch L, Dill S, et al. Acquired sequelae include pectoris, mitral valve PXE International (www.pxe.org). disorders of elastic tissue: Part I. Increased elastic tissue prolapse, renovascular hypertension and and solar elastotic syndromes. J Am Acad Dermatol. 1 claudication. Conclusion 2004 Jul;51(1):1-21. Histologically, PXE demonstrates fragmented PXE is a rare, autosomal-recessive disorder 13. Jiang Q and Uitto J. Restricting dietary magnesium basophilic elastic fibers in the mid and deep affecting elastic fibers in the skin, eyes and accelerates ectopic connective tissue mineralization reticular dermis. Verhoeff-Van Gieson and vasculature. Phenotypic expression is highly in a mouse model of pseudoxanthoma elasticum Orcein elastic stains may help identify these fibers variable, suggesting multiple genetic and (Abcc6(-I-)). Exp Dermatol. 2012 Sep;21(9):694-9. in early-stage disease.4,11 Calcified tissue also environmental etiologic factors. Patients require 14. Bhatnagar P, Freund K, Spaide R, et al. Intravitreal stains black with von Kossa stain.9 multidisciplinary long-term monitoring to screen for the management of choroidal for ocular and cardiovascular complications and The differential diagnosis of PXE includes solar neovascularization in pseudoxanthoma elasticum. are encouraged to reduce known risk factors. elastosis, elastoderma, PXE-like papillary dermal . 2007;27:897-902. Future studies are needed in order to investigate elastolysis, white fibrous papulosis of the neck, therapeutic options to counteract low levels of and PXE-like phenotype seen in β- circulating anti-mineralization hepatic factors and and sickle-cell .12 Most of these disorders Correspondence: D. Ryan Skinner, DO, LewisGale restore mineral homeostasis in affected tissue. lack retinal or vascular involvement. Patients Montgomery Hospital/VCOM, 3700 S. Main St., with β-thalassemia or sickle-cell anemia may Blacksburg, VA, 24060; 540-953-5445; ryan.skinner. demonstrate similar cutaneous findings, angioid References [email protected]. streaks and vascular changes, but do not have 1. Li Q, Grange D, Armstrong N, et al. Mutations an associated ABCC6 mutation.2 Elastoderma in the GGCX and ABCC6 genes in a family with occurs in more localized areas of the neck, trunk pseudoxanthoma elasticum-like phenotypes. J Invest and arms and shows elastic fibers extending into Dermatol. 2009 Mar;129(3):553-63. the subcutis on histologic examination. PXE- 2. Li Q, Jiang Q, Pfender E, et al. Pseudoxanthoma like papillary dermal elastolysis and white fibrous elasticum: clinical phenotypes, molecular genetics papulosis of the neck demonstrate decreased and putative pathomechanisms. Exp Dermatol. 2009 11 elastic fibers in the papillary dermis. Jan;18(1):1-11. There is no definitive treatment for PXE, and 3. Le Saux O, Urban Z, Tschuch C, et al. Mutations management is based on routine follow-up with in a gene encoding an ABC transporter cause a multidisciplinary team of physicians. Patients pseudoxanthoma elasticum. Nat Genet. 2000 should be evaluated by an ophthalmologist for Jun;25(2):223-7. routine fundoscopic examination at least once 4. Christen-Zäch S, Huber M, Struk B, et al. every two years and are advised to avoid activities Pseudoxanthoma elasticum: evaluation of diagnostic associated with retinal injury such as contact criteria based on molecular data. Br J Dermatol. 2006 sports and heavy lifting.10 Following a healthy Jul;155(1):89-93. diet, regular exercise and smoking cessation can help reduce cardiac risk. A Doppler ankle- 5. Jiang Q, Endo M, Dibra F, et al. Pseudoxanthoma brachial index study or echocardiography may be elasticum is a metabolic disease. J Invest Dermatol. 2009 considered in patients with claudication or heart Feb;129(2):348-54. 11 murmur. 6. Pugashetti R, Shinkai K, Ruben B, et al. Calcium may Symptom-specific therapeutic options include preferentially deposit in areas of elastic tissue damage. J surgery to remove redundant skin folds and Am Acad Dermatol. 2011 Feb;64(2):296-301. low-dose acetylsalicylic acid or clopidogrel 7. Ronchetti I, Boraldi F, Annovi G, et al. Fibroblast for intermittent claudication. Some authors involvement in soft connective tissue calcification. Front recommend limiting patients’ dietary calcium and Genet. 2013;4:22. phosphorus based on the belief that high calcium 8. Sherer D, Singer G, Uribarri J, et al. Oral phosphate intake during childhood or adolescence leads to binders in the treatment of pseudoxanthoma elasticum. a more severe phenotype. This recommendation J Am Acad Dermatol. 2005 Oct;53(4):610-5. is controversial, and many experts do not recommend reducing calcium intake.2 Recent 9. Bercovitch L, Martin L, Chassaing N, et al. studies have shown clinical improvement in Acquired pseudoxanthoma elasticum presenting after patients treated with aluminum hydroxide, an oral liver transplantation. J Am Acad Dermatol. 2011 phosphate binder.8 Studies in mice also suggest May;64(5):873-8. increased dietary magnesium may prevent tissue 10. Yoo J, Blum R, Singer G, et al. A randomized 13 mineralization. Laser photocoagulation and controlled trial of oral phosphate binders in the intravitreal injection of bevacizumab, a VEGF treatment of pseudoxanthoma elasticum. J Am Acad inhibitor, have been used to treat choroidal Dermatol. 2011 Aug;65(2):341-8. neovascularization.2,14 Gastrointestinal bleeding can usually be managed conservatively and rarely

SKINNER, ECKER, HURD Page 51 Vibrio Vulnificus Septicemia Presenting as Fevers, Bullae, and Com- partment Syndrome: A Case Presentation and Review of the Literature

Alissa T. Lamoureux, DO,* Brad P. Glick, DO, MPH**

*1st-year Dermatology Resident, Wellington Regional Medical Center, Wellington, FL **Program Director, Dermatology Residency, Wellington Regional Medical Center, Wellington, FL

Abstract Vibrio vulnificus is an oxidase-positive, halophilic (requiring salt,) gram-negative bacillus. V. vulnificus, a noncholera variant of the Vibrio species, is often associated with food-borne and flesh-borne illness, including necrotizing fasciitis, gastroenteritis, and septicemia. In the United States, it is the most common cause of death resulting from the consumption of contaminated .1 Effects of the bacteria are worsened if the host has underlying liver dysfunction or an immunocompromising condition.2

these, Vibrio was the only pathogen to increase Introduction in incidence, at a rate of 76 percent, from 1996 to V. vulnificus is an aquatic bacterium that naturally 5 2011. Of recent note by the CDC, infection due inhabits warm coastal waters throughout the to all Vibrio species in 2012 increased 43 percent world, in particular the United States and from the period of 2006 to 2008. However, the Taiwan. In the U.S., the bacterium is found in incidence of V. vulnificus, the most pathogenic the ocean waters of the Northern Pacific, Gulf strain, did not increase.6 of Mexico, Mid-Atlantic and New England. In these waters, circulating V. vulnificus is eaten by Figure 1 shellfish and then transferred to humans when Case Presentation and raw shellfish, in particular oysters, are consumed Hospital Course sluggish, but there was no altered range of motion and introduced into the gastrointestinal A 36-year-old Hispanic male presented to the of the upper extremities. Initial examination of tract. However, appropriate preparation with emergency room (ER) in South Florida with the legs revealed tenderness without skin lesions. conventional cooking methods renders these complaints of fever, chills and severe upper- Subsequently, a patch of purple ecchymosis bacteria inactive. Recent literature notes that extremity pain. He admitted to being in good developed in the location where a blood pressure “low-temperature pasteurization, high-pressure health until one day prior, when symptoms cuff had been placed. Within a few hours, the processing, and irradiation” eradicate the developed while he worked to repair air ecchymotic area on the leg erupted into a tense bacterium to undetectable levels.3 conditioners. At home, his temperature rose to bullous lesion (Figure 1). An immunocompetent host who ingests the a maximum of 103 degrees Fahrenheit (39°C). The patient was admitted to the medical ICU bacterium may suffer from upset , In the ER, he admitted to pain in his forearms, with sepsis of unknown etiology. Disseminated or , whereas the immunocompromised with the right being worse than the left, while intravascular coagulation (DIC) panel was host may experience more severe and life- denying any history of trauma, injury or similar pending. Pain and swelling worsened in the threatening effects such as severe skin infections, symptomatology in the past. However, four days extremities and prompted the ER staff to consult multi-organ failure, sepsis, and death. In addition prior to the onset of symptoms, he ate raw oysters. to rule out compartment to immunosuppressed states, alcohol-induced Medical history was largely negative other than a syndrome and possible necrotizing fasciitis in liver disease, dialysis-dependent renal disease, fracture to the right arm and persistent chronic the arms and legs. In addition, due a multitude diabetes, HIV, hemochromatosis, thalassemia, contractures in his right hand. Social history was of laboratory abnormalities, Infectious Diseases, hemolytic anemia, and conditions in which free- positive for alcohol consumption, stated as “heavy , and were consulted. iron levels are increased confer susceptibility to at times” but without diagnosis of liver disease. infection.4 Intravenous drug use was denied. Emergent evaluation by Orthopedics resulted in an immediate transfer of the patient to the According to the U.S. Centers for Disease Control Initial physical exam revealed an alert and operating room for urgent decompression (CDC), there are approximately 50 culture- oriented 36-year-old male of stated age, thin and of early compartment syndrome by bilateral confirmed cases of V. vulnificus infection annually, in obvious discomfort. His vitals were significant upper-extremity volar and dorsal fasciotomies. including 45 hospitalizations and 16 deaths, from for fever, sinus tachycardia and . Intraoperative findings were negative for the U.S. Gulf Coast region alone. The total cases Mucous membranes were moist and without necrotizing tissue or muscle. Post-operatively, reported nationwide in 2011 numbered 154, and lesions. Abdominal exam was positive for both arms were provisionally closed with among those, the most common subtypes were right lower quadrant pain without rigidity, sterile vessel loops secondary to the inability to V. parahaemolyticus (75 [49%]), V. alginolyticus rebound or guarding. Bilateral upper extremities 5 approximate due to significant swelling (Figure (26 [17%]), and V. vulnificus (13[8%]). The demonstrated swelling, with the right being 2). In the ICU, the patient remained intubated, CDC reported a 24% decrease in incidence in worse than the left. There was significant pain on sedated, and on multiple pressors, and broad- the most common food-transmitted bacteria in palpation of bilateral forearm volar compartments spectrum antibiotics were started, including 2011 as compared with the period of 1996 to accompanied by pain in the digits with active vancomycin and ceftazidime. However, the 1998. The key food-borne pathogens, listed from range of motion. Pulses at the bilateral wrists Infectious Diseases specialist promptly initiated most to least, include Shigella, Yersinia, STEC were not palpable; however, they were faintly treatment with doxycycline and imipenem for O157, Listeria, Campylobacter and Vibrio. Of heard on Doppler ultrasound. Capillary refill was suspected V. vulnificus septicemia. The first two Page 52 VIBRIO VULNIFICUS SEPTICEMIA PRESENTING AS FEVERS, BULLAE, AND COMPARTMENT SYNDROME: A CASE PRESENTATION AND REVIEW OF THE LITERATURE Figure 2 Figure 5

Figure 4 Figure 6 A and B

coagulopathy persisted, as did thrombocytopenia. mortality rate.7 In 70 percent of cases, skin lesions Heparin-induced thrombocytopenia (HIT) was are present.8 Epidemiologic data across multiple Figure 3 suspected, and blood analysis yielded positive studies suggest a male predominance for the antibodies. Bilateral volar forearm compartment disease. swelling decreased, and delayed primary closure sets of blood cultures revealed gram-negative rods The virulence of V. vulnificus is attributed was being considered. Bilateral lower extremities identified as V. vulnificus. to several features, including a chitinase, “a showed healthy granulation tissue (Figure digestive enzyme that breaks down glycosidic Within the first few days, the bullae on the 5). Repeat negative blood cultures and patient bonds in chitin, which allows Vibrio to embed patient’s legs multiplied to cover more than improvement indicated clearing of V. vulnificus 50 percent of his lower extremities, for which themselves in the exoskeleton of most , infection. 3 Care was consulted (Figure 3). The particularly crustaceans.” The species also bullae became tense and burst, yielding In spite of multiple alterations to fluids and possesses a protein called hemolysin, which is sanguinous fluid. Shortly thereafter, Plastic medications by Nephrology to address persistent thought to be responsible for the gastroenteritis Surgery evaluated the patient for grafting of the renal dysfunction, electrolyte abnormalities, symptomatology as well as the wound infection forearms and wound care. The legs were dressed acidosis and azotemia, blood-urea nitrogen slowly characterized by necrotizing fasciitis or in double antibiotic ointment, silver sulfadiazine, started to rise. Orders were placed to decrease hemorrhagic bullae. The septicemia caused by V. and bismuth tribromophenate-petrolatum, while protein in tube feeds, which had previously been vulnificus is attributed to protease mechanisms the upper extremities were dressed and elevated added to augment albumin to aid in wound that induce increased vascular permeability.9 daily in foam wafers (Figure 4). Intraoperative healing. Secondary to liver failure and intra- Characteristics of aquatic environments where cultures of the forearm tissue were positive for V. abdominal hypertension, the patient’s abdomen V. vulnificus live include warmer temperatures, vulnificus. became tense with fluid. On hospital day 20, the patient underwent paracentesis, yielding a typically above 18°C (64°F), and a low-to- The patient’s critical illness resulted in a three- transudate as calculated by Light’s criteria. moderate salt concentrations. As temperatures week stay in the ICU and was complicated by climb in the summer months, bacteria multiple-system organ failure. Acute respiratory Three days later, hemodialysis was reinitiated. concentrations rise.11 Infection by this bacterium distress syndrome (ARDS) developed shortly That evening, a “code blue” was called secondary is conferred to the host by either trauma or after the fasciotomies and led to prolonged to bradycardia that progressed to asystole. The ingestion. In the setting of trauma, the host may intubation and difficulty weaning the patient patient was coded and re-intubated, and a viable step on a contaminated shell at the beach or may from ventilatory support. Hematology continued rhythm was restored. On the following day, self-inoculate during harvesting or preparation of to monitor his anemia and thrombocytopenia, reevaluated the patient for the shellfish. In these cases, the infection may suspected to be secondary to underlying liver upper and lower gastrointestinal bleeding. At manifest as a bulla, edema or pain in an extremity. dysfunction from prolonged alcohol use. Acute that time, the patient was unresponsive, with On histologic examination of involved tissue, hepatitis profile and HIV testing were negative. pupils that were fixed and dilated. In his critically epidermal necrosis in a focal distribution He required multiple transfusions of packed ill state, investigational procedures to determine and a mild perivascular lymphohistiocytic red blood cells and single-donor platelets to the source of bleeding were not engaged. Mid- inflammatory cell infiltrate can be appreciated maintain adequate blood counts. Hemodialysis morning on hospital day 24, the patient again (Figure 6a). Additional features may include was initiated on hospital day 4 for oliguric renal coded, and he expired. extensive necrosis of the secretory cells of sweat failure. Secondary to his critical illness, antibiotic glands and eosinophilic homogenization of the coverage was broadened to include gram-positive Discussion cytoplasm (Figure 6b).11 When contaminated and antifungal agents. Vibrio vulnificus was first recognized as an agent shellfish are ingested, the host may develop a Although ventilator-associated pneumonia had of disease in 1976, with the first documented spectrum of systemic disorders ranging from developed, the patient was successfully extubated case reported in 1979. Most cases result in gastrointestinal upset to fulminant septic shock. on day 13. Secondary to swallow-function gastrointestinal (GI) upset, including , As in our patient, many require management in impairment, tube feedings continued. Physical vomiting and diarrhea. Studies suggest that the ICU secondary to sepsis or limb-threatening therapy began. In spite of platelet transfusion, progression to septicemia yields a 50-percent fasciitis.

Lamoureux, Glick Page 53 One study concluded that V. vulnificus-infected 10. Shapiro RL, Altekruse S, Hutwagner L. The role patients with “hemorrhagic bullous skin lesions, Conclusions of Gulf Coast oysters harvested in warmer months necrotizing fasciitis, skin or soft tissue infections The Vibrio genus of bacteria is responsible in Vibrio vulnificus infections in the United States, involving two or more limbs, or higher Acute for a variety of infections. Vibrio vulnificus, a 1988-1996. Vibrio Working Group. J Infect Dis. 1998 Physiology and Chronic Health Evaluation noncholera variant, is the most pathogenic species Sep;178(3):752-9. in the genus, yielding the highest mortality rate II (APACHE II) scores…have a high risk of 11. Gun-Wook K, Hyun-Je P, Hoon-Soo K, Su-Han K, Quick, Accurate, Dependable — Your death,” though the prognosis improves if surgical from shellfish contamination in the United States. Immunocompromised states predispose Hyun-Chang K, Moon-Bum K, Byung-Soo K. Bullae treatment occurs within 24 hours of hospital and sweat gland necrosis in the differential diagnosis 12 the host to greater risk of septicemia and death. admission. Jien-Wei Liu et al. postulated that Early recognition of the illness, prompt surgical for Vibrio vulnificus infection in an alcoholic patient. J Global Pathology Diagnosis. within 48 hours of admission of cases of V. debridement, immediate initiation of antibiotic Korean Med Sci. 2011 March;26(3):450–453. vulnificus that involve hypotension and necrotic therapy, fluid and electrolyte replacement and 12. Chen SC, Chan KS, Chao WN, Wang PH, Lin skin lesions, mortality rates can be as high as close monitoring in the ICU aid in decreasing DB, Ueng KC, Kuo SH, Chen CC, Lee MC. Clinical 50%.7 Global Pathology puts the patient and physician first by mortality. In spite of prompt treatment, mortality outcomes and prognostic factors for patients with U.S. research in 2007 concluded that of the rates, in particular in septic patients, remain high. Vibrio vulnificus infections requiring intensive care: building relationships, not barriers. Vibrio species, V. vulnificus “are the most serious A 10-yr retrospective study. Crit Care Med. 2010 threat to raw oyster consumers, as they account References Oct;38(10):1984-90. for nearly all fatalities associated with seafood We are physician owned and operated, so we know how 1. Haq SM, Dayal HH. Chronic liver disease and 13. DePaola A, Jacobs E, Williams-Hill D, Bowers consumption in the U.S.” That study found the consumption of raw oysters: a potentially lethal JC, Kasturi K, Byars RH, Burkhardt W III, Calci KR, important your case is. Our professional service emphasizes majority of virulent oysters to be harvested from combination - a review of Vibrio vulnificus septicemia. Krantz JA, Jones JL, Nabe K, Woods J. Oysters: 2007 the Gulf Coast and the Mid-Atlantic region in doctor-to-doctor communication and a quick, accurate Am J Gastroenterol. 2005 May;100(5):1195-9. United States Market Survey, Appl. Environ. Microbiol. the summer season. Of note, oysters from the 2010 May;76(9):2754–2768. diagnosis. It’s that personal touch that makes Global Pacific Northwest have never been implicated in 2. Lien-I H, Ting-Tsung C, Shan-Tair W. Survival of V. vulnificus infection.13 Vibrio vulnificus in whole blood from patients with 14. Department of Health Services, State of California. Pathology the dependable dermatopathology choice. chronic liver diseases: Association with phagocytosis by Limiting the sale of raw oysters harvested from the V. vulnificus is reportable to the CDC. Prevention neutrophils and serum ferritin levels. J Infect Dis. 1999 Gulf of Mexico. California Code of Regulations strategies include warnings on menus alerting Jan;179(1):275-278. (CCR), Title 17, Section 13675. (Accessed June 2013) consumers of the dangers of eating raw oysters. Available from: http://www.cdph.ca.gov/pubsforms/ California legislation bans the importation of 3. Daniels NA. Vibrio vulnificus oysters: pearls and Guidelines/Documents/fdb%20Raw%20Oyst%20 oysters from the Gulf of Mexico during April perils. Clin Infect Dis. 2011 Mar 15;52(6):788-92. 16250 NW 59th Avenue Sale%20Dlr.pdf. through October unless they’ve been pretreated 4. Weinber G. Iron and infection. Microbiol Rev. Suite 201 14 15. Kuo Chou T, Chao WN, Yang C, Wong RH, Ueng to eradicate the bacterium. The U.S. Food and 1978;42:45-66. Miami Lakes, Florida 33014 Drug Administration (FDA) recommends that KC, Chen SC. Predictors of mortality in skin and soft- 5. CDC. Foodborne Diseases Active Surveillance www.globalpathlab.com people at high risk of contracting V. vulnificus tissue infections caused by Vibrio vulnificus. World J Network (FoodNet): FoodNet Surveillance [email protected] only eat oysters that are thoroughly cooked. Surg. 2010 Jul;34(7):1669-75. Despite these measures, the mortality rate from Report for 2011 (Final Report). Atlanta, Georgia: U.S. infection has not declined.3 Department of Health and Human Correspondence: Alissa T. Lamoureux, DO, Graduate Treatment Services, CDC. 2012 (Accessed June 2013). Available , 10101 Forest Hill Blvd, Wellington, from: http://www.cdc.gov/foodnet/PDFs/2011_ Prompt recognition is essential in treating FL 33414; Ph: 561-798-8504; Fax: 561-798-8583. annual_report_508c.pdf. patients with V. vulnificus infection. Tetracycline antibiotics that cover this gram-negative 6. CDC. Infections from some foodborne germs bacterium, such as doxycycline, are first-line. increased, while others remained unchanged in 2012: In an eight-year retrospective analysis, three CDC Newsroom Press Release. 2013 April (Accessed antibiotics were studied for their effectiveness in June 2013). Available from: http://www.cdc.gov/ treating V. vulnificus infection with necrotizing media/releases/2013/p0418-foodborne-germs.html. fasciitis in conjunction with surgical intervention. 7. Jien-Wei L, Ing-Kit L, Hung-Jen T, Wen-Chien K, The study concluded that fluoroquinolones or a Hsin-Chun L, Yung-Ching L, Po-Ren H, Yin-Ching third-generation cephalosporin in combination C. Prognostic factors and antibiotics in Vibrio vulnificus with minocycline, a member of the tetracycline septicemia. Arch Intern Med. 2006 Oct;166(19):2117- 7 family, were the most effective. Surgical 2123. debridement within 24 hours of admission, 8. Todar K. The Microbial World: Lectures in including fasciotomy, is suggested to aid in Microbiology [Internet]. Madison (WI): University of survival.15 Management of the patient in the Wisconsin-Madison, Department of Bacteriology; 2009 ICU, with aggressive electrolyte monitoring December 31 (Accessed June 2013). Available from: and fluid replacement, is critical. Common http://textbookofbacteriology.net/themicrobialworld/ treatment guidelines suggest using a tetracycline vulnificus.html. such as doxycycline (oral or intravenous) in combination with a third-generation 9. Miyoshi S, Nakazawa H, Kawata K, Tomochika K, cephalosporin such as ceftazidime (intravenous).3 Tobe K, Shinoda S. Characterization of the hemorrhagic Say yes to personal, professional service. Various other combination regimens, including reaction caused by Vibrio vulnificus metalloprotease, a fluoroquinolones and aminoglycosides, have also member of the thermolysin family. Infect Immun. 1998 Call 1.866.825.4422 and let been recommended. Oct;66(10):4851-5. Global Pathology help you.

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