Volume 31

JAOCDJournal Of The American Osteopathic College Of Dermatology

Focus on Osteopathy: Osteopathic Manipulative Medicine for Inflammatory Skin Diseases

Also in this issue: Lichen Planopilaris: A Therapeutic Management Review Clinical Manifestations of Livedoid Vasculopathy “8 to Z” Yin and Yang: A Novel Double Rotation Flap last modified on December 19, 2014 10:29 AM

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

2014-2015 AOCD OFFICERS

PRESIDENT Rick Lin, DO, FAOCD

PRESIDENT-ELECT Alpesh Desai, DO, FAOCD

FIRST VICE-PRESIDENT Karthik Krishnamurthy, DO, FAOCD

SECOND VICE-PRESIDENT Daniel Ladd, DO, FAOCD

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

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

Bayer Immediate Past-President AuroraDx Suzanne Sirota Rozenberg, DO, FAOCD EEC Representatives Ranbaxy James Bernard, DO, FAOCD Michael Scott, DO, FAOCD Valeant 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 acknowledgment of the original source, and a payment of $15 per page, table or figure of reproduced material. Permission fees are waived for authors wishing to reproduce their own articles. Request for permission should be directed to JAOCD c/o AOCD, PO Box 7525, Kirksville, MO 63501. Copyright © 2003 by the Journal of the American Osteopathic College of Dermatology Print and layout by: S&S Printing and Graphics LLC, 701 N. Marion St., Kirksville, MO 63501 Copy editing by: Julia Layton, Freelance Writing and Editing

Page 2 JOURNAL OF THE AMERICAN OSTEOPATHIC COLLEGE OF DERMATOLOGY Journal of the American Osteopathic College of Dermatology

Table of Contents Volume 30 JAOCD Editors...... 4 Letter from the President...... 5 Letter from the Executive Director...... 6 FEATURE ARTICLE: Osteopathic Manipulative Medicine for Inflammatory Skin Diseases...... 11 J. Hibler, DO, Jessie Perkins, DO, David Eland, DO, FAAO, Dawn Sammons, DO, FAAO

EDITOR’S PICKS: Lichen Planopilaris: A Case Report and Therapeutic Management Review...... 14 Stacey Seastrom, DO, Natalie Edgar, DO, David Dorton, DO, Richard A. Miller, DO Clinical Manifestations and Management of Livedoid Vasculopathy...... 16 Elyse Julian, BS, Tania Espinal, MBS, Jacqueline Thomas, DO, FAOCD, Nason Rouhizad, MS, David Thomas, MD, JD, EdD “8 to Z” Yin and Yang Flap: A Novel Double Rotation Flap...... 19 Leela Athalye, DO, Jack Griffith, DO

ORIGINAL ARTICLES AND CASE REPORTS: Combination of Topical Imiquimod and Oral Acitretin in the Treatment of Multiple Large Basal- and Squamous-Cell Carcinomas of the Face...... 21 Anne Donato, MD, J. Kate Jackson, PA-C, Laura Sandoval, DO, Jonathan S. Crane, DO, FAOCD Herpes Zoster Ophthalmicus in a Patient with Wegener’s Granulomatosis...... 24 Sunny Chun, DO, Karan Lal, BS, David Posnick, DO, Adriana Ros, DO Examination of Incompletely Excised Non-melanoma Skin Cancers...... 26 Cathy Koger, DO, Roxanne Rajaii, MS, Vanessa Pazdernik, MS, Kelby Martens, Jonathan L. Cleaver, DO, FAOCD, Lloyd J. Cleaver, DO, FAOCD Idiopathic Spiny Keratoderma: A Report of Two Cases and Literature Review...... 30 Jessica Schweitzer, DO, Matthew Koehler, DO, David Horowitz, DO Allergic Contact Dermatitis Secondary to Latex Headset in Popular Bluetooth Device...... 33 John Moesch, BA, Joseph Dyer, DO, Melinda Greenfield, DO, FAOCD A Case Report of Extragenital Lichen Sclerosus with Anogenital Sparing...... 35 Amanda Nahhas, BS, Jenifer Lloyd, DO Pseudoepitheliomatous Hyperplasia Resembling Multiple Keratoacanthomas Arising in a Tattoo...... 37 Christine Moussa, DO, Najiyah Kazi, MD, Shahrzad Akbary, BS, Richard Bernert, MD, FASDP, Bill Halmi, MD Nodular Amyloidosis: A Case Report and Review of the Literature...... 40 Sean McGregor, PharmD, John Minni, DO, FAOCD, Michael Nowak, MD Systematic Review of Phototherapy in Pruritic Disorders...... 42 Soham Chaudhari, BA, Argentina Leon, MD, Ethan Levin, MD, John Koo, MD Zosteriform Lichen Planus: An Unusual Clinical Variant...... 51 Ashvin Garlapati, DO, Ramya Tripuraneni, MBBS, Francisco A. Kerdel, BSc, MBBS, Stanley Skopit, DO, MSE, FAOCD

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

Associate Editors

Derrick Adams, DO Aaron Bruce, DO Michael Scott, DO Scott Wickless, DO Red Bluff, CA Bozeman, MT Seattle, WA Dallas, Texas

Editorial Board Sami Abbasi, DO Marcus Goodman, DO Angela Leo, DO John Perrotto, DO Brownstown, MI Roswell, GA New York, NY West Palm Beach, FL

Brett Bender, DO Melinda Greenfield, DO Scott Lim, DO Andrew Racette, DO Farmington Hills, MI Albany. GA Erie, PA Phoenix, AZ

Ryan Carlson, DO Denise Guevara, DO Chava Lustig, DO Richard Rudnicki, DO Hilliard, OH Weston, FL Weston, FL Mesquite, TX

Igor Chaplik, DO Andrew Hanly, MD Jere Mammino, DO Amara Sayed, DO Aventura, FL Miami, FL Winter Springs, FL San Marcos, TX

Michael P. Conroy, MD Joel Harris, DO John Minni, DO Joseph Brant Schneider, DO Columbus, OH Madison Heights, MI Port St. Lucie, FL Shawnee Mission, KS

John Coppola Heather Higgins, DO Tony Nakhla, DO Gregg Severs, DO Ormond Beach, FL Troy, MI Orange County, CA Scranton, PA

Matthew Elias, DO David Horowitz, DO Navid Nami, DO Sean Stephenson, DO Lighthouse Point, FL Torrence, CA Newport Beach, CA Troy, MI

Michelle Foley, DO Matt Leavitt, DO Jon Keeling, DO Jacqueline Thomas, DO Ormond Beach, FL Maitland, FL Lexington, KY Fort Lauderdale, FL

Brad Glick, DO Mark Lebwohl, MD Dimitria Papadopoulos, DO Jim Towry, DO Margate, FL New York, NY Bellmore, NY Ocala, FL

Page 4 JAOCD EDITORS Letter from the President

Rick Lin, DO, MPH, FAOCD President, AOCD

Dear Members of the AOCD,

Welcome to another issue of the Journal of the American Osteopathic College of Dermatology ( JAOCD). The JAOCD has come a long way. It began as the collective vision of Drs. Jay Gottlieb, Stanley Skopit, and James Del Rosso, who wanted to create a platform to better serve the educational needs of the College. During the years of their dedication and now under the stewardship of Dr. Karthik Krishnamurthy, this journal has grown to be an impressive publication.

I would like to congratulate the current and past residents who have been published in the JAOCD. I remember authoring the very first lead article, entitled “Patient Assessment in the Treatment of Premenstrual Acne Flare with Vitamin B6 Therapy: A Two-Year Retrospective Study,” during my second year of residency. It is hard to believe it has been more than 10 years. Many of the resident authors who have published in the JAOCD have now been practicing dermatologists for more than a decade. Some of the residents of yesterday are the program directors of today.

The Journal has provided a publication outlet for the scholastic talent of the College. I remember the residents sometimes feeling overwhelmed by having to comply with the requirements for submission to the JAOCD. However, now the Journal has proven to be the historic record of the AOCD’s scholastic and research activities. The contents and the editorial process are first-rate.

Let us not ever take this precious AOCD publication for granted. I hope to see more attendings and residents contribute manuscripts. In the near future, we will be asking for more support from our members and residents as our dermatology residency moves toward a single accreditation system. The participation of our members will be vital for the survival of the JAOCD.

Fraternally yours, Rick Lin, DO, MPH, FAOCD

LETTER FROM THE PRESIDENT Page 5 Letter from the Executive Director

Marsha Wise Hello, Everyone, Executive Director, AOCD Here’s to a happy and healthy 2015!

The new year will bring many changes in graduate medical education for osteopathic physicians. Members from the AOA have been nominated to the ACGME Board of Directors; the Osteopathic Principles Committee has been appointed and has begun its work; and each specialty will soon have representatives on the ACGME’s educational Review Committee. Educational forums for Program Directors, Directors of Medical Education and Specialty Colleges will begin in January to assist with the transition. Programs may begin to apply for pre-accreditation status in July 2015.

The AOA and ACGME each have pages on their websites devoted to this transition, and they are regularly updated. Please visit the links below for up-to-date information on the process:

American Osteopathic Association: The Single GME Accreditation System http://www.osteopathic.org/inside-aoa/single-gme-accreditation-system/Pages/default.aspx

Accreditation Council for Graduate Medical Education: Single Accreditation System for AOA-Approved Programs http://acgme.org/acgmeweb/tabid/445/GraduateMedicalEducation/SingleAccreditationSystemforAOA-ApprovedPrograms. aspx

The AOCD will also see change. During the General Membership Meeting recently held in Seattle, the membership voted to accept the changes to the by-laws that had been presented last summer. Committees will soon be accepting additional members due to the elimination of required maximum seats allowed. The focus of AOCD CME meetings will also change, which will allow for greater flexibility in scheduling.

Change is never easy, especially after getting comfortable with the routine. Hopefully by July, we will all have a clearer picture of the future and what our roles will be. The AOCD will continue to work to keep the membership informed as new information is released.

We hope you will make plans to attend our Spring 2015 meeting in Charlotte, North Carolina, April 23-26. Lectures will begin at noon on April 23 and will conclude at noon on April 26. The meeting will take place at the Ritz Carlton in Charlotte. More information on the meeting can be found on our website at www.aocd.org and in our weekly Thursday Bulletin email blasts.

Please call or email the AOCD office at [email protected] if you need assistance.

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

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FIN_JournalAd_JAOCD_8.5X11.indd 1 14-10-21 9:19 PM Osteopathic Manipulative Medicine for Inflammatory Skin Diseases

J. Hibler, DO,* Jessie Perkins, DO,** David Eland, DO, FAAO,*** Dawn Sammons, DO, FAAO****

*Dermatology Resident, 2nd Year, O’Bleness Memorial Hospital, Athens, OH **Traditional Osteopathic Intern, Largo Medical Center, Largo, FL ***Attending Physician, University Medical Associates, Athens, OH ****Program Director, Dermatology Residency Program, O’Bleness Memorial Hospital, Athens, OH

Abstract Osteopathic manipulative medicine (OMM) is a defining feature of osteopathic physician training and can be used in practically all areas of medicine. While the use of OMM by osteopathic-trained physicians continues to decline, its use will be an important feature that distinguishes DOs from their allopathic counterparts as osteopathic and allopathic training programs come to be governed by a unified body. Even in dermatology, OMM can be a useful tool for numerous disorders. We present several different OMM techniques that can be used for inflammatory skin diseases. their level of post-graduate training.2 In another we propose the use of manipulative medicine in Introduction The planned emergence of the Unified survey-based study, dermatologists reported the treatment of inflammatory skin disease. Accreditation System in 2015, a merger zero use of OMM, citing a variety of reasons for between the American Osteopathic Association not incorporating OMM into their daily practice Discussion 3 The skin is the primary interface between the (AOA) and the Accreditation Council for (Table 1). It was found that specialists were environment and the body, making it the initial Graduate Medical Education (ACGME), most likely to avoid performing OMM due to defense against insults like radiation, heat, has created numerous obstacles for virtually barriers in use, practice protocols, attitudes microbial invasion and trauma. When these the entire medical community. These recent toward OMM, and deficiencies in training. organizational changes to graduate medical Table 1. Reasons for decreased use of OMM by osteopathic physicians and specialists.3 education in the United States will undoubtedly affect how osteopathic post-graduate medical Barriers to OMM Use Example(s) training is conducted. Whether in primary care Practice protocols Exam-room size constraints, lack of administration support or in specialty medicine such as dermatology, preserving the identity of the osteopathic Lack of emphasis in Use of video/online tutorials instead of hands-on training profession will likely be a challenge as these post-graduate training programs merge. Osteopathic dermatologists Time constraints Some OMM techniques may take 30 minutes or more are in a special position to promote osteopathic Procedure-based Mohs, dermatopathology manipulative medicine (OMM) because specialties numerous dermatologic disease processes can Decreased practical Lack of use reduces comfort with techniques be treated with manual therapies. This review focuses on inflammatory skin diseases that can exposure be treated with OMM. Included here is also Attitudes toward OMT Belief that technique may not be useful a brief review of the basic techniques used in With the Unified Accreditation System, the insults occur, cutaneous inflammation arises, a OMM. 5 instruction in and use of OMM in specialty result of an innate and adaptive immune system. Table 2 summarizes a variety of cutaneous Background medicine is in danger of even further decline. Also known as osteopathic manipulative However, all osteopathic dermatologists do inflammatory processes by the primary cause of treatment (OMT), OMM is based on an have the training and potential to perform most inflammation. understanding of the musculoskeletal system’s of these techniques, especially for reduction One of the four primary principles of osteopathy role in local and systemic fluid management of tissue congestion and inflammation due to states that the body has a propensity for self- and tissue mobility, as well as its influence, via inflammatory skin diseases. healing and is capable of homeostasis and 6 the nervous system, on pain, proprioception Despite the decline in use of manipulative health maintenance. While medications such and autonomic elements. The core techniques medicine, it remains a potential adjunct in treating as antibiotics for bacterial infection and steroid- of OMM utilize these relationships between the internal as well as cutaneous disease. Some sparing immune-modulating medications for musculoskeletal system and other body systems. manual- and physical-medicine techniques, such psoriasis remain the mainstay of treatment, The use of OMM, regardless of specialty, has as compression wrapping for stasis dermatitis manipulative medicine offers a supplementary 7 been declining for the past several decades. In and scar massage for scarring, are used widely. approach to treatment. For example, rib raising dermatology, it is hardly used at all. One survey Campbell et al. promoted the use of OMT for is a technique used to normalize or reduce found that half of all responding osteopathic dysethesia syndromes, hyperhydrosis and stasis autonomic output to blood and lymphatic vessels. physicians used OMT on less than 5% of their dermatitis using the rationale that alteration of Normalization of this output can enhance blood patients.1 Spaeth et al., focusing on osteopathic the underlying pathophysiologic mechanisms and lymphatic flow to areas of trauma, infection physicians in Ohio, found a negative correlation can alter and possibly prevent the disease or stress, supporting the healing process. It may between osteopathic physicians’ OMM use and processes.4 It is under this same rationale that also help with delivery of medication to these areas where tissue congestion is often found.

HIBLER, PERKINS, ELAND, SAMMONS Page 11 Table 2: Inflammatory skin conditions by primary cause. in inflammatory skin disease is release of the diaphragms, including the abdominal diaphragm Primary Cause Condition and the thoracic inlet. A flattened diaphragm is Infectious ·Bacterial (cellulitis, abscess formation, acne) less effective as a lymphatic pump. Myofascial ·Fungal (kerion) release of the diaphragm allows the diaphragm ·Viral (herpetic lesions, Molluscum contagiosum, Verruca vulgaris) to move more efficiently, maximizing its potential as a lymphatic pump through improved Autoimmune ·Psoriasis intrathoracic pressure changes.8 The thoracic ·Systemic lupus erythematosus inlet is considered the endpoint of lymph flow as it reaches the venous system; the lymphatic Idiopathic/Other ·Brachioradial pruritus system is a low-pressure system in which flow ·Notalgia paresthetica can be interrupted or impeded by changes in fascial tension. Congestion in this area will cause ·Raynaud’s phenomenon end resistance to lymphatic flow even when Osteopathic manipulative medicine has two indirect treatment. Indirect methods disengage all other areas of lymph flow are adequate.8,9 main branches of techniques: direct and indirect. the restrictive barrier, placing the dysfunctional Myofascial release is often considered the Direct treatments engage a restrictive barrier, body part in a state of ease in all directions until primary step in correcting lymphatic drainage and a final activating force is applied to correct tissue tension is equal, thus potentially taking and should be done in conjunction with other the somatic dysfunction.8 Types of direct the tension off the lymphatic vessels in the area lymphatic treatments. treatments include muscle energy, HVLA, rib of treatment. Indirect treatments also include Recently, lymphatic-pump techniques have been raising and myofascial release. counterstrain. shown to enhance the lymphatic and immune Myofascial release can also be accomplished via An example of myofascial release that may aid systems through increase of lymph flow and re-

Table 3. OMT techniques and their potential benefits in inflammatory skin disease.8,9 Treatment Type Mechanism of Action Therapeutic Benefits Contraindications Myofascial Release Direct or indirect; tissue is guided Promotion of balanced, homeostatic Open wounds, recent surgery, deep to a point of maximal restriction equilibrium and decreased venous thrombosis, neoplasms or with constant force until release resistance internal injury is achieved, or is guided along the path of least resistance until release is achieved Lymphatic Techniques Group of techniques employed to Decreased resistance to lymphatic Relative: cancer ·Effleurage encourage movement of lymphatic and venous flow; mobilization of Absolute: coagulopathy (e.g., ·Pedal pump fluid local congestion, encouraging re- deep venous thrombosis), chronic entry into circulation infections or infections with risk of reactivation (e.g., tuberculosis) Counterstrain Indirect; patient is placed in a point Relief of identified tender point, Ligamentous or tendinous tears, of ease that lessens the identified encouraging patient comfort fracture tender point by greater than 70% and is held in that position for 90- 120 seconds Rib Raising Direct technique; physician Prolonged reduction in sympathetic Anuria, necrotizing fasciitis applies slow, methodical pressure tone after initial SNS stimulation, anteriorly and laterally on the rib encouraging increased blood and angles while encouraging caudal lymphatic flow motion High Velocity-Low Amplitude Direct; a rapid force carries a joint Increased range of motion, Severe osteoporosis, metastatic or through the restrictive barrier decreased pain bone cancer, cervical rheumatoid within the anatomic range of arthritis, fracture, carotid or motion vertebrobasilar disease Muscle Energy Direct; patient is placed into the Increased range of motion Recent surgery, poor vitality of restrictive barrier; patient’s muscles patient, unstable joints are then actively used against a physician’s counterforce for 3-5 seconds

Page 12 OSTEOPATHIC MANIPULATIVE MEDICINE FOR INFLAMMATORY SKIN DISEASES distribution of immune mediators, respectively, further aiding in the body’s ability to heal. The 1.References Johnson SM, Kurts ME. Diminished use of lymphatic pump has been shown to significantly osteopathic treatment and its impact on the uniqueness of the osteopathic profession. J Assoc Am Med Coll. increase total leukocyte count, interleukin-8, 2001 Aug;76(8):821-8. keratinocyte-derived chemoattractant and other 2. Spaeth DG, Pheley AM. Evaluation of osteopathic immune factors in lymphatic flow following manipulative treatment training by practicing treatment.11 Several of these factors have been physicians in Ohio. J Am Osteopath Assoc. 2002 found to be involved in the pathophysiology Mar;102(3):145-50. of inflammatory skin disease, including IL-8 3. Spaeth DG, Pheley AM. Use of osteopathic and keratinocyte-derived chemoattractant.12,13 manipulative treatments by Ohio osteopathic physicians in various specialties. J Am Osteopath Assoc. 2003 Extravasation of these products of inflammation Jan;103(1):16-26. into lymph flow by lymphatic pumps can 4. Campbell SM, Winkelmann RR, Walkowski S. help promote the immune process involved in Osteopathic manipulative treatment: Novel application inflammatory skin disease. to Dermatologic Disease. J Clin Aesthet Derm. 2012 Oct:5(10): 24-32. Table 3 summarizes manual medicine techniques and their advantages in treatment of 5. Robert C, Kupper T. Inflammatory Skin Diseases, T cells, and Immune Surveillance. Mechanisms of inflammatory skin conditions. Disease. N Engl J Med. 1999 Dec:341(24):1817-1828. 6. Kuchera WA, Kuchera ML. Osteopathic Principles in Conclusion Practice. 2nd ed. Dayton: Original Works Books; 1991. OMM remains a potential adjunct in treatment 7. Bolognia JL, Jorizzo JL, Schaffer J. Dermatology. 3rd of disease, internal and cutaneous. At a time of Ed. Philadelphia: Saunders; 2012. merging osteopathic and allopathic paradigms, 8. Chila A. Foundations of Osteopathic Medicine manipulative treatment becomes a key to [e-book]. Philadelphia: Wolters Kluwer Health/ maintaining osteopathic identity and promoting Lippincott Williams & Wilkins, c2011; 2011. OHIO osteopathic principles. Continued emphasis on UNIV – Main’s Catalog, Ipswich, MA. Accessed May osteopathic principles in diagnosis and renewed 20, 2014. focus on manipulation in post-graduate training 9. Wallace E, McPartland JM, Jones JM, Kuchera WA, Buser BR. Foundations for Osteopathic Medicine. may alleviate the decline of manual medicine in Philadelphia: Lippincott Williams & Wilkins; 2003. osteopathy as well as promote the uniqueness Lymphatic system: lymphatic manipulative techniques; of the profession. Osteopathic manipulation p. 1064-65. has been shown to aid in normalization of 10. Huff JB, Schander A, Downey HF and Hodge autonomic function and enhance the immune LM. Lymphatic pump treatment augments lymphatic process, thereby promoting the health of the flux of lymphocytes in rats. Lymphat Res Biol. 2010 Dec;8(4):183-7. individual. By employing methods of manual 11. Schander A, Downey HF, Hodge LM. Lymphatic medicine, both direct and indirect, osteopathic pump manipulation mobilizes inflammatory mediators physicians may enhance the treatment and into lymphatic circulation. Exp Biol Med. 2012 comfort of the patient as a whole. With few Jan;237(1):58-63. exceptions, employing OMM in the treatment 12. Kemeny L, Ruzicka T, Dobozy A, Michel G. Role of inflammatory skin conditions can assist of interleukin-8 receptor in skin. Int Arch Allergy in resolving a pathologic state, as manual Immunol. 1994 Aug;104(4):317-22. treatments have been shown to alter the flow of 13. Nakamura K, Williams IR, Kupper TS. Keratinocyte- lymph and inflammatory mediators that may be derived monocyte chemoattractant protein 1 (MCP-1): analysis in a transgenic model demonstrates MCP-1 involved in inflammatory skin disease. can recruit dendritic and Langerhans cells to skin. J Although the dermatology office is a fast- Invest Derm. 1995 Nov;105(5):635-43. paced environment, we hope to promote the use of OMM, either in-office or by referral Correspondence: J. Hibler, DO; [email protected] to a manipulative-medicine specialist, to encourage the health of patients as well as bolster that which is unique to osteopathic medicine. Continued research into the efficacy of manipulative medicine in dermatologic disease remains necessary as we seek new and innovative treatments for common dermatologic conditions.

HIBLER, PERKINS, ELAND, SAMMONS Page 13 Lichen Planopilaris: A Case Report and Therapeutic Management Review

Stacey Seastrom, DO,* Natalie Edgar, DO,** David Dorton, DO,*** Richard A. Miller, DO****

*Dermatology Resident, Nova Southeastern University College of Osteopathic Medicine/Largo Medical Center, Largo, FL **Traditional Rotating Intern, Nova Southeastern University College of Osteopathic Medicine/Largo Medical Center, Largo, FL ***Clinical Professor, Nova Southeastern University College of Osteopathic Medicine, Largo, FL ****Program Director, Dermatology Residency Program, Nova Southeastern University College of Osteopathic Medicine/Largo Medical Center, Largo, FL

Abstract Lichen planopilaris is a chronic lymphocytic cicatricial alopecia with an unknown pathophysiology. The therapeutic management of lichen planopilaris is challenging due to the high relapse rate and heavy psychological burden on the patient. Herein, we highlight a case of a 40-year-old female with a 20-year history of biopsy-proven lichen planopilaris, and we discuss her tortuous course of treatment regimens. with and without inflammatory targets. Specific Introduction therapies aimed at reducing inflammation in Lichen planopilaris (LPP) is a chronic, scarring the disease include corticosteroids, calcineurin alopecia that predominantly affects females 1 inhibitors, antimalarials, immunosuppressants, between the ages of 40 and 60 years. Classically, antimetabolites, and antibiotics.4 Other proposed the clinical presentation of LPP manifests with therapies targeting non-inflammatory disease atrophic polygonal patches of alopecia with components include oral retinoids, peroxisome acuminate hyperkeratotic follicular papules 2 proliferator activated receptor-gamma (PPAR- and perifollicular erythema. Histopathologic gamma) agonists, and minoxidil.4,5 diagnosis is confirmed with an interface, lichenoid infiltrate involving the infundibulum A therapeutic ladder for LPP has evolved within the literature due to the condition’s recalcitrant and isthmus, in combination with a “squamatized” Figure 2 basal layer, Max Joseph spaces and interfollicular nature. Opinions regarding the order of stepwise changes of lichen planus.3 Due to the cicatricial therapeutics vary somewhat from study to study. of chronic pruritus despite these numerous and recalcitrant nature of LPP, an extensive Similarly, treatment results differ significantly treatment regimens. therapeutic ladder has evolved in the literature. between studies, likely accounting for the At the time of initial presentation, physical variation in opinion regarding treatment order. examination demonstrated diffuse erythema of Case Report the scalp with perifollicular scaling (Figure 1). First-line Therapy A 40-year-old female presented to the clinic Two 4 mm punch biopsies were obtained from Mid- to high-potency topical corticosteroids with a 20-year history of redness and flaking of the right vertex of the scalp, and the findings with or without concomitant use of intralesional the scalp. The patient reported previous biopsies, revealed scarring alopecia with mid isthmic corticosteroids is generally accepted as first-line which revealed both lichen planopilaris and fibroplasia consistent with lichen planopilaris therapy for LPP. Reported efficacy of topical folliculitis. She had previously tried numerous (Figure 2). We initially started the patient on a corticosteroid treatment, though not statistically topical corticosteroid solutions, suspensions and taper of oral methylprednisolone in combination significant, varies from disease resolution in 66% oils. In addition, her previous dermatologist with intralesional triamcinolone 5 mg/cc without of patients and improvement in 70% of patients had utilized intralesional triamcinolone 5 mg/ 1,6,7 improvement. The patient was then started on to a fair-to-good response in 83% of patients. cc injections, systemic corticosteroids, topical methotrexate, which was incrementally increased The length of treatment and taper duration of tacrolimus, oral plaquenil and oral cyclosporine, up to 15 mg weekly, in combination with topical corticosteroid ranged from fewer than all without improvement. The patient complained 90 days to seven months within the various clobetasol scalp solution five days a week. The 1,4 patient did not respond to a three-month trial studies. Unfortunately, relapse rates following topical steroid cessation were reported to be as of methotrexate 15 mg weekly, at which time 4 we obtained blood work to initiate treatment high as 80%. Concomitant monthly intralesional with 1 gram of mycophenolate mofetil twice corticosteroid injections of triamcinolone acetonide up to 10 mg/mL are recommended daily. After two months of mycophenolate 4 mofetil treatment, she reported symptomatic to further decrease severe inflammation. Even improvement and cessation of further hair in light of the high relapse rate, topical and loss. However, after completing four months intralesional corticosteroids are an ideal first- of mycophenolate mofetil therapy, the patient line treatment because they have few adverse again started complaining of uncontrollable scalp effects when used correctly. There is limited pruritus. Upon re-biopsy of the mid scalp, the data regarding LPP treatment with other topical histopathology demonstrated changes consistent therapeutics including calcineurin inhibitors. with lichen simplex chronicus and resolution of Second-line Therapy the lichen planopilaris. Recommended second-line therapy for LPP varies greatly in the literature and primarily includes Discussion systemic corticosteroids, immunosuppressants, Though the pathophysiology of LPP is unclear, and antimetabolites. Systemic corticosteroids it appears to be a lymphocyte-predominant have been widely recommended and used with Figure 1 inflammatory process. Proposed therapeutic good results as acute therapy or as a bridge to management of LPP utilizes various medications other immunosuppressive therapy. Megerhan et

Page 14 LICHEN PLANOPILARIS: A CASE REPORT AND THERAPEUTIC MANAGEMENT REVIEW al. reported improvement in 82% of patients with Cevasco et al. reported statistically significant (p 3. Sperling LC. Scarring alopecia and the the use of oral corticosteroids.6 As with topical = 0.033 ) improvement with tetracycline therapy.7 dermatopathologist. J Cutan Pathol. 2001;28:333-42. steroids, a very high relapse rate is associated LPP treatment with methotrexate has also been 4. Assouly P, Reygagne P. Lichen Planopilaris: Update with systemic corticosteroid treatment taper reported in the literature as a second- or third- on Diagnosis and Treatment. Semin Cutan Med Surg. and cessation.4 Unfortunately, long-term use line option with optimal dosing of 7.5 mg to 20 2009;28:3-10. of systemic corticosteroids is limited by the mg combined with 5 mg folic acid once weekly.13 5. Spring P, Spanou Z, de Viragh PA. Lichen associated side-effect profile. Treatment of frontal fibrosing alopecia (FFA), a Planopilaris treated by the peroxisome proliferator activated receptor-g agonist pioglitazone: Lack of subtype of LPP, with 5-alpha reductase inhibitors Steroid-sparing immunosuppressants including lasting improvement or cure in the majority of patients. was successful in 44% to 47% of FFA patients.14,15 cyclosporine and hydroxychloroquine have J Am Acad Dermatol. 2013;69:830-2. It is unclear, though, whether 5-alpha reductase been suggested as second-line options for the 6. Mehregan DA, Van Hale HM, Muller SA. Lichen inhibitors are helpful in LPP, as some have treatment of LPP. Cyclosporine therapy is planopilaris: clinical and pathologic study of forty-five postulated different pathogeneses between the recommended in the literature as a second- or patients. J Am Acad Dermatol. 1992;27:935–942. diseases.15 third-line treatment option, with reports of a 7. Cevasco NC, Bergfeld WF, Remzi BK, de Knott HR. 4 A case-series of 29 patients with lichen planopilaris: The 77% treatment success rate. Optimal dosing of Adjunctive Therapy cyclosporine was reported as 4 mg/kg/day to 5 Cleveland Clinic Foundation experience on evaluation, Supplemental topical corticosteroids in diagnosis, and treatment. J Am Acad Dermatol. mg/kg/day for three to six months.4 The associated conjunction with systemic therapies may help 2007;57:47-53. side-effect profile may warrant exhaustion of 12 to reduce the symptoms of LPP. Addition of 8. Chiang C, Sah D, Cho BK, Ochoa BE, Price VH. other treatment options prior to initiation of minoxidil to first- and second-line therapies Hydroxychloroquine and Lichen Planopilaris: Efficacy cyclosporine treatment. Hydroxychloroquine 400 may be beneficial to regrow hair in telogen arrest and introduction of Lichen Planopilaris Activity Index mg/day is also often used as a treatment for LPP 2,4,9 scoring system. L Am Acad Dermatol 2010;62:387-92. 4 and improve overall hair growth. Also, an that does not respond to topical corticosteroids. oral peroxisome proliferator-activated receptor γ 9. Sperling LC, Nguyen JV. Commentary: Treatment of In the literature, reported results achieved using (PPARγ) agonist, specifically pioglitazone lichen planopilaris; Some progress but a long way to go. J Am Acad Dermatol. 2010; 62:398-401. hydroxychloroquine are inconsistent, varying hydrochloride (15mg/day), may be considered for dramatically between studies. Chiang et al. some refractile cases of LPP, as the inflammation 10. Cho BK, Sah D, Chwalek J, Roseborough I, reported statistically significant (p < 0.001) associated with LPP is postulated to be due in Ochoa B, Chiang C, Price VH. Efficacy and safety of mycophenolate mofetil for lichen planopilaris. J Am efficacy of hydroxychloroquine use after six and part to abnormal PPARγ activity.16,17 12 months of treatment, whereas Assouly et al. Acad Dermatol. 2010;62:393-7. reported little success following six months of Randomized, controlled prospective studies 11. Buell C, Koo J. Long-term safety of mycophenolate hydroxychloroquine therapy in 12 patients.4,8 for the treatment of LPP are needed to further mofetil and cyclosporine: a review. J Drugs Dermatol. streamline clinical data for accurate classification 2008;7:741-8. Antimetabolite therapy with mycophenolate of this disease entity and its optimal treatment 12. Spencer LA, Hawryluk EB, English JC. Lichen mofetil has been shown to be effective in the recommendations. Additionally, the need for Planopilaris: Retrospective Study and Stepwise treatment of LPP.9 Cho et al. showed that six streamlining data between studies is imperative Therapeutic Approach. Arch Dermatol. 2009;145:333- months of mycophenolate mofetil therapy 18 4. for better comparability. Use of a standardized significantly decreased (p < 0.005) the signs and grading system, like the Lichen Planopilaris 13. Manousaridis I, Manousaridis K, Peitsch W, symptoms of LPP in 83% of patients who had Activity Index scoring system (LPPAI), among Schneider S. Individualizing treatment and choice of 10 Interestingly, medication in lichen planus: a step by step approach. J previously failed other therapies. studies will, ideally, remove some degree of of the 12 patients in the study, 11 had previously Dtsch Dermatol Ges. 2013;11:981-991. subjectivity from grading results. Though not failed treatment with hydroxychloroquine.10 These 14. Vano-Galvan S, Molina-Ruiz AM, Serrano-Falcon purely objective, the LPPAI will provide for some patient received 0.5 mg mycophenolate mofetil 8,9 C, Arias-Santiago S, Rodrigues-Barata AR, Garnacho- level of continuity between LPP studies. twice daily for four weeks and then 1 mg twice Saucedo G, Martorell-Calatayud A, Fernandez- 10 Crehuet P, Grimalt R, Aranegui B, Grillo E, Diaz- daily for 20 weeks or more. Review of data has Ley B, Salido R, Perez-Gala S, Serrano S, Moreno shown that mycophenolate mofetil is associated Conclusion JC, Jaen P, Camacho FM. Frontal fibrosing alopecia: with fewer side effects, including lower risk of Treatment of LPP remains a challenge due to A multicenter review of 355 patients. J Am Acad end-organ damage and cancer, as compared to its recalcitrant nature, unclear pathophysiology, Dermatol. 2014;70:670-8. cyclosporine, although further investigation is and lack of prospective double-blinded studies. 15. Racz E, Gho C, Moorman PW, Noordhoek Hegt needed.10,11 We believe that due to the relatively The clinical data regarding medication efficacy V, Neumann HAM. Treatment of frontal fibrosing benign side-effect profile and general tolerability, in LPP is inconsistent and difficult to compare alopecia and lichen planopilaris: a systematic review. J Eur Acad Dermatol Venereol. 2013;27:1461-1470. mycophenolate mofetil should be considered the between studies. Ideally, the most effective treatment of choice for recalcitrant LPP. therapies with the safest side-effect profiles will 16. Mirmirani P, Karnik P. Lichen planopilaris treated be utilized as early treatment options in the LPP with a peroxisome proliferator–activated receptor γ Third-line Therapy therapeutic ladder. Mycophenolate mofetil is a agonist. Arch Dermatol. 2009;145(12):1363-6. For recalcitrant LPP, other therapies may be well-tolerated and generally safe medication that 17. Spring P, Spanou Z, De Viragh PA. Lichen planopilaris treated by the peroxisome proliferator considered, including oral retinoids, tetracycline, should be utilized as second-line therapy for the γ treatment of LPP following the failure of topical activated receptor- agonist pioglitazone: Lack of methotrexate, and 5-alpha reductase inhibitors. lasting improvement or cure in the majority of patients. Oral retinoids have been utilized for treatment of and intralesional corticosteroids. Ultimately, J Am Acad Dermatol. 2013;69(5):830-2. LPP with varying success. Spencer et al. reported randomized and controlled prospective studies 18. Meinhardt J, Stroux A, Lünnemann L, Vogt A, 67% improvement in patients taking acitretin, with streamlined data reporting are necessary to Blume-Peytavi1 U. Lichen planopilaris: Epidemiology whereas Assouly et al. reported no improvement further the literature in regard to treatment of and prevalence of subtypes – a retrospective analysis in and worsening of the clinical disease.4,12 LP P. 104 patients. J Dtsch Dermatol Ges. 2014;12(3):229- Iatrogenic telogen effluvium has been reported 35. as a side effect of acitretin, thus limiting its use 4,13 References in LPP treatment. Oral tetracyclines have 1. Chieregato C, Zini A, Barba A, Magnanini M, Correspondence: Stacey J Seastrom, DO; Largo been utilized as early treatment in LPP by some Rosina P. Lichen planopilaris: report of 30 cases and Medical Center, Graduate Medical Education, practitioners because of its relatively benign side- review of the literature. Int J Dermatol. 2003;42:342-5. 201 14th St SW, Largo, FL 33770; 970-381-6971; effect profile. As with other LPP therapies, reports 2. Whiting DA. Cicatricial alopecia: clinico- [email protected] of treatment success vary, ranging from 27% to pathological findings and treatment. Clin Dermatol. 9,12 90% of patient improvement. Additionally, 2001;19:211-25.

SEASTROM, EDGAR, DORTON, MILLER Page 15 Clinical Manifestations and Management of Livedoid Vasculopathy

Elyse Julian, BS,* Tania Espinal, MBS,* Jacqueline Thomas, DO, FAOCD,** Nason Rouhizad, MS,* David Thomas, MD, JD, EdD***

*Medical Student, 4th year, Nova Southeastern University College of Osteopathic Medicine, Ft. Lauderdale, FL **Assistant Professor, Nova Southeastern University, Department of Dermatology, Ft. Lauderdale, FL ***Professor and Chairman of Surgery, Nova Southeastern University, Ft. Lauderdale, FL

Abstract Livedoid vasculopathy (LV) is an extremely rare and distinct hyalinizing vascular disease affecting only one in 100,000 individuals per year.1,2 Formerly described by Feldaker in 1955 as livedo reticularis with summer ulcerations, LV is a unique non-inflammatory condition that manifests with thrombi formation and painful ulceration of the lower extremities.3 Clinically, the disease often displays a triad of livedo racemosa, slow-healing ulcerations, and atrophie blanche scarring.4 Although still not fully understood, the primary pathogenic mechanism is related to intraluminal thrombosis of the dermal microvessels causing occlusion and tissue hypoxia.4 We review a case in which the patient had LV undiagnosed and therefore inappropriately treated for more than 20 years. To reduce the current average five-year period from presentation to diagnosis, and to improve management options, we review the typical presentation, pathogenesis, histology, and treatment of LV.4

Upon physical exam, the patient was found to have the patient finally consented to biopsy. The ACase 62-year-old Report Caucasian male presented in an a wound on the right medial malleolus measuring pathology report identified ulceration with fibrin assisted living facility setting with chronic, right- 6.4 cm x 4.0 cm x 0.7 cm with moderate serous in vessel walls associated with stasis dermatitis lower-extremity ulcers present for more than 20 exudate, approximately 30% yellow necrosis characterized by thick-walled capillaries and years. The patient had a past medical history of and 70% granulation, with macerated wound hemosiderin deposition consistent with livedoid chronic osteomyelitis, hypertension, and a below- margins (Figure 1), and a second wound on vasculopathy (Figures 3). The patient refused any the-knee amputation of the left lower extremity the right lateral malleolus measuring 6.0 cm x further treatment and was lost to follow-up. secondary to a motorcycle accident. He denied 5.5 cm x 0.4 cm with moderate serous exudate, having seen a primary care physician for more approximately 20% sloughing tissue and 80% than 15 years as well as any medications, vitamins granulation (Figure 2). The patient was treated for LivedoidDiscussion vasculopathy affects women three or supplements. Social history was significant for one year, although inconsistently due to housing times more than men, with a median age of 45 “many years” of tobacco use, heavy alcohol use, circumstances, with a series of necrotic-tissue years, though it can vary from ages 10 to 85.1,2 inconsistent housing with reoccurring assisted- debridements and a variety of topical antibiotics; Likely secondary to the rarity of the condition, living-facility admissions, low economic status, however, despite therapy, the wounds failed to there is much discussion regarding the name of and medical non-adherence. The patient reported close. Throughout the duration of management, the condition, as authors have written about LV that throughout the last 20 years his wound-care the patient repeatedly refused biopsy and under a wide array of monikers. Common names management for these lesions was limited to the hyperbaric oxygen therapy. Following one year used synonymously with livedoid vasculopathy periods of time in which he was living in assisted- of multiple topical antibiotics and debridement include: livedoid vasculitis, segmental living facilities. treatment resulting in minimal improvement, hyalinizing vasculitis, livedo reticularis with summer ulcerations, and atrophie blanche en plaque.3,4 Although commonly used, the denotation of “vasculitis” is a bit misleading, since the primary mechanism of action is not actually inflammation.4 Due to the bilateral and symmetrical lower-extremity distribution of the eruptions, LV has also been nicknamed “PURPLE syndrome” (Painful Purpuric Ulcers with Reticular Pattern of the Lower Extremities).4 The pathogenesis of LV is not yet fully understood, but there is a consensus that it consists of dermal blood-vessel thrombosis leading to superficial tissue ischemia and necrosis, thus propagating pain and ulceration.1 According to the Virchow triad theory, the three factors that contribute to the development of thrombi, and therefore theoretically LV, include endothelial damage, inadequate blood flow, and hypercoagulability.2,5 It has been demonstrated that patients with LV exhibit decreased flow-mediated vasodilation of the brachial artery, signifying endothelial dysfunction.5 A decreased production or activity of Figure 1. Right medial malleolus. 6.4 cm x 4.0 nitrous oxide in endothelial cells has been detected cm x 0.7 cm ulceration exhibiting moderate Figure 2. Right lateral malleolus. 6.0 cm x 5.5 cm x 0.4 cm ulcerations with moderate serous in some cases, supporting the contribution of serous exudate, approximately 30% yellow endothelial damage to LV.6 Additionally, the fact exudate, approximately 20% sloughing tissue necrosis, 70% granulation, and macerated that fibrinolytics, antiplatelets and thrombolytic wound margins. and 80% granulation.

Page 16 CLINICAL MANIFESTATIONS AND MANAGEMENT OF LIVEDOID VASCULOPATHY may show immunoglobulin, fibrin and complement deposition in the superficial vessels; however, these are not specific to LV and must be supported by other findings.7,11 Livedoid vasculopathy is diagnosed based on a combination of clinical and histopathological findings.2 The first step in the clinical workup should be to rule out venous insufficiency and other common causes of atrophie blanche.7 A detailed personal and family history of hypercoagulable disorders, fibrinolytic disorders, connective- tissue disorders and inflammatory disease should be performed. Chronic venous insufficiency may be evaluated by the presence of varicose veins, ochre dermatitis, lower-extremity edema and an abnormal venous Doppler ultrasound.2 Peripheral artery disease may also be associated with LV and may present with claudication, painful ulcers, pale and cold extremities and abnormal arterial Doppler ultrasound.2 Specific laboratory analysis is dependent on clinical presentation and is targeted towards the exclusion of the conditions that are associated with LV. If a connective-tissue disease is suspected based on family and/or personal history and presentation, consider laboratory analyses for antinuclear Figure 3. Biopsy reveals vessel walls thickened with pink fibrin, polymorphous infiltrate and a small antibodies, antiphospholipid antibodies, amount of hemosiderin deposition. anti-beta-2 glycoprotein I, anticardiolipin agents have shown to have a positive effect on papules frequently evolving into punched-out antibodies (IgM and/or IgG) and IgM 6 LV patients demonstrates the contribution of ulcerations.7,11 The painful eruptions are typically antiphosphatidylserine. Laboratory analyses hypercoagulability and decreased blood flow to located bilaterally and symmetrically on the lower for hypercoagulable or fibrinolytic disorders its pathogenesis. extremities, most frequently on the malleoli.11 As may include factor V Leiden, prothrombin the ulcers begin to heal, at approximately four G20210A mutation, elevated factor VIII level, In fact, several conditions may lead to the creation months, they result in stellate, white, atrophic protein C and S deficiency, antithrombin of these three contributing factors. Patients scars around their borders, known as atrophie III deficiency, hyperhomocysteinemia, with LV may be categorized as having primary blanche, resulting in permanent fibrosclerosis of plasminogen-activator inhibitor or reduction (idiopathic) LV or secondary LV, in which a known the skin.2,4,7 Additionally, patients may complain of in plasminogen-activator activity, monoclonal underlying condition is the root of the disease. 6 parenthesis or hyperesthesia, indicating potential cryoglobulinemia, and cryofibrinogenemia. For A thorough investigation must be performed mononeuritis multiplex, likely secondary to the paraproteinemias, laboratory workup may in any patient suspected to have LV to rule out deposition of fibrin and thrombin in the vasa include determination of immunoglobulin, kappa conditions such as systemic lupus erythematous, nervorum resulting in ischemia.2,11 and lambda chain levels, protein electrophoresis scleroderma, protein C or S deficiency, factor V and immunofixation.2 Additionally, polyclonal Leiden, homocysteinemia, sickle-cell anemia, Lower-extremity, reticulated, ulcerated lesions cryoglobulins may be associated with hepatitis B cryoglobulinemia, cryofibrinogenemia, increased that closely resemble LV and should be and C and should also be taken into consideration.6 anticardiolipin, underlying malignancy, altered considered in the differential diagnosis include: fibrinolysis, or platelet activation that may be lupus-associated antiphospholipid syndrome, Biopsy of tissue for regular histology and 6 the underlying cause of the hypercoagulability sickle-cell-anemia leg ulcers, venous stasis with immunofluorescence is required for diagnosis. or occlusion.6-10 However, unknown individual varicosities, hydroxyurea-related ulcerations, Deposition of fibrin, immunoglobulin (IgG, factors must exist for the development of LV dysproteinemia, vasculitis, microscopic IgM) and complement C3 may be detected 6 given that, for instance, few people with protein polyarteritis, polyarteritis nodosa, granulomatous by immunofluorescence. Biopsies revealing C deficiency develop LV.4 vasculitis, and peripheral vascular disease.12 intraluminal thrombosis, endothelial proliferation, and hyalinized degeneration of the Patients with LV clinically present with bilateral, The cardinal histologic findings of LV are seen dermal vessels provide a definitive diagnosis of painful, “punched out” ulcerations that are at the dermal-epidermal junction and consist LV. 1,12 However, due to the focal and segmental slow to heal and result in stellate atrophic scar of: deposition of fibrinoid material in the nature of LV, this “classic” presentation may not 7 tissue. Affected regions may also demonstrate vascular lumen, hyalinization of the vessel wall, be visualized with a single biopsy. It is important 2 erythema, telangiectasia, hyperpigmentation, and tissue infarctions and lack of vasculitis. More to note that biopsies actually complicate the 7 possibly purpura. The triad of livedo racemosa, specifically, the fibrinoid thrombus is found healing of the ulcerations.7 Therefore, it is ulcerations, and atrophie blanche characterizes in the lumen of small vessels of the superficial debatable whether practitioners should opt to 4 the unique clinical presentation of LV. Livedo dermis. This may be accompanied by ulceration obtain repeated biopsies in order to obtain all 2 racemosa, a fixed, irregular, reticular pattern or infarction of the overlying epidermis. The three histological patterns.12 Special attention on skin, is secondary to the microcirculation fibrinoid material may similarly be found should be given to the biopsy method in which disorder and results in local tissue hypoxia and on the vessel walls and in the surrounding specimens are obtained. Small, wedge-shaped possible necrosis. Although LV is not the only stroma, creating fibrinoid rings. Hyalinized tissue samples obtained from the periphery of disorder in which livedo racemosa may be seen, walls and endothelial proliferation may also the ulcer and including healthy adjacent tissue it is commonly clinically regarded as an indicator be identified, in addition to extravasated are often preferred.2,12 This is due to the fact that 2,4 of impending LV. The cutaneous ischemia leads erythrocytes in the stroma that may indicate the base of the ulcer predominantly demonstrates 2 to painful purpuric and erythematous plaques and microhemorrhage. Direct immunofluorescence inflammation from tissue repair and granulation.2

JULIAN, ESPINAL, THOMAS, ROUHIZAD, THOMAS Page 17 There is currently no agreed-upon treatment with compression. 6 References protocol for the diagnosis of LV, and Debridement may be achieved through 1. Hairston BR, Davis MP, Pittelkow MR, Ahmed current therapeutic regimens remain largely mechanical, autolytic, or enzymatic mechanisms. I. Livedoid vasculopathy: Further evidence for understudied, compounding the fact that in many Ideal wound care strategy is to cleanse with procoagulant pathogenesis. Arch Dermatol. 2006; cases, LV is difficult to treat. Management should normal saline, in the least traumatic manner 142(11):1413-8. be focused on preventing further propagation possible, and then apply occlusive dressings 2. Criado PR, Rivitti EA, Sotto MN, Valente NY, of microthrombi, the pathological cause of that provide a moist environment. Silicone Aoki V, Carvalho JF, et al. Livedoid vasculopathy: an the disease, and addressing any underlying intriguing cutaneous disease. An Bras Dermatol. 2011; 7 adhesives along with room-temperature wet coagulation disorders. Although mostly compresses will minimize the trauma associated 86(5):961-77. [PMID: 22147037] anecdotal, long-term antiplatelet therapy with with dressing changes.6 Patients should be 3. Feldaker M, Hines EA, Kierland RR. Livedo acetylsalicylic acid, dipyridamole, cilostazol, frequently monitored for signs of infection, reticularis with summer ulcerations. Arch Dermatol. thienopyridines, or prostacyclin analogues have including leukocytosis, fever, or inflammation, 1955;72(1):31-42. been shown to be successful in most instances.2,7 until wound resolution is achieved. Additionally, 4. Kerk N, Goerge T. Livedoid vasculopathy - a Antithrombotics, such as recombinant tissue- smoking-cessation education, proper diet, and thrombotic disease. Vasa. 2013; 42(5):317-22. plasminogen activator, are often effective management of systemic conditions are essential 5. Yang C, Shen SC, Hui, RCY, Huang Y, Chu P, Ho alternatives; however, the need for inpatient in order to facilitate proper wound healing. therapy may make it a less practical option.2,7 Low- W. Association between peripheral vascular endothelial As discussed, LV is characterized clinically by dysfunction and livedoid vasculopathy. J Am Acad molecular-weight heparin, heparin, and warfarin Dermatol. 2012 Jul;67(1):107-112. may also be used to breakdown or prevent thrombi intensely painful, recurring ulcerations. However, and have been found to be relatively equivalent in pain management in LV has not been thoroughly 6. Alavi A, Hafner J, Dutz JP, Mayer D, Sibbald RG, Criado PR, et al. Livedoid vasculopathy: an in-depth effectiveness.4,6,13 Pentoxifylline may be utilized studied and is, at most, modestly examined in the literature. Pain should be appropriately analysis using a modified Delphi approach. J Am Acad for its effect on coagulation in order to improve Dermatol. 2013;69(6):1033-42. cutaneous oxygenation.6 There is still no agreed- assessed, and conservative methods, such as upon dose for anticoagulation in the treatment gentle handling with appropriately absorbent 7. Haunson GT, Judy DW, Prall NC, Miller RA. Livedoid vasculopathy: review of pathogenesis, clinical of LV, though most studies and reports that have dressings, ought to be employed first to minimize pain exposure.16 However, pain management may presentation, diagnostic workup, and treatment. Cutis. achieved wound resolution administered dosages 2012; 90(6):302-6. indicated for deep-vein-thrombosis prevention.6 be necessary as part of the treatment protocol for individuals with severe discomfort. Prior reports 8. Maessen-Visch MB, Koedam MI, Hamulyak K, A review of the literature yielded a wide have found three to six weeks of aspirin (up to Neumann HA. Atrophie Blanchie. Int J Dermatol. assortment of other approaches that have been 1999;38:161-72. 325 mg per day) along with dipyridamole to be an employed with varying results. Anabolic effective treatment combination, providing pain 9. Acland KM, Darvay A, Wakelin SH, Russell- agents, such as danazol and stanozolol, have relief while inhibiting thrombus.17 It is important Jones R. Livedoid vasculitis: a manifestation of been demonstrated as beneficial in many to note that aspirin should be avoided in patients the antiphospholipid syndrome? Br J Dermatol. 1999;140:131-5. reported cases. In patients with systemic lupus being managed with warfarin. However, it is erythematous, antimalarials should be employed. important to identify the root of the patient’s 10. Calamia KT, Balabanova M, Perniciaro C, Walsh Systemic phototherapy with PUVA, consisting of pain. Pain secondary to the ulcer is typically J. Livedo (livedoid) vasculitis and the factor V Leiden oral 8-methoxypsorale and UVA therapy, as well limited to the margins and intensified during mutation: additional evidence for abnormal coagulation. as cyclosporine and intravenous immunoglobulin J Am Acad Dermatol. 2002;46:133-7. 2 dressing changes and debridement. Pain resulting are being explored as possible therapies. from vascular occlusion is more complicated, as 11. Tubone MQ, Escobar GF, Peruzzo J, Schestatsky P, Incorporation of antibiotics, specifically it is both nociceptive and neuropathic in nature. Maldonado G. Livedoid vasculopathy associated with doxycycline, has been reviewed for its potential In these cases, pain control strategies should be peripheral neuropathy: a report of two cases. An Bras Dermatol. 2013;88(6 Suppl 1):227-9. therapeutic effects in LV along with its ability obtained using the World Health Organization to safeguard against infection.14 Doxycycline, analgesic ladder.6,18 12. Callen JP. Livedoid vasculopathy: What it is and a second-generation tetracycline, is known to how the patient should be evaluated and treated. Arch Dermatol. 2006;142(11):1481-2. provide anti-inflammatory and anti-microbial protection; however, its use has been reported to Conclusion 13. Browning CE, Callen JP. Warfarin therapy Livedoid vasculopathy is a painful, chronic, for livedoid vasculopathy associated with show improvement in patients with LV who have and recurrent condition that may leave the failed other treatment. The mechanism for which cryofibrinogenemia and hyperhomocysteinemia. Arch patient severely debilitated if not recognized Dermatol. 2006;142(1):75-8. doxycycline may be beneficial in a thrombotic early and treated properly. With a current five- 14. Keller MS, Lee J, Webster GF. Livedoid thrombotic condition is unknown, and the use of doxycycline year average between onset of symptoms and is not meant to replace anti-thrombotic agents in vasculopathy responding to doxycycline therapy. J Clin 14 diagnosis, patients are typically left to suffer Aesthet Dermatol. 2008;1(4):22-4. patients with known hypercoagulability. Also, through painful ulcers with permanent atrophie 15. Juan WH, Chan YS, Lee JC, Yang LC, Hong HS, as a treatment adjunct, hyperbaric oxygen therapy blanche.4 Although a rare condition, it is for these Yang CH. Livedoid vasculopathy: long-term follow- shows promising results, facilitating the body’s reasons that it is critical for clinicians to have LV innate healing response and relieving pain.15 up results following hyperbaric oxygen therapy. Br J in their differential diagnoses of lower-extremity Dermatol. 2006;154(2):251-5. Proper wound care, such as with zinc oxide, purpura with reticulated stellate ulcerations that 12 16. Cooper CM, Hofman D, Burge SM. Leg Ulcers glycerin, gelatin dressings, frequent dressing are difficult or slow to heal. Once identified, and Pain: A Review. Int J Low Extrem Wounds. changes, and debridement of necrotic tissue is treatment modalities are aimed at improving 2003;2(4):189-197. paramount.7 Pressure on the ulcer should be microcirculation, preventing infection, wound 17. Kern AB. Atrophie blanche. Report of two patients relieved with leg elevation utilizing products care, and pain control.2,16 treated with aspirin and dipyridamole. J Am Acad such as foam wedges, pillows or flotation devices Dermatol. 1982 Jun;6(6):1048-53. if necessary. Due to the association of LV with 18. Woo KY, Sibbald RG. Chronic wound pain: a venous disease, compression stockings are TheAcknowledgements authors would like to thank Jose Perez, DO, for conceptual model. Adv Skin Wound Care. 2008;21:175- an important addition to therapy as they have the diagnosis of LV and his therapeutic efforts in the 88. Quiz: 89-90. been shown to stimulate fibrinolytic activity.7 management of the discussed patient. However, in patients at high risk for peripheral arterial disease, ankle brachial pressure index Correspondence: Jacqueline Thomas; jacqui.thomas@ must first be completed before safely proceeding comcast.net

Page 18 CLINICAL MANIFESTATIONS AND MANAGEMENT OF LIVEDOID VASCULOPATHY “8 to Z” Yin and Yang Flap: A Novel Double Rotation Flap

Leela Athalye, DO,* Jack Griffith, DO**

*Second-year resident, Western/College Medical Center, Long Beach, CA **Practicing dermatologist, Coast Dermatology, Torrance, CA

Abstract The incidence of basal cell carcinoma, squamous cell carcinoma, and melanoma continues to increase. Surgical excision is a common preferred method for achieving cure. However, surgical closure without distorting the surrounding structures can be arduous in certain areas. Further complicating the situation is having two contiguous defects. We hope to provide an option for closing such a defect.

the patient, the challenge for a dermatologic from the two edges to create the final product WeObjective present a novel technique for repairing surgeon is to properly close a defect in a functional seen in Figure 3. Of note, similar closures have contiguous surgical defects with a double rotation manner that not only achieves approximation of been described in the literature as a double flap called an “‘8 to Z’ yin and yang” flap. the wound but also maintains the cosmesis of Burow’s “advancement” flap; however, we feel an area. Additionally, in sun-damaged patients that this is best depicted as a double rotation flap there is often more than one carcinoma present when additional tissue for Burow’s triangles are Materials at a given site, which further complicates the not taken. Standard excision tray. closure. We intend to show the closure of two defects that are in close proximity, as well as Our “‘8 to Z’ yin and yang” flap utilizes a similar present a novel technique for repair and closure concept of rotating tissue in two directions to WeConclusion describe a novel method for repairing two of two contiguous surgical defects. close a defect. However, we build upon this juxtaposed defects with a double rotation flap concept to close two contiguous defects. Our to not only minimize wound tension but also patient is a 55-year-old man who presented maintain the cosmesis of the skin. There are The “8 to Z” Yin and Yang with a melanoma in situ that was adjacent to many manners in which a lesion can be closed: by Flap a basal cell carcinoma. On the first day, the altering the defects to do a primary closure, skin We present our idea for a flap we call an “8 to Z” melanoma in situ on the apical scalp was excised grafting, designing a flap, secondary intention double rotation “yin and yang” flap as a surgical without closure, while histopathology confirmed healing, or any combination thereof. We believe option to close two juxtaposed defects, and we clearance of the lesion. On the second day, our method of closure is simple and can retain the contrast it with a similar flap that we used to Mohs micrographic surgery was performed on undistorted appearance of the skin. close two lesions close in proximity. We will the basal cell carcinoma. Eventually, the basal first discuss the latter, a flap that has been dealt cell carcinoma defect converged with that of the with previously in the literature. We used this flap melanoma and created a bilobed defect shaped Introduction to address two lesions that were nearby but not like a figure 8. Skin cancers including basal cell carcinoma, contiguous.1-3 squamous cell carcinoma, and melanoma are Secondary intention was not considered, as commonly encountered in dermatologic practice. Figure 1 demonstrates two 1.5-cm lesions that this lesion occurred in a non-concave area and The incidence of these cancers continues to rise. were 2.5 cm apart. The flap was designed and prolonged healing was not attractive to the Complete surgical extirpation is curative in the excised, which resulted in the surgical defect patient. A primary elliptical closure would have majority of cases. In addition to surgically curing seen in Figure 2. The tissue was then rotated necessitated the removal of additional tissue and resulted in excess skin tension. We designed an “8

Figure 3. Final closure that avoids tissue Figure 1. Two non-melanoma skin cancers in Figure 2. The defects are excised. close proximity. distortion.

ATHALYE, GRIFFITH Page 19 to Z” double rotation “yin and yang” flap for the closures that may be hidden parallel to linear purpose of closing this defect in the notoriously relaxed skin tension lines. A rotation flap moves tight area of the scalp. Wound A had a diameter nearby tissue around a pivot point to close a measuring 4.1 cm, and wound B measured 3.3 defect. Rotation flaps are able to redistribute and cm, as seen in Figure 4. The right inferior border redirect tension to close tight areas such as the of wound A was undermined and stretched to scalp. A transposition flap is elevated and carried attach to the left superior edge of the wound A. over intervening skin and then sutured into place. In doing this, the left superior border of wound B Similar to rotation flaps, transposition flaps also was approximated with the right inferior border redirect and redistribute tension, but instead of of A. Figure 5 demonstrates the vector lines directly moving into a site, they have to surpass that were designed to do this. 4-0 VICRYLTM nearby tissue. One advantage of this technique was buried to suture these edges together to is that the transposition flap may be smaller create a final Z configuration. Interrupted 4-0 and require less tissue. Two classic examples of PROLENETM was used to evert the closure. transposition flaps include rhomboid flaps and Figure 6 demonstrates the final lazy “Z” closure, bilobed flaps that are frequently used in nasal or yin and yang configuration. reconstruction. We present a unique double rotation flap that we call the “‘8 to Z’ yin and yang” flap. In addition to the flap we demonstrated in Figures 1-3, other literature has described flaps that utilize an Figure 6: Final lazy “Z” yin and yang closure advancement flap with Burow’s triangles in order that minimizes the wound tension and maintains 3 to achieve closure of two defects. Our flap is the cosmesis of the scalp. similar in that we have two lesions; however, our lesions are attached rather than adjacent. While Discussion our flap builds upon the same principle as those There are myriad options to close a surgical in the literature, one advantage of the “‘8 to Z’ yin wound. The simplest manner is by secondary and yang” flap is that it doesn’t require additional intention, which allows the body to close the incisions and tissue sacrifice to create a Burow’s wound gradually over time. This method is triangle. Instead, it utilizes the borders of the frequently suitable for concave areas like the defects to rotate together to close the lesion. We medial canthus, conchal bowl, and the junction believe this strategy minimizes the number of between the nose and cheek. Secondary incisions as well as the overall defect size, which intention is also considered when closure of a ultimately leads to a better cosmetic result for the wound would result in too great of tissue tension patient. or if a patient cannot tolerate further surgery. In a society that is increasingly being diagnosed A primary fusiform elliptical closure is another with skin cancers such as basal cell, squamous cell, straightforward closure that can lead to a linear and melanoma, a dermatologist’s role as surgeon scar that is cosmetically elegant. This manner of is critical. The challenge of this role is not only to Figure 4. “Figure 8” defect after removal of closing is relatively low risk for complications excise the lesion but also to close it in a cosmetic melanoma and basal cell carcinoma. such as necrosis. However, one drawback of this and functional manner. We present the “‘8 to procedure is that additional tissue is typically Z’ yin and yang” flap as a potential treatment spared to create the elliptical configuration. modality to close two contiguous defects. Beyond fusiform closures, there are flaps and grafts. In full-thickness skin grafts, tissue is excised down to subcutis from a donor area and re-implanted in the surgical defect. However, References 1. McGinness, JL, Parlette HL. A Novel Technique this results in interruption of vascular supply that Using a Rotation Flap for Repairing Adjacent Surgical is not optimal for wound healing. Surgical defects Defects. Dermatol Surg. 2006;32:272-275. that expose cartilage, bone, tendon, or have other 2. Zivony D, Siegle RJ. Burrow’s wedge advancement poorly vascularized beds are not good candidates flaps for reconstruction of adjacent surgical defects. for this treatment modality. Another drawback Dermatol Surg. 2002;28:1162-4. of this technique is that the use of dissimilar tissue may result in a repair that contrasts with 3. Metz BJ, Katta K. Burrow’s advancement flap closure of adjacent defects. Dermatol Online J. 2005;11(1). surrounding skin. 4. Ebrahimi A, Nejadsavari, N. Upper Forehead Skin Flaps are often preferred to grafts, as they take Reconstruction with H-Flap. J Cutan Aesthet Surg. advantage of the laxity of adjacent tissue to 2013;6(3):152-154. approximate the wound without a complete 5. Baker SR. Local Flaps in Facial Reconstruction. 2nd interruption of vascular supply. An ideal flap is ed. Philadelphia, PA: Elsevier; 2007. one that is able to close the primary defect, yet minimize the subsequent secondary defect. The 6. TerKonda RP, Skyes JM. Concepts in scalp and forehead reconstruction. Otorlaryngol Clin North Am. primary motion of the donor tissue surrounding a 1997;30:519-39. defect distinguishes a flap as either advancement, rotation, or transposition. An advancement flap is one that moves in a linear direction to close Figure 5. Demonstrates the tension vectors in Correspondence: Leela Athalye, DO; [email protected] a primary defect. These flaps are best used in order to transition the “8” to “Z” areas of tissue redundancy and can produce linear

Page 20 “8 TO Z” YIN AND YANG FLAP: A NOVEL DOUBLE ROTATION FLAP Combination of Topical Imiquimod and Oral Acitretin in the Treatment of Multiple Large Basal- and Squamous-Cell Carcinomas of the Face

Anne Donato, MD,* J. Kate Jackson, PA-C,** Laura Sandoval, DO,*** Jonathan S. Crane, DO, FAOCD****

*Internal Medicine Resident, 1st year, New Hanover Regional Medical Center, Wilmington, NC **Dermatology Physician Assistant, DermOne, Wilmington, NC ***Dermatology Resident, 1st year, Campbell University School of Osteopathic Medicine, Buies Creek, NC; Sampson Regional Medical Center, Clinton, NC ****Dermatologist, DermOne, Wilmington, NC; Campbell University School of Osteopathic Medicine, Buies Creek, NC; Dermatology Residency Program Director, Sampson Regional Medical Center, Clinton, NC

Abstract Historically, both basal- and squamous-cell carcinoma skin cancers have been treated surgically with high cure rates and good cosmetic results. However, patients with multiple large facial tumors may experience significant cosmetic scarring with surgery, and therefore represent a patient population that may benefit from a trial of medical therapy. The following case involves a 65-year-old white male who presented with multiple basal- and squamous-cell carcinomas of the face who refused surgical or radiation treatment. We treated the patient using combination therapy of topical imiquimod and oral acitretin, resulting in remarkable clearance of all cancerous facial lesions.

TheIntroduction treatment of basal- and squamous-cell carcinomas generally involves surgical removal and occasionally radiotherapy.1,2 Additionally, medical therapies such as topical imiquimod, topical 5-fluorouracil, oral acitretin, and most recently vismodegib have become a part of the armamentarium in cutaneous tumor therapy.3,4 Despite these medical innovations, the standard of care remains surgical.5 The majority of basal- and squamous-cell carcinomas may be excised, especially with the increasing availability of Mohs surgery.2 In the event that a patient cannot undergo surgery or if the tumor is too large, radiation therapy may also be considered.5 Generally, surgical and/or radiation therapies result in cure of non-melanoma skin cancers without a major adverse effect on cosmesis or quality of life. The case presented herein represents one of the rare patients with multiple facial basal- and squamous-cell carcinomas who would experience significant surgical scarring with excision. Ultimately, the patient refused surgery and also opted against radiation therapy. We report that the combination therapy of topical imiquimod and oral acitretin resulted in complete resolution of the basal- and squamous-cell tumors after 16 months of follow-up.

ACase 65-year-old Report man presented with multiple basal- and squamous-cell carcinomas of the face. Physical exam revealed large, erythematous, crusted plaques over the left side of the face (Figure 1) and smaller plaques on the right side of the face. Over a three-month time period, he was diagnosed with the following pathologies and sizes: a large, well-differentiated squamous- Figure 1 cell carcinoma of the left temple (5.5 cm x 6 cm) (Figure 2), a large squamous-cell carcinoma in

DONATO, JACKSON, SANDOVAL, CRANE Page 21 likely have resulted in poor cosmesis. Initially, the alone was effective in case reports for the patient was offered Mohs surgery and superficial treatment of multiple squamous-cell carcinomas radiation therapy, both of which he refused. He and keratoacanthomas.10-12 had a consultation with a radiation oncologist, The combination of topical imiquimod and who performed a PET-CT scan showing no oral acitretin for the treatment of basal-cell evidence of metastatic disease. After informing carcinomas is limited to a few case reports.13-16 the patient of the possible risk of death without A young boy with xeroderma pigmentosum with surgery or radiation, we proceeded with treatment multiple facial and oral basal-cell carcinomas was with the combination of topical imiquimod and treated with topical imiquimod and oral acitretin oral acitretin. He was prescribed imiquimod 5% for four to six weeks.13 At six-month follow-up, cream nightly with acitretin 10 mg daily for 12 Figure 2 all tumors were clinically clear. In another report, weeks. After 12 weeks, he continued the acitretin two patients with giant basal-cell carcinomas 10 mg daily and decreased imiquimod 5% cream were treated with topical imiquimod and oral application to weekly. acitretin to promote tumor regression prior to After 16 months of therapy without any evidence surgical or radiation therapy.14 Additionally, of recurrence or adverse effects, the patient topical imiquimod and oral acitretin have continues on this regimen as maintenance. As of been successfully combined to treat extensive publication, there is complete clinical resolution bowenoid papulosis in a patient with HIV.15 While of his skin cancers (Figure 6), and the patient is the literature contains examples of cases using very pleased with the cosmetic result. this combination therapy in basal- and squamous- cell carcinomas, our case is unique given the large sizes of tumors, mixed pathology, and the Figure 6 extraordinary results with extensive follow-up at Figure 3 16 months. The rationale behind the combination of imiquimod cream and acitretin for anti-tumor therapy exists if one considers their individual mechanisms. In particular, imiquimod is an immune-response modifier.17 Imiquimod stimulates cytokine production (interferon- alpha, interferon-gamma, and interleukin-12), thereby activating cell-mediated immunity, specifically anti-tumor activity.17,18 The efficacy of imiquimod in treating superficial basal-cell Figure 4 carcinomas has been well-established with 43% to 100% efficacy, while the efficacy in squamous- cell carcinomas ranges from 73% to 88% for squamous-cell carcinoma in situ and 71% for invasive squamous-cell carcinoma.3 Acitretin is a retinoid and thus mediates its effects via binding to nuclear-receptor genes and controlling cellular differentiation and proliferation and reducing keratinization.19 The role of acitretin in skin- Discussion cancer therapy has emerged in the renal transplant To our knowledge, our case is the first to report population as a means of non-melanoma skin effective treatment with prolonged success of 16 cancer prophylaxis.8,9 Taken together, imiquimod months of multiple large basal- and squamous- Figure 5 works to activate the immune system to attack cell carcinomas of the face with the combination the tumor cells, while acitretin works to prevent situ involving the base of the biopsy of the left of topical imiquimod and oral acitretin without further production of tumor cells. cheek (8.5 cm x 4.5 cm) (Figure 3), squamous- surgical removal. We suggest this combination cell carcinoma in situ of the left ear (0.5 cm x 0.5 therapy may be a novel treatment approach for patients who are not surgical or radiation cm) (Figure 4), and basal-cell carcinomas of the Overall,Conclusion this patient’s case suggests an innovative candidates. The combination of topical right upper chest (2.1 cm x 1.8 cm), right ear (0.5 medical therapy of basal- and squamous-cell imiquimod and oral acitretin has been previously cm x 0.5 cm) (Figure 5), right nasal sidewall (0.5 carcinomas with topical imiquimod and oral reported in preventing the recurrence of a highly cm x 0.5 cm), and right forearm (2.2 cm x 2 cm) . acitretin. For patients who would suffer from aggressive squamous-cell carcinoma after the significant surgical scarring or radiation side The basal-cell carcinomas of the right nasal tumor was initially surgically excised in a patient effects, we believe that dermatologists should be sidewall and right forearm were treated with Mohs status post renal transplant.6 Another case found aware of the potential prolonged response with surgery without complications. As can be seen this combination effective for the treatment this therapy that may result in a more resectable in Figure 1, the coalescence of the large, well- of multiple keratoacanthomas.7 Acitretin as tumor or in a complete tumor response. differentiated squamous cell carcinoma of the left monotherapy for prevention of squamous-cell temple and the large squamous-cell carcinoma in carcinoma in renal transplant patients has been situ of the left cheek covered a significant portion established.8,9 In additional, acitretin therapy of the patient’s face, and surgical removal would

Page 22 COMBINATION OF TOPICAL IMIQUIMOD AND ORAL ACITRETIN IN THE TREATMENT OF MULTIPLE LARGE BASAL- AND SQUAMOUS-CELL CARCINOMAS OF THE FACE carcinoma. Scand J Plast Reconstr Surg Hand Surg. 1.References Lansbury L, Bath-Hextall F, Perkins W, Stanton 2003;37(5):293-5. W, Leonardi-Bee J. Interventions for non-metastatic 17. Sauder DN. Immunomodulatory and pharmacologic squamous cell carcinoma of the skin: systematic review properties of imiquimod. J Am Acad Dermatol. 2000 and pooled analysis of observational studies. Br Med J. Jul;43(1 Pt 2):S6-11. 2013 Nov;347:f6153. 18. Suzuki H, Wang B, Shivji GM, Toto P, Amerio 2. Chren MM, Linos E, Torres JS, Stuart SE, P, Tomai MA, et al. Imiquimod, a topical immune Parvataneni R, Boscardin WJ. Tumor recurrence 5 response modifier, induces migration of Langerhans years after treatment of cutaneous basal cell carcinoma cells. J Invest Dermatol. 2000 Jan;114(1):135-41. and squamous cell carcinoma. J Invest Dermatol. 2013 May;133(5):1188-96. 19. Pang ML, Murase JE, Koo J. An updated review of acitretin--a systemic retinoid for the treatment of 3. Love WE, Bernhard JD, Bordeaux JS. Topical psoriasis. Expert Opin Drug Metab Toxicol. 2008 imiquimod or fluorouracil therapy for basal and July;4(7):953-64. squamous cell carcinoma: a systematic review. Arch Dermatol. 2009 Dec;145(12):1431-8. Correspondence 4. Sekulic A, Migden MR, Oro AE, Dirix L, Lewis KD, : Jonathan S. Crane, DO, FAOCD; Hainsworth JD, et al. Efficacy and safety of vismodegib 1099 Medical Center Dr., Wilmington, NC 28401; in advanced basal-cell carcinoma. New Engl J Med. Ph: 910-251-9944; F: 910-763-4666; katejackson@ 2012 Jun;366(23):2171-9. dermone.com 5. James WD, Berger T, Elston D. Andrews’ Diseases of the Skin. 11th rev. ed. Saunders; 2011. 968 p. 6. Haustein UF, Paasch U. Aggressive undifferentiated squamous cell carcinoma in an immunosuppressed patient after kidney transplantation. J Dtsch Dermatol Ges. 2005 Jan;3(1):44-6. 7. Barysch MJ, Kamarashev J, Lockwood LL, Dummer R. Successful treatment of multiple keratoacanthoma with topical imiquimod and low-dose acitretin. J Dermatol. 2011 Apr;38(4):390-2. 8. Bavinck JN, Tieben LM, Van der Woude FJ, Tegzess AM, Hermans J, ter Schegget J, et al. Prevention of skin cancer and reduction of keratotic skin lesions during acitretin therapy in renal transplant recipients: a double-blind, placebo-controlled study. J Clin Oncol. 1995 Aug;13(8):1933-8. 9. De Sevaux RG, Smit JV, de Jong EM, van de Kerkhof PC, Hoitsma AJ. Acitretin treatment of premalignant and malignant skin disorders in renal transplant recipients: clinical effects of a randomized trial comparing two doses of acitretin. J Am Acad Dermatol. 2003 Sep;49(3):407-12. 10. Street ML, White JW, Gibson LE. Multiple keratoacanthomas treated with oral retinoids. J Am Acad Dermatol. 1990 Nov;23(5 Pt 1):862-6. 11. Robertson SJ, Bashir SJ, Pichert G, Robson A, Whittaker S. Severe exacerbation of multiple self- healing squamous epithelioma (Ferguson-Smith disease) with radiotherapy, which was successfully treated with acitretin. Clin Exp Dermatol. 2010 Jun;35(4):e100-2. 12. Niv D, Keehan P. Use of acitretin in a patient with multiple squamous cell carcinomas: A case report and review of literature. J Am Osteopath Coll Dermatol. 2013;26:18-20 13. Giannotti B, Vanzi L, Difonzo EM, Pimpinelli N. The treatment of basal cell carcinomas in a patient with xeroderma pigmentosum with a combination of imiquimod 5% cream and oral acitretin. Clin Exp Dermatol. 2003 Nov;28 Suppl 1:33-5. 14. Sanmartin V, Aguayo R, Baradad M, Casanova JM. Oral acitretin and topical imiquimod as neoadjuvant treatment for giant basal cell carcinoma. Actas Dermosifiliogr. 2012 Mar;103(2):149-52. 15. Lim JL, K; Chong, W. Dramatic Clearance of HIV- Associated Bowenoid Papulosis Using Combined Oral Acitretin and Topical 5% Imiquimod. J Drugs Dermatol. 2014 Aug;13(8). 16. Ingves C, Jemec GB. Combined imiquimod and acitretin for non-surgical treatment of basal cell

DONATO, JACKSON, SANDOVAL, CRANE Page 23 Herpes Zoster Ophthalmicus in a Patient with Wegener’s Granulomatosis

Sunny Chun, DO,* Karan Lal, BS,** David Posnick, DO,* Adriana Ros, DO***

*Dermatology Resident, Palisades Medical Center, Palisades, NJ **OMSIV, New York Institute of Technology- College of Osteopathic Medicine, Old Westbury, NY ***Program Director, Dermatology Residency Program, Palisades Medical Center, Palisades, NJ

Abstract Herpes zoster ophthalmicus (HZO) is a serious presentation of varicella-zoster virus infection in the periocular region that may manifest cutaneously but can progress to have ocular involvement, justifying ophthalmologic consultation. Co-morbid diseases may complicate the diagnosis and management of HZO, requiring thorough monitoring of the patient’s progress and potential drug interactions of patient’s medications. Early oral antiviral treatment decreases the rate of development of ocular complications. Post-herpetic neuralgia is a frequent complication of herpes zoster and is best managed with multi-modal drug regimens that work on different mechanisms of the disease.

Introduction Case Presentation Herpes zoster ophthalmicus is a reactivation of A 44-year-old Puerto Rican female presented to herpesvirus-3, also known as the varicella-zoster the emergency department for right periorbital virus, in the distribution of the ophthalmic branch erythema and edema for two days’ duration. of the trigeminal nerve (CN V). It represents up She reported difficulty opening the right eye, to 25% of all herpes zoster presentations.1 Risk radiating throbbing pain along the right side factors for re-activation of the virus include old of her face, and fever. The blistering rash was age, immunosuppressive drugs and diseases, present in the right periorbital region, on the emotional stress, neoplastic disorders, fatigue, right anterior scalp and right dorsum of the nose. poor nutrition, and recreational drug abuse.2-5 The patient also complained of tenderness of Clinical presentation may be preceded by malaise, affected areas along the right hemi-facial region. fatigue, headache, fever, and/or photophobia.3 The patient also stated that over the past year, Lesions typically follow the phases of non- she’d experienced gradually increasing weakness ophthalmic zoster or “shingles,” beginning with in the lower extremities, hearing loss, and joint unilateral dermatomal pruritus, pain, and/or pain. Past medical history included depression, tingling that may be present for up to five days asthma, and Wegener’s granulomatosis, which before an erythematous vesicular rash appears. was diagnosed in 2010 in Puerto Rico based on The vesicles eventually rupture, form crusts, and a skin biopsy of the patient’s thigh, for which she then heal without scarring. was placed on chronic prednisone therapy by her primary physician. Past surgical history included multiple skin grafts for perforated nasal septum secondary to Wegener’s granulomatosis. The patient’s home medications included: prednisone, Figure 2. Atrophic hypopigmented plaques gabapentin, fluoxetine, tramadol, trazodone, iron located in a relatively symmetrical pattern on sulfate, and alprazolam. The patient had a family the lower extremities. history of diabetes mellitus and stroke. Physical examination revealed multiple vesicles patient was rapid plasma reagin (RPR) negative on an erythematous base in the right periorbital and human immunodeficiency virus negative. region, forehead, scalp and nasal dorsum (Figure The patient was admitted and placed on 1). Additionally, white exudative plaques were intravenous acyclovir 200 mg (TID), visible on the anterior tongue. Coalescing methylprednisolone 20 mg (BID), terbinafine for yellow exophytic verrucous plaques were her presumed tinea pedis, nystatin mouth wash present on the soles of her feet. Examination of for oral candidiasis, and pertinent antibiotics for extremities revealed multiple, bilateral, atrophic her periorbital cellulitis. Blood cultures showed hypopigmented plaques on the anterior tibial and no growth after five days, and antibiotics were thigh regions (Figure 2). discontinued. A punch biopsy of the thigh lesion Urinalysis revealed hematuria and proteinuria. revealed dermal fibrosis with mild inflammation A bilateral renal sonogram was unremarkable; (Figure 3). Elastin staining showed fragmented, however, ultrasound of the bladder displayed thin elastic fibers indicative of scar. The scar most focal bladder irregularity. Computed tomography likely was a result of healing from a previous (CT) scan, with and without contrast, of the head active Wegener’s lesion. Subsequent laboratory testing revealed low absolute lymphocyte counts Figure 1. Vesicular rash with several crusted and neck indicated right periorbital cellulitis and pansinusitis. The ophthalmology service was (468), low absolute CD4 counts (147), and low areas presenting in a dermatomal distribution consulted, and they noted no ocular involvement. CD8 counts (147). Because the patient was and respecting the midline. Upper eyelid Laboratory tests revealed elevated p-ANCA immunosuppressed, she was given prophylactic involvement with edema and erythema. (2.7), but negative c-ANCA. The erythrocyte sulfamethoxazole/trimethoprim. The patient Concomitant conjunctivitis noted. sedimentation rate (ESR) was also elevated. The continued to complain of facial pain and was

Page 24 HERPES ZOSTER OPHTHALMICUS IN A PATIENT WITH WEGENER’S GRANULOMATOSIS are usually focally present on the forehead multiple mechanisms of disease with combination and periocular region of the affected side, with therapies is logical, and often gabapentin, tricyclic some involvement of the nose.6 Nasociliary antidepressants and/or topical lidocaine patches nerve involvement, identified by lesions on the are used as first-line agents, followed by opioids tip of the nose, also known as Hutchinson’s and capsaicin as second-line agents.27 sign, prognosticates ocular involvement due to the nerve’s location.6 Zoster ophthalmicus may References also present as a blepharitis causing difficulty 1. Ragozzino MW, Melton LJ 3d, Kurland LT, Chu CP, opening the eye with non-neural ptosis.6 About Perry HO. Population-based study of herpes zoster and 66% of patients with HZO have been found its sequelae. Medicine. 1982;61:310–6. to have corneal denervation associated with 2. Cohen JI, Brunell PA, Straus SE, Krause PR. Recent keratitis and mesencephalic nuclear brainstem advances in varicella-zoster virus infection. Ann Intern injury.16 Corneal nerve involvement and injury Med. 1999;130:922-932. results in neurotrophic keratopathy, which may 3. Gnann JW, Whitley RJ. Herpes Zoster. N Engl J cause several complications, including blindness; Med. 2002;347(5):340-46. Figure 3. H&E staining (10x): Examination of therefore, it is imperative to seek ophthalmologic an atrophic hypopigmented lower-extremity 4. Shaik S, Ta CN. Evaluation and Management of evaluation to determine the extent of the disease Herpes Zoster Ophthalmicus. Am Fam Physician. plaque revealing fibroblastic proliferation 17 and whether ocular involvement is present. 2002 Nov;66(9):1723-1730. within the dermis with blood vessels in an Other ocular presentations of HZO include arrangement perpendicular to the epidermis 5. Zwick OM, Fischer DH, Flanagan JC. “Ecstasy” conjunctivitis, uveitis, episcleritis, acute retinal induced immunosuppression and herpes zoster with a focal perivascular inflammatory infiltrate necrosis, progressive retinal necrosis, optic ophthalmicus. Br J Ophthalmol. 2005;89:923–924. indicative of a scar. neuritis, and cranial nerve palsies.6 6. Shafiei K, Luther E, Archie M, Gulick J, Fowler The diagnosis of HZO is clinical; however, some MR. Wegener Granulomatosis: Case Report and treated with nortriptyline. Serial complete blood cases of HZO may be difficult to delineate in Brief Literature Review. J Am Board Fam Med. counts revealed decreasing red blood cell counts, the presence of other co-morbid diseases such as 2003;16(6):555-59. hemoglobin levels, and hematocrit levels. granulomatosis with polyangiitis or periorbital 7. Anderson G, Coles ET, Crane M, et al. Wegener’s The patient was eventually discharged with cellulitis, as was the situation in our patient. Viral granuloma. A series of 265 British cases seen between residual erythema and pain for which she was cultures may be performed from lesions, but 1975 and 1985. A report by a sub-committee of the prescribed famciclovir PO 500 mg TID for five they are less sensitive and more time-consuming British Thoracic Society Research Committee. Q J 3,18 Med. 1992;83:427-38. days, sulfamethoxazole/trimethoprim for three than direct immunoflourescence assay. days, gabapentin and amitriptyline. She was Differential diagnoses include herpes simplex, 8. Bullen CL, Liesegang TJ, McDonald TJ, DeRemee instructed to continue her home medications. vasculitis, trigeminal neuralgia, erysipelas, RA. Ocular complications of Wegener’s granulomatosis. cellulitis, sarcoidosis, trigeminal trophic Ophthalmology. 1983;90:279–90. syndrome, cutaneous lupus erythematosus, 9. Marinaki S, Neumann I, Kalsch AI, Grimminger Discussion syphilis, cutaneous anthrax, leshmaniasis, leprosy, P, Breedijk A, Birck R, et al. Abnormalities of CD4+ Wegener’s granulomatosis, also known as zygomycosis, and sporotrichosis. T cell subpopulations in ANCA-associated vasculitis. granulomatosis with polyangiitis, represents Clin Exp Immunol. 2005;140:181–91. a systemic, anti-neutrophil, cytoplasmic- Treatment of HZO is important because 10. Christensson M, Pettersson E, Sundqvist KG, autoantibody vasculitis that affects small and approximately half of untreated patients suffer Christensson B. T cell activation in patients with medium vessels, particularly within the kidneys from ophthalmologic complications.19 Acyclovir, 6 ANCA-associated vasculitis: inefficient immune and within the respiratory system. Although valacyclovir, and famciclovir are FDA-approved suppression by therapy. Clin Nephrol. 2000;54:435-42. upper airway involvement, including pansinusitis for the treatment of herpes zoster.3 Patients with an active rash can be treated with acyclovir 800 11. Schlesier M, Kaspar T, Gutfleisch J, Wolff-Vorbeck and/or gingivitis, is the most common initial G, Peter HH. Activated CD4+ and CD8+ T-cell presentation of disease, ocular involvement may mg five times daily for up to 10 days’ duration. subsets in Wegener’s granulomatosis. Rheumatol Int. represent up to 16% of initial presentations of Based on numerous studies, this regimen has 1995;14:213-9. the disease.6-8 Our patient’s chronic prednisone been shown to prevent the formation of new 12. Gutfleisch J, Baumert E, Wolff-Vorbeck G, lesions, decrease pain, reduce viral shedding, therapy, similar to regimens of many other Schlesier M, Strutz HJ, Peter HH. Increased expression patients with vasculitides, may have played a and decrease the incidence of certain late of CD25 and adhesion molecules on peripheral blood role in her immunosuppression and concurrent ocular complications including anterior uveitis lymphocytes of patients with Wegener’s granulomatosis 20-22 pansinusitis, which ultimately led to the and early-to-late keratitis. Patients with (WG) and ANCA positive vasculitides. Adv Exp Med recurrence of varicella-zoster virus manifesting immunosuppressive states should be treated with Biol. 1993;336:397-404. 23,24 as HZO. It has been identified that regardless intravenous acyclovir. Due to our patient’s 13. Ikeda M, Watanabe Y, Kitahara S, Inouye T. of disease status, patients with Wegener’s concurrent vasculitis and low CD4 counts, she Distinctive increases in HLA-DR+ and CD8+57+ granulomatosis have been reported to have was placed on intravenous therapy, but was lymphocyte subsets in Wegener’s granulomatosis. Int decreased numbers of total, absolute, and relative discharged on oral valacyclovir, 1000 mg twice Arch Allergy Immunol. 1993;102:205-8. CD4+ T cell counts compared to controls. This daily dosing for one week, which has been shown 14. Iking-Konert C, Vogl T, Prior B, Wagner C, Sander can be attributed not only to immunosuppressive to prevent ocular complications such as keratitis O, Bleck E, et al. T lymphocytes in patients with 25 systemic medications but also to the relocation of and conjunctivitis. It has also been found to primary vasculitis: expansion of CD8+ T cells with the blood T cells to diseased organs.9-13 In contrast, decrease average time of zoster-related pain in propensity to activate polymorphonuclear neutrophils. CD8+ T cell counts tend to be comparatively comparison to acyclovir.26 Rheumatology. 2008;47:609-16. increased, with reduced CD4:CD8 ratios in all 15. Ikeda M, Tsuru S, Watanabe Y, Kitahara S, Inouye 10,11,14,15 Post-herpetic neuralgia is a significant spectrums of disease. complication of herpes zoster, particularly in T. Reduced CD4-CD8 T cell ratios in patients with Wegener’s granulomatosis. J Clin Lab Immunol. Herpes zoster ophthalmicus typically presents the elderly population. It occurs in up to 20% 1992;38:103–9. with a vesicular rash along the distribution of patients with herpes zoster within the same of the ophthalmic division of the trigeminal region of the infection and can last anywhere 16. Pavan-Langston D. Herpes zoster ophthalmicus. Neurology. 1995;45:S50–1. nerve and its branches, including the lacrimal, from a few months to a few years, at times nasociliary, and supraorbital nerves. Lesions being intractable to many medications.27 In the 17. Hamrah P, Cruzat A, Dastjerdi MH, Prüss H, management of post-herpetic neuralgia, targeting Zheng L, Shahatit BM, Bayhan HA, Dana R, Pavan- CHUN, LAL, POSNICK, ROS Page 25 Langston D. Unilateral Herpes Zoster Ophthalmicus Results in Bilateral Corneal Nerve Alteration. Ophthalmology. 2013;120(1):40-47. Examination of Incompletely Excised 18. Dahl H, Marcoccia J, Linde A. Antigen detection: the method of choice in comparison with virus isolation Non-melanoma Skin Cancers and serology for laboratory diagnosis of herpes zoster in human immunodeficiency virus-infected patient. J Clin Cathy Koger, DO,* Roxanne Rajaii, MS,** Vanessa Pazdernik, MS,*** Kelby Martens,**** Jonathan L. Cleaver, DO, Microbiol. 1997;35:345-349. FAOCD,*****Lloyd J. Cleaver, DO, FAOCD****** 19. Cobo M, Foulks GN, Liesegang T, et al. Observations on the natural history of herpes zoster ophthalmicus. *Dermatology Resident, 3rd year, Northeast Regional Medical Center, Kirksville, MO Curr Eye Res. 1987;6:195-199. **Medical Student, 4th year, A.T. Still University, Kirksville, MO ***Biostatistician, Research Support, A.T. Still University, Mesa, AZ 20. Huff JC, Bean B, Balfour HH, et al. Therapy of herpes ****Histology Technician, Cleaver Dermatology, Kirksville, MO zoster with oral acyclovir. Am J Med. 1988;85(2A):84- *****Principal Investigator, Dermatologist, Northeast Regional Medical Center/Cleaver Dermatology, Kirksville, MO 88. ******Program Director, Dermatology Residency Program, Northeast Regional Medical Center/Cleaver 21. Morton P, Thomson AN. Oral acyclovir in the Dermatology, Kirksville, MO treatment of herpes zoster in general practice. N Z Med J. 1989;102:93-95. 22. McKendrick MW, McGill JI, White JE, Wood Abstract MJ. Oral acyclovir in acute herpes zoster. Br Med J. Wide-local excision is standard of treatment for non-invasive or non-aggressive basal cell carcinomas (BCCs) 1986;293:1529-1532. and squamous cell carcinomas (SCCs) (collectively “non-melanoma skin cancers,” or NMSCs) that do not meet 23. Balfour HH Jr, Bean B, Laskin OL, Ambinder RF, the guidelines for Mohs micrographic surgery. Criteria for excisional margins used during NMSC removal Meyers JD, Wade JC, et al. Acyclovir halts progression have been suggested, but no absolute guidelines exist for specific margins. Although different surgical margins of herpes zoster in immunocompromised patients. N have been suggested, no consensus has been reached. Tumor start size, patient age and gender, tumor type and Engl J Med. 1983;308:1448–53. location have been examined in analyses of incomplete excision of NMSCs. Despite consideration of these 24. Balfour HH Jr. Varicella zoster virus infections in factors and use of recommended margins, our clinic still has cases of incompletely excised NMSCs. Therefore, we immunocompromised hosts. A review of the natural retrospectively reviewed our surgical databases to determine whether a correlation existed between margins history and management. Am J Med. 1988;85:68-73. used and incomplete excisions of NMSCs. We also looked at other factors including patient age and gender, location of NMSC, and tumor type (BCC or SCC) that may have contributed to incomplete excision in these 25. Colin J, Prisant O, Cochener B, Lescale O, Rolland B, Hoang-Xuan T. Comparison of the efficacy and safety cases. of valaciclovir and acyclovir for the treatment of herpes zoster ophthalmicus. Ophthalmology. 2000;107:1507- depending on tumor type, risk, size, location, and Introduction 2,4,6,9,15,16,19,20,26,27 11. Wide-local excision (WLE) has long been a number of other factors. Despite taking into account these recommendations for 26. Beutner KR, Friedman DJ, Forszpaniak C, Andersen recognized and accepted as a standard treatment NMSC surgeries, our clinic has still had instances PL, Wood MJ. Valaciclovir compared with acyclovir for for non-melanoma skin cancers (NMSCs), improved therapy for herpes zoster in immunocompetent specifically those not meeting the criteria for of incompletely excised NMSC tumors, which adults. Antimicrob Agents Chemother. 1995;39:1546- Mohs micrographic surgery.21 In WLE, the have led to additional procedures for the patients 1553. skin cancer and a small margin of healthy in order to completely eradicate their cancer. 27. Massengill JS, Kittredge JL. Practical considerations tissue around it is cut out, typically using a Therefore, we performed a retrospective review in the pharmacological treatment of post-herpetic fusiform-shaped ellipse. The wound edges are of our surgical databases to determine whether neuralgia for the primary care provider. J Pain Res. 2014 closed, and the tissue is sent for processing and the margins used during our NMSC surgeries 17,25 Mar;7:125-132. margin evaluation by a pathologist. Surgical were directly correlated to incomplete excision of failure, or incomplete excision, is often defined NMSC tumors. We also looked at other variables Correspondence: Karan Lal, BS; [email protected] by pathologists as residual tumor within 1 mm that previous studies had cited as contributors to of the lateral or deep margin of the excised incomplete excisions, namely patient age, patient 2 specimen. Although clear surgical margins have gender, tumor location, and tumor type (SCC not been shown to completely eliminate tumor or BCC). 2,5,9,15,19,24 Our purpose was to identify recurrence, most studies advocate re-treatment any factors contributing to incomplete NMSC of incompletely excised NMSCs, especially those excision so that we could reduce the burden to that are defined as high-risk (deep-margin- patients of having multiple procedures performed involvement tumors, recurrent tumors, aggressive to eliminate skin cancers. histological subtype tumors, or tumors in critical anatomic sites).4,6,9,15,16,24 This re-treatment can be very costly, time-consuming, and stressful Methods We extracted surgical data for non-melanoma for patients. Thus, eliminating the need for re- skin cancers over a four-year period, from treatment through complete excision of NMSCs February 2010 to October 2013. This surgical data is important. was archived within our SOAPware™ database Since the 1970s, numerous studies have looked (2010-2011) and our EMA Dermatology™ at optimal surgical margins for successful NMSC database (2012-2013). We initially searched the excision. 2,4,6,9,15,16,19,20,26,27 Unlike in melanoma, pathology records for patients who had WLEs of where guidelines for excisional margins NMSCs to find all incompletely excised tumors. exist based on Breslow depth of the original Patients with incompletely excised NMSCs were tumor, NMSCs do not have set guidelines considered positive-margin patients. Information for margins, merely recommendations.1,3 The regarding each patient’s age, gender, location recommendations for NMSC surgical margins of tumor (neck, trunk, upper extremity, lower have been largely debated in numerous studies extremity), tumor type (BCC or SCC), and and range from 2 mm to 10 mm for basal cell margins used for excisions was also recorded. We carcinoma (BCC) excision and 4 mm to 15 mm noted, but did not include in our analyses, the for squamous cell carcinoma (SCC) excision, date of excision. All patients within our study Page 26 EXAMINATION OF INCOMPLETELY EXCISED NON-MELANOMA SKIN CANCERS were Caucasian with Fitzpatrick skin type II. There were 25 cases from 23 patients with incomplete excision rate for NMSCs was 5.1% in As this is a case control study, we used all non- positive post-operative margins. The 448 negative our study (95% confidence interval [3.4%, 7.6%]). positive margin patients between February 2010 post-operative margin controls came from 357 and October 2013 as controls for our study. patients. Of these 357 control patients, 296 had 1 Discussion Because our study was specifically related to BCC surgery, 38 had 2, 17 had 3, 5 had 4, and 1 patient NMSC is the most common cancer worldwide, and SCC, exclusion criteria for both controls and had 5 surgeries. Six of these 357 patients also with BCCs comprising roughly 80% of all positive-margin patients included patients who provided at least 1 case surgery (Table 2). Of the NMSCs.1 Various treatment options exist for had melanoma excisions and dysplastic nevi 66 patients who underwent surgery more than NMSC; however, WLE and Mohs micrographic excisions. One cellular blue nevus patient was also once, 38 were treated for the same type of cancer, surgery have the highest potential cure rate excluded. The current study was approved by the and 25 were treated at the same location. and are the most widely accepted therapeutic local institutional review board. Table 2. Patient distribution by number and type of surgery A random-intercepts multivariable logistic- regression model was used to test for potential # of Surgeries for Controls risk factors for positive margins after return from surgery. The patient was treated as a random # of Surgeries for Positive Margin Cases 0 1 2 3 4 5 Total effect to allow for correlation of surgery results 0 0 292 37 16 5 1 351 within an individual patient. The potential risk factors were age, gender, location of tumor (neck, 1 16 4 1 0 0 0 21 trunk, upper extremity, lower extremity), tumor 2 1 0 0 1 0 0 2 type (BCC or SCC), and size of margins used for Total 17 296 38 17 5 1 374 excisions. Age was categorized into two groups determined by the median age. Size of margins was broadened into two categories: greater than The multivariable logistic-regression model did options.4,6,9,16,19,21,26,28 WLE for NMSCs is 3 mm and less than or equal to 3 mm. Tukey- not show a significant independent effect of commonly used when tumors do not meet the Kramer adjustments were used in pairwise potential risk factors (age, gender, tumor location, criteria for Mohs.21 Although the method for comparisons of location types. Significance was tumor type, or size of margins) on the probability excising a tumor is well-defined, recommendations set at .05. Analyses were conducted using SAS of returning from surgery with positive margins of surgical margins for NMSC are often debated 9.3 (SAS Institute Inc, Cary, NC). (all P ≥ .08) (Table 3). The test for location of and frequently revised. 2,4,6,9,15,16,19,20,25-27 tumor trended toward significance (P=.09), with The primary aim of the current study was to Results the upper extremity having the highest rate of Surgical data on 473 surgeries from 374 patients determine whether a correlation existed between was collected. Of the 473 surgeries, 213 surgeries positive margins at 7.5%, the lower extremity surgical margins used and incompletely excised were for female patients. The average age of at 5.8%, the neck at 1.7%, and the trunk at NMSCs. We also wanted to determine whether patients was 71 years (standard deviation, 13.6 0.9%. Table 3 provides Tukey-Kramer adjusted age, gender, location of tumor, or tumor type years). Demographic information is presented in p-values for pairwise comparisons of locations contributed to incompletely excised NMSCs, Table 1. of tumor. There were no significant differences because previous studies of positive-margin in rates of positive margins between tumor types Table 1. Demographics NMSC excisions have also evaluated these (4.33% and 2.21%), surgical margins (3.22% factors.2,5,9,15,22-24 Our intention was to use any and 2.98%), age ranges (3.09% and 3.11%) or Variable Summary* positive correlations found in the current study genders (3.13% and 3.06%). After adjusting for to appropriately adjust our WLEs and decrease Age 71 (13.6) multiple surgeries from an individual, the overall incompletely excised NMSC rates. Sex, Female 213 (45%) Table 3. Multivariable logistic-regression analyses Margin (mm)

1 2 (.4%) Covariable Rate Odds Ratio P Values (95% CI*) 2 52 (11%) 3 285 (60%) Tumor Type BCC vs. SCC 4.33% vs. 2.21% 2.01 .15 (0.77, 5.24) 4 115 (24%) Surgical Margin 5 8 (1.7%) ≤3mm vs. >3mm 3.22% vs. 2.98% 1.08 .88 (.39, 2.99) ≥6 11 (2.3%) Location** Tumor Neck 1.70% 0.21 .47 (0.01, 3.50) BCC 226 (48%) Trunk 1.20% 0.15 .09 (0.02, 1.21) SCC 240 (51%) Lower Extremity 5.81% 0.76 .98 (0.14, 4.19) Other 7 (1.5%) Upper Extremity 7.48% Location Age Neck 55 (12%) ≤73 vs. >73 3.09% vs. 3.11% 1.01 .99 (0.40, 2.55) Upper Extremity 220 (47%) Gender Trunk 129 (27%) Female vs. Male 3.13% vs. 3.06% 1.03 .96 (0.39, 2.71) Lower Extremity 69 (15%) *Confidence interval *Data are presented as mean (standard deviation) **The category reference is listed last. For example, the odds for positive margins on neck tumors or No. (%). are 0.21 times the odds on upper extremity tumors.

KOGER, RAJAII, PAZDERNIK, MARTENS, CLEAVER, CLEAVER Page 27 Surgical margins used in our NMSC excisions and SCCs into high- or low-risk groups.20 They younger than 50 years.23 followed literature recommendations, but given suggested 4-mm margins for low-risk BCCs or The current study had several limitations. Chart the variability of these recommendations, we SCCs and Mohs or complete peripheral/deep records were primarily created for purposes of hypothesized that surgical margins would be resection using 10-mm margins for high-risk clinical care, rather than for study objectives, our main contributor to incompletely excised BCCs or SCCs larger than 2 cm on the trunk or so the data was not always comprehensive. For

NMSCs. However, surgical margins were extremities. example, we did not look at start size of NMSCs, not a statistically significant contributor to In the current study, location of tumor contributed because it was not available for all records. This incompletely excised NMSCs in our study. most to incomplete excision, specifically in factor has been shown to be important in other Similarly, age, gender, and tumor type were not the upper extremity, although the association studies of incompletely excised NMSCs and statistically significant contributors. Location was not significant. Other studies have also perhaps should be taken into account in future of tumor had the closest positive correlation to assessed location of the tumor and incomplete analyses.2,4,5,8,15,17,24,26 A second consequence is incompletely excised NMSCs, with the upper excision.5,9,15,19,24 Unlike our results, these studies the possibility of erroneous data recording for extremity having the highest rate of positive reported the head and neck as the locations most each surgery. For example, the size of margins margins, but this correlation was not statistically significantly associated with incompletely excised used for NMSCs was sometimes reported in our significant. NMSCs. However, these studies used WLE for database using units of cm and in other instances WLE with adequate surgical margins is one of both head and neck tumors with smaller than using units of mm. The patient population used the most commonly used treatments for all types recommended margins, thus increasing their in our study was obtained from one hospital, of skin cancer, including NMSCs that do not rates of incompletely excised NMSCs.5,9,15,19,24 which not only limited the sample size of data meet Mohs criteria as well as melanomas of all Our clinic uses Mohs surgery where appropriate available (N=25 in our case) but also limited subtypes.1,3,4,6,9,16,19,21,26,28 Over the last few decades, for head and neck tumors, and we excluded Mohs generalizability to other hospitals or larger patient considerable research has been performed that surgeries from our data analyses.5,9,15,19,21,24 populations. The patient data was recorded over has established appropriate and effective margin Previous studies have reported a difference in a four-year time period for accuracy, which also sizes for melanoma excisions based on the depth rates of incomplete excision between BCCs and limited our sample size. The small sample size of the tumor, defined as the Breslow depth. SCCs. Therefore, we investigated tumor type as a inevitably decreased the power of the study and Currently accepted guidelines for melanoma potential risk factor. Pua et al. reported an overall contributed to the lack of statistical significance. margins include the following: 5-mm margin for incomplete excision rate of 2.20% for NMSCs, Although the study has the aforementioned melanoma in situ; 1-cm margin for melanomas a 1.54% rate for BCCs, and a 3.90% rate for limitations, the fact that we used a consecutive less than 1.0 mm Breslow depth; 1-cm to 2-cm 9 SCCs. We had a similar incomplete excision four-year time period for retrieving surgical data margins for melanomas of 1.0 mm to 4.0 mm rate of 5.1% for NMSCs but saw a slightly did reduce selection bias. Also, the retrospective Breslow depth; and 2-cm margins for melanomas higher rate for BCCs vs. SCCs (4.3% vs. 2.2%). analysis prevented physicians’ knowledge of the greater than 4.0 mm Breslow depth.1,3 While Thomas et al. reported incomplete excision rates study, eliminating the potential for influencing surgical margins for melanoma skin cancers for BCCs ranging from 4.5% to 13.7% and for performance. The retrospective analysis done in have been well-studied and categorized, surgical SCCs ranging from 5.2% to 7.0%, slightly higher the current study has helped us elucidate specific margins for non-melanoma skin cancers have not. 9,19 than previous studies or our current study. variables and data-collection methods for future Hence there is a greater discrepancy in margins Most studies did find SCCs specifically to have prospective studies, thus allowing for more used for excision of BCCs and SCCs. While a higher incomplete excision rate than BCCs. accurate data reporting. some have endeavored to propose guidelines to We found the reverse, but our difference was not standardize NMSC margins, variability in the statistically significant. The reported incomplete literature has highlighted discrepancies and a lack excision rates in the literature remain low, and our Conclusion of consensus. 2,4,6,9,15,16,19,20,26,27 The use of adequate surgical margins for complete data concurred with this. excision of NMSCs continues to be controversial A study by Thomas et al. claimed that advisable 2,4,6,9,15,16,19,20,26,27 A possible association between incomplete in the published literature. The surgical margins for BCC excisions ranged excision of NMSCs and gender has not been most accepted and consistent recommendations from 2 mm to 10 mm, and for SCC excisions extensively studied. Tan et al. and Bogdanov- suggest 4-mm margins in low-risk NMSCs and from 4 mm to 15 mm.19 Other authors have Berezovsky et al. both reported that gender was 10-mm margins or Mohs micrographic surgery recommended a 4-mm surgical margin for 2,4,6,9,15,20,28 not a statistically significant factor for incomplete in high-risk NMSCs. Other factors, primary NMSCs less than 2 cm in diameter 15,22 excision of SCCs. Hansen et al. had similar such as age, gender, location of tumor, and that can be safely classified as low-risk. Low- results, but found that female patients had a tumor type show inconsistent relationships to risk NMSCs are defined as tumors that are less 28% increased risk of an incomplete excision for incompletely excised NMSCs, results that were than 2 cm in diameter; are primary, well-defined, BCCs.23 In contrast, Farhi et al. failed to find supported by our study findings. The percentage slow growing, and well-differentiated; occur in gender as a predictor of incomplete excisions of incompletely excised NMSCs remains low in non-immunocompromised patients; and are for BCCs.24 The results of the current study many studies, including ours. Because recurrence without neurological symptoms and without 2,4,6,9,15,20,28 supported previous findings that suggested rates of NMSCs also vary, the recommendation perineural or vascular involvement. gender was not a statistically significant factor for is to re-treat these incompletely excised areas. This 4-mm margin recommendation has been 4,9,16 incomplete excision of NMSCs. Although re-treatment of an incompletely shown to increase the peripheral clearance rate of excised NMSC adds the burden of a second In the current study, age contributed least NMSC tumors to approximately 95%, compared procedure to the patient, it minimizes tumor to incomplete NMSC excision. A possible with an 85% rate using a margin of 3 mm, and recurrence, which is better for overall patient association between age and risk of incomplete has thus decreased the number of incompletely well-being. Efforts should continue to determine 6,9,16,27 excision has been previously studied. As in our excised NMSCs. In contrast, Gulleth et al. the most optimal ways to minimize incomplete study, Tan et al. found that age was related to demonstrated that for low-risk BCCs, similar excision of NMSCs. tumor clearance was observed using 3-mm, prevalence of NMSCs, specifically SCCs, but not 15 4-mm, and 5-mm margins.4 For low-risk SCCs, to the risk of incomplete excision. Other studies both Motley et al. and Pua et al. agreed that a have found no statistically significant association References 22,23 4-mm surgical margin was adequate, but a 6-mm between incomplete excision of SCCs and age. 1. Alberta Cutaneous Tumour Team. Optimal excision 6,9 margins for primary cutaneous melanoma. Edmonton margin was necessary for high-risk SCCs. Hansen et al., however, reported a significantly higher risk of incomplete BCC excisions among (Alberta): Alberta Health Services, Cancer Care; Most recently, Weinstein et al. used clinical c2011. (Clinical practice guideline; no. CU-010). and histologic correlations to stratify BCCs patients older than 70 years compared with those

Page 28 EXAMINATION OF INCOMPLETELY EXCISED NON-MELANOMA SKIN CANCERS 2. Ang P, Tan AW, Goh CL. Comparison of completely for nonmelanotic skin cancer. Plast Reconstr Surg. versus incompletely excised cutaneous squamous 2003 Jul;112(1):57-63 cell carcinomas. Ann Acad Med Singapore. 2004 20. Weinstein MC, Brodell RT, Bordeaux J, Honda Jan;33(1):68-70. K. The art and science of surgical margins for the 3. Balch CM, Urist MM, Karakousis CP, et al. dermatopathologist. Am J Dermatopathol. 2012 Efficacy of 2-cm surgical margins for intermediate- Oct;34(7):737-45. thickness melanomas (1 to 4 mm). Results of a multi- 21. Connolly SM, Baker DR, Coldiron BM, et al. institutional randomized surgical trial. Ann Surg. 1993 AAD/ACMS/ASDSA/ASMS 2012 appropriate use Sep;218(3):262-7. criteria for Mohs micrographic surgery: a report of 4. Gulleth Y, Goldberg N, Silverman RP, Gastman the American Academy of Dermatology, American BR. What is the best surgical margin for a basal cell College of Mohs Surgery, American Society for carcinoma: a meta-analysis of the literature. Plast Dermatologic Surgery Association, and the American Reconstr Surg. 2010 Oct;126(4):1222-31. Society for Mohs Surgery. J Am Acad Dermatol. 2012 Oct;67(4):531-50. 5. Husein-ElAhmed H, Aneiros-Fernandez J, Gutierrez-Salmeron MT, Aneiros-Cachaza J, Naranjo- 22. Bogdanov-Berezovsky A, Cohen AD, Glesinger R, Sintes R. Basal cell carcinoma: analysis of factors Cagnano E, Rosenberg L. Risk factors for incomplete associated with incomplete excision at a referral hospital excision of squamous cell carcinomas. J Dermatolog in southern Spain. Cutis. 2014 Mar;93(3):155-61. Treat. 2005;16(5-6):341-4. 6. Motley R, Kersey P, Lawrence C, et al. 23. Hansen C, Wilkinson D, Hansen M, Soyer Multiprofessional guidelines for the management of HP. Factors contributing to incomplete excision of the patient with primary cutaneous squamous cell nonmelanoma skin cancer by Australian general carcinoma. Br J Dermatol. 2002 Jan;146(1):18-25. practitioners. Arch Dermatol. 2009 Nov;145(11):1253- 60. 7. Neville JA, Welch E, Leffell DJ. Management of nonmelanoma skin cancer in 2007. Nat Clin Pract 24. Farhi D, Dupin N, Palangie A, Carlotti A, Avril Oncol. 2007 Aug;4(8):462-9. MF. Incomplete excision of basal cell carcinoma: rate and associated factors among 362 consecutive 8. Nguyen TH, Ho DQ. Nonmelanoma skin cases. Dermatol Surg. 2007 Oct;33(10):1207-14. cancer. Curr Treat Options Oncol. 2002 Jun;3(3):193- 203. 25. ASDS: Skin Cancer [Internet]. Illinois: American Society for Dermatologic Surgery; c1971-2014. Wide- 9. Pua VS, Huilgol S, Hill D. Evaluation of the local Excision for Skin Cancer; 2014 June 13; [1 treatment of non‐melanoma skin cancers by surgical screen]. Available from: https://www.asds.net/Wide- excision. Australas J Dermatol. 2009 Aug;50(3):171-5. local-Excision-for-Skin-Cancer/ 10. Rowe DE, Carroll RJ, Day CL Jr. Long‐term 26. Brodland DG, Zitelli JA. Surgical margins recurrence rates in previously untreated (primary) basal for excision of primary cutaneous squamous cell cell carcinoma: implications for patient follow‐up. J carcinoma. J Am Acad Dermatol. 1992 Aug;27(2 Pt Dermatol Surg Oncol. 1989 Mar;15(3):315-28. 1):241-8. 11. Silverman MK, Kopf AW, Grin CM, Bart RS, 27. Wolf DJ, Zitelli JA. Surgical margins for basal cell Levenstein MJ. Recurrence rates of treated basal cell carcinoma. Arch Dermatol. 1987 Mar;123(3):340-4. carcinomas: part 1: overview. J Dermatol Surg Oncol. 1991 Sep;17(8):713-8. 28. Miller SJ. The National Comprehensive Cancer Network (NCCN) guidelines of care for nonmelanoma 12. Silverman MK, Kopf AW, Grin CM, Bart RS, skin cancers. Dermatol Surg. 2000 Mar;26(3):289-92. Levenstein MJ. Recurrence rates of treated basal cell carcinomas: part 2: curettage‐electrodesiccation. J Dermatol Surg Oncol. 1991 Sep;17(9):720-6. Correspondence: Cathy L. Koger, DO, kittykoger@ 13. Silverman MK, Kopf AW, Bart RS, Grin CM, yahoo.com Levenstein MJ. Recurrence rates of treated basal cell carcinomas: part 3: surgical excision. J Dermatol Surg Oncol. 1992 Jun;18(6):471-6. 14. Silverman MK, Kopf AW, Gladstein AH, Bart RS, Grin CM, Levenstein MJ. Recurrence rates of treated basal cell carcinomas: part 4: x‐ray therapy. J Dermatol Surg Oncol. 1992 Jul;18(7):549-54. 15. Tan PY, Ek E, Su S, Giorlando F, Dieu T. Incomplete excision of squamous cell carcinoma of the skin: a prospective observational study. Plast Reconstr Surg. 2007 Sep;120(4):910-6. 16. Telfer NR, Colver GB, Bowers PW. Guidelines for the management of basal cell carcinoma. Br J Dermatol. 1999 Sep;141(3):415-23. 17. Thissen MR, Neumann MH, Schouten LJ. A systematic review of treatment modalities for primary basal cell carcinomas. Arch Dermatol. 1999 Oct;135(10):1177-83. 18. Thissen MR, Nieman FH, Ideler AH, Berretty PJ, Neumann HA. Cosmetic results of cryosurgery versus surgical excision for primary uncomplicated basal cell carcinomas of the head and neck. Dermatol Surg. 2000 Aug;26(8):759-64. 19. Thomas DJ, King AR, Peat BG. Excision margins

KOGER, RAJAII, PAZDERNIK, MARTENS, CLEAVER, CLEAVER Page 29 Idiopathic Spiny Keratoderma: A Report of Two Cases and Literature Review

Jessica Schweitzer, DO,* Matthew Koehler, DO,** David Horowitz, DO***

*Intern, Largo Medical Center, Largo, FL **Dermatology Resident, Third Year, College Medical Center/Western University, Long Beach, CA ***Dermatology Residency Program Director, College Medical Center/Western University, Long Beach, CA

Abstract Spiny keratoderma is a rare and likely underreported condition that presents with punctate hyperkeratotic growths localized to the palms and soles. We present two cases of clinically diagnosed spiny keratoderma. Although the lesions were asymptomatic, patients are at risk of an underlying internal malignancy with this condition, so diagnosis is crucial. Neither men were seeking treatment for the lesions when they were discovered, suggesting that this condition may be much more common than reported. Patients with histories of manual labor, increased UV exposure, and non-melanoma skin cancer (NMSC) may also be at higher risk for developing spiny keratoderma.1 The epidemiology, histopathologic features, differential diagnosis, and current treatments for spiny keratoderma are reviewed. Introduction Case 2 enthusiast for his entire life, spending significant Spiny keratoderma is a rare palmoplantar A 67-year-old Caucasian male presented with a time using his hands to maintain and fire his keratoderma that presents with keratotic, pinpoint one-year history of insidiously growing, pinpoint weapons and many hours outside without sun papules on the palms and soles. There are both hyperkeratotic papules projecting from his palms protection. The patient was referred back to his hereditary and acquired forms. When found, bilaterally (Figures 4-5). He presented to the clinic primary care physician for internal evaluation. a thorough history and physical examination for skin examination at six-month follow-up for After colonoscopy, chest X-ray and blood work, are warranted as there are case reports of spiny removal of cutaneous squamous cell carcinomas. no internal derangements were noted. keratoderma being associated with underlying Upon shaking his hand, the spiny projections internal disease and malignancy of the kidney, were noted. He stated they were present during Discussion colon, breast, lung, and skin.2 Acquired spiny the last surgery but were less noticeable and not Brown reported the first case of spiny keratoderma keratoderma usually manifests after 50 years of concerning to him at the time. His past medical in 1971 when he described punctate keratotic age and may be associated with manual labor.1,3 history included surgical removal of squamous projections on the palms of a 20-year-old male.3 We present two cases in older men with spiny cell carcinomas from his right temple and Spiny keratoderma presents with numerous, flesh- keratoderma of one to 20 years’ duration, and left forearm. He had been a gun and weapons colored, well-marginated keratotic papules on with no underlying malignancy or systemic 6,8-14 disease to date. Table 1. Treatment options for spiny keratoderma Treatment Course Results Follow-up Case Report Oral acitretin 10 mg start dose; Improvement At 18 months, still Case 1 An 84-year-old male presented for a full-body gradually increased to over 4 weeks clear skin examination. Upon shaking hands with the 30 mg for 8 weeks patient, we noted diffuse, 2 mm to 3 mm spiny Topical 0.1% applied once Brisk irritant Not reported papules on both palms (Figures 1-3) without tazarotene gel daily for 1 week dermatitis involvement of the soles. The patient stated he with residual slowly developed these lesions in his 60s, and the improvement of lesions are and have always been asymptomatic. His past medical history was negative for any lesions internal malignancies, and he was followed Topical 5-FU 5.0% applied twice Decrease in size Recurrence within regularly with a family practitioner. He was also cream daily for 2 weeks and number of a few weeks of current with age-appropriate screenings and (with occlusion for lesions discontinuation examinations. His social history was significant resistant lesions) for a long career performing outdoor manual labor while working for a phone company. He Topical 0.002% applied once Dramatic Not reported had no known direct arsenic exposure or prior tacalcitol daily improvement radiation treatment. Previous dermatologic ointment over 3 months history included three basal cell carcinomas in his 70s and 80s that were successfully treated with Topical 5% twice a day Complete Recurrence within surgical excision. To treat the spiny projections, ammonium resolution in 2 a few weeks of he had attempted to “sand” them for a period lactate lotion out of 5 patients discontinuation with some success, but they would always return, and eventually he lost the enthusiasm to do so. He also used trials of salicylic acid and urea, Salicylic acid in 40% applied at night, Improvement of Not reported which helped to soften the spines but never provided complete resolution. Although he was petrolatum and followed by curettage lesions (thinner embarrassed for many years about his condition, curettage in the morning and less painful) it now no longer bothered him. Salicylic acid gel 6% applied under Resolution after Recurrence with occlusion at night four days treatment cessation

Page 30 IDIOPATHIC SPINY KERATODERMA: A REPORT OF TWO CASES AND LITERATURE REVIEW Figure 1 Figure 2 Figure 4

Figure 3 Figure 5

the palms, fingers, and soles. Spiny keratoderma under UV exposure. study also worked as manual laborers. It has has recently been classified as one of the digitate been postulated that repeated trauma through The pathophysiology of spiny keratoderma keratoses. It has been alternatively referred to manual labor may explain the hyperproliferation is unknown but may involve either abnormal as punctate porokeratotic keratoderma, music and parakeratosis seen on microscopy, which or ectopic keratinization. One study reported box spine keratosis, multiple minute palmar- would support a theory of manual labor causing biopsy results with overexpression of keratins 7,8 plantar digitate hyperkeratosis, and filiform 6 hand trauma as a risk factor for this condition. 6 and 16. These keratins are responsible for hyperkeratosis, but spiny keratoderma is now Although repeated trauma may be a risk factor, 4 epidermal hyperproliferation, which manifests preferred. clinically as keratotic projections.6 The role of the authors did not postulate why some patients’ Spiny keratoderma consists of both inherited ectopic keratinization on the palms and soles was skin is more susceptible than others. and acquired forms, with the acquired form more also suggested in a case series involving six other The differential diagnosis includes arsenical common in males over 50 and possibly associated patients. 7 AE13, a monoclonal hair-specific keratosis and multiple filiform verrucae, both of with internal malignancy.5 Risk factors for the antibody expressed in the normal hair cortex, which can present in a similar localized fashion on acquired variant, as seen in both of our patients, was also expressed in the compact columns of the palmoplantar surfaces. Patients with Cowden’s include a history of manual labor.1 Others include keratoderma in these patients.7 In this particular syndrome can also present with palmoplantar immunosuppression and underlying malignancy study, electron microscopy showed features of keratosis, and therefore a physical exam should of the kidney, colon, breast, lung, and skin. 5 Our keratinization of a normal hair cortex, including be performed to rule out mucocutaneous patients both had a history of significant UV keratinization but without the production of abnormalities and other manifestations of this exposure, which could be another risk factor keratohyalin granules.7 These findings are similar syndrome. Hereditary keratoses, including for spiny keratoderma. However, UV exposure to that of human hair, which suggests that that Buschke-Fisher-Brauer disease, hereditary may be a confounding variable in patients with spiny keratoderma could be representative of spiny keratoderma, and acrokeratoelastoidosis histories of manual labor, too, as our patients ectopic hair formation on the palms and soles. lichenoides, should be considered in a younger invariably performed their years of manual labor Furthermore, five out of six patients in this patient.9 It should be noted that hereditary spiny

SCHWEITZER, KOEHLER, HOROWITZ Page 31 keratoderma usually manifests between the ages treated, newer medications show some promise in of 12 and 50 years; however, age is not always eradicating the lesions; however, treatment must a reliable distinguishing factor between the be continued to prevent recurrence. acquired and hereditary subtypes, as there are reports of acquired spiny keratoderma in patients 2,7 Conclusion as young as 35 years old. Acquired or idiopathic spiny keratoderma is a Although biopsy is not essential to establish rare condition that can present exclusively on a diagnosis in all cases, it will reveal a compact the palms and fingers, as seen in our patients. column of hyperparakeratosis originating from Other common presentations involve the the stratum corneum, and a hypogranular soles as well. A thorough intake of family and epidermis directly beneath it. The column is personal history, appropriate cancer screenings, sharply demarcated from adjacent skin that and regular medical examinations should be consists of an orthokeratotic stratum corneum. performed to rule out underlying disease and The pathologic differential includes porokeratosis, malignancy in patients presenting with acquired as the hyperparakeratosis observed can resemble spiny keratoderma. Furthermore, questioning the cornoid lamella present in porokeratosis. about risk factors, such as manual labor, UV These two entities can be distinguished by the exposure, and immunosuppression, can help to presence of dyskeratosis, vacuolated cells, or solidify a diagnosis. Providers must consider the inflammatory infiltrate seen in porokeratosis, psychological impact and social embarrassment features that are absent in spiny keratoderma. this condition can precipitate and educate Distinction between spiny keratoderma and patients that, if successful, continued treatment porokeratosis should be made either clinically will likely be necessary to prevent recurrence. or histologically, as porokeratosis can evolve into SCC or BCC at the clinical site. References Acquired or idiopathic spiny keratoderma has 1. Horton SL, Hashimoto K, Toi Y, et al. Spiny been associated with an underlying neoplasm keratoderma: a common underreported dermatosis. J 2 Dermatol. 1998;25:353-361. in up to 50% of cases. The paraneoplastic phenomena include malignancies of the kidney, 2. Urbani C and Moneghini L. Palmar spiny keratoderma rectum/colon, breast, and lung. Squamous cell associated with type IV hyperlipoproteinemia. J Eur carcinoma, melanoma and chronic lymphocytic Acad Dermatol Venereol. 1998;10:262-266. leukemia have also been associated with the 3. Brown F. Punctate keratoderma. Arch Dermatol. acquired form.6 Despite many associations 1971;104:682–683. of spiny keratoderma with these underlying 4. Caccetta T. Multiple minute digitate hyperkeratosis: malignancies, there is only one case of clearing A proposed algorithm for the digitate keratoses. J Am of the keratoderma after successful cancer Acad Dermatol. 2012;67:e49-e55. 6 treatment. Acquired spiny keratoderma has also 5. Alikhan A, Burns T, Zargari O. Punctate porokeratotic been associated with underlying disease, including keratoderma. Dermatol Online J. 2010;16(1):13. autosomal-dominant polycystic kidney disease 6. Naglar A, Boyd K, Patel R, et al. Spiny keratoderma. with liver cysts, chronic renal failure, Darier’s Dermatol Online J. 2013;19(12):2. disease, type IV hyperlipoproteinemia, and 6,9 7. Hashimoto K, et al. Spiny keratoderma- pulmonary tuberculosis. As such, a complete -a demonstration of hair keratin and hair type physical exam should be performed along with keratinization. J Cutan Pathol. 1999;26:25. implementation of screening guidelines for 8. McGovern TW, Gentry RH. Spiny keratoderma: colonoscopy and/or mammogram in any patient case report, classification, and treatment of music box presenting with spiny keratoderma. spine dermatoses. Cutis. 1994 Dec;54(6):389-94. There is reported variability in treatments for 9. Torres G, Behshad R, Han A, et al. “I forgot to shave this stubborn and persistent condition, outlined my hands”: a case of spiny keratoderma. J Am Acad in Table 1. Treatments with topical emollients Dermatol. 2008;58(2):344-348. and keratolytics such as salicylic acid and urea 10. Scott-Land V and McKay D. Spiny keratoderma 10 cream have resulted in little improvement. successfully treated with acitretin. Clin Exp Dermatol. However, combination therapy with salicylic acid 2012;38:89-101. 40% ointment overnight followed by curettage 10 11. Helm T, Lee J, Helm K. Spiny Keratoderma. Cutis. in the morning has proven more effective. 2000;66:191. Other options include mechanical debridement 12. Osman Y, Daly TJ, Don PC. Spiny keratoderma with dermabrasion and paring. Recent reports of the palms and soles. J Am Acad Dermatol. of topical tazarotene or acitretin for four weeks 1992;26:879-881. have shown more long-standing success.10,11 13. Yukawa M, et al. Spiny keratoderma of the palms Of note, patients on oral acitretin should be successfully treated with topical tacalcitol. Acta Derm followed with routine blood tests that include Venereol. 2007;87:172. lipid panels, especially because spiny keratoderma already has an association with hyperlipidemia. 14. Korstanje MJ, Vrints LW. Porokeratotic palmoplantar keratoderma discreta--a new entity or In one patient, 5% 5-FU procured successful a variant of porokeratosis plantaris discreta? Clin Exp results, and topical tacalcitol achieved success Dermatol. 1996 Nov;21(6):451-3. in another.12,13 5-FU and tacalcitol have shown marked improvement in the spiny projections in treated patients, but recurrences have occurred Correspondence: Jessica Schweitzer, DO; upon discontinuation.12,13 For those wishing to be [email protected] Page 32 IDIOPATHIC SPINY KERATODERMA: A REPORT OF TWO CASES AND LITERATURE REVIEW Allergic Contact Dermatitis Secondary to Latex Headset in Popular Bluetooth Device

John Moesch, BA,* Joseph Dyer, DO,** Melinda Greenfield, DO, FAOCD***

*Medical Student, 3rd year, Philadelphia College of Osteopathic Medicine, Suwanee, GA **Dermatology Resident, 1st year, Largo Medical Center/NSUCOM, Largo, FL *** Board-certified Dermatologist, Albany Dermatology Clinic, Albany, GA

Abstract We offer a case of latex-induced allergic contact dermatitis caused by a popular Bluetooth headset device and discuss salient features of patient history, physical exam, and treatment. After diagnosis is made, we provide commentary on the condition and elaborate on its diagnosis through patch testing, treatment protocols, and relevance to today’s tech-savvy society. Introduction Physical exam revealed a well-nourished African sensitization and elicitation. Sensitization is the Joseph Jadassohn first described allergic contact American female with a hyperpigmented, process by which the immune system is primed dermatitis in 1895.2 Since then, it has become one lichenified patch bilaterally on the posterior neck to react against the allergen on the next exposure. (Figure 1). The plaque’s morphology mirrored The sensitization phase of ACD can last from of the most commonly seen and costly medical 3 conditions. In 2005, treating contact dermatitis the shape of the Bluetooth device the patient 10 to 15 days. The elicitation phase follows and cost approximately $1.4 billion annually and frequently wore around her neck (Figure 2). describes the proinflammatory state that results resulted in a loss of around $500 million due to A diagnosis of allergic contact dermatitis from re-exposure to the sensitized allergen. 11 missed workdays and low productivity. For many secondary to latex in the Bluetooth headset was The classic histological finding for acute ACD is years, specific allergens known to cause allergic made. The patient was treated successfully with spongiosis, intraepidermal vesicles, and superficial contact dermatitis have been described in detail triamcinolone acetonide 0.1% cream and told perivascular infiltrate. The pathology of acute in numerous journals and texts. Furthermore, to abstain from use of the Bluetooth device. No lesions is extremely valuable since subacute and allergic contact dermatitis related to modern biopsy or patch testing was necessary. chronic lesions can produce non-diagnostic technology devices like cell phones and computers patterns that are often confusing. Acanthosis, has been discussed in medical literature and case hyperkeratosis, and mild superficial infiltrate are 10 reports. Our case report reveals a patient with features in the sub-acute and chronic setting. allergic contact dermatitis secondary to latex Pathologic diagnosis of ACD should correlate in a popular Bluetooth headset. Our patient is with clinical findings.5 unique because literature searches failed to reveal The physical expression of ACD will differ any prior cases of allergic contact dermatitis depending on what stage of the disease is present. specific to Bluetooth headsets. Furthermore, our Acute-phase ACD is identified by lesions marked case is relevant because the Bluetooth industry with edema, erythema, and vesicle formation. is growing rapidly, and similar cases will likely Acute dermatitides usually subside within three become more common in the near future. 1 to four weeks. However, if a patient has repeated exposure to the allergen, chronic ACD will Case Report develop. Chronic ACD presents with scaling, A 44-year-old African American female fissuring, and lichenification.3 Figure 2. Patch mirroring the contour of the presented with a pruritic rash on her neck for two When trying to discover the causative allergen of months. She reported no prior treatment of the Bluetooth device ACD, recognizing the anatomic distribution of rash. The patient denied photosensitivity, insulin dermatitis has proven valuable. The neck region resistance, or use of perfumes. However, the is a very common site for ACD. Cosmetics, nail patient admitted to a recent habit of wearing a Background polish ingredients, perfumes, and metal allergens Bluetooth device around her neck. The neck strap Allergic contact dermatitis (ACD) makes up at in jewelry have all been implicated as common of the device was made with rubber material. Past 5 least 20% of new-incident contact dermatitides. causes of ACD in the cervical region. If the medical and surgical history was unremarkable. Allergic contact dermatitis can affect individuals diagnosis of ACD is questionable, or the specific from all backgrounds. The National Ambulatory causative agent is unknown, patch testing should Medical Care Survey conducted in 1995 be considered. estimated 8.4 million outpatient visits to American physicians for contact dermatitis; this was the second most frequent dermatologic Patch Testing 2 Patch testing is an underutilized diagnostic diagnosis. There are approximately 3,000 5 different chemicals that have been documented tool in the field of dermatology. When patch as specific causes of ACD.2 However, about 25 testing is indicated, it should be performed with chemicals appear to be responsible for as many as a large number of common allergens as well as half the cases of ACD.2 occupational and personal-care products relevant to the patient. Allergic contact dermatitis is a pruritic, cutaneous inflammatory reaction caused by contact with a Proper patch testing requires three visits: one specific exogenous antigen to which the person to apply the allergens; another to remove the Figure 1. Hyperpigmented, lichenified patch on has developed sensitization. ACD is a type 4 tests, read, and grade the results after 48 hours; neck hypersensitivity reaction made up of two phases: and the last for a final, delayed reading around

MOESCH, DYER, GREENFIELD Page 33 72 hours to one week after the application of 4 Discussion References initial patch. The second reading is important With almost universal availability of technology 1. James M, Miller J. Lookingbill and Marks’ principles to catch the delayed reactions common in elderly devices, ACD to modern electronic devices has of dermatology. 5th ed. New York: Elsevier Academic patients. The Finn method and TRUE are the become increasingly common. Modern devices Press; c2013. Chapter 8, Eczematous rashes; p. 89-105. two most common methods in use today. The such as personal laptop computers, cellular 2. Hogan D. Allergic Contact Dermatitis [Internet]. Finn Chamber method is set up by placing phones, and video consoles have been linked to New York (NY): Medscape from WebMD; 2014 Mar a small amount of allergen into individual many different dermatologic conditions. There 19 [cited 2014 Oct 3]. Available from: http://www. aluminum wells affixed to a strip of paper tape. have been numerous case reports verifying ACD medscape.com/article/1042916. The Finn Method allows screening for hundreds to nickel and chromium in cell phones and 3. Goldsmith L, Katz S, Gilchrest B, Paller A, Leffell D, of allergens and is usually performed after the other modern devices.10 Interestingly, our case Wolff K. Fitzpatrick’s dermatology in general medicine TRUE method. The TRUE test method requires report demonstrating ACD to latex in a popular [Internet]. New York: McGraw-Hill; c2012. [cited no advanced preparation because the allergens Bluetooth headset is a newly documented finding 2014 Sept 30]. Available from: http://accessmedicine. mhmedical.com. have already been incorporated into the back of according to literature resources. A literature the paper tape strips. The TRUE test is limited search on Pubmed, MEDLINE, EMBASE, 4. Habif T. Clinical dermatology: a color guide to because there are only 28 screening allergens and Ovid MEDLINE failed to demonstrate diagnosis and therapy. 5th ed. New York: Elsevier 5 Academic Press; c2010. Chapter 4, Contact dermatitis available. For both tests, the strips are applied any literature connecting Bluetooth devices to and patch testing; p.130-153. to the patient’s upper back. Topical steroids and latex-induced ACD. However, it is likely that systemic steroids should both be avoided for at 5. Bolognia J, Jorizzo J, Schaffer J. Dermatology. 3rd ed. 5 this specific case of ACD will become a more least one week before beginning a patch test. frequent finding as the use of modern technology New York: Elsevier Academic Press; c2012. Chapter 14, Antihistamines do not affect the outcome of Allergic contact dermatitis; p 233-248. 5 devices rapidly increases. In 2010, the Strategy the test. The classic positive patch test reaction Analytics North American Automatic Market 6. Strategy analytics: U.S. bluetooth headset usage shows spreading erythema, edema, and closely set forecasted that 85% of all mobile phones would plummets [Internet]. Boston: Business vesicles that persist after the removal of the patch be Bluetooth enabled by 2015, with that number Wire; c2009 Sept 2 [cited 2014 Sept 29]. Available after two to seven days. False negative tests can growing to 90% by 2016.6 Furthermore, ABI from: http://www.businesswire.com/news/ occur when there is not a sufficient amount of the Technology Research Company predicts over home/20090902005867/en/Strategy-Analytics allergen to elicit a reaction. 3 billion Bluetooth-enabled devices will ship in Bluetooth-Headset-Usage-Plummets#.VBovV8bndg1. 2014, and in 2018 there will be over 10 billion 7 7. Millions of devices and counting [Internet]. Kirkland: Therapy enabled devices in the market. Bluetooth; c2014 [cited 2014 Sept 29]. Available from: The definitive treatment for controlling ACD While the risk of latex allergy in the general http://www.bluetooth.com/Pages/Medical.aspx. is avoidance of the allergen implicated. If the population is low at 1% to 2%, the risk of 8. My softcover [Internet]. Boise: LG Electronics; allergen is unknown, the provider should begin developing an allergy to latex is higher in people c2014 [cited 2014 Oct 1]. Available from: http:// treatment and further evaluate with patch testing. with increased latex exposure, such as health-care mysoftcover.com. Topical treatment should be the initial treatment, workers. Health-care workers have a three times 9. Benjamin B, Li K. Cutaneous manifestations of while all moisturizers, lotions, and topical higher risk of developing latex allergy than the modern technology use. J Cutan Med Surg. 2011 Nov medications except plain petroleum for dryness general population. Also, patients with spina 11;15(6):347-353. should be discontinued. The topical corticosteroid bifida have a 20% to 67% chance of latex allergy. should be used twice a day for two to three weeks.5 10. Richardson C, Hamann CR, Hamann D, Thyssen Research has shown that latex-glove ACD is D. Mobile phone dermatitis in children and adults: a Unfortunately, topical corticosteroids have been caused by a delayed-type hypersensitivity reaction review of the literature. Pediatric Allergy, Immunology, increasingly recognized as allergens themselves. to rubber accelerators (e.g., thiurams, carbamates, and Pulmonology. 2014 Jun 1;27(2):60-69. An allergy to topical corticosteroids should be mercapto compounds) and antioxidants (not 11. Bickers DR, Lim HW, Margolis D, et al. The burden considered when one has persistent eruption of latex proteins). More specifically, the latex allergy of skin diseases: 2004 a joint project of the American worsening lesions. The strength of topical steroid to gloves was caused by thiurams in 72% of Academy of Dermatology Association and the Society should be tailored to anatomic treatment area. cases, carbamates in 25% of cases, and mercapto for Investigative Dermatology. J Am Acad Dermatol. For example, high-potency steroids should be compounds in 3% of cases.4 2006;55:490-500. used on hands and feet; medium potency for the In the future, we will likely see Bluetooth devices arms, legs, and trunk; and low potency for the being used for many different applications, Correspondence: John Moesch, BA; johnmoe@pcom. face. including sensors that monitor activity levels and edu Also, corticosteroid ointments are preferred over medical wellness devices that monitor health- cream form due to additives in creams that may care statistics.7 It is essential that physicians be allergenic. Second-line treatments for ACD investigate the possibility of ACD related to are topical immune modulators like tacrolimus Bluetooth devices and ask patients about possible and pimecromlimus.3 The immunomodulators usage of Bluetooth devices. As a preventative are especially effective for ACD in areas of measure, companies are developing protective the face and eyelids. If the ACD is severe or coverings that can be attached to the latex area generalized throughout the body, a three- of the Bluetooth headset strap to protect patients week tapering course of oral corticosteroids is from this allergen.9 Awareness of this diagnosis necessary. A more rapid taper can result in rapid is essential, because the longer the individual has rebound dermatitis.3 Another effective treatment dermatitis the longer it is believed it will take the option for refractory ACD is phototherapy. dermatitis to resolve once the causative agent is Numerous studies have shown the effectiveness identified. Knowledge of potential latex allergy of oral psoralen photochemotherapy (PUVA) and to Bluetooth neck straps and familiarity with shortwave ultraviolet (UVB) in the treatment of prophylactic and effective treatments can help chronic ACD. Systemic antihistamines such as diagnose and treat patients with ACD to latex in hydroxyzine or diphenhydramine are useful for Bluetooth devices. pruritus.1

Page 34 ALLERGIC CONTACT DERMATITIS SECONDARY TO LATEX HEADSET IN POPULAR BLUETOOTH DEVICE A Case Report of Extragenital Lichen Sclerosus with Anogenital Sparing

Amanda Nahhas, BS,* Jenifer Lloyd, DO**

*OMS-IV, Ohio University Heritage College of Osteopathic Medicine, Athens, OH **Director, Residency Program, University Hospitals Regional Hospitals, Department of Dermatology, Case Western Reserve University, Cleveland, OH

Abstract Lichen sclerosus is an uncommon, chronic inflammatory condition primarily affecting the anogenital region; however, it can have concurrent or sole extragenital involvement. The etiology is controversial, and lichen sclerosus, specifically the anogenital type, has been linked to future development of squamous cell carcinoma. We present a case of extragenital lichen sclerosus, along with a review of the literature to discuss presentation, etiology, diagnosis, management, and risk of future squamous cell carcinoma.

Figure 2. Histopathology image revealing subepidermal clefting with homogenization and edema of the papillary dermis with expansion, as well as mild superficial lymphocytic and eosinophilic infiltrate in the superficial dermis (4x).

Figure 1. Large, hypopigmented, atrophic plaques extending over the central lower thoracic and lumbar areas of the back with a cigarette-paper-like, wrinkled texture.

known to be effective. However, regardless of the InIntroduction most cases, lichen sclerosus is identified in simplicity or complexity of the patient’s medical the anogenital region, but solely extragenital history, choosing effective therapy can prove presentations are not unheard of. When present, to be quite challenging when patients do not most extragenital lesions are visualized on the respond to topical corticosteroids. Recalcitrant superior trunk, axillae, buttocks, and extremities, lichen sclerosus may require additional therapies often in conjunction with anogenital lesions. This including trials of calcineurin inhibitors, patient presents with a case of classical-appearing methotrexate, cyclosporine, and phototherapy. Figure 3. Hyalinosis is visible in the upper lichen sclerosus on the inferior, posterior aspect dermis, along with basal vacuolization (20x). of the trunk with anogenital sparing. Case Presentation subepidermal clefting with homogenization and Review of the literature revealed other reported An 83-year-old Caucasian female presented to the clinic complaining of an “itchy discomfort” edema of the papillary dermis with hyalinosis cases of lichen sclerosus devoid of anogenital (Figure 2). Mild superficial lymphocytic and involvement, including those with bullous on her lower back that had previously bled. She denied discomfort elsewhere. She reported eosinophilic infiltrate was also identified in the presentations and those following the lines of superficial dermis (Figure 3). Blaschko on the face.1,2 In addition, a rare case a history of hypertension, thyroid disease, and of extragenital lichen sclerosus involving the oral arthritis but denied any history of skin cancer or The clinical and pathological findings were mucosa has previously been documented.3 other dermatologic issues. On physical exam, consistent with lichen sclerosus et atrophicus. The she was found to have large, hypopigmented, patient was managed with topical triamcinolone Lichen sclerosus, like many dermatologic atrophic plaques extending over the central lower acetonide lotion and a tapered dose of prednisone diseases, has multiple proposed etiologies, thoracic and lumbar areas of the back with a along with a ceramide moisturizer. Phototherapy including those related to genetics, infection, and cigarette-paper-like, wrinkled texture (Figure 1). and methotrexate are being considered if autoimmune disease. The patient presented in The area was devoid of blisters, erosions, and symptoms persist. this case lacked any of the above predispositions excoriations. Concomitant vulvar disease was and was placed on topical corticosteroids, which not present. are the mainstay of therapy and are generally A 4-mm punch biopsy was taken and revealed LichenDiscussion sclerosus is a chronic, relapsing,

NAHHAS, LLOYD Page 35 inflammatory condition affecting mucocutaneous lesions often reveals scaling and keratotic plugs.4 extragenital lichen sclerosus and have been shown junctions and cutaneous surfaces, leading to Interestingly, an erythematous halo visible on to decrease exacerbations.5,9 Other considerations 4,5 epidermal atrophy. This lymphocyte-driven dermoscopy is indicative of an active lesion.10 include methotrexate for cases of widespread condition has a predilection for the anogenital disease and cyclosporine for refractory cases.9 area; however, extragenital lichen sclerosus has On histology, lichen sclerosus usually reveals an edematous papillary dermis, effaced epidermis, Narrow-band UVB phototherapy and low-dose been reported to occur in 15% to 20% of patients psoralen-UVA has also been shown to be effective with lichen sclerosis.4-6 Of note, this condition is and blurred border of separation between the two 9,12 layers.8,9 The damage and subsequent atrophy for widespread extragenital lichen sclerosus. commonly referred to as lichen sclerosis without In consideration of the possibility of infection by 6 of the epidermis results in contraction of the the ‘atrophicus’ portion. This is attributed Borrelia burgdorferi as a cause of lichen sclerosus, to findings that lichen sclerosus can result in skin and therefore the characteristic wrinkled 9 some patients have benefited from treatment hypertrophic rather than atrophic epithelium.6 appearance of the skin lesions. Additional histopathological features consistent with both of intramuscular penicillin G following failed 9 The etiology of lichen sclerosus is unknown. genital and extragenital lesions include hyalinosis attempts of management with topical steroids. Finally, surgery is a last resort and is generally Studies have determined that there is a change in the upper dermis, vascular ectasia, and basal 4,7 limited to patients with severe cases of genital in the expression of certain proteins, specifically vacuolization. 9 extracellular matrix protein-1 (ECM-1), and lichen sclerosus who have failed medical therapy. The use of biopsy to establish a diagnosis for connective-tissue growth factor in patients with The development of squamous cell cancer is a lichen sclerosus has been controversial for lichen sclerosus.7 Some studies have proposed feared complication seen in 4.5% of individuals some time. Many clinicians discourage biopsy, autoimmune, endocrine, and even an infectious affected by lichen sclerosus.8 These neoplastic arguing that lichen sclerosus is more of a clinical etiology. To elaborate, studies have located tissue- changes are most commonly seen with female diagnosis. However, should biopsy be pursued specific antibodies, and clinicians have persistently genital lichen sclerosus and are not a part of the in questionable cases, it is important to be aware recognized its association with other autoimmune natural history of extragenital lesions.11 This that biopsies of lichen sclerosus are not always conditions such as vitiligo, thyroid disease, and oncologic manifestation is seen an average of 10 straightforward and that an inconclusive biopsy pernicious anemia in genetically predisposed years following diagnosis of lichen sclerosus.8 5,6,8 does not necessarily rule out the diagnosis individuals. With prepubescent children and 8,9 of lichen sclerosus. Cases where biopsy is Management and follow-up is fairly postmenopausal women being affected, many warranted include those that have signs of individualized due to the variability of the course have also attributed the onset to decreased 5,8 neoplasia such as chronic ulceration, fissuring, of lichen sclerosus. Interestingly, most cases estrogen levels. Although controversial, several 9 6 or hyperplasia. Biopsy is also recommended seen in children usually improve. However, reports suggest the disease may be triggered in lesions unresponsive to treatment, lesions it is imperative that patients with anogenital by an infectious agent, specificallyBorrelia 5,8,9 with pigmentation, and in lesions that must involvement be evaluated every six months to burgdorferi. In addition, koebnerization has 13 be differentiated from other conditions that monitor for progression of disease. been described in the development of extragenital present similarly to lichen sclerosus, including lesions.6 lichen planus, lichen simplex chronicus, guttate Lichen sclerosus can affect individuals across all Conclusion morphea, discoid lupus erythematosus, vitiligo, Lichen sclerosus is a chronic inflammatory age groups.5 However, the condition typically anetoderma, cutaneous T-cell lymphoma, chronic disorder that presents with genital involvement, demonstrates a bimodal onset among pre- graft-versus-host disease and extramammary extragenital involvement, or both. ECM-1 has pubertal children and postmenopausal women, 4,6,9,11 Paget’s disease. In addition, it is important to been linked to lichen sclerosus; however, other with the latter being the most commonly affected consider the social history, especially in children autoimmune and endocrine etiologies, as well group 5,7,8 The incidence of lichen sclerosus is with anogenital lesions, as sexual abuse must be as infection by Borrelia burgdorferi, are still difficult to assess because of the large number of ruled out. being considered. Lesions have a predisposition asymptomatic individuals and the multi-specialty 6 Preliminary management of lichen sclerosus is for the anogenital region, are pruritic, and most patient coverage. 8 with high-potency topical steroids. Clobetasol commonly affect postmenopausal women. Lesion distribution is most commonly in the propionate ointment 0.05% has been found to Biopsy is generally unnecessary but may be vulvar, perianal, and groin regions.9 Extragenital be effective for symptomatic relief across all age required to differentiate lichen sclerosus from lesions are usually visualized on the upper trunk, groups and has been shown to induce recovery other pathologies, including squamous cell axillae, buttocks, extremities or lateral thighs.6 The of skin changes such as atrophy and even reverse carcinoma. There is generally a good response most commonly reported presenting symptoms the histological changes.9 It is unclear as to to high-potency topical steroids combined with are pruritus and irritation, especially at night, how topical steroids recover skin atrophy, but emollients, but other options are available for though many individuals are asymptomatic.6 it can be assumed that this reversal is a product resistant cases. Symptoms can also be location-dependent. For of steroid action on reducing inflammation, example, patients with vulvar lichen sclerosus edema, and subsequent tissue damage that often experience dyspareunia, dysuria, or bleeding would lead to skin atrophy. This high-potency secondary to irritation and introital narrowing, topical steroid is commonly used twice daily for References whereas those with perianal lichen sclerosus may one month, followed by once daily for another 1. Jiménez Y, Gavaldá C, Carbonell E, Margaix experience dyschezia due to similar mechanisms.5 month, followed by tapering until a three-month M, Sarrión G. Lichen sclerosus of the oral The predominance of chronic pruritus inevitably follow-up is scheduled with the dermatologist.9 mucosa: a case report. Med Oral Patol Oral Cir leads to lichenification, fissures, and future A majority of patients do benefit from therapy Bucal. 2008 Jul 1;13(7):E403-406. 5,8 5 atrophy, scarring, and potential malignancy. with topical steroids. Moisturizing agents aid in 2. Kim YJ, Lee ES. Case of sequentially In lichen sclerosus, lesions evolve with time. symptomatic relief, are often used in conjunction occurring lesions of facial lichen sclerosus Classically, preliminary lesions appear as small, with topical steroids, and are a mainstay of long- following the lines of Blaschko. J Dermatol. 2007 minimally raised, pink- or ivory-colored papules.9 term supportive therapy. Mar;34(3):201-204. These early lesions are usually flat-topped with In patients who have failed therapy with or 3. Sauder MB, Linzon-Smith J, Beecker J. white or brown follicular plugs referred to as those with contraindications to topical steroids, Extragenital bullous lichen sclerosus. J Am Acad 9 “delling.” Over time, these papules become a trial of a topical calcineurin inhibitor such Dermatol. 2014 Jul. pii: S0190-9622(14)01653- confluent, forming white, porcelain-like plaques as tacrolimus ointment 0.1% or pimecrolimus 3. doi: 10.1016/j.jaad.2014.06.037. [Epub ahead 9 with a characteristic atrophic and wrinkled cream 1% is reasonable. Calcineurin inhibitors of print] appearance.9 Dermoscopy of extragenital are appropriate for management of genital or 4. Larre Borges A, Tiodorovic-Zivkovic D, Lallas Page 36 A CASE REPORT OF EXTRAGENITAL LICHEN SCLEROSUS WITH ANOGENITAL SPARING A, Moscarella E, Gurgitano S, Capurro M, et al. Clinical Dermoscopic and Histopathologic Features of Genital and Extragenital Lichen Sclerosus. J Eur Acad Dermatol Venereol. 2013 Pseudoepitheliomatous Hyperplasia Nov;27(11):1433-1439. doi: 10.1111/j.1468- 3083.2012.04595.x.Epub 2012 May 31. Resembling Multiple Keratoacanthomas 5. Fistarol SK, Itin PH. Diagnosis and Treatment Arising in a Tattoo of Lichen sclerosus: an update. Am J Clin Dermatol. 2013 Feb;14(1):27-47. Christine Moussa, DO,* Najiyah Kazi, MD,** Shahrzad Akbary, BS,*** Richard Bernert, MD, FASDP,**** Bill 6. Neill SM, Lewis FM, Tatnall FM, Cox NH. Halmi, MD***** British Association of Dermatologists. British Association of Dermatologists’ guidelines for *Dermatology resident, 2nd year, LECOMT/Alta Dermatology, Mesa, AZ the management of lichen sclerosus 2010. Br J **Pathology resident, 3rd year, Columbia University Medical Center-New York Presbyterian Hospital, New York, NY Dermatol. 2010 Oct;163(4):672-82. ***Medical student, 4th year, Midwestern University Arizona College of Osteopathic Medicine, Glendale, AZ ****Board-certified dermatopathologist, Arizona Dermatopathology, Scottsdale, AZ 7. Gambichler T, Skrygan M, Czempiel V, *****Board-certified dermatologist, Arizona Advanced Dermatology, Phoenix, AZ Tigges C, Kobus S, Meier JJ, et al. Differential Expression of Connective Tissue Growth Factor and Extracellular Matrix Proteins in Lichen Abstract Sclerosus. J Eur Acad Dermatol Venereol. Tattoo-associated reactions are well-recognized in the literature, including granulomatous, lichenoid, 2012 Feb;26(2):207-212. doi: 10.1111/j.1468- pseudolymphomatous, sarcoidal, and eczematous. There are rare reports of pseudoepitheliomatous hyperplasia 3083.2011.04037.x. Epub 2011 Mar 24. and keratoacanthoma arising in tattoos. We report a case of a 28-year old woman who presented with three growths confined to a tattoo placed one year prior. Clinical and histologic features were suggestive of 8. Stiles M, Redmer J, Paddock E, Schrager S. a differential diagnosis that would include keratoacanthoma, pseudoepitheliomatous hyperplasia secondary Gynecologic issues in geriatric women. J Women’s to chronic wound healing or trauma, and, less likely, infection. Distinguishing between these entities can be Health (Larchmt). 2012 Jan;21(1):4-9. doi: a subject of histopathologic debate. Overlap of histologic features requires excisional biopsy with culture for 10.1089/jwh.2011.2803. Epub 2011 Oct 14. comprehensive analysis and diagnosis, and close follow-up is necessary. 9. Habif TP. Clinical Dermatology: A Color th Guide to Diagnosis and Therapy, 5 ed. Lichen Introduction well as pseudoepitheliomatous hyperplasia, sclerosus et atrophicus. Philadelphia: Elsevier, particularly in the setting of red tattoo pigment or Dermatologic conditions associated with tattoo 8 Inc. 2010; pp. 327-331. placement are a well-recognized complication infection. Distinguishing between these entities requires careful clinicopathologic correlation, 10. Garrido-Ríos AA, Alvarez-Garrido H, Sanz- seen in dermatology practices. They have been 4 often necessitating surgical excision. Herein, Muñoz C, Aragoneses-Fraile H, Manchado- reported to occur within hours to over 45 years 5,8 we describe a case that demonstrates histologic López P, Miranda-Romero A. Dermoscopy of after tattoo placement. The reported histologic features suggestive of pseudoepitheliomatous Extragenital Lichen Sclerosus. Arch Dermatol. patterns include foreign-body granulomatous, hyperplasia (PEH) or squamous cell carcinoma 2009 Dec;145(12):1468. lichenoid, pseudolymphomatous, sarcoidal, and eczematous, such as allergic contact dermatitis of the keratoacanthoma (KA) type. 11. Rose AE, Boyd KP, Meehan SA, Latkowski or photoallergic dermatitis.1,6 Within the last JA. Lichen sclerosus et atrophicus. Dermatol decade, there have been rare reports of eruptive Online J. 2013 Dec 16;19(12):20714. Case Report keratoacanthomas presenting in tattoos as A 28-year-old female presented to the 12. Kreuter A, Gambichler T, Avermaete A, Happe M, Bacharach-Buhles M, Hoffmann K, et al. Low-dose ultraviolet A1 phototherapy for extragenital lichen sclerosus: results of a preliminary study. J Am Acad Dermatol. 2002 Feb;46(2):251-255. 13. Gutiérrez-Pascual M, Vicente-Martín FJ, López-Estebaranz JL. Lichen Sclerosus and Squamous Cell Carcinoma. Actas Dermosifiliogr. 2012 Jan;103(1):21-28. doi: 10.1016/j. adengl.2011.05.004. Epub 2012 Mar 24.

Correspondence: Jenifer R. Lloyd, DO; Lloyd Dermatology & Laser Center, 8060 Market St, Youngstown, Ohio 44512; Ph: 330-758-9189; Fax: 330-758-4487; [email protected]

Figure 1. Three round, verrucous plaques confined to the boundaries of the tattoo.

MOUSSA, KAZI, AKBARY, BERNERT, HALMI Page 37 dermatology clinic for evaluation of three reticular dermis (Figures 2 and 3). A brisk and growths on her left foot. The patient reported diffuse inflammatory infiltrate occupied most of getting a tattoo of three stars on her left foot the dermis, which had histiocytic, lymphocytic, one year prior to presentation and stated that and neutrophilic components, and displayed the tattoo never healed well. Over the course marked, focal exocytosis into the epidermis of six months she noticed development of (Figure 4). Occasional deposits of black and green the aforementioned growths confined to the pigment corresponding to tattoo ink were noted tattoo. A thorough review of systems was in the dermis as well as degeneration of collagen performed and was negative except for localized bundles (Figure 5). Higher magnification of the tenderness over the growths. Past medical epidermis revealed very focal cytologic atypia of history was noncontributory, and medications the keratinocytes in the follicular infundibulum consisted of ibuprofen as needed. She denied (Figure 6), whereas the majority of the remaining tobacco, alcohol, or illicit drug use. keratinocytes were eosinophilic, contained glassy Figure 6. Focal atypia of keratinocytes in the Physical exam was exceptional for three 2.4 cytoplasm, and lacked atypia (Figure 3). In cm round verrucous plaques, two with an addition, viral cytopathic effects were absent. follicular infundibulum (H&E, 200x). erythematous halo, on the dorsolateral aspect of possible fungal or mycobacterial cutaneous the left foot contained within the boundaries of infection. Given the widespread inflammation the tattoo (Figure 1). Of note, the tattoo did not and the presence of a few ill-defined granulomas, contain any red pigment. Differential diagnosis the possibility of an atypical mycobacterial included keratoacanthoma, foreign-body infection arising in a tattoo and resulting in reaction, or infection, such as coccidioidomycosis extensive pseudoepitheliomatous hyperplasia or mycobacteria. Two 4-mm punch biopsies was a diagnostic consideration; however, a biopsy were obtained; one specimen was submitted for sent for bacterial and fungal cultures showed no hematoxylin-eosin (H&E) analysis and the other growth. for fungal, bacterial, and atypical mycobacterial culture. The patient was also given a course of The clinical and histopathologic exam as well as doxycycline on initial presentation for signs of negative cultures in this case favored a diagnosis secondary impetiginization. of tattoo-associated pseudoepitheliomatous hyperplasia. The lesions were treated by Histologic examination of the biopsy disclosed Figure 4. Higher magnification of the mixed electrodessication and curettage, with no evidence a central, keratin-filled crater surrounded by inflammatory infiltrate in the dermis with of recurrence. marked epidermal hyperplasia with irregular, exocytosis into the epidermis (H&E, 100x). epidermal tongues extending deep into the Discussion Tattoos are widely popular, both in the United States and internationally, for decorative, religious, cosmetic, or cultural purposes. Some tattoos are accidental, such as occurs from deposition of exogenous pigment substances in puncture wounds; or iatrogenic, such as occurs from Monsel’s solution when used for hemostasis.1,6 Commonly reported tattoo reactions include allergic and hypersensitivity reactions.1,6,8 Reports of pseudoepitheliomatous hyperplasia or keratoacanthoma-like eruptions are rare. Distinguishing between these reactions is difficult due to similar histologic features and Figure 2. Keratin-filled crater surrounded by Figure 5. Black ink in dermis corresponding to often requires complete excision for diagnosis. marked epidermal hyperplasia (H&E, 40x). tattoo pigment (H&E, 200x). Pseudoepitheliomatous hyperplasia is a reactive pattern showing benign, irregular, epidermal The constellation of histologic features in the biopsy hyperplasia characterized by prominent specimen can be seen in both keratoacanthoma acanthotic downgrowths and keratinocytes and pseudoepitheliomatous hyperplasia. Given with abundant cellular cytoplasm. It can the symmetric, keratin-filled, cup-like crater be seen in chronic healing wounds, chronic with epithelial proliferation and prominent irritation, trauma, and infection. Histologically, infiltrates, keratoacanthoma was high on the it can mimic keratoacanthoma or squamous cell differential. However, the relative lack of major carcinoma. Fraga et al. detail a series of 11 tattoo- cytologic atypia, abundant mitoses, and frank associated keratoacanthomas arising in eight architectural abnormalities seemed to distinguish patients, the majority of which were initially diagnosed as invasive squamous cell carcinoma this lesion as pseudoepitheliomatous hyperplasia. 2 Besides the histologic characteristics favoring or pseudoepitheliomatous hyperplasia. They this entity, the lack of spontaneous involution of note that 82% of the keratoacanthomas occurred the lesion also favored pseudoepitheliomatous in areas of red tattoo pigment, with half of these Figure 3. Irregular, prominent epidermal tongues hyperplasia as the diagnosis. showing displacement of red tattoo ink into with marked inflammation in the dermis. Note the overlying keratin through transepidermal that keratinocytes are eosinophilic, contain Finally, there was an extensive histiocytic, acute elimination, suggesting a foreign-body reaction 2 glassy cytoplasm, and lack atypia (H&E, 40x). and chronic inflammatory infiltrate occupying to the tattoo pigment. They acknowledge the dermis in our specimen, signifying a that there is considerable overlap of histologic

Page 38 PSEUDOEPITHELIOMATOUS HYPERPLASIA RESEMBLING MULTIPLE KERATOACANTHOMAS ARISING IN A TATTOO features seen in pseudoepitheliomatous References hyperplasia and keratoacanthomas, but conclude 1. Breza TS Jr, O’Brien AK, Glavin FL. that the features noted are likely describing a Pseudoepitheliomatous Hyperplasia: An single reactive pattern better grouped under the Unusual Tattoo Reaction. JAMA Dermatol. 2013 2 classification of keratoacanthoma. Kluger et May;149(5):630-1. al. and Balfour et al. collectively describe four similar presentations, and describe histologic 2. Fraga GR, Prossick TA. Tattoo-associated findings of pseudoepitheliomatous hyperplasia, keratoacanthomas: A series of 8 patients with the majority seen in areas of red tattoo pigment.8,9 11 keratoacanthomas. J Cutan Pathol. 2010 They note the lack of abundant mitosis, Jan;37(1):85-90. major architectural disruption and cytologic 3. Centers for Disease Control and Prevention atypia in pseudoepitheliomatous hyperplasia, (CDC). Tattoo-associated nontuberculous distinguishing it from keratoacanthoma. Balfour mycobacterial skin infections--multiple states, et al. also note that a regressing keratoacanthoma 2011-2012. MMWR Morb Mortal Wkly Rep. could not be excluded in their particular 2012 Aug 24;61(33):653-6. case.9 These reports underscore the challenging 4. Bassi A, Campolmi P, Cannarozzo G, et al. distinction between keratoacanthoma and Tattoo-associated skin reaction: The importance pseudoepitheliomatous hyperplasia, and the need of early diagnosis and proper treatment. BioMed for full-thickness biopsies or excision to rule out Research International [Internet]. Vol. 2014 a neoplastic process. (2014). Article ID 354608, 7 pages. Available Pseudoepitheliomatous hyperplasia can be a from: http://www.hindawi.com/journals/ reactive process seen in the setting of infection bmri/2014/354608/. as well, and such etiologies must not be 5. Goldstein M. Mercury-cadmium sensitivity in overlooked.7 Of note, the Centers for Disease tattoos. A photoallergic reaction in red pigment. Control reported an outbreak of 22 cases of Ann Intern Med. 1967 Nov;67(5):984-9. tattoo-associated non-tuberculous mycobacterial skin infections in 2011-2012 from gray tattoo 6. Bolognia J, Jorizzo JL, Schaffer JV. Dermatology. ink.3 There are no explicit regulations by the Food Philadelphia: Elsevier Saunders, 2012. Print. and Drug Administration requiring sterility of 7. Then M, Mark Boustred A, Clarke LE. tattoo inks; contamination can occur through use Keratoacanthomatous hyperplasia in response to of nonsterile water, contaminated ink products a tattoo. Dermatol Surg. 2009 Apr;35(4):685-6. or poor manufacturing processes. Therefore it is essential that cultures and tissue stains 8. Kluger N, Durand L, Minier-Thoumin C, are performed for tattoo-associated reactions Plantier F, Cotten H, Berteloot E, Blatière V, suspicious for infection. Dereure O. Pseudoepitheliomatous epidermal hyperplasia in tattoos: report of three cases. Am J Clin Dermatol. 2008;9(5):337-40. Conclusion Pseudoepitheliomatous hyperplasia in a tattoo 9. Balfour E, Olhoffer I, Leffell D, Handerson is rarely reported, and it has marked histologic T. Massive Pseudoepitheliomatous Hyperplasia: similarity to keratoacanthoma. It can be An Unusual Reaction to a Tattoo. Am J distinguished from keratoacanthoma by lack Dermatopathol. 2003;25(4):338–340. of abundant cellular atypia, frequent mitoses, and abnormal architecture. Still, distinguishing Correspondence: Christine Moussa, DO; between pseudoepitheliomatous hyperplasia [email protected] and keratoacanthoma is a challenge and likely requires a complete excision to rule out a neoplastic process.

MOUSSA, KAZI, AKBARY, BERNERT, HALMI Page 39 Nodular Amyloidosis: A Case Report and Review of the Literature

Sean McGregor, PharmD,* John Minni, DO, FAOCD,** Michael Nowak, MD***

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

Abstract Amyloidosis is perhaps one of the most esoteric disease processes that physicians encounter throughout their training and well into their practice. Most physicians are familiar with the term amyloidosis. However, many are unfamiliar with the exact etiology and different forms of amyloidosis that may present in their practice. Our goal is to provide a review of the different forms of amyloidosis that may present cutaneously and to briefly describe a case that presented in our office.

Serum and urine protein electrophoresis were clinical settings, and it is important for any ordered, and the patient was subsequently practitioner to be able to identify this disease referred to hematology and oncology for further process and its appropriate management. evaluation and management. Unfortunately, the Amyloidosis may be further classified clinically patient was lost to follow-up. as either systemic or localized deposition. Discussion Systemic amyloidosis can be further classified The term “amyloid” was first introduced into as primary systemic amyloidosis, which is medicine by Virchow in 1853.2 In general, associated with plasma-cell dyscrasias such amyloidosis refers to the abnormal tissue as multiple myeloma, and secondary systemic deposition of misfolded β-sheet fibrillar protein amyloidosis, which is associated with chronic 1,3 inflammatory and infectious states such Figure 1 known as amyloid. However, amyloid is not a single protein, but rather a broad term used as rheumatoid arthritis and tuberculosis, 1 Localized amyloidosis is limited to describe one of the many types of amyloid respectively. to one organ, which may be the skin, endocrine Case Report proteins that may become abnormally deposited A patient presented to our office with a organs, or the brain, for which Alzheimer’s in tissues (Table 1). Amyloid deposits display circumscribed, pink nodule localized to left disease is the classic example. Amyloidosis a characteristic apple-green birefringence after angle of the mouth (Figure 1). Upon our is thus a highly variable disease with a wide being stained with Congo red and viewed under initial evaluation of the patient, we considered 4 variety of clinical presentations. Nevertheless, polarized light microscopy. The misfolded angular cheilitis or basal cell carcinoma, and a proteins arise from specific precursor proteins, cutaneous manifestations are often the initial shave biopsy was subsequently performed. The 3 which help us to classify amyloidosis based on presentation in systemic disease. biopsy results revealed an amorphous, dull, pink the individual protein chemical compositions Localized cutaneous amyloidosis is of material extending through the thickness of the (Table 1). particular importance to dermatologists and reticular dermis with many associated plasma may be further sub-classified as either primary cells arranged in a perivascular and interstitial Amyloidosis itself is not necessarily a disease, cutaneous amyloidosis or secondary cutaneous distribution (Figure 2). Additionally, the dermal but rather a manifestation of several underlying amyloidosis. Primary cutaneous amyloidosis material was positive on Congo red staining, and disease processes. There are numerous forms of may present as one of three types: macular immunoperoxidase-stained sections revealed a amyloidosis, which consist of various primary amyloidosis, papular/lichenoid amyloidosis, marked predominance of Lambda over Kappa and secondary manifestations. Likewise, or nodular amyloidosis. However, macular light chains (Figures 3, 4). amyloidosis may present in a wide variety of Figure 2 Figure 3 Figure 4

Page 40 NODULAR AMYLOIDOSIS: A CASE REPORT AND REVIEW OF THE LITERATURE Table 1. Amyloid Proteins and Clinical Syndromes1 • Hepatomegaly • “Shoulder pad” sign Precursor Protein Amyloid Protein Clinical Syndrome • Weakness and fatigue Immunoglobulin AL Primary systemic amyloidosis (plasma-cell dyscrasia light chain and multiple myeloma) • Macroglossia The majority of cases of systemic amyloidosis Primary cutaneous nodular amyloidosis occur as a result of plasma-cell dyscrasias, including but not limited to multiple myeloma Transthyretin ATTR Senile systemic amyloidosis and monoclonal gammopathy of undetermined Cytokeratin (CK5) AK Primary cutaneous lichenoid and macular significance (MGUS), which account for 6 amyloidosis approximately 30% of these cases. β β 2-microglobulin A 2M Chronic hemodialysis Treatment options for cutaneous amyloidosis β β are limited, and there are few randomized A precursor protein A Alzheimer’s disease controlled trials involving the treatment of (AβPP) this disease. First-line treatments include Calcitonin ACal Medullary carcinoma of the thyroid topical steroids under occlusive dressings and intralesional steroid injections. However, and papular amyloidosis may also be present associated with autoimmune connective-tissue dermabrasion, shave excision, and curettage simultaneously in what is referred to as disorders, such as systemic lupus erythematosus, with cautery have been used successfully in some 1 1 biphasic amyloidosis. Secondary cutaneous scleroderma, and dermatomyositis. Familial cases.3 Systemic amyloidosis with cutaneous amyloidosis refers to amyloid deposition seen in forms of both disorders may be associated with manifestations requires a multidisciplinary association with basal cell carcinomas, Bowen’s RET oncogene mutations. approach to treatment, possibly involving disease, other cutaneous tumors, and following Nodular amyloidosis is perhaps one of the systemic chemotherapy with melphalan. Thus, PUVA therapy. Both macular and lichenoid rarest forms of amyloidosis. It presents as either the treatment options will vary depending on amyloidosis, in addition to secondary localized single or multiple waxy nodules or plaques that the underlying cause. cutaneous amyloidosis, result from the abnormal 6 most commonly affect the trunk or extremities. misfolding and deposition of keratin protein. Nodular amyloidosis may present as a primary Conclusion The macular, lichenoid, and biphasic forms cutaneous disorder, but it may also present as This case highlights the important role of amyloidosis are characterized by amyloid a cutaneous manifestation of primary systemic that dermatologists play in diagnosis and deposition limited to the papillary dermis amyloidosis associated with plasma-cell management of cutaneous manifestations of and may present as yellowish or brownish dyscrasias, such as multiple myeloma. Nodular both localized and systemic disease. macules, papules, or plaques. Additionally, a amyloidosis is particularly associated with lymphohistiocytic perivascular infiltrate may immunoglobulin γ light-chain deposition, 1 be appreciated on histopathology. In contrast, which is believed to be secreted by an infiltrate References primary cutaneous nodular amyloidosis is of plasma cells.2 The presence of nodular 1. Groves R, Black M. Amyloidosis. Philadelphia: WB characterized by amyloid deposition in the amyloidosis confers an approximate 7% risk of Sauders; c2012. 699-708. (Bolognia J, Jorizzo J, and dermis, subcutis, and even the vessel walls.1,3 progression to systemic involvement. In a study Schaffer J, editors. Dermatology; vol. 2). Additionally, a perivascular infiltrate of plasma of 16 patients with nodular amyloidosis without 2. Fernandez-Flores A. Cutaneous Amyloidosis: A cells may be appreciated on histopathology.1 systemic involvement, one patient was noted to Concept Review. Am J Dermatopathol. 2012;34:1-17. λ 3. Schreml S, Szeimies R, Vogt T, et al. Cutaneous There is much variability among the different have a serum monoclonal IgG protein upon initial evaluation and subsequently developed Amyloidosis and Systemic Amyloidosis with Cutaneous cutaneous forms of amyloidosis, and clinical Involvement. Eur J Dermatol. 2010;20(2):152-160. presentation alone is unlikely to provide a symptoms of systemic amyloidosis within one 5 Thus, it is important to delineate the 4. Merlini G, Bellotti V. Molecular Mechanisms of definitive diagnosis. Pruritus is a common year. etiology in all cases of nodular amyloidosis, as Amyloidosis. N Engl J Med. 2003;349:583-596. symptom associated with cutaneous amyloidosis; it may be indicative of underlying malignancy. 5. Moon A, Calamia K, Walsh J. Nodular Amyloidosis: however, it is not always present. Review and Long-term Follow-up of 16 Cases. Arch Approximately 25% of patients with primary Lichenoid or papular amyloidosis is the Dermatol. 2003;139:1157-1159. systemic amyloidosis have cutaneous most common type of primary cutaneous 6. Mason A, Rackoff E, Pollack R. Primary Systemic manifestations, which present as waxy, amyloidosis. It presents as firm, scaly, skin- Amyloidosis Associated with Multiple Myeloma: translucent or purpuric papules, nodules, and colored or hyperpigmented papules that A Case Report and Review of the Literature. Cutis. plaques localized to the palms and volar aspect 2007;80:193-200. coalesce into plaques with a rigid appearance. of the fingertips. Additionally, the face, neck, It most commonly affects the extensor surfaces and scalp may be involved. Signs and symptoms of the extremities. Macular amyloidosis Correspondence: Sean McGregor, PharmD; of systemic involvement may be evident, and usually presents in early adulthood, affecting [email protected] patients may present with nephrotic syndrome, women more often than men. It presents as autonomic and sensory neuropathies, and hyperpigmented papules that coalesce into a congestive heart failure. Other signs and “rippled” appearance and most commonly affects symptoms may include: the scapular region of the upper back. Frequently, this occurs after persistent rubbing of the area • Left ventricular hypertrophy with either brushes or towels and has been sub- • Low-voltage QRS complex classified as “friction amyloidosis.”1 The extensor surfaces of the extremities may also be affected. • Urinary immunoglobulin light chains Both macular and papular amyloidosis may be • Renal failure MCGREGOR, MINNI, NOWAK Page 41 Systematic Review of Phototherapy in Pruritic Disorders

Soham Chaudhari, BA,* Argentina Leon, MD,** Ethan Levin, MD,** John Koo, MD***

*Medical Student, 4th year, Touro University Nevada – College of Osteopathic Medicine, Henderson, NV **Research Fellow, Department of Dermatology, University of California, San Francisco, CA ***Professor and Vice Chairman, Department of Dermatology; Director, Psoriasis Treatment Center, University of California, San Francisco, CA

Abstract Phototherapy is a proven method for the management of many pruritic disorders, including atopic dermatitis (AD), prurigo nodularis (PN), and generalized pruritus (GP). Objective: This review aims to give an update on the use of phototherapy for managing pruritus in these disorders to establish it within the spectrum of possible therapeutic options. Methods: A thorough literature search of the PubMed database was conducted to identify studies that examined a variety of phototherapy methods in these disorders. Results: AD is best managed with narrow band (NB)-UVB. NB-UVB and broad band (BB)-UVB are also effective in decreasing pruritus in PN. BB-UVB is the preferred modality to decrease GP caused by uremic pruritus (UP). Conclusion: Phototherapy is a safe and beneficial option when other measures fail to control pruritus in these disorders. Introduction Methods Atopic Dermatitis Pruritus, or the sensation of itch, is the most For this systematic review, we concentrated on AD is a common, chronic inflammatory skin common symptom among dermatology patients.1 the therapeutic role of phototherapy for AD, disease characterized by intense pruritus leading Both cutaneous and systemic conditions may PN, LSC, and GP in adults. The computerized to secondary cutaneous findings. It is a genotypic present with pruritus as the primary symptom. bibliographic database PubMed was used to diathesis in which a heightened immune response is triggered once the skin is irritated Chronic pruritus is a major cause of distress conduct a search for English articles from by an environmental stimulus, subsequently to patients and has a significant impact on inception to August 2014. Research articles producing the sensation of itch. Genetically quality of life. All ages are affected by pruritus, of randomized controlled trials (RCT), predisposed individuals have an imbalance in the ranging from children to seniors, and it is the open prospective studies, pilot studies, and T-helper (Th) 2 versus Th1 immune responses. most common dermatologic complaint in the retrospective observations on NB-UVB, BB- 2,3 UVB, UVA, PUVA, and MEL were used. The AD develops secondary to this intensified latter group. For many sufferers of pruritus, following key words were used: phototherapy immune response once the patient continuously topical therapy is not adequate in controlling 6 pruritus, phototherapy eczema, phototherapy scratches. Hence, AD is colloquially known in their symptom. Therefore, providing additional atopic dermatitis, phototherapy prurigo dermatology as “the itch that rashes,” because therapeutic options becomes essential for the nodularis, phototherapy lichen simplex chronicus, the itch is the chief symptom and the foremost successful dermatologist. Phototherapy is a phototherapy neurodermatitis, and phototherapy indicator of treatment efficacy. safe and efficacious management modality that pruritic disorders. Based on the keywords chosen, decreases pruritus and can be used across age 1,194 articles were revealed. After screening title NB-UVB: 4 groups. and abstract, those studies in which phototherapy The reduction of pruritus in AD by NB-UVB Ultraviolet-based therapy (phototherapy and was not used as a treatment for the chosen disease radiation has been demonstrated in multiple photochemotherapy) can provide relief for processes were excluded. Reference lists in review studies (Table 1). A double-blind RCT was pruritic patients without many of the risks and articles were also searched. Abstracts-only and conducted by Reynolds et al. to compare the adverse effects of systemic medications. UVB duplicates were excluded. This left 105 articles efficacy of NB-UVB to BB-UVA and a placebo for the screening phase. These records were then 7 (290-320 nm) and UVA (320-400 nm) are of visible fluorescent light. The NB-UVB group assessed for eligibility, excluding children, hand implemented in UV-based therapy. Broadband experienced a 90% reduction in pruritus from eczema, nummular eczema, and other modes of UVB (BB-UVB) and broadband UVA (BB- baseline, compared to 63% reduction in the BB- treatment as primary analysis, thereby leaving 58 UVA group. When compared to placebo, there was UVA) use a light source covering their entire studies. Relevant data including study design, spectrum. Narrowband UVB (NB-UVB) uses a 38% greater reduction in pruritus for NB-UVB number of participants, duration of treatment, versus an 11% reduction for BB-UVA. Seventy- 311-313 nm, and UVA1 uses 340-400 nm with cumulative phototherapy dosing, adverse effects, one percent of patients had an improvement in a peak at 365 nm. UVA1 can be administered at and clinical outcome were retrieved from 2 their loss of sleep when on NB-UVB, as opposed high-dose (HD-UVA1) (130 J/cm ), medium- the articles and formulated into spreadsheet 2 to 53% on BB-UVA. NB-UVB also showed an dose (MD-UVA1) (50 J/cm ), and low-dose databases. Thus, the total number of trials included 2 improvement in disease activity in the three- (LD-UVA1) (20 J/cm ). Monochromatic excimer in the final analysis is 58. When specific pruritus month follow-up period. Although patients light (308 nm), or MEL, is a more targeted assessment scales were mentioned, we cited them in this study were allowed to use moderate-to- phototherapy device that delivers 308 nm UVB in the results. If no particular assessment scale potent topical steroids simultaneously, their use to a localized area and can expand treatment was used, extent of disease, sleep improvement, was quantified and included in the evaluation of options by sparing unaffected areas. This review and remission were evaluated. Because pruritus is treatment efficacy. This is in line with the real- the main symptom of these disorders, the above article focuses on the efficacy of these forms of world usage of phototherapy, as dermatologists phototherapy to treat non-psoriatic, chronic, criteria may be considered synonymous with the resolution of pruritus. rarely use phototherapy-only in practice. Other pruritic disorders triggered by an inflammatory studies that evaluated the use of NB-UVB support response including atopic dermatitis (AD), these positive results.8-11 In a nonrandomized, prurigo nodularis (PN), lichen simplex chronicus Results single-blind, half-side comparison study between (LSC), and generalized pruritus (GP). To our We separated our data based on our disease NB-UVB and the combination treatment of knowledge, this type of review has not been processes of interest, and further viewed each UVA and UVB (UVAB), NB-UVB significantly published before for phototherapy of pruritus. category of phototherapy based on current reduced pruritus (mean visual analogue scores widespread availability and use. 2.7 and 3.8; p=0.043).12 Legat et al. conducted

Page 42 SYSTEMATIC REVIEW OF PHOTOTHERAPY IN PRURITIC DISORDERS Table 1: Phototherapy for treatment of pruritus in atopic dermatitis (AD) Study Type Participants (no.) Treatment Regimen Cumulative Dose (J/cm2 ) Concomitant TCS Pruritus Outcomes allowed NB-UVB

RCT7 - NB-UVB: 22 2x/week (wk) for 24 - NB-UVB: 24.8 Yes NB-UVB > BB-UVA > placebo - BB-UVA: 19 weeks (wks) - BB UVA: 315 - Visible light - Placebo: 320 minutes (placebo): 19 RCT, open8 21 3x/wk for 12 wks NB-UVB: 35.05 Yes - 68% reduction in AD severity scores - 88% reduction in TCS use

RCS9 37 2x/wk NB-UVB: 21.9 Yes 81% improved

RCS10 40 3x/wk NB-UVB: 16.371 Yes 80% improved

RCT, BCS12 10 3x/wk for 6 wks - NB-UVB: NR Yes NB-UVB > UVAB - UVAB: NR RCT, BCS13 9 3x/wk for 8 wks - NB-UVB: 26.7 No NB-UVB = MD-UVA1 - MD-UVA1: 1000 RCT, BCS14 13 3x/wk for 8 wks - NB-UVB: 10.5 In follow-up NB-UVB = MD-UVA1 - MD-UVA1: 930.6 period RCT, CoS15 47 3x/wk for 6 wks - NB-UVB: 23.4 No NB-UVB = MD-UVA1 - MD-UVA1: 880 RCT11 5 5x/wk for 3 wks NB-UVB: 9.2 No 100% patients improved BB-UVB

RCT, BCS16 17 3x/wk for 8 wks - BB-UVB: NR Yes BB-UVB > placebo - Daylight tubes (placebo): NA CS17 1* 2x/wk for 3 months - BB-UVB: NR No BB-UVB > NB-UVB - NB-UVB: NR RCT19 - BB-UVB: 52 5x/wk - BB-UVB: 2.70 No UVAB > BB-UVB - UVAB: 54 - UVAB: 1.77 (UVB), 104 (5) RCT20 89 UVAB > BB-UVB RCT21 - BB-UVB: 33 5x/wk - BB-UVB: 2.3 Yes UVAB > BB-UVB - UVAB: 23 - UVAB: 1.4 (UVB) 160 (5) PUVA

RCT, BCS23 - Whole-body PUVA - PUVA: 3x/wk - PUVA: 13 No PUVA > BB-UVB & placebo vs. control: 5 - BB-UVB: 5x/wk - No treatment: NR - PUVA vs. no - BB-UVB: NR treatment: 5 - PUVA vs. BB- UVB: 5 RCT24 113 PUVA: 3x/wk for 8 wks PUVA: 115.3 80% decrease in severity RCT, BCS27 12 PUVA: 3x/wk for 6 wks - NB-UVB: 14 No PUVA = NB-UVB - Bath PUVA: 48.3 CoS2 40 - MOP+UVA: 3x/wk for - PUVA: 48.1 No PUVA > MD-UVA1 5 wks - MD-UVA1: 1138.8 - MD-UVA1: 5x/wk for 3 wks UVA1 RCT, BCS29 - UVA + UVAB: 28 - UVA + UVAB: 5x/wk - UVA (361) + UVAB: Yes - UVA = UVAB - BB-UVB + UVAB: for 3 wks 0.466 (UVB), 109 (5) - UVAB > BB-UVB 20 - BB-UVB + UVAB: 3x/ - BB-UVB (0.282) + UVAB: wk for 8 wks 0.558 (UVB) 130(5) RCT30 - HD-UVA1: 15 Daily for 15 total - HD-UVA1: 1950 No HD-UVA1 > UVAB - UVAB: 10 exposures - UVAB: NR RCT31 - HD-UVA1: 20 Daily for 10 total - HD-UVA1: 1300 No HD-UVA1 > fluocortolone > UVAB - UVAB: 16 exposures - UVAB: 0.33 (UVB) 6.8(5) - Topical - Topical fluocortolone: 0.5% fluocortolone: 17 cream or ointment RCT32 - MD-UVA1: 50 - MD-UVA1: 5x/wk for - MD-UVA1: 750 No MD-UVA1-cold-light > MD-UVA1 - MD-UVA1-cold- 3 wks - MD-UVA1-cold-light: 750 > UVAB light: 50 - MD-UVA1-cold-light: - UVAB: 0.29 (UVB) 7.9 (5) - UVAB: 20 5x/wk for 3 wks - UVAB: 1x/day

CHAUDHARI, LEON, LEVIN, KOO Page 43 RCT, BCS33 10 5x/wk for 3 wks - HD-UVA1: 1710 No HD-UVA1 = MD-UVA1 - MD-UVA1: 855 RCT34 MD-UVA1: 5x/wk for 3 wks - MD-UVA1: 50 No MD-UVA1 > LD-UVA1 LD-UVA1: - LD-UVA1: 10 RCT35 32 5x/wk for 3 wks MD-UVA1: 750 No SCORAD improved by 34%; 10% deterioration after 1 month; 40% deterioration after 3 months UVAB RCT, BCS28 39 3x/wk for 8 wks - UVAB: NR Yes UVAB > BB-UVB - BB-UVB: NR BCS: bilateral comparison study; CR: case report; CS: case series; CoS: crossover study; NA: not applicable; NR: not reported; RCT: randomized controlled trial; RCS: retrospective cohort study; TCS: topical corticosteroid *The other cases in this case series were excluded because they did not pertain to AD a randomized, nonblinded comparison of NB- UVAB was found to be superior to BB-UVB in AD, induces chronic excoriated pruritic nodules UVB to MD-UVA1 and found them equally decreasing pruritus.28 Another study by the same that appear most commonly on the extremities, efficacious in reducing pruritus, a claim supported group compared two groups receiving either neck, and shoulders. The exact etiology and by other, similar studies.13-15 Taken together, these UVA + UVAB or BB-UVB + UVAB, without a mechanism of PN remain elusive; however, trials suggest NB-UVB as a preferred treatment control group.29 There was an equal improvement it has been associated with atopy, pregnancy, for AD. in pruritus when comparing UVA to UVAB, but HIV, psychiatric disorders, internal diseases, a significant difference in favor of UVAB when and malignancy.36-39 The mechanisms for these BB-UVB: comparing BB-UVB to UVAB. When assessed associations are unclear as they are mainly derived BB-UVB has largely been replaced by NB-UVB by the Costa overall score, HD-UVA1 proved from case reports. The primary goal of treatment in today’s dermatology clinics, as more studies to be more effective than UVAB in decreasing is to decrease pruritus, which can be achieved have demonstrated the superior efficacy of NB- the severity of itch symptoms (50% after six via topical and intralesional corticosteroids, UVB in treating psoriasis. However, there is a treatments vs. 30% after 15 treatments).30 This tacrolimus, calcipotriol, cryotherapy, capsaicin, small subset of eczematous patients who are suggested a fast-acting therapeutic action for thalidomide, cyclosporine, or phototherapy.39-41 unable to tolerate NB-UVB but can tolerant HD-UVA1 and a slow-acting mechanism for UV-light exposure diminishes pruritus in PN BB-UVB. Previous studies have demonstrated UVAB. This was further examined in a study due to its anti-inflammatory effects, in a manner the superiority of BB-UVB to placebo in treating randomizing patients into groups of HD-UVA1, similar to that seen in AD.42,43 AD, with a 76% improvement in patients (p < UVAB, or mid-potency corticosteroids. HD- 16 0.001). Pugashetti et al. reported the case UVA1 was the most effective for decreasing NB-UVB: of an AD patient in whom NB-UVB caused pruritus in acute, severe exacerbations of AD NB-UVB has not only resulted in the irritation and was less effective when compared when assessed by SCORAD.31 Serum levels of improvement of lesions but has also provided for 17 44 to BB-UVB. The authors hypothesized that the eosinophil cationic protein were significantly long-term remission upon one-year follow-up. higher doses required by NB-UVB to achieve reduced after HD-UVA1 or fluocortolone, but Combining NB-UVB with thalidomide has also minimal erythema and induce apoptosis resulted not UVAB (62.5% had reduction of at least 25% provided excellent results in the treatment of PN in burning and cutaneous sensitivity, which was of the value obtained before therapy vs. 57.1% vs. and is considered by some as the treatment of 17,18 40,45 not experienced during BB-UVB treatments. 25%). When assessing blood eosinophilia, 50% choice for PN. However, there is concern for Finally, a few studies found the combination of HD-UVA1 and 30% of fluocortolone patients its teratogenic effects and potential for inducing 46,47 of BB-UVB with UVA superior to BB-UVB had at least 50% reduction in pretreatment dose-related peripheral neuropathy. Thus, 19-21 alone. However, BB-UVB was comparable to values, but none of the patients treated with reducing total treatment time and dosage of 22 LD-UVA1 in improving the pruritus score. UVAB therapy did. The advent of the UVA1 cold thalidomide by combining it with NB-UVB is a 40 light decreased the heat generated by traditional better therapeutic option. PUVA: UVA1 machines and thus reduced a potential The use of PUVA in AD treatment dates back trigger for pruritus.32 Medium-dose (MD) BB-UVB: to the 1970s, when Morrison et al. demonstrated UVA1 cold light was more efficacious in reducing While NB-UVB is thought to be more efficacious 8-methoxypsoralen (8-MOP) PUVA as superior in the treatment of PN, BB-UVB has also proved 23 disease severity than UVA1 and UVAB (85.4% 39,45,48 to both placebo and BB-UVB. 8-MOP PUVA improved or completely cleared vs. 77.3% vs. beneficial. A study in England found seven has resulted in an 80% decrease in pruritus out of eight patients cleared of PN and with 37.5%). Both MD UVA1 and MD UVA1 cold 49 severity, and 5-MOP PUVA has caused a greater light also decreased plasma levels of soluble IL-2 decreased pruritus with the use of BB-UVB. reduction in SCORAD than MD-UVA1 (mean receptors and IL-4 receptors. UVA1-treated Combination treatment of UVB with topical +/- SD 54.3 +/- 25.7% vs. 37.7 +/- 22.8%; p = PUVA provided successful results.50 24-26 patients displayed a more prolonged therapeutic 0.041). The average length of remission was benefit than those treated with UVAB. Studies PUVA: also longer for PUVA than MD-UVA1 (12 conducted to determine the dosage for UVA1 weeks vs. 4 weeks; p = 0.012). Bath PUVA was PUVA has also been reported to be beneficial found MD UVA1 and high-dose (HD) UVA1 39,43,45,51 compared with bath NB-UVB in an investigator- in the treatment of PN. A complete 27 comparable in efficacy and superior to low- blinded half-side study. It yielded no significant 33,34 response or significant improvement was found dose UVA1. In all of these studies, UVA1 52,53 in most patients treated with bath-PUVA. difference when evaluated using SCORAD demonstrated the greatest effects earlier in the There was a greater reduction in papules, (65.7% vs. 64.1%; p = 0.48), even though a faster course of treatment. Long-term remission was infiltration of T cells, and pruritus (PIP) score response to bath PUVA was noted during the not seen with UVA1; most patients returned to 35 in patients treated with bath PUVA and MD first two weeks. baseline within three months. UVA1 compared to those treated with NB-UVB UVA: (P<0.01, 95% CI 1.1.-3.63 and P<0.05, 95% CI Prurigo Nodularis 43 Older studies have compared the traditional Prurigo nodularis (PN) is a chronic inflammatory 0.42-2.70, respectively). On a six-week follow- combination UVA and BB-UVB (UVAB) skin condition with nodular pruritic lesions. up, however, all patients relapsed except for 30% to UVA1 and other types of phototherapy. An intense itch-scratch cycle, similar to that in of those treated with NB-UVA and 9% of those

Page 44 SYSTEMATIC REVIEW OF PHOTOTHERAPY IN PRURITIC DISORDERS Table 2: Phototherapy for treatment of pruritus in prurigo nodularis (PN) Study Type Participants Treatment Regimen Cumulative Dose (J/cm2 ) Concomitant TCS Pruritus Outcomes (no.) allowed NB-UVB PCS44 10 NB-UVB: 1x/week for mean NB-UVB: 23.88 No Improved, with long remission 24.3 irradiations RCT40 4 - NB-UVB: 3x/wk for 32 - NB-UVB: 40.5 NR Excellent response to thalidomide after irradiations - Thalidomide therapy: NA 8-10 wks; well-controlled with NB-UVB - Thalidomide therapy: 100mg/ day for 12 wks BB-UVB CR39 8 NR BB-UVB: NR NR 50% improved CS49 - BB-UVB: 8 19 courses of phototherapy - BB-UVB: NR NR - BB-UVB: 87.5% partial/complete - Bath PUVA: 4 - Bath PUVA: 7.5 mL resolution - Oral PUVA: 7 1.2% 8-MOP bath solution - Bath PUVA: 75% partial/complete diluted in 70L of water resolution - Oral PUVA: 8-MOP, 25 - Oral PUVA: 85.7% partial/complete mg/m2 resolution CS50 Case 1 - BB-UVB: 3x/wk for 6 wks - BB-UVB: 6234 Yes Well-controlled lesions and itch - 8-MOP Topical PUVA: 3x/wk - 8-MOP Topical PUVA: for 8 wks 240

Case 2 30 irradiations - BB-UVB: 7239 NR Well-controlled lesions and itch - 8-MOP Topical PUVA: 240 PUVA RCT43 - PUVA: 9 - PUVA: 4x/wk for 4 wks - PUVA: 18.2 No PUVA > UVA1 > NB-UVB - NB-UVB: 13 - NB-UVB and MD-UVA1: 5x/ - NB-UVB: 16.15 - MD-UVA1: 11 wk for 4 wks - MD-UVA1: 1000

RCS45 - PUVA: 9 - PUVA: 22.33 irradiations - PUVA: 141.61 NR PUVA > NB-UVB > UVAB - UVAB: 3 - UVAB: 31.5 irradiations - UVAB: 199.99 UVA, - NB-UVB: 5 - NB-UVB: 29.0 irradiations 1.428 UVB - NB-UVB: 25.304 RCT51 63 14 irradiations PUVA: 6.9 NR 81% improved RCT(52 17 8 wks PUVA: 30.3 NR 88% significantly improved, sustained improvement on 6-wk follow-up RCT53 10 Until clinical improvement or PUVA: 19 NR Median of 13 baths for clearing of minor erythema pruritic lesions RCT54 15 Until beneficial results PUVA: 14.6 NR 53% showed good result by average 3 wks MEL PS55 11 once/wk for 8 wks MEL: 13.5 No 81% had partial or complete remission RCT57 22 - PUVA + MEL: 2x/wk for 5 wks - PUVA + MEL: 23.7 NR Average of 5 fewer PUVA treatments - PUVA: 4x/wk for 5 wks - PUVA: 16.9 in combination group; 100% remission in PUVA group; 90% remission in combination group UVA RCS42 17 13.94 mean irradiations 650 NR 82.4% improved RCT58 19 23 median treatments 6.07 No 78.9% improved

BCS: bilateral comparison study; CR: case report; CS: case series; CoS: crossover study; NA: not applicable; NR: not reported; PCS: prospective cohort study; PS: pilot study; RCT: randomized controlled trial; RCS: retrospective cohort study; TCS: topical corticosteroid treated with MD UVA1. While this seems to needed to reach remission. A combination efficacy of UVA1 for PN treatment, with 82.4% indicate that PUVA loses its effect quickly, 86% study comparing PUVA + MEL to PUVA alone improvement in pruritus in one study and 78.9% of patients in another study extended into the demonstrated the decreased need for overall in another.42,58 The latter group used a UVA lamp maintenance phase.54 treatments in the combination group, although with a spike at 390 nm for deeper penetration as both groups were successful in improving the biological effects of UV radiation are directly MEL: eruptions and achieving complete clearance.57 proportional to its wavelength. Bath PUVA MEL has also been used to target the pruritic Long-term benefits of reduced itching were also and MD UVA1 have longer wavelengths and 55,56 nodules. Nistico et al. observed a decrease in noted. therefore are more capable of penetrating the pruritic symptoms in all nine PN patients they thickened epidermis of PN.39,59 studied. MEL provides a more targeted approach UVA: and reduces the total number of treatments There are a limited number of studies on the

CHAUDHARI, LEON, LEVIN, KOO Page 45 Table 3: Phototherapy for treatment of pruritus in uremic pruritus (UP) Study Type Participants (no.) Treatment Regimen Cumulative Dose (J/cm2 ) Pruritus Outcomes NB-UVB RCS77 6 33 irradiations NB-UVB: 52 33% had significant improvement (66-100% resolution of lesions and/or reduction of pruritus intensity) RCT78 - UP: 22 3x/wk for 22 irradiations - NB-UVB - for UP: 24.54 - UP: 60% had >50% improvement - IP: 22 - NB-UVB for IP: 20.801 - IP: 68% had >50% improvement RCT79 10 3x/wk for 6 wks NB-UVB: NR 70.8% decrease with 43% in remission after 6 months RCT81 21 3x/wk for 6 wks - NB-UVB: NR NB-UVB = UVA - UVA: 1-6 BB-UVB RCT82 18 2x/wk for 4 wks - BB-UVB: NR 90% had decreased pruritus - UVA (placebo): NR RCS84 - BB-UVB: 9 3x/wk for 2 wks - BB-UVB: NR BB-UVB > UVA - UVA:8 - UVA: NR CoS85 20 2x/wk for 4 wks - BB-UVB: NR BB-UVB = UVA - UVA: NR RCT86 10 12 irradiations - BB-UVB: 7.9 70% had relief - UVA: 1.3 RCT BCS87 - BB-UVB and BB-UVB and UVA: 2x/wk for - BB-UVB: NR - BB-UVB and UVA: decrease from severe to UVA: 7 4 wks - Whole body BB-UVB: NR moderate - BB-UVB: 38 - UVA: NR - BB-UVB: 1x/wk for 6 wks: 8 1x/wk for 6 wks: 75% responded 3x/wk for 2 wks: 3x/wk for 2 wks: 66% responded 12 2x/wk for 4 wks: 83% responded 2x/wk for 4 wks: 18 RCT88 10 2x-3x/wk BB-UVB: NR 80% had complete relief RCT89 14 NR BB-UVB: NR 57% had objective benefit, 100% had decreased itch intensity CR90 1 - BB-UVB: - 1st course: 0.12 BB-UVB > NB-UVB a) 1st course: 8 irradiations - 2nd course: 0.23 b) 2nd course: 10 irradiations - 3rd course: 0.76 Cumulative dose of BB-UVB for a good response c) 3rd course: 10 irradiations - NB-UVB: 2 increases with repeated treatment - NB-UVB: 6 irradiations

BCS: bilateral comparison study; CR: case report; CS: case series; CoS: crossover study; NA: not applicable; NR: not reported; PCS: prospective cohort study; PS: pilot study; RCT: randomized controlled trial; RCS: retrospective cohort study; TCS: topical corticosteroid; UP: uremic pruritus; IP: idiopathic pruritus

Lichen Simplex Chronicus are needed for the use of various forms of and phototherapy can often lead to cessation of LSC, also termed neurodermatitis, is a secondary phototherapy in this distressing disease. generalized itch and reveal a previously localized skin disorder that results from excessive itch. Generalization can be caused by a lowering scratching. Thus, therapeutic options depend Generalized Pruritus of itch threshold on other body parts through a on interrupting the itch-scratch cycle. LSC is GP is chronic itch that occurs without any combination of neurologic and/or psychological often associated with an atopic disorder and is associated diagnosable skin diseases or primary mechanisms. similar to PN in pathogenesis. Lichenification skin lesions. Although frequently idiopathic, it Those with a negative workup for GP fall into results from thickening of epidermis (acanthosis) can be secondary to neurologic disorders, chronic idiopathic pruritus (IP). In those over the and stratum corneum (hyperkeratosis) from the renal failure, cholestasis, systemic infections, age of 65, this form of idiopathic itch is often constant trauma of rubbing and scratching for malignancies, and endocrine disorders. A 60 judicious history, thorough physical examination, dubbed “senile pruritus” or Willan’s itch, as it roughly 90 hours, or 140,000 scratches. A case 64 The stratum and suitable laboratory investigation must be is often associated with dry skin. of vulvar LSC was treated with NB-UVB light corneum thickens with age and has decreased performed to elucidate the cause. Systemic disease source, signifying the tolerability of NB-UVB keratohyalin granules. Elderly patients with dry even in sensitive areas.61 Similar to MEL, a 311- has been implicated in up to 20% of patients 63 skin have a decreased number of surface lipids, nm comb light device was used thrice a week. with GP. Special emphasis should be placed on drug exposure, travel history, environmental impairing the stratum corneum’s ability to hold Pruritus was assessed by a visual analogue scale 65 Clearance of debris from the dermis also irritants, lifestyle, extracutaneous symptoms, and water. and improved significantly. Seven months after decreases, along with sweat and sebum production prior hospitalizations. Initial laboratory tests treatment, the patient remained asymptomatic. and vascular response to histamine. Xerosis was may include complete blood count, liver- and This claim is supported by another case report found to be proportional to the degree of itch, of successful treatment of LSC using UVB for renal-function tests, serum glucose, iron, ferritin, 62 with increased intracorneal cohesion and no However, it is not stated weather thyroid-function tests, erythrocyte sedimentation 66 a month. difference in response to intradermal histamine. NB-UVB or BB-UVB was used. Further studies rate, protein electrophoresis, and urinalysis. Many cases of GP begin in a localized area, Of all the systemic disorders linked to pruritus, Page 46 SYSTEMATIC REVIEW OF PHOTOTHERAPY IN PRURITIC DISORDERS uremia is the most common.67 Fifteen percent to free of pruritus on an average of seven months Efficacy of Phototherapy in AD 49% of those with chronic renal failure (CRF) follow-up. The UVA arm did not experience an Morison et al. published the earliest known and 90% of those receiving dialysis have uremic improvement in itch intensity and was considered reports of UV phototherapy for AD.23 This, pruritus (UP).68 Up to 50% of UP patients placebo, as proven initially by Taylor et al.83 An combined with the general observation that complain about generalized pruritus.67,69 In the additional study done comparing BB-UVB to atopic patients improved during summer months, remaining, UP predominantly affects the back, placebo found BB-UVB beneficial in decreasing led to the use of phototherapy as a treatment face, and shunt-arm.70 The term uremic pruritus pruritus.84 One crossover study found BB-UVB modality for AD. As PUVA became integrated is not apt because UP does not result from an and UVA to be equal to placebo; however, this into the dermatologic practice in 1974, its long- increase in serum-urea levels. Clinically, UP study did not have an intervening washout period term side effects of photo-aging began to limit skin resembles that of hemodialysis patients and therefore the placebo rate can be enhanced, its use in AD. UVA and UVB monotherapies without pruritus, dry and scaly. No primary skin consequently diminishing the therapeutic were introduced in the 1980s, but also had some lesions are seen; however, chronic excoriations, significance of BB-UVB.85 Berne et al. reported downsides. UVB at times caused burning, xerosis, linear crusts, and ulcerations can evolve into a decrease in epidermal vitamin A content in a and erythema, although it required less time a presentation similar to that of PN. Pruritus study with 10 UP patients treated with whole- than UVA. UVA had a better therapeutic effect of hemodialysis and that of peritoneal dialysis body UVA and BB-UVB.86 Epidermal retinal with light reactions, but with the drawback of occur with similar frequencies.71,72 Although the concentrations were returned to normal after 12 lengthy procedure times. This led to the use of incidence of pruritus increases as renal function sessions of phototherapy, and 70% reported relief combination UVA/UVB therapy for AD. This deteriorates, it does not improve with dialysis and from pruritus. was less time-consuming, decreased the total UV is an independent marker of mortality at three dose, and also minimized the risks of developing A study comparing half-body BB-UVB to whole- years for those on hemodialysis.73 The severity of both short-term and long-term side effects. body treatments with varying dosimetry found a UP is associated with the duration of dialysis and reduction in pruritus in 84 percent of patients NB-UVB is the modality of choice for AD when xerosis. Unfortunately, the prevalence and burden treated with whole-body BB-UVB, with 29% not choosing phototherapy, as it is easily available of pruritus in end-stage renal disease (ESRD) 87 relapsing on an average of 10 month follow-up. in most dermatology clinics and is widely used is often underestimated by nephrologists, even Because patients did not detect a difference in the for other conditions as well. BB-UVB is an though it is perceived by patients as a severe 74,75 degree of pruritus between the half-body BB- alternative for those unable to tolerate the intense and distressing symptom of renal failure. Its UVB and placebo side, BB-UVB phototherapy dosing of NB-UVB or in combination with UVA chronic nature is an independent predictor of poor 72,76 was concluded to exert a systemic effect on UP to increase efficacy. Despite the different doses, quality of life with severe sleep disturbances. secondary to the generalized response. The more regimens, and clinical scoring systems used in intensive schedules accelerated the response the studies examined, UVA1 is a possible mode NB-UVB: temporarily but did not increase the percentage of treatment for AD. It is more suited for acute Forty-nine percent of the GP patients treated of patients who responded. In addition, the AD flares as it achieves results faster than UVAB with NB-UVB resulted in moderate to 77 beneficial effects of UV exposure were only and is more efficacious than either UVAB or significant improvement. A study conducted 78 experienced after a lag time of two weeks in topical corticosteroids. In addition, cold-light by Seckin compared UP to IP. Sixty-eight some patients. In another study, 80% of patients UVA1 is superior to UVA1 in reducing AD percent of those with IP showed greater than responded with complete relief of itching when severity as it eliminates a potential trigger. Long- 50% improvement with a 61% remission rate on a treated with BB-UVB.88 Twenty-five percent term follow-up reports are needed and further six-month average follow-up. Sixty percent in the of these claimed relief everywhere except for investigation is recommended to determine UP group showed greater than 50% improvement the palms and soles. All patients in this study maintenance treatments. PUVA is also an option with 66.7% recurrence on follow-up. Although had relief at least one month after therapy was for AD. However, additional studies are needed remission after a single course of NB-UVB discontinued, with 60% maintaining relief for at to document its efficacy in treating pruritus. therapy is not prolonged, 54.2% in the UP group least six months. Cohen et al. reported that 57% and 67.9% in the IP group had a change in visual of a series of pruritic patients experienced relief Efficacy of Phototherapy in PN analog score (VAS). Thus, NB-UVB can be after BB-UVB therapy with a decrease in dermal NB-UVB is also the treatment of choice for considered a valuable alternative treatment, even mast-cell counts accompanying improvement in PN, especially when combined with thalidomide though long-term cure is not possible. An open VAS scores.89 Finally, a case report by Hsu et al. to maximize the therapeutic potential of both pilot study evaluated pruritus using the VAS and found BB-UVB more effective than NB-UVB in treatment forms. BB-UVB is effective in a detailed cumulative score (DCS) and found a decreasing pruritus in UP.90 treating PN as well, with a supportive reduction 70.8% decrease on the VAS scale and a 71.8% in pruritus. Although patients typically prefer 79,80 Forty-three percent decrease on the DCS. topical PUVA over more painful treatment were in remission six months after completing Discussion modalities such as intralesional steroid injections, treatment, with 57% having a recurrence of Although pruritus is the most common chief BB-UVB was found to be more effective in pruritus within an average of 2.5 months. A more complaint in dermatology, there are still many 50 treating cases of generalized PN and itch. recent single-blinded study noted comparable unknowns regarding its pathophysiology. Due to its more localized approach, MEL and significant reduction of pruritus intensity Bernhard classified itch into dermatologic, eliminates UVB exposure to healthy skin. It in patients treated with both NB-UVB and systemic, neurogenic, psychogenic, mixed, and is also more powerful than NB-UVB (TL01), control during the course of phototherapy and other categories.91 While this can help determine thereby reducing the number of treatments follow-up.5,81 While the NB-UVB group showed the etiology to address management options, required to reach remission. The advantage of a significant improvement in the involved body the inability to quantify pruritus remains a weekly treatments as opposed to daily for topical surface area affected by pruritus (p=0.006) and significant barrier to evolving understanding. treatments and phototherapy regimens also had lower pruritus intensity scores at certain time Because objective measurements of pruritus increases patient compliance in MEL. The use of points, the beneficial effects were comparatively are lacking, it is difficult to adequately assess combined synergistic therapies to reach remission marginal. and compare treatments; a uniform, consistent, is necessary in a chronic condition like PN, which and reliable scale of evaluating pruritus and requires similar UV radiation doses as psoriasis BB-UVB: scratching is needed. Nonetheless, based on chronically to allow patients to undergo further BB-UVB phototherapy was first described as current methodologies, which involve subjective 56,92,93 phototherapy sessions. The use of UVA1 useful for achieving a reduction in UP in the evaluations, we have attempted to compare 82 for PN treatment needs further investigation, late ‘70s. Ninety percent of patients in the the different forms of phototherapy in treating although the studies we found thus far support BB-UVB arm responded, and 80% remained pruritus. its utility in treating PN. PUVA has also been CHAUDHARI, LEON, LEVIN, KOO Page 47 found beneficial in reducing not only pruritus any review article, as trials leading to positive 11. Grundmann-Kollmann M, Behrens S, Podda M, but also the number of papules. PUVA also has results are more likely to be published.104 Poor Peter RU, Kaufmann R, Kerscher M. Phototherapy a greater maintenance phase than other forms of statistical power resulting from small sample size for atopic eczema with narrow-band UVB. J Am Acad Dermatol. 1999;40(6 Pt 1):995-7. phototherapy. Mild erythema is a possible side must also be taken into account. Uncommon effect of all forms of phototherapy but quickly adverse effects are often not disclosed or perhaps 12. Hjerppe M, Hasan T, Saksala I, Reunala T. Narrow- subsides. Mild hyperpigmentation at the lesional unrecognized. The variability in parameters of band UVB treatment in atopic dermatitis. Acta Derm sites was common to most PN studies. Because of each of the different trials must also be taken into Venereol. 2001;81(6):439-40. the longer wavelengths of UVA, it is potentially account. Different methods for selecting patients, 13. Legat FJ, Hofer A, Brabek E, Quehenberger F, Kerl able to penetrate PN lesions better. Finally, the dosing UV radiation, and assessing response limit H, Wolf P. Narrowband UV-B vs medium-dose UV- limited number of studies completed for the use the ability to draw detailed conclusions through A1 phototherapy in chronic atopic dermatitis. Arch of phototherapy in LSC supports the use of UVB a comprehensive review of available studies. Dermatol. 2003;139(2):223-4. to decrease pruritus. Despite these drawbacks, the authors found 14. Majoie IM, Oldhoff JM, van Weelden H, Laaper- overwhelming evidence after reviewing the data Ertmann M, Bousema MT, Sigurdsson V, et al. Efficacy of Phototherapy in UP to conclude that phototherapy is helpful for most Narrowband ultraviolet B and medium-dose ultraviolet Even though NB-UVB is beneficial in decreasing types of pruritus. A1 are equally effective in the treatment of moderate GP and UP, is less erythemogenic, has a lower to severe atopic dermatitis. J Am Acad Dermatol. 2009;60(1):77-84. pruritogenic potential, and is less carcinogenic than BB-UVB, BB- UVB is the treatment of Conclusion 15. Gambichler T, Othlinghaus N, Tomi NS, Holland- 94,95 We conclude that phototherapy is a beneficial, choice for UP, while UVA is equal to placebo. Letz T, Boms S, Skrygan M, et al. Medium-dose efficacious, efficient, and safe method of In patients who are not candidates for kidney ultraviolet (UV) A1 vs. narrowband UVB phototherapy treatment for AD, PN, LSC, and GP. NB-UVB in atopic eczema: a randomized crossover study. Br J transplant, BB-UVB is considered the treatment 96 is a superior form of phototherapy for AD. Dermatol. 2009;160(3):652-8. of choice by some. While UVB radiation is It is also effective in PN and LSC. However, safe, the risk for skin malignancies and long- 16. Jekler J, Larko O. UVB phototherapy of atopic BB-UVB is the most efficacious for UP. MEL term immunosuppression remains controversial dermatitis. Br J Dermatol. 1988;119(6):697-705. provides targeted therapy with a reduction in in immunocompromised patients due to renal 17. Pugashetti R, Lim HW, Koo J. Broadband the total number of treatments required for PN. transplant. We did not find any studies on the use UVB revisited: is the narrowband UVB fad limiting PUVA induces a greater maintenance phase for of PUVA in UP. Thus, more randomized, placebo- our therapeutic options? J Dermatolog Treat. PN and is beneficial for AD. UVA is favorable for 2010;21(6):326-30. controlled trials are needed to determine the AD and PN but equal to placebo for UP. These safest and most efficacious form of phototherapy 18. Tuchinda C, Lim HW, Strickland FM, Guzman data conclude the overwhelming evidence of the for decreasing pruritus in patients on dialysis. EA, Wong HK. Comparison of broadband UVB, benefit of phototherapy in decreasing pruritus of narrowband UVB, broadband UVA and UVA1 Safety of Phototherapy multiple causes. on activation of apoptotic pathways in human Phototherapy is a safe form of treatment. When peripheral blood mononuclear cells. Photodermatol Photoimmunol Photomed. 2007;23(1):2-9. given long-term, PUVA has been associated with increased risk of cutaneous squamous cell 19. Falk ES. UV-light therapies in atopic dermatitis. References Photodermatol. 1985;2(4):241-6. carcinoma, but even high-dose exposure does not 1. Charlesworth EN, Beltrani VS. Pruritic dermatoses: 5,97 increase basal cell carcinoma risk. However, overview of etiology and therapy. Am J Med. 2002;113 20. Hannuksela M, Karvonen J, Husa M, Jokela R, none of the published studies in a comprehensive Suppl 9A:25S-33S. Katajamaki L, Leppisaari M. Ultraviolet light therapy in atopic dermatitis. Acta Derm Venereol Suppl review of BB-UVB and skin cancer risk 2. Beauregard S. A survey of skin problems and (Stockh). 1985;114:137-9. demonstrates increased skin cancer risk, with skin care regimens in the elderly. Arch Dermatol. one outlier of genital tumors in men receiving 1987;123(12):1638-43. 21. Midelfart K, Stenvold SE, Volden G. 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The risk of Dermatol. 1978;98(1):25-30. neurodermatitis treated with coal tar ointments squamous cell and basal cell cancer associated with and ultraviolet light (Goeckerman regimen) psoralen and ultraviolet A therapy: a 30-year prospective 24. Uetsu N, Horio T. Treatment of persistent severe concluded that the incidence of skin cancer is study. J Am Acad Dermatol. 2012;66(4):553-62. atopic dermatitis in 113 Japanese patients with not significantly increased above the expected oral psoralen photo-chemotherapy. J Dermatol. 6. Abramovits W. Atopic dermatitis. J Am Acad incidence for selected populations in the United 2003;30(6):450-7. 101 Dermatol. 2005;53(1 Suppl 1):S86-93. States. NB-UVB also has an excellent safety 25. Severity scoring of atopic dermatitis: the SCORAD 7. Reynolds NJ, Franklin V, Gray JC, Diffey BL, Farr PM. profile. In a 2008 study of 4,665 patients who index. Consensus Report of the European Task Force Narrow-band ultraviolet B and broad-band ultraviolet received NB-UVB for 17 years, there was no on Atopic Dermatitis. Dermatology. 1993;186(1):23- A phototherapy in adult atopic eczema: a randomised increase in non-melanoma or melanoma skin 31. 102 controlled trial. Lancet. 2001;357(9273):2012-6. cancer. Finally, in a retrospective study of 26. Tzaneva S, Kittler H, Holzer G, Reljic D, Weber 8. George SA, Bilsland DJ, Johnson BE, Ferguson six years, no evidence for increased skin cancer M, Honigsmann H, et al. 5-Methoxypsoralen plus J. Narrow-band (TL-01) UVB air-conditioned risk was found for either BB- or NB-UVB ultraviolet (UV) A is superior to medium-dose UVA1 in phototherapy for chronic severe adult atopic dermatitis. 103 the treatment of severe atopic dermatitis: a randomized phototherapy. Br J Dermatol. 1993;128(1):49-56. crossover trial. Br J Dermatol. 2010;162(3):655-60. 9. Hudson-Peacock MJ, Diffey BL, Farr PM. Narrow- Limitations 27. Der-Petrossian M, Seeber A, Honigsmann H, band UVB phototherapy for severe atopic dermatitis. The conclusions that one can draw by Tanew A. Half-side comparison study on the efficacy Br J Dermatol. 1996;135(2):332. systematically analyzing the current medical of 8-methoxypsoralen bath-PUVA versus narrow- literature regarding the use of phototherapy 10. Collins P, Ferguson J. Narrowband (TL-01) UVB band ultraviolet B phototherapy in patients with in pruritic disorders are limited due to several air-conditioned phototherapy for atopic eczema in severe chronic atopic dermatitis. Br J Dermatol. factors. Publication bias must be considered in children. Br J Dermatol. 1995;133(4):653-5. 2000;142(1):39-43.

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Hann SK, Cho MY, Park YK. UV treatment among patients undergoing maintenance hemodialysis. therapy for atopic dermatitis: results of a multicenter of generalized prurigo nodularis. Int J Dermatol. Arch Dermatol. 1982;118(3):154-6. trial. J Am Acad Dermatol. 1998;38(4):589-93. 1990;29(6):436-7. 71. Greaves MW. Recent advances in pathophysiology 32. Von Kobyletzki G, Pieck C, Hoffmann K, 51. Karvonen J, Hannuksela M. Long term results and current management of itch. Ann Acad Med Freitag M, Altmeyer P. Medium-dose UVA1 cold- of topical trioxsalen PUVA in lichen planus and Singapore. 2007;36(9):788-92. light phototherapy in the treatment of severe atopic nodular prurigo. Acta Derm Venereol Suppl (Stockh). dermatitis. J Am Acad Dermatol. 1999;41(6):931-7. 72. Tessari G, Dalle Vedove C, Loschiavo C, Tessitore 1985;120:53-5. N, Rugiu C, Lupo A, et al. The impact of pruritus on 33. Tzaneva S, Seeber A, Schwaiger M, Honigsmann 52. 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Page 50 SYSTEMATIC REVIEW OF PHOTOTHERAPY IN PRURITIC DISORDERS Zosteriform Lichen Planus: An Unusual Clinical Variant

Ashvin Garlapati, DO,* Ramya Tripuraneni, MBBS,** Francisco A. Kerdel, BSc, MBBS,*** Stanley Skopit, DO, MSE, FAOCD****

*Dermatology Resident, 2nd year, Larkin Community Hospital/NSU-COM, South Miami, FL **Traditional Rotating Intern, Fairview Hospital - Cleveland Clinic, Cleveland, OH ***Director of Inpatient Dermatology, University of Miami Hospital, Miami, Florida ****Program Director, Dermatology Residency Program, Larkin Community Hospital/NSU-COM, South Miami, FL

Abstract Lichen planus (LP) is a relatively common papulosquamous dermatosis affecting the skin and mucous membranes. It has several morphological variants. Zosteriform LP is a rare form of linear LP. Linear LP accounts for less than 1% of cases and presents in a unilateral, linear distribution.1 The zosteriform type of linear LP is an uncommon variant with dermatomal or zonal distribution. Zosteriform LP is distinguished clinically from linear LP in that it forms a broader band that corresponds to specific dermatomes.1 Zosteriform LP may arise de novo in previously normal skin, at sites of trauma (koebnerization), or as Wolf ’s isotopic response at the site of healed herpes zoster.2 We report a rare case of a 52-year-old female diagnosed with zosteriform LP arising de novo in previously normal, non-traumatized skin with no history of herpes zoster.

Case Description with the scalp, causing a scarring alopecia. lines are invisible lines in the skin believed to A 52-year-old woman presented with a six- Clinically, zosteriform LP is characterized trace the migration of embryonic cells. Still, some believe that true zosteriform LP only occurs if the week history of a pruritic eruption on her right by flat-topped, pruritic, violaceous papules or 7 leg. The patient had a previous history of discoid plaques. The eruption has a predilection for the lesions develop at sites of healed herpes zoster. lupus erythematosus (DLE) on the scalp, which flexure surfaces of the extremities and is usually In our patient, there was no history of herpes was previously treated with hydroxychloroquine symmetric in nature. It may occur in association zoster, and multiple dermatomes were involved. 200 mg twice daily and clobetasol ointment. with certain medications and diseases such as Therefore, a more appropriate term may be The patient at the time of presentation had no hepatitis C, but the etiology is unknown and is dermatomal LP rather than zosteriform LP. DLE lesions. There was no significant family thought to arise from a T- cell mediated immune The differential diagnosis of zosteriform lichen or drug history. The patient had no associated response. planus is vast and includes linear psoriasis, comorbidities. Hepatitis C serology was negative. In addition to the classic appearance, there are lichen striatus, linear epidermal nevus, linear Darier’s disease, and inflammatory linear On physical examination, numerous purple more than 20 variants that are categorized based 2 pruritic papules and plaques with an overlying on the morphology and configuration of the verrucous epidermal nevus, to name a few. LP white scale were present on her right thigh lesions. There are many atypical presentations can be differentiated based on histopathologic (Figure 1). The lesions were arranged in a linear of LP that have been described, such as linear, examination, which shows a band-like infiltrate pattern in the L1, L2, and L3 dermatomal hypertrophic, actinic, and vesiculobullous.4 of lymphocytes at the dermal-epidermal junction. distribution. A linear white patch was seen on Other noticeable features include hyperkeratosis, Linear LP refers to lichen planus with a unilateral, her left buccal mucosa (Figure 2), and her genital wedge-shaped hypergranulosis, vacuolar linear distribution. It can present in a segmental mucous membranes were normal. There was degeneration of the basal layer, and acanthosis with distribution corresponding to a dermatome, neither scalp nor nail involvement. saw-toothed rete ridges. Civatte bodies (colloid referred to as zosteriform lichen planus. or cytoid bodies) are present at the junction of the A biopsy was taken from a typical lesion on her Zosteriform LP may arise as Wolf ’s isotopic dermis and epidermis and also in the papillary right thigh. Histopathology showed wedge- response at areas of healed zoster, secondary to dermis.8 On direct immunofluorescence (DIF), shaped hypergranulosis, acanthosis, saw toothing koebnerization from trauma, or in very rare cases lichen planus shows shaggy fibrin, cytoid bodies, of the rete ridges, and a lichenoid infiltrate (Figure as a de novo eruption on previously normal skin. and deposition of IgM immunoglobulins at the 3). A diagnosis of zosteriform lichen planus was The zosteriform pattern can occur without dermoepidermal junction. This can distinguish made based on the clinical and pathological evidence of herpes zoster, and the incidence is LP from hypertrophic lupus erythematosus, correlation. extremely infrequent. The lesions are arranged which would show a continuous granular band of The patient was given an intramuscular injection IgG, IgM, IgA, and C3 at the dermoepidermal in a band several centimeters wide and run along 9 of triamcinolone acetonide 40 mg and started on the course of a peripheral cutaneous nerve and junction on DIF. tacrolimus ointment 0.1%, which was applied to its branches. It is thought that the cutaneous the cutaneous and oral lesions twice daily. manifestation of the zosteriform pattern could possibly be triggered by neural factors.5 It Figure 2 has recently been suggested that the lesions Discussion in zosteriform LP actually follow the lines of Lichen planus is an idiopathic inflammatory 6 disease affecting the skin and mucous membranes. Blaschko rather than a dermatome. Blaschko’s Middle-aged individuals are most commonly Figure 1 affected, with the average age of onset being 50 years. The occurrence is evenly distributed worldwide with no racial predilection. Females are affected more often than males. The mucous membranes are affected in 65% of cases. In cases of oral LP, the buccal mucosa exhibits a lacy white reticulation, known as Wickham’s striae, and may develop into squamous cell carcinoma in 0.2% of cases per year.3 The nails may be affected along GARLAPATI, RIPURANENI, KERDEL, SKOPIT, Page 51 Figure 3 novo in normal, non-traumatized skin, as in our References patient. Given that our patient had no history 1. Pai K, Pai S. Zosteriform Lichen Planus: Case report of herpes zoster and that multiple dermatomes of a rare variant of lichen planus. Our Dermatol Online. were involved, a more appropriate term may be 2013;4(2):183-184. dermatomal LP rather than zosteriform LP. 2. Turel A, Ozturkcan 5, Sahin MT, Turkdogan P. Our patient is currently doing well on a treatment Wolf ’s isotopic response: a case of zosteriform lichen planus. J Dermatol. 2002;29:339-42. regimen of tacrolimus ointment 0.1% applied to her cutaneous and oral lesions. Per the current 3. Scully C, Beyli M, Ferreiro MC, et al. Update on oral recommendations, we are closely following the lichen planus: etiopathogenesis and management. Crit oral lesion for any malignant transformation. Rev Oral Biol Med. 1998;9:86-122. 4. Boyd AS, Neldner KH. Lichen planus. J Am Acad Dermatol. 1991 Oct;25(4):593-619. 5. Happle R. Zosteriform Lichen planus: Is it Zosteriform? Dermatology. 1996;192:385-6. 6. Turel A, Ozturkcan S, Ozturkcan S, Sahin MT. Wolf ’s isotopic response: a case of zosteriform lichen planus. J Dermatol. 2002;29:339-42. Treatment and Prognosis 7. Braun RP, Barua D, Masouye I. Zosteriform lichen There is no definitive cure for LP, and the disease planus after herpes zoster. Dermatology. 1998;197:87- is self-limiting. There are various treatment 8. modalities available to alleviate the associated 8. Perry D, Fazel N. Zosteriform lichen planus. pruritus and induce remission. Treatments may Dermatol Online J. 2006 Sep 8;12(5):3. consist of topical and systemic therapies. Oral antihistamines such as diphenhydramine and 9. Elston DM, Ferringer T. Dermatopathology. Edinburgh: Saunders/Elsevier; 2009. Chapter 7, hydroxyzine may be used to relieve pruritus. Interface Dermatitis; p. 135-139. Topical antipruritic agents such as menthol, camphor, pramoxine or doxepin may also be 10. Taneja A, Taylor CR. Narrow-band UVB for lichen used. First-line therapy for cutaneous lesions planus treatment. Int J Dermatol. 2002 May;41(5):282- 3. includes high-potency topical steroids applied twice daily. Systemic corticosteroids can be used 11. Sugerman PB, Savage NW. Oral lichen planus: as a second-line treatment or in those with more Causes, diagnosis and management. Aust Dent J. 2002;47:(4):290-297. extensive disease. Alternative treatments include immunosuppressive agents such as cyclosporine, 12. James WD, Berger TG, Elston DM, eds. Andrews’ methotrexate, azathioprine, dapsone, retinoids Diseases of the Skin: Clinical Dermatology. 11th ed. and topical tacrolimus. Narrow-band Philadelphia: Saunders/Elsevier; 2011. Chapter 12, Lichen Planus and Related Conditions; p. 213-218. ultraviolet-B phototherapy and psoralen plus ultraviolet A (PUVA) can also be used as adjuvant 10 therapy. Newer LP treatment modalities such as Correspondence: Ashvin Garlapati, DO; enoxaparin sodium and oral metronidazole have [email protected] also been used with success. In cases of oral LP, corticosteroids are the mainstay of therapy, based on their ability to reduce cell-mediated immune response. They can be given topically, intralesionally or systemically. Systemic and topical steroids, when given together, are extremely effective. A steroid mouth rinse used twice daily can be used to treat generalized oral lesions. Topical ointments can be used to treat localized oral lesions and are applied two to four times daily after meals. Candida albicans superinfection can occur with immunosuppressive therapy and should be managed with topical antimycotics.11 Lichen planus often resolves over an average period of 18 months, but approximately 20% of patients will have a second occurrence.12 In a subset of patients, the disease may persist for many years. Oral LP is more therapy-resistant, and close follow-up is advised given the increased risk of developing squamous cell carcinoma.

Conclusion Zosteriform LP is a rare form of linear LP. It may arise secondary to trauma as Koebner phenomenon, at sites of healed herpes zoster as Wolf ’s isotopic response, or very rarely de

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