Journal of the American Osteopathic College of Dermatology
Volume 12, Number 1 SPONSORS: ',/"!, 0!4(/,/'9 ,!"/2!4/29 s -%$)#)3 September 2008 34)%&%, ,!"/2!4/2)%3 s '!,$%2-! www.aocd.org Journal of the American Osteopathic College of Dermatology Journal of the American Osteopathic College of Dermatology
2007-2008 Officers President: Jay Gottlieb, DO President Elect: Donald Tillman, DO First Vice President: Marc Epstein, DO Second Vice President: Leslie Kramer, DO Third Vice President: Bradley Glick, DO Secretary-Treasurer: Jere Mammino, DO (2007-2010) Immediate Past President: Bill Way, DO Trustees: James Towry, DO (2006-2008) Mark Kuriata, DO (2007-2010) Karen Neubauer, DO (2006-2008) David Grice, DO (2007-2010)
Sponsors: Global Pathology Laboratory Stiefel Laboratories Editors Medicis Jay S. Gottlieb, D.O., F.O.C.O.O. Stanley E. Skopit, D.O., F.A.O.C.D. Galderma
Editorial Review Board Ronald Miller, D.O. JAOCD Eugene Conte, D.O. Founding Sponsor Evangelos Poulos, M.D. Stephen Purcell, D.O. Darrel Rigel, M.D. !/#$ s % )LLINOIS s +IRKSVILLE -/ s &!8 Robert Schwarze, D.O. WWWAOCDORG Andrew Hanly, M.D. #/092)'(4 !.$ 0%2-)33)/. WRITTEN PERMISSION MUST BE OBTAINED Michael Scott, D.O. FROM THE *OURNAL OF THE !MERICAN /STEOPATHIC #OLLEGE OF $ERMATOLOGY FOR COPYING OR REPRINTING TEXT OF MORE THAN HALF PAGE TABLES OR lGURES Cindy Hoffman, D.O. 0ERMISSIONS ARE NORMALLY GRANTED CONTINGENT UPON SIMILAR PERMISSION Charles Hughes, D.O. FROM THE AUTHORS INCLUSION OF ACKNOWLEDGEMENT OF THE ORIGINAL SOURCE AND A PAYMENT OF PER PAGE TABLE OR lGURE OF REPRODUCED MATERIAL Bill Way, D.O. 0ERMISSION FEES ARE WAIVED FOR AUTHORS WISHING TO REPRODUCE THEIR OWN Daniel Hurd, D.O. ARTICLES 2EQUEST FOR PERMISSION SHOULD BE DIRECTED TO *!/#$ CO !/#$ 0/ "OX +IRKSVILLE -/ Mark Lebwohl, M.D. #OPYRIGHT BY THE *OURNAL OF THE !MERICAN /STEOPATHIC #OLLEGE OF Edward Yob, D.O. $ERMATOLOGY Jere Mammino, D.O. Printed by: Stoyles Graphics Services, Mason City, IA 50401 Schield M. Wikas, D.O. Proofreading: Julia Layton, Freelance Proofreading and Editing Journal of the American Osteopathic College of Dermatology Iqbal A. Bukhari, M.D. VOLUME 12, NUMBER 1 SEPTEMBER 2008 AOCDJOURNAL OF THE AMERICAN OSTEOPATHIC COLLEGE OF DERMATOLOGY
CONTENTS
Letter from the JAOCD Editors ...... 4 Letter from the President ...... 5 Seborrheic Dermatitis & Immobility in Neurological Disease and Immunodeficiency ...... 7 Dr. Robert A. Norman, DO, MPH, Shawn P. Todd, OMS-II, Osman Tahir, OMS-II Treatment of TEN with IVIG – A Case Report ...... 9 Asfa Akhtar, DO, Marcus Goodman, DO, Stanley Skopit, DO, FAOCD, Francisco Kerdel, MD, FAAD Cutaneous Rosai-Dorfman Disease Represents a Distinct Clinical Entity ...... 12 Angela M. Leo, DO, Stephen M. Purcell, DO Atrophoderma of Pasini and Pierini ...... 14 Chris Buatti, DO, MBA, Kimball W. Silverton, DO Impetigo and Poor Hygiene ...... 16 Robert A. Norman, DO, MPH, Steven Nodine, OMS III En Coup de Sabre: A Case Report and Discussion ...... 19 Paul Aanderud, OMSIII, Daniel Hansen, DO, MBA Ryan M. Carlson, DO Steven K. Grekin, DO, FAOCD Case Report: Granular Parakeratosis ...... 21 Jonathan S. Crane, DO, FAOCD, Erin Griffin, BS MSIII Patricia Hood, PA-C, Kelly Britt, PA-CWarren White, MD Schamberg’s Disease ...... 23 Robert A. Norman, DO, MPH, Steven Nodine, OMS III Multiple Trichoepitheliomas, Cylindromas, and Spiradenomas in Brooke-Spiegler Syndrome: A Unique Case of Malignant Transformation and Review ...... 24 Peter Saitta, MSIV, BA, Wray Hughes MSI, MBS, BA, Boris Ioffe, DO, Bill V. Way, DO, Narciss Mobini, MD, Ronald Brancaccio, MD Spiradenocarcinoma: A Case Report ...... 28 Amara Sayed, DO, FACOFP, Layne D. Nisenbaum, DO, FAOCD A Case Report: Osler-Weber-Rendu Disease ...... 30 Krina K. Chavda, DO, Shari Sperling, DO, Marvin Watsky, DO Treatment of Lichen Amyloidosis with Thalidomide – A Case Report ...... 32 Denise M. Guevara, DO, Deborah Zell, MD, Khongruk Wongkittiroch, DO, Kimberly Sackheim, DO, Francisco Kerdel, MD, Bradley Glick, DO Leprosy: Case Report and Review of Literature ...... 34 Prethi Sundaram-Mohip, DO, Danielle Degennaro, DO, Bradley Glick, DO, MPH, FAOCD A New Treatment For Eyelid Laxity ...... 39 Jonathan S. Crane, DO, FAOCD, Erin Griffin, B.S. MSIII, Patricia Hood, PA-C, Kelly Britt, PA-C Neutrophilic Eccrine Hidradenitis: Expanding the clinical spectrum in non-chemotherapy patients ...... 41 Amy Basile, MPH, Mehrvash Haghighi, MD, Soheil Simzar, MD, Noah Craft, MD, PhD, Shi-Kaung Peng, MD, Paul K. Shitabata, MD Pseudomonas Folliculitis after Swimming in a Pond: A Unique Case Report and Review ...... 46 Alyn Hatter, MSIV, Elaine Miller, DO, Bill V. Way, DO Varicella- Zoster Vasculitis Presenting As Ecthymatous Ulcers ...... 51 Stephen A. Switlyk, MD, Jonathan L. Cleaver, MS IV, Michael B. Morgan, MD Waardenburg Syndrome: A Case Presentation ...... 53 James J. Briley, Jr., DO, David B. Kessler, DO, Marvin S. Watsky, DO Case Report: Hyperproliferative HSV Infections in HIV Patients ...... 56 Robert A. Norman, DO, MPH, Lana Halabi, MS IV Classic Presentation of Nevoid Basal Cell Carcinoma Syndrome in a 49-year-old Female: A Case Presentation and Review ...... 57 Jacob William Watters, OMS-III, Melinda Greenfield, DO A 58-year-old Female with a History of Renal Transplant and Multiple Non-melanoma Skin Cancers, Recently Diagnosed with Merkel-cell Carcinoma ...... 64 Brian A. Kopitzki, DO, Kimball W. Silverton, DO Unilateral Generalized Morphea: A Case Report ...... 69 Brett B. Bender, DO, Maureen Cliffel, DO, John Pui, MD, Michael J. Mahon, DO, FAOCD Urticaria in Eastern Saudi Arabia ...... 71 Omar M. Alakloby, MD Eccrine Nevus with Mucinous Deposition: A Case Report ...... 74 Christopher Weyer, DO, Molly Kathleen Smith, MD, Joan Tamburro, DO, FAOCD Case Report: Miliaria Crystallina Treated With Botox® Botulism Toxin Type A ...... 76 Jonathan S. Crane, DO, FAOCD, Erin Griffin, BS, MSIII, Patricia Hood, PA-C, Kelly Britt, PA-C, Warren White, MD, Craig Webb, PA-C LETTER FROM THE EDITORS
JAY S. GOTTLIEB, D.O. STANLEY E. SKOPIT, D.O.
This is the 12th issue of the JAOCD. Each successive journal improves and shows signs that our resi- dents are being exposed to more and more variety and pathology in their residency programs. We are entering the third quarter of 2008. The Olympics are now behind us, and our country did very well. Records were set and new world champions arose from Beijing.
So much effort goes into becoming great. It is not about perfection, it is about persistence! Never stop because you are not as good as somebody else. Never stop trying harder to become better. All of this practice and all of this effort leads to greatness.
There was a televised golf tournament about 30 years ago. Arnold Palmer made a hole-in-one shot on a long par 3 hole. He was interviewed and you could see his excitement. The person conducting the interview said, “Well, you must feel just so lucky?” You could see the smile leave Arnold Palmer’s face as he said, “Well, it seems the more I practice, the luckier I keep getting.”
How well said? Nothing great comes without persistence and a lot of effort. The same is true of our organization and the JAOCD. But it doesn’t have to take a lot of effort on the part of a few, it can take a very little amount of effort on the part of many. That is how greatness occurs.
We encourage all of our membership to contribute a small amount to the AOCD and to the JAOCD. This will assure that our organization and the journal representing our organization continue to improve and cast a great reflection upon all of us.
As in every issue, we thank our corporate sponsors for making the JAOCD possible. Global Pathology Laboratory, Medicis-The Dermatology Company, Stiefel Laboratory and Galderma all have come forward and given their support to the JAOCD. They continue their commitment to the derma- tology profession and support the AOCD in all of its endeavors.
Jay S. Gottlieb, DO, FAOCD, FOCOO (Editor) Stanley E. Skopit, DO, FAOCD (Editor)
4 LETTER FROM THE EDITORS LETTER FROM THE PRESIDENT OF THE AOCD
JAY GOTTLIEB, D.O., F.A.O.C.D., F.O.C.O.O., PRESIDENT
INCOMING PRESIDENT OUTGOING PRESIDENT Decisions and Transitions! It is said that time passes quickly, and that certainly is true of this year being president of the AOCD. I must say that it has been smooth sailing and I appreciate all of the help that I have received from others within the AOCD. I feel like I just wrote my first letter stating my goals of being president and now I am writing my last letter as the outgoing president. So what have I learned this year? I have realized that we have a great organization. We must always strive to make it better and never be content with the way things are. I have learned to be more tolerant of others and realize that everybody is doing the best they can, from where they are, with what they have. Last October Dr. Peter Ajluni, the incoming president of the AOA, talked about ‘life is what happens when we are busy making other plans”. He challenged everybody present at that meeting to ‘get fit for life, and on that day I made my decision. If I am to accomplish all that I wish to accomplish in my lifetime, I must be ‘fit for life’. I took on this challenge and a by-product of this is that I feel great, I accomplish more on a daily basis and I look pretty darn good! Making a decision is cutting off any other possibility other then that outcome. From these decisions come transitions. Moving on to do more and better things with what we have. It takes us to new levels where we can do even better and reach further then we ever thought possible. I have come to realize how little time it really takes to make a difference in an organization and in others’ lives. The best part of taking action and getting involved, is the self-satisfaction and personal growth that I have experienced. I encourage all of the members of the AOCD to take part, play a role, and make a difference in the AOCD. There are so many ongoing issues, and new ones popping up all of the time, that require our efforts. That is what keeps us “green and growing” and from becoming “ripe and rotten.” It has been fun and an honor serving as your president during the 2007-2008 year. I thank my friends and mentors who have helped me have the life that I have today. I want to recognize my friend and mentor, Dr. Stan Skopit, for all that he has done for me. Jere Mammino is always in the background and always “the wind beneath my wings.” Drs. Ed Yob, Lloyd Cleaver, and Jim DelRosso have done so much to help me, and continue to work for you and the AOCD. Becky and Rick Mansfield and Marsha Wise run our organization efficiently and professionally. I wish to thank my partner, Dr. Sandy Goldman and my Physician Assistant Daughter Amy Gottlieb for picking up the slack this year when I was tied up doing other things. I thank my oldest daughter Lori for always being there on the phone to keep me smiling and laughing. These acknowledgements would not be complete with thanking my wife Shirley, our AOCD Coordinator of Corporate Development, for putting up with me on a daily and a minute-to-minute basis. I know that this is no easy task Remember “thoughts become things,” so choose good ones. Thank you for allowing me to serve as your president. Sincerely, Jay Gottlieb, DO, FAOCD, FOCOO AOCD President, 2007-2008
LETTER FROM THE PRESIDENT 5 :[hcWjebe]oEffehjkd_jo•CWZ_ied @Wd[il_bb["M?
Dean Health System, a 500+ physician owned multi-specialty group, is actively recruiting a BC/BE Dermatologist to join our practice. This position will work 2 days per week in Madison, WI and 2 days per week in Janesville, WI. Call is 1:6, and taken for a week at a time.
Wisconsin offers the best of all worlds from big city life to small town values. Here you’ll find year-round recreation and cultural offerings, a leading university system, and a great quality of life. Wisconsin truly is an ideal place to live, work, and raise a family.
We offer competitive compensation and an outstanding benefits package with employment leading to shareholder status in two years.
For more information please contact: Kate Kaegi, Physician Services Manager Dean Health System 1808 West Beltline Highway Madison, WI 53713
1IPOF FYUt'BY tLBUFLBFHJ!EFBODBSFDPN XXXEFBODBSFDPN
Members of the AOCD may advertise "position available"
This is a free service for all active members of the AOCD. A 3" column black and white ad will be provided in the journal as a free service. If members wish to use a larger space, they may do so. The cost for this advertising is:
Black and White - 1/4 page-$125, 1/2 page-$200, full page-$350
Full 4 color ad - 1/4 page-$275, 1/2 page-$350, full page-$500
Resident members may run a 3" column black and white ad stating their desired professional position.
These ads must be submitted as an e-mail attachment and sent to [email protected]. Any photos to be included in an active member's ad, must be in a .pdf format. SEBORRHEIC DERMATITIS & IMMOBILITY IN NEUROLOGICAL DISEASE AND IMMUNODEFICIENCY
%S3PCFSU"/PSNBO %0 .1) 4IBXO15PEE 0.4** 0TNBO5BIJS 0.4**
Seborrhea is oiliness of the skin, dandruff, and because they think that the itchiness and scaling around the scalp. He especially of the scalp and face, without scale arises from dry skin, they decrease has been on MetroGel since the last visit, redness or scaling. Seborrheic derma- the frequency of shampooing, which three weeks ago, with little to no relief. titis (SD) includes inflammation of the allows further scale accumulation resulting skin consisting of redness, pruritus, and in greater inflammation and worsening Case III powdery scales. Patients with seborrhea symptoms. may later get seborrheic dermatitis. It This article attempts to relate SD as a A 14-year-old girl presented with a appears the main culprit is a yeast-like common clinical finding in patients history of an IRAK-4 immunodeficiency fungus in the Malassezia family, with with neurological disease and immuno- disorder and a mild neurological deficit. immobility and individual susceptibility deficiency; immobility plays a significant Interleukin-1 receptor-associated kinase playing secondary roles. role in generating conditions for disease (IRAK)-4 deficiency is a rare primary The pathogenesis of SD results from pathogenesis. Neurological disease often immunodeficiency disorder particularly an overgrowth of Pityrosporum ovale results in a decrease in neuronal activity characterized by severe, invasive infections (Malassezia furfur) in the sebum. Sebum to areas where sebaceous glands exist in with S. pneumonia. She presented with is composed of triglycerides and esters, as abundance, causing pooling of the sebum itchiness and redness around the nasolabial well as fatty acids, cholesterol and squalene. and thereby fostering conditions suitable folds and eyebrows. She also complained of As the triglycerides and esters are broken for SD. Patients with immunodeficiency are itchiness and scaling of the scalp. down on secretion, individual free fatty also more prone to SD due to unopposed acids accumulate. Recent research has growth of Malassezia. However, immobility Conclusion shown Malassezia to thrive in a free fatty may also be present in these patients due to As stated previously, the pathogenesis acid medium.1 Malassezia fungi contain a decrease in activity, further encouraging of SD has been linked to lipid metabo- lipases that break down triglycerides and sebum collection and inflammation. esters in a non-specific manner and create lism of the Malassezia family. The above Dermatologists should recognize the cases have been submitted to demonstrate such an environment. They degrade sebum, relationship between immobility caused by free fatty acids from triglycerides, consume specifically how immobility creates condi- neurologic or immunologic disease to SD. tions that increase one’s susceptibility to specific saturated fatty acids, and leave Patients with histories of epilepsy, Down behind the unsaturates. Penetration of the SD, whether the immobility is the result of syndrome and immunodeficiency are a neurological deficit, immunodeficiency modified sebaceous secretions results in presented as cases here, demonstrating the inflammation, irritation, and scalp flaking. or a combination of both. The patient role of immobility in facilitating the patho- discussed in Case I is limited to few activi- Skin cells die and are subsequently genesis of SD. replaced by new skin cells in a never- ties because of his neurologic problems ending cycle. In normal people, this cycle Case I and therefore is less mobile than his peers. takes about one month, and is usually not The patient’s immobility can be seen as a noticeable. On scalps where Malassezia A 29-year-old African American male decrease in movement and in facial expres- thrives, the whole process can take less presented with a history of epilepsy and sion. Furthermore, the patient is unable than half that time. Seborrheic dermatitis a five-year history of SD. The patient to groom himself. Without proper assis- typically affects areas of the skin where stated that SD outbreaks occur during tance in personal hygiene, the environment sebaceous glands appear in high frequency stressful situations and during changes becomes a suitable medium for growth. and are most active. The sebum secre- in weather. Findings began typically, with This could cause increased pooling of the tion rate increases throughout the teens, dry red patches around the nose, beard, sebaceous glands, thereby predisposing remains steady through the 20s and 30s, and scalp area with some flaking of skin him to SD. Furthermore, the decreased then lessens with age. In males, the rate around the eyebrows. At a follow-up visit, neuronal activity could also play a role remains higher longer, into the 50s and he still complained of scaling, itchiness and in disrupting the natural balance of the 60s, but in females, the secretion rate drops erythema in the same areas with no relief immune system’s ability to control the quickly after menopause.1 using OTC creams and lotions. He was then population of Malassezia species. Human sebaceous glands (SG) are found prescribed Naftin cream and Ketoconazole Similarly, the patient in Case II requires over the entire skin surface (except the shampoo to use for three weeks, until the special care each day because of his mental palms of the hands and soles of the feet), next follow-up. limitations. He spends most of his time but sebum secretion is highest on the scalp, He recently had a vagal stimulator put in indoors and is limited in his activities. The face, chest, and back. The distribution is to help control his seizures. He is currently combination of his neuronal impairment classically symmetric, and common sites taking the following medicines: Topamax, and lack of activity both predispose him of involvement are the hairy areas of the Respiridol, Zonegran, and Depakote. to SD. head, including the scalp and scalp margin, Case III provides a combination of both eyebrows, eyelashes, mustache and beard. Case II immunodeficiency and neurological deficit. Other common sites are the forehead, the Due to her immunodeficiency, the patient nasolabial folds, the external ear canals, A 36-year-old male with Down syndrome is hindered from participating in many and the postauricular creases.2 One of the presented with a two-year history of SD. He activities, and as a result is less active on a characteristics of SD is dandruff; patients was seen at follow-up with redness around daily basis. The limited activity, especially may complain of the scalp itching with his lips and cheek bones and complaints of during the ages surrounding menarch, can NORMAN, TODD, TAHIR 7 lead to increased pooling of the sebaceous glands, as they are very active during this period and can provide a substantial food supply for the fungus. Treatment options for SD vary depending on region. The head and scalp areas can be treated with OTC shampoos containing salicylic acid (Scalpicin) or selenium sulfide (Selsun Blue, Exsel). If these are ineffective, ketoconazole or a coal tar shampoo (DHS Tar, Neutrogena T/Gel, Polytar) may be used. Other areas of the body may also be treated with the antifungal ketoconazole (Nizoral), ciclopirox (Loprox) and nafti- fine Hcl (Naftin) in addition to steroids (hydrocortisone) used to treat inflamma- tion. Isotrentoin (Accutane) has been used in severe cases.
References: 1. Ro BI, Dawson TL. The Role of Sebaceous Gland Activ- ity and Scalp Microfloral Metabolism in the Etiology of Seborrheic Dermatitis and Dandruff. Journal of Inves- tigative Dermatology Symposium Proceedings 2005; 10:194–197. 2. Johnson BA, Nunley JR. Treatment of Seborrheic Der- matitis. American Academy of Family Physicians 2000; 91(9): 2703-10, 2713-4. 3. Cowley NC, Farr PM, Shuster S. The permissive effect of sebum in seborrhoeic dermatitis: an explanation of the rash in neurological disorders. British Journal of Derma- tology 1990; 122 (1):71–76. 4. Kieffer M, et al. Immune reactions to Pityrosporum ovale in adult patients with atopic and seborrheic dermatitis. Journal of the American Academy of Dermatology 1990 May; 5(1):739 – 42. 5. Van Cutsem J, et al. The in vitro antifungal activity of ketoconazole, zinc pyrithione, and selenium sulfide against Pityrosporum and their efficacy as a shampoo in the treatment of experimental pityrosporosis in guinea pigs. J Am Acad Dermatol 1990 Jun 22; 6 (1):993 – 8. 6. DeAngelis Y, Leland M, Gemmer C, et al. The three etiologic facets of dandruff and seborrheic dermatitis: Malassezia fungi, sebaceous lipids, and individual sen- sitivity. Intercontinental Meeting of Hair Research Societ- ies. Conference poster, 2004.
8 SEBORRHEIC DERMATITIS & IMMOBILITY IN NEUROLOGICAL DISEASE AND IMMUNODEFICIENCY TREATMENT OF TEN WITH IVIG – A CASE REPORT
"TGB"LIUBS %0 .BSDVT(PPENBO %0 4UBOMFZ4LPQJU %0 '"0$% 'SBODJTDP,FSEFM .% '""% *3rd-year Dermatology Resident, NSU-COM/BGMC **1st-year Dermatology Resident, NSU-COM/BGMC ***Program Director, NSU-COM/ BGMC ****Director of Inpatient Dermatology, Cedars Medical Center, Miami
ABSTRACT
Toxic epidermal necrolysis (TEN) and Stevens–Johnson syndrome (SJS) are acute, rare, life-threatening mucocutaneous diseases that are almost always drug related. Massive apoptosis of keratinocytes, mediated by the interaction of the death receptor-ligand pair Fas-FasL and the perforin/granzyme pathways, leads to rapid extensive necrosis of the epidermis and separation of the skin at the dermal epidermal junction.2 Mucous membrane involvement is common, and mucositis generally precedes skin lesions by a few days.3 Features of TEN include an abrupt onset of fever, generalized rash, extreme skin pain, purulent conjunctivitis and asthenia. All organs may be involved, and sepsis is the most important complication, leading to death. Toxic epidermal necrolysis is associated with a mortality rate of 30%.1 Elderly and immunosuppressed patients have a higher mortality rate. Optimal treatment remains to be clarified. Discontinuation of the offending agent and care in a burn unit is agreed upon by most authorities. IVIG has been shown to be beneficial in the treatment of SJS/TEN, to varying levels. A case of SJS/TEN rapidly progressing to TEN and treated with IVIG is presented here. Despite the patient’s multiple co-morbid conditions, including AIDS and end-stage renal disease, treatment with IVIG resulted in an arrest of progression of TEN and re-epithelialization in two weeks.
Case Report The patient rapidly developed TEN within hours of initial evaluation while A 29-year-old male with a past medical awaiting transfer to a burn unit. The history significant for AIDS, renal failure patient was admitted to the ICU with and pulmonary embolism presented to the wound care, hydration and nutritional emergency room with a five-day history of support. Phenytoin was immediately with- a rapidly progressing rash and constitu- drawn, and IVIG therapy was initiated at tional symptoms. The patient stated that 1g/kg/day for four days. The patient was the rash initially started on his trunk and aggressively managed with wound care and spread to the face and extremities. The nutritional support. A cessation of skin patient had been started on phenytoin one and mucosal detachment was seen within week prior to the onset of the rash. He three days of starting IVIG therapy, and did admit to being non-compliant with re-epithelialization of the skin was noted Figure 1 his HIV medications. The patient recalled within two weeks of therapy. The patient experiencing a burning sensation in his eventually attained near normalization of eyes combined with painful swallowing skin. However, he developed pulmonary prior to the onset of the rash. There were and renal complications due to his multiple no known allergies up to this point. co-morbid conditions and was transferred Physical exam revealed an ill-appearing to hospice. male with widespread erythematous, dusky, atypical targetoid and purpuric macules Discussion on extremities, trunk and face, covering more than 30% of body surface area (BSA) First described by Lyell in 1956, TEN (Figure1). Flaccid bullae were present on is one of the most formidable condi- the skin as well (Figure 2). Nikolsky’s sign tions faced by dermatologists. It is a life- was positive. The detachment of skin was threatening cutaneous drug reaction that roughly 10%-15% on admission. Affected appears to be mediated by cytotoxic T Figure 2 areas of the skin resembled wet cigarette lymphocytes.1 paper. The patient had bilateral conjunc- TEN/SJS is rare, with an annual inci- have a much higher risk of developing TEN tival injection with hemorrhagic crusts and dence of two per million people. TEN as compared to the general population. erosions on the labial and gingival mucosa. occurs in all age groups including infants, Our patient had several risk factors that The skin lesions were very tender. children and adults. Patient groups could have contributed to developing TEN, Based on the history and clinical presen- particularly at risk are immunocompro- including HIV positivity, end-stage renal tation, a diagnosis of SJS/TEN overlap mised patients (HIV infection, lymphoma), disease and anticonvulsant therapy. due to Phenytoin therapy was made. patients undergoing radiation therapy for The overwhelming majority of cases of SCORTEN4 severity-of-illness score was brain tumors and concomitantly receiving SJS/TEN are caused by drugs, especially determined to be 3. Punch biopsies (Figure phenytoin,5-7 patients treated with aromatic the anticonvulsants phenytoin, pheno- 3, 4) were performed for definitive diag- anticonvulsants, slow acetylator types and barbital and carbamazepine. The risk of nosis. Histopathology revealed confluent slow metabolizer genotypes. HIV patients TEN is highest in the first two months of necrosis of the epidermis and a sparse have reduced levels of detoxifying chemi- therapy. More than a hundred drugs have perivascular infiltrate of lymphocytes. cals such as glutathione and cysteine and been identified as being linked to SJS/TEN AKHTAR, GOODMAN, SKOPIT, KERDEL 9 Table 1 SCORTEN level and predicted mortality SCORTEN Predicted Mortality (%) (sum of individual scores) 0-1 3.2 2 12.1 3 35.8 4 58.3 Figure 3 ≥5 90
involvement progresses and eventually body surface area; (4) presence of cancer leads to detachment of the dermis from the or hematologic malignancy; (5) glucose epidermis. Nikolsky’s sign is usually posi- >252mg/dL (14mmol/L); (6) blood urea tive and is elicited by the epidermis being nitrogen >28 mg/dL (10mmol/L); and displaced laterally upon slight pressure bicarb 20mEq/L. Each variable is allotted from the thumb. Involvement of the GI one point, and the mortality increases with tract and respiratory tract can occur13 due each additional point (Table 1).4 to the release of large amounts of proin- The clinical presentation and patient flammatory cytokines in the epidermis.14 history are usually enough to make the Complications include sepsis, multio- diagnosis of TEN. However, other rgan failure, pulmonary embolism diagnoses to be considered include and gastrointestinal hemmorage.15 Vulvar Staphylococcal scalded skin syndrome Figure 4 adenosis of the labia minora has been (SSSS), paraneoplastic pemphigus (PNP), reported following SJS/TEN.16-18 With drug-induced pemphigus, acute general- the proper treatment and care, the skin ized exanthematous pustulosis (AGEP) and and include anticonvulsants, antibiotics starts to re-epithelialize in a few days. Skin linear IgA dermatosis. (particularly sulfonamides), NSAIDS, nevi- sequelae include scarring, hypopigmenta- Histologically, early lesions of TEN reveal parine and allopurinol. Non-drug-related tion or hyperpigmentation, vulvovaginal apoptotic keratinocytes in the basal and causes include exposure to industrial stenosis and phimosis. Ophthalmologic suprabasal layers of the epidermis. Late- chemicals, vaccinations and certain Asian sequelae are the most serious and include stage lesions reveal full thickness epidermal herbal products.8-11 corneal ulcers, photophobia, xerophthalmia necrosis with subepidermal blisters.20 The pathophysiology of TEN remains and foreign-body sensation.19 There is usually a sparse dermal mono- only partially understood. TEN is consid- SJS and TEN lie at the two ends of a nuclear cell infiltrate seen in the dermis. ered a T-cell-mediated disorder. Viard spectrum of reactive disorders. The extent However, Quinn et al. have demonstrated a et al.12 demonstrated that massive kera- of skin detachment divides the spectrum range of mononuclear cell infiltrates, from tinocyte apoptosis is mediated through 21 into one of three major groups: sparse to dense. upregulation and activation of specialized (1) SJS: epidermal detachment of <10% Due to the high mortality rate associ- cell membrane receptors such as Fas. Fas ated with TEN, early diagnosis and specific ligand (FasL) expression is upregulated on of the body surface area. (2) SJS/TEN overlap: epidermal detach- therapy is imperative. Most authorities the cell surface of keratinocytes in TEN, agree that the patient should be admitted ment of 10%-30% of the body and upon contact with Fas, FasL induces to a unit that is equipped to handle patients surface area with widespread atypical polymerization and triggering of the with burns and extensive cutaneous inju- purpuric and targetoid lesions. caspase cascade. This leads to keratino- ries.22-24 Daily wound care, nutritional cyte apoptosis. Increased levels of certain (3) TEN: epidermal detachment support, hydration and pain relief is essen- cytokines such as tumor necrosis factor- involving >30% of the body surface tial. Patients’ skin manipulation should be (TNF- ) and interleukin 6 (IL-6) are also area. This is further divided into two minimized, and special attention should be present in the lesional skin of TEN patients. categories. paid to the eyes, respiratory tract and elec- Perforin/granzyme pathways have also been a. TEN with spots: large areas of trolyte balance. Debridement of necrotic implicated in the pathogenesis of TEN. It epidermal detachment involving epidermis and use of artificial membranes, has been shown that IVIG inhibits kera- >30% of the body surface area, porcine xenograft or human skin allograft tinocyte cell death by inhibiting Fas-FasL with widespread, flat, atypical may be required. interaction. Other proposed mechanisms targetoid or purpuric lesions. Adjuvant treatments, including plas- of IVIG therapy include regulation of b. TEN without spots: large areas of mapheresis, cyclosporin, corticosteroids, cellular immune responses and elimination epidermal detachment involving TNF-alpha inhibitors and IVIG, have of active complexes.12 >10% of the body surface area, been tried with variable results. Adjuvant Initial symptoms of SJS/TEN include without targetoid or purpuric treatments remain complementary to malaise, fever, odynophagia and a stinging lesions. supportive care in a unit capable of sensation in the eyes. Skin lesions tend In 2000, a severity of illness score for handling burn patients. to favor the trunk, spreading centrifu- TEN (SCORTEN) was proposed to assess The patient presented here was treated gally. Widespread, purpuric macules and illness severity and predict mortality. with supportive care in addition to dusky, atypical targetoid lesions are seen, SCORTEN is a sum of seven measurable receiving IVIG therapy. IVIG is derived including bullae. Involvement of the clinical variables, each with equal weight. from pooled plasma of human donors and ocular, genital and buccal mucosa is seen in The variables are: (1) age > 40 years; (2) consists mainly of the IgG class of immu- more than 90% of patients. The involved heart rate > 120 beats per minute; (3) noglobulins. IVIG contains anti-Fas IgG, skin acquires a gray hue as the epidermal epidermal detachment involving >10% which blocks Fas-FasL interaction, thus 10 TREATMENT OF TEN WITH IVIG – A CASE REPORT interfering with keratinocyte apoptosis matol 1998;25:533-538. 14. Faye O, Wechsler J, Roujeau JC. Cell-mediated immu- in TEN. A number of studies have been nologic mechanism and severity of TEN. Arch Dermatol conducted with varying levels of evidence 2005;141:775-776. 15. Wolkenstein P, Revuz J. Toxic epidermal necrolysis. Der- for the efficacy of IVIG in the treatment matol Clin 2000;18:485-495. of SJS/TEN. Prins et al. conducted a 16. Bonafe JL, Thibaut I, Hoff J. Introital adenosis associated with the Stevens-Johnson syndrome. Clin Exp Dermatol retrospective study of 48 patients, from 1990;15:356-357. 14 university-based dermatology centers, 17. Noel JC, Buxant F, Fayt I, Bebusschere G, Parent D. Vul- 25 val adenosis associated with toxic epidermal necrolysis. treated with IVIG between 1997 and 2000. Br J Dermatol 2005;153:457-458. The survival rate was determined to be 18. Wilson EE, Malinak LR. Vulvovaginal sequelae of Ste- vens-Johnson syndrome and their management. Obstet 88%. In another study, out of 16 patients Gynecol 1988;71:478-480. with TEN treated with IVIG (1g/kg/day), 19. Haber J, Hopman W, Gomez M, Cartotto R. Late out- 26 comes in adult survivors of toxic epidermal necrolysis 15 patients survived. The efficacy of IVIG after treatment in a burn center. J Burn Care Rehabil in the treatment of TEN is also well estab- 2005;26:33-41. 27 20 Becker DS. Toxic epidermal necrolysis. Lancet lished in the pediatric literature. 1998;351:1417-1420. 21. Quinn AM, Brown K, Bonish BK, Curry J, Gordon KB, Some studies have shown minimal or Sinacore J. Uncovering histologic criteria with prognostic no benefit from IVIG in the treatment of significance in toxic epidermal necrolysis. Arch Dermatol 28 2005;141:683-687. TEN. Due to the rarity of the disease and 22. McGee T, Munster A. Toxic epidermal necrolysis syn- lack of prospective controlled studies, there drome: mortality rate reduced with early referral to regional burn center. Plast Reconstr Surg 1998;102:1018- are no specific therapies for TEN that have 1022. reached evidence-based medical standards 23. Palmieri TL, Greenhalgh DG, Saffle JR, Spence RJ, Peck MD, Jeng JC. A multicenter review of toxic epidermal of acceptance. The patient presented in this necrolysis treated in U.S. burn centers at the end of the case report was treated with IVIG due to its twentieth century. J Burn Care Rehabil 2002;23:87-96. 24. Ellis MW, Oster CN, Turiansky GW, Blanchard JR. A therapeutic value combined with minimal case report and a proposed algorithm for the trans- toxic side effects. The lack of uniformity in fer of patients with Stevens-Johnson syndrome and toxic epidermal necrolysis to a burn center. Mil Med the treatment of TEN calls for multi-center, 2002;167:701-704. controlled, randomized studies to test the 25. Prins C, Kerdel FA, Padilla RS, Hunziker T, Chimenti S, Viard I. Treatment of toxic epidermal necrolysis with high- effectiveness of IVIG therapy versus other dose intravenous immunoglobulins: multicenter retro- modalities. spective analysis of 48 consecutive cases. Arch Dermatol 2003;139:26-32. 26. Trent JT, Kirsner RS, Romanelli P, Kerdel FA. Analysis of intravenous immunoglobulin for the treatment of toxic "DLOPXMFEHFNFOUT epidermal necrolysis using SCORTEN: The University of Miami Experience. Arch Dermatol 2003;139:39-43. The authors wish to thank Angelos 27. Metry DW, Jung P, Levy ML. Use of intravenous immuno- Poulos, M.D., Director, Global Pathology globulin in children with Stevens-Johnson syndrome and toxic epidermal necrolysis: seven cases and review of the Laboratory Services, and Kristen Aloupis, literature. Pediatrics 2003;112:1430-1436. D.O., 2nd-year resident at NSU-COM/ 28. Brown KM, Silver GM, Halerz M, Walaszek P, Sandroni A, Gamelli RL. Toxic epidermal necrolysis: does immu- BGMC, for their help in this case. noglobulin make a difference? J Burn Care Rehabil 2004;25:81-88. References: 1. Pereira F, Mudgil A, Rosmarin D. Toxic epidermal necrol- ysis. J. Am. Acad. Dermatol. 2007 Feb;56(2): 181-200. 2. Roujeau JC, Chosidow O, Saiag P, Guillaume JC. Toxic epidermal necrolysis (Lyell syndrome). J. Am. Acad. Der- matol. 1990 Dec;23(6 Pt 1): 1039-58. 3. Revuz J, Roujeau JC, Guillaume JC, Penso D, Touraine R. Treatment of toxic epidermal necrolysis. Creteil’s experience. Arch Dermatol 1987;123:1156-1158. 4. Bastuji-Garin S, Fouchard N, Bertocchi M, Roujeau JC, Revuz J, Wolkenstein P. SCORTEN: A Severity-of-illness score for toxic epidermal necrolysis. J Invest Dermatol 2000;115:149-153. 5. Micali G, Linthicum K, Han N, West DP. Increased risk of erythema multiforme major with combination anti- convulsant and radiation therapies. Pharmacotherapy 1999;19:223-227. 6. Gomez-Criado MS, Ayani I, Leon-Colombo T, Ramos ML, Reneses MJ. Stevens-Johnson syndrome, toxic epidermal necrolysis and phenytoin. Factors linked to a higher risk. Rev Neurol 2004;38:1056-1060. 7. Aguiar D, Pazo R, Duran I, Terrasa J, Arrivi A, Manzano H. Toxic epidermal necrolysis in patients receiving anti- convulsants and cranial irradiation: a risk to consider. J Neurooncol 2004;66:345-350. 8. Dobrosavljevic D, Milinkovic MV, Nikolic MM. Toxic epi- dermal necrolysis following morbilli-parotitis-rubella vac- cination. J Eur Acad Dermatol Venereol 1999;13:59-61. 9. Radimer GF, Davis JH, Ackerman AB. Fumigant-induced toxic epidermal necrolysis. Arch Dermatol 1974;110:103- 104. 10. Ball R, Ball LK, Wise RP, Braun MM, Beeler JA, Salive ME. Stevens-Johnson syndrome and toxic epidermal necrolysis after vaccination: reports to the vaccine adverse event reporting system. Pediatr Infect Dis J 2001;20:219-223. 11. House RA, Jakubovic H, Wong L, Holness DL. Work- related toxic epidermal necrolysis? J Occup Med 1992;34:135-139. 12. Viard I, Wehrli P, Bullani R, Schneider P, Holler N, Salo- mon D. Inhibition of toxic epidermal necrolysis by block- ade of CD95 with human intravenous immunoglobulin. Science 1998;282:490-493. 13. Sugimoto Y, Mizutani H, Sato T, Kawamura N, Ohk- ouchi K, Shimizu M. Toxic epidermal necrolysis with severe gastrointestinal mucosal cell death: a patient who excreted long tubes of dead intestinal epithelium. J Der-
AKHTAR, GOODMAN, SKOPIT, KERDEL 11 CUTANEOUS ROSAI-DORFMAN DISEASE REPRESENTS A DISTINCT CLINICAL ENTITY
"OHFMB.-FP %0 BOE4UFQIFO.1VSDFMM %0 t%FSNBUPMPHZSFTJEFOU OEZFBS 1IJMBEFMQIJB$PMMFHFPG0TUFPQBUIJD.FEJDJOF'SBOLGPSE)PTQJUBMT 1IJMBEFMQIJB 1" "TTJTUBOU1SPHSBN%JSFDUPS %JWJTJPOPG%FSNBUPMPHZ 1IJMBEFMQIJB$PMMFHFPG0TUFPQBUIJD.FEJDJOF 1IJMBEFMQIJB 1"
ABSTRACT
Cutaneous Rosai-Dorfman (RDD) disease is a rarely reported, distinct clinicopathologic entity. We report a case of purely cutaneous RDD that showed no signs of systemic involvement. Cutaneous RDD is distinguished from its classic, systemic counterpart by its overall benign course, tendency towards spontaneous resolution and lack of systemic involvement. It tends to occur in older, white females and likely represents a reactive process to a yet-to-be-identified antigen.
#BDLHSPVOE that the histiocytic cells stain CD 68 +, S-100 +, CD1a -, and factor XIIIa +. These Originally, sinus histiocytosis with findings are consistent with a histopatho- massive lymphadenopathy was reported in logic diagnosis of RDD. African children in 1965 by Destombes.1 It Upon further questioning, the patient was not until Rosai and Dorfman described revealed to have had a biopsy of a “cyst” it in 1969 that the disease acquired the on his left forearm over a year ago. The eponym Rosai-Dorfman disease (RDD).2 histopathologic diagnosis of that lesion was RDD is considered a self-limited, reactive reported as Rosai-Dorfman disease. histiocytosis of unknown etiology. RDD is There were no abnormalities noted typically classified into two forms: 1. sinus on a CBC with differential and compre- histiocytosis with mass lymphadenopathy hensive metabolic panel. A CT scan of or RDD; and 2. cutaneous histiocytosis or the chest/abdomen/pelvis revealed no Figure 1 cutaneous RDD. Herein, we report a case lymphadenopathy. of purely cutaneous RDD that showed no signs of systemic involvement. Discussion Case Report Classic RDD presents with massive, painless cervical lymphadenopathy, fever, A 69-year-old Caucasian male presented leukocytosis, anemia, elevated ESR, and for a routine skin examination. His medical a polyclonal gammopathy.3 It is more and surgical history included a stroke with commonly seen in black males during the ventricular peritoneal shunt placement 20 first to second decade of life. The cervical years prior, coronary artery bypass grafting, lymph nodes are affected in the majority of hypertension, hypercholesterolemia and cases, and extranodal involvement occurs osteoarthritis. He reported no known drug in 30-40% of cases.3 The most common allergies and denied any new medications. site of extranodal involvement is in the Figure 2 His medications included phenytoin, skin.3 Other sites of involvement include metoprolol, clopidogrel, simvastatin and but are not limited to bone marrow,4 sali- a multivitamin. A review of systems was vary gland,5 CNS,6,7,8 genitourinary tract,9,10 negative. respiratory tract,11 liver and gastrointestinal On physical exam, there were two tract,12 and breast.13 1.2-cm pink-purple nodules, one on his Associations reported with classic RDD right posterior shoulder and one on his include infection,14 hematological malig- right lateral back (Picture 1). The initial nancy15,16 and autoimmune diseases.17,18 clinical impression was that of a basal-cell Although the condition is considered to be carcinoma. benign, the course can be unpredictable. Histopathologic examination showed It may be characterized by a prolonged a nodular infiltrate of foamy histio- clinical course with exacerbation and cytes surrounded by a margin or rim of spontaneous remission phases. It rarely Figure 3 lymphocytes. This high-magnification may be complicated by organ compres- appearance has sometimes been likened sion, immune dysfunction and unusual 21 22 23 to a “lymph node in the skin” (Picture infections. There are some reports of death tion, chemotherapy, surgery and inter- 2). Intact lymphocytes with rare plasma associated with complicated cases of classic feron-α therapy24 have all been tried. cells and erythrocytes were seen within RDD.19 Cutaneous RDD is a rare variant of RDD the cytoplasm of histiocytes, a phenom- Treatment is often not necessary because with localized involvement of the skin. enon known as emperipolesis (Picture 3). of the self-limited nature of the illness. Usually, there are no systemic symptoms; Immunohistochemical staining revealed However, corticosteroid therapy,20 radia- but rarely, fatigue and weight loss have 12 CUTANEOUS ROSAI-DORFMAN DISEASE REPRESENTS A DISTINCT CLINICAL ENTITY been reported. It is more commonly seen resolves spontaneously and shows no signs Arch Dermatol. 1988;124:1246-1249. 29. Stefanato CM, et al. Cutaneous sinus histiocytosis in white females in the fifth to seventh of systemic involvement. It tends to occur (Rosai-Dorfman disease) presenting clinically as vascu- decade of life.25 in older, white females and likely represents litis. J Am Acad Dermatol. 2002;46:775-8. 30. Chu P, et al. Histologic features of cutaneous sinus his- The clinical presentation of cutaneous a reactive process to a not-yet-identified tiocytosis (Rosai-Dorfman disease): study of cases both antigen. with and without systemic involvement. J Cutan Pathol. RDD is variable, and any body region 1992;19:201-206. can be involved. There may be solitary Special thanks to Peter Motel, M.D. 31. Middel P, et al. Sinus histiocytosis with massive lymph- adenopathy: evidence for its relationship to macrophages or multiple, yellow-red-brown papules/ and for a cytokine-related disorder. Histopathology. 1999 nodules; or it may localize to the soft tissue, References Dec;35(6):525-33. 26,27 28 32. Laplaud AL, et al.[Purely cutaneous Rosai-Dorfman dis- mimicking a tumor or panniculitis; or 1. Destombes P. Adenites avec surcharge lipidique, de ease present for 19 years]Ann Dermatol Venereol. 2007 it may present clinically as a vasculitis.29 l’enfant ou de l’adulte jeune, observees aux Antilles et Nov;134(11):843-6. au Mali (quatre observations). Bull Soc Pathol Exot. 33. Wang KH, et al. Coexistence of localized Langerhans The histopathologic features of cuta- 1965;58:1169-1175. cell histiocytosis and cutaneous Rosai-Dorfman disease. neous RDD and extranodal RDD are 2. Rosai J, et al. Sinus histiocytosis with massive lymphade- Br J Dermatol. 2002 Oct;147(4):770-4. nopathy. A newly recognized benign clinicopathological 34. Sachdev R, et al. Co-existent Langerhans cell histiocy- the same. They are characterized by entity. Arch Pathol. 1969;87:63-70. tosis and Rosai-Dorfman disease: a diagnostic rarity. a nodular or diffuse infiltrate of foamy 3 .Lu C I, et al. Clinical and histopathologic spectrum of Cytopathology. 2008 Feb;19(1):55-8. Epub 2007 Mar 27 cutaneous Rosai-Dorfman disease in Taiwan. J Am Acad 35. Ortonne N, et al. Cutaneous Destombes-Rosai Dorfman histiocytes whose overall silhouette is Dermatol. 2004 Dec;51(6):931-9. disease: absence of detection of HHV-6 and HHV-8 in that of a “lymph node in the skin.” The 4. Huang Q, et al. Extranodal Rosai-Dorfman disease skin. J Cutan Pathol. 2002 Feb;29(2):113-8. involving the bone marrow: a case report. Am J Surg 36. Ang P, et al. Cutaneous Rosai-Dorfman disease present- diagnostic feature is intact lymphocytes Pathol. 2006 Sep;30(9):1189-92. ing as pustular and acneiform lesions. J Am Acad Derma- and, on occasion, plasma cells or erythro- 5. Juskevicius R, et al. Rosai-Dorfman disease of the tol. 1999 Aug;41(2 Pt 2):335-7. parotid gland: cytologic and histopathologic findings with 37. Satter EK, et al. Response of cutaneous Rosai-Dorfman cytes in the cytoplasm of histiocytes. This immunohistochemical correlation. Arch Pathol Lab Med. disease to topical and intralesional steroids. Br J Derma- phenomenon is known as emperipolesis.30 2001 Oct;125(10):1348-50. tol. 2003 Sep;149(3):672-4. 6. Gaetani P, et al. Isolated cerebellar involvement in Rosai- 38. Chan CC, et al. Dapsone as a potential treatment for Immunohistochemical staining of the histi- Dorfman disease: case report. Neurosurgery. 2000 cutaneous Rosai-Dorfman disease with neutrophilic pre- ocytes in RDD shows that they are S100 +, Feb;46(2):479-81. dominance. Arch Dermatol. 2006 Apr;142(4):428-30. 7. Wu M, et al. A report of intracranial Rosai-Dorfman 39. Tjui JW, et al. Cutaneous Rosai-Dorfman disease: remis- Cd1a -, and CD 68 +, a phenotype that has disease with literature review. Ann Diagn Pathol. 2001 sion with thalidomide treatment. Br J Dermatol. 2003 been described as indeterminate and may Apr;5(2):96-102. May;148(5):1060-1. 31 8. Kitai R, et al. Meningeal Rosai-Dorfman disease: report 40. Mebazaa A, et al. Extensive purely cutaneous Rosai- represent a form of active macrophage. of three cases and literature review. Brain Tumor Pathol Dorfman disease responsive to acitretin. Int J Dermatol. Cutaneous RDD recapitulates the histo- 2001;18(1):49-54. 2007 Nov;46(11):1208-10. 9. Murrary J, et al. Rosai-Dorfman disease of the uterine 41. Brenn T, et al. Cutaneous Rosai-Dorfman s a distinct pathological characteristics of RDD but has cervix. Int J Gynecol Pathol. 1991;10(2):209-13. clinical entity. Am J Dermatopathol. 2002;24:385-391. a more favorable clinical behavior than its 10. Harik L, et al. Extranodal Rosai-Dorfman disease of 42. Frater JL, et al. Cutaneous Rosai-Dorfman disease: the kidney and coexistent poorly differentiated pro- comprehensive review of cases reported in the medical systemic counterpart. There are no reported static adenocarcinoma. Arch Pathol Lab Med. 2006 literature since 1990 and presentation of an illustrative Aug;130(8)1223-6. case. J Cutan Med Surg. 2006 Nov-Dec;10(6):281-90. cases of cutaneous RDD developing into 11. Aluffi P, et al. Rosai-Dorfman disease of the larynx. J systemic disease. Cutaneous RDD tends to Laryngol Otol. 2000 Jul;114(7):565-7. 12. Lauwers GY, et al. The digestive system manifestations spontaneously regress, but it may persist of Rosai-Dorfman disease (sinus histiocytosis with mas- 32 23 for years or recur after excision. There sive lymphadenopathy): review of 11 cases. Hum Pathol. 2000 Mar;31(3):380-5. are rare reports of localized Langerhans- 13. Ng SB, et al. Rosai-Dorfman disease of the breast: mimic cell histiocytosis coexisting with cutaneous of a breast malignancy. Pathology. 2000 Feb;32(1):10-5. 33,34 14. Perry BP, et al. Rosai-Dorfman disease (extranodal sinus RDD. histiocytosis) in a patient with HIV. Ear Nose Throat J. The pathophysiology of RDD is not 1998 Oct;77(10):855-8. 15. Koduru PR, et al. Morphological, ultrastructural, and known, but a viral etiology like HHV-6 or genetic characterization of an unusual T-cell lymphoma EBV has long been postulated. However, no in patients with sinus histiocytosis with massive lymph- 31 adenopathy. Am J Hematol. 1995 Mar;48(3):192-20. specific virus has been fully confirmed. 16. Lu D, et al. Sinus histiocytosis with massive lymphade- There is one case where monocyte- nopathy and malignant lymphoma involving the same lymph node: a report of four cases and review of litera- colony stimulating factor (M-CSF) played ture. Mod Pathol. 2000 Apr;13(4):414-9. a role in recurrent RDD. In cell culture, 17. Grabczynska SA, et al. Rosai-Dorfman disease is compli- cated by autoimmune haemolytic anaemia: a case report M-CSF can stimulate macrophages to and review of a multisystem disease with infiltrates. Br J engulf lymphocytes in a process similar to Dermatol. 2001 Aug;145(2):323-6. 18. Maric I, et al. Histologic features of sinus histiocytosis 35 emperipolesis. with massive lymphadenopathy in patients with autoim- mune lymphoproliferative syndrome. Am J Surg Pathol. Treatment of purely cutaneous RDD is 2005 Jul;20(7):903-11. not necessary. It may be treated for cosmetic 19. Foucar E, et al. Sinus histiocytosis with massive lymph- adenopathy. An analysis of 14 deaths occurring in a purposes or symptomatic relief. Modalities patient registry. Cancer 1984 Nov 1;54(9):1834-40. that have been tried include radiotherapy, 20. Ocheni S, et al. Usefulness of oral corticosteroid in 36 Rosai-Dorfman disease. Eur J Cancer Care (Engl). 2007 cryotherapy, excision, topical/oral/or May;16(3):286-8. intralesional corticosteroids,37 dapsone,38 21. Kidd DP, et al.Rosai-Dorfman disease presenting with 39 40 widespread intracranial and spinal cord involvement. thalidomide, and acitretin. Neurology. 2006 Nov 14;67(9):1551-5. The clinical and histopathologic 22. Tasso M, et al. Sinus histiocytosis with massive lymph- adenopathy (Rosai-Dorfman disease) treated with 2-chlo- appearances of the cutaneous lesions in rodeoxyadenosine. Pediatr Blood Cancer. 2006 Oct the two forms of RDD are indistinguish- 15;47(5):612-5. 23. Pulsoni A, et al. Treatment of sinus histiocytosis with able. However, the epidemiology is quite massive lymphadenopathy (Rosai-Dorfman disease): different, with cutaneous RDD having on report of a case and literature review. Am J Hematol. 2002 Jan;69(1):67-71. older age at onset and a reversed male- 24. Palomera L, et al. Sinus histiocytosis with massive lymph- to-female ratio. Cutaneous RDD remains adenopathy: complete response to low-dose interferon- alpha. J Clin Oncol. 1997 May;15(5):2176. localized to the skin even with long-term 25. Rubenstein MA, et al. Cutaneous Rosai-Dorfman dis- follow up, and no significant systemic, ease. Dermatol Online J. 2006 Jan 27;12(1):8. 26. Huang HY, et al. Isolated Rosai-Dorfman disease pre- extracutaneous, or serologic manifestations senting as a peripheral mononeuropathy and clinically have been described. Hence, some authors mimicking a neurogenic tumor: case report. Surg Neurol. 2001;56:344-7. believe that cutaneous RDD is in fact its 27. Mac-Mourne Lai F, et al. Cutaneous Rosai-Dorfman own, distinct clinical entity.41,42 disease presenting as a suspicious breast mass. J Cutan Pathol. 1994;21:377-82. It is important to remember that cuta- 28. Suster S, et al. Histiocyte lymphophagoctyic panniculitis: an unusual extranodal presentation of sinus histiocytosis neous RDD has an overall benign course, with massive lymphadenpathy (Rosai-Dorfman disease).
LEO, PURCELL 13 ATROPHODERMA OF PASINI AND PIERINI
$ISJT#VBUUJ %0 .#" ,JNCBMM84JMWFSUPO %0 'JSTUZFBS3FTJEFOU(FOFTZT3FHJPOBM.FEJDBM$FOUFS (SBOE#MBOD .* .JDIJHBO4UBUF6OJWFSTJUZ4UBUFXJEF$BNQVT4ZTUFN 1SPHSBN%JSFDUPS (FOFTZT3FHJPOBM.FEJDBM$FOUFS (SBOE#MBOD .* .JDIJHBO4UBUF6OJWFSTJUZ4UBUFXJEF$BNQVT4ZTUFN
ABSTRACT
Idiopathic atrophoderma of Pasini and Pierini (IAPP) is a rare, localized form of dermal atrophy with unknown etiology seen typically as several oval, hyperpigmented, atrophic plaques developing on the trunk. The lesion usually affects adolescents or young adults. The course of the benign disease is progressive, and lesions can continue to appear for decades before reaching a standstill. No treatment has been proven effective. Penicillin has been used to treat atrophoderma of Pasini and Pierini because of case reports of an underlying Borrelia burgdorferi infection. However, the results have been inconclusive.
Case Presentation A 14-year-old male presented with a three-year history of patches on the trunk. They were asymptomatic, but would come in waves with increasing numbers at times. The patient had a history of asthma but no other cutaneous or serious medical illness. There was no history of Lyme disease. Exam There were 2mm-to-5mm macules scattered over the entire integument. The macules were somewhat atrophic and had a “step-off” configuration (Figures 1, 2). Histopathology The superficial dermis showed a few telangiectatic vessels. The dermis showed the adnexal structures to be intact. Sweat coils were seen in the dermis. The subcu- taneous fat included was unremarkable. Acid-Orcein-Giemsa showed elastic fibers Figure 1 Figure 2 to be intact. There was reduced dermal thickness (Figure 3). Discussion usually spared. The distribution is often symmetric and bilateral, but a linear distri- Diagnosis Idiopathic atrophoderma of Pasini and bution along Blaschko’s lines has been 6 Atrophoderma of Pasini and Pierini Pierini (IAPP) is a form of dermal atrophy described (atrophoderma of Moulin). that presents as one or several sharply The lesions are single or multiple, Differential Diagnosis demarcated, depressed patches. The patches usually round or ovoid and range in size usually appear on the backs of adolescents from a few centimeters to patches covering ❍ Morphea or young adults. Whether atrophoderma large areas of the trunk. They are usually ❍ Anetoderma is an atypical, primarily atrophic form of asymptomatic and lack inflammation. morphea or a distinct entity is still debated.4 When lesions coalesce, they can form large, $PVSTFBOE5SFBUNFOU The disorder is more frequently encoun- irregular patches. tered in women than in men, with a ratio The patches usually have a brown color, Some reported cases of atrophoderma of 6:1 in adults. It usually starts insidi- but some are more violet.2 The surface of of Pasini and Pierini could be related to ously in young individuals in the second or the skin is normal in appearance. There Borrelia burgdorferi infection. Therefore, third decades of life. However, it has been is a lack of skin induration and no scle- the patient was given doxycycline 75mg reported in patients as young as seven years rosis. The borders or edges of these lesions BID for three weeks. There was neither a and as old as 66 years.3 are sharply defined, and they are usually change in nor a progression of the lesions The lesions usually occur on the trunk, described as abrupt “cliff drop” borders after antibiotics. The patient was given especially on the back and lumbosacral ranging from 1 mm to 8 mm in depth, reassurance that the lesions were benign, region, followed by the chest, arms, and although they can have a gradual slant.6 not cancer and not a contagious condition. abdomen. The face, hands, and feet are The histological picture is generally 14 ATROPHODERMA OF PASINI AND PIERINI Pasini-Pierini is a primary atrophic abortive morphea. Dermatology. 1995; 190:203-206. 10. Calka O, et al. Idiopathic Atrophoderma of Pasini and Pierini. Eastern Journal of Medicine. 6(2); 55-57, 2001.
Figure 3 not diagnostic, so diagnosis is primarily a clinical one. The epidermis is usually normal or slightly atrophic. Basal-cell pigmentation may be increased. A perivas- cular infiltrate consisting of T-cells and histiocytes may be seen. Dermal thickness is eventually reduced when compared with adjacent normal skin.3 The course of the benign disease is progressive, and lesions can continue to appear for decades before reaching a standstill. Transformation to gener- alized morphea has not been observed. The natural course of the disease is often protracted (10 to 20 years), making the evaluation of therapy difficult.8 No treat- ment has been proven effective. IAPP has no known effect on the patient’s overall health. Penicillin has been used to treat atrophoderma of Pasini and Pierini because of case reports of an underlying Borrelia burgdorferi infection.7 Psoralen and UVA (PUVA), potassium benzoic acid and oral antibiotics may be helpful to some patients if Borrelia burgdorferi antibodies are elevated.10 However, the results have been inconclusive.9 Excessive sun exposure may cause the more deeply pigmented lesional skin to become darker, resulting in further uneven discoloration of the skin. In some cases, the Q-switched alexandrite laser was effective in diminishing the hyperpigmen- tation by 50 percent.1
References: 1. Arpey C, Patel D, Stone M, et al. Treatment of Atropho- derma of Pasini and Pierini-Associated Hyperpigmenta- tion with the Q-switched Alexandrite Laser. Lasers in Surgery and Medicine. 2000; 27:206-212. 2. Kim S, Rhee S, et al. Congenital Atrophoderma of Pasini and Pierini. Journal Korean Med Sci. 2006; 21:169-171. 3. Kenchka D, Blaszczyk M, Jablonska S. Atrophoderma Pasini-Pierini is a primary abortive morphea. Dermatol- ogy. 1995; 190:203-206. 4. Beuchner SA, Rufli T. Atrophoderma of Pasini and Pierini: Clinical and histiopathological findings and antibodies to Borrelia Burgdorferi in thirty four patients. J Am Acad Dermatology. 1994; 30:441-446. 5. Pullara TJ, Lober CW, Freske NA. Idopathic atropho- derma of Pasini and Pierini. Int J. Dermatol. 1984; 23:643-5. 6. Bolognia JL, et al. Idiopathic Atrophoderma of Pasini and Pierini 1st edition. London. Mosby; 2003. pp1544-1526. 7. Wokalek H, Schmidt HG, Niedner R. et al. Idiopathic pro- gressive atrophoderma of Pasini-Pierini with the presence of antinuclear antibodies. Hautarzt. 1985; 36:154-160. 8. Iriondo M, Bloom RF, Nelder KH. Unilateral atrophoderma of Pasini and Pierini. Cutis. 1987; 39:69-70. 9. Kencka D, Blaszczk M, Jablonska S. Atrophoderma of
BUATTI, SILVERTON 15 IMPETIGO AND POOR HYGIENE
3PCFSU"/PSNBO %0 .1) 4UFWFO/PEJOF 0.4*** -BLF&SJF$PMMFHFPG0TUFPQBUIJD.FEJDJOF #SBEFOUPO '-
Report of a Case: A streptococcus bacteria. Impetigo is a highly contagious infection that presents An 18-year-old male presented to the with the symptoms of pruritus, burning, office with his mother and siblings and and lymphadenopathy. The infection complained of a rash that covered his can appear either as a primary infection body. Multiple, honey-crusted papules and that occurs in superficial breaks in the pustules that were erythematous, inflamed epidermis, or as a secondary infection due and excoriated were noted. He reported to a preexisting dermatological problem. the rash started on the back of the neck and The initial lesion presents as a small, spread over the entire body. He stated that erythematous macule that changes into it was very itchy and uncomfortable. There fluid-filled vesicles. When the vesicles were several places on his neck where he burst, the exudate forms a honey-colored had scratched so hard that it left red finger crust over the vesicles. The yellow, honey- Figure 1 markings. The rash extended into his crusted exudate is often seen in impetigo, nostril, and he reported purulent drainage but it is not pathognomonic. beneath the dermal-epidermal junction. on occasion. His genital area was swollen Bullous impetigo presents as lesions that Treatment for cellulitis is oral and topical and erythematous. are tense, clear bullae containing yellow, therapy. If no improvement is noticed or The patient’s mother stated that he had slightly turbid fluid arising on normal- if the patient becomes septic, intravenous poor hygiene, which was evident along appearing skin. It is commonly distributed therapy is recommended. Ciprofloxacin with the body odor that emanated from in areas of the body where there is skin- and cephalosporin are recommended him. The mother stated that her son did on-skin contact. There is also nonbullous antibiotics. If there is purulent discharge, not sleep much. The patient laughed inap- impetigo, which is characterized by small cultures should be taken and appropriate propriately and stated that he didn’t think vesicles which, when ruptured, result in therapy provided. it was necessary to take a bath every day. erosions that become covered in the yellow The patient did state that a few days earlier crust. The lesions are scattered and may Differential Diagnosis: he was outside moving plants around the become confluent without treatment. house. He also stated that he did not wear Satellite lesions can appear due to auto- Scabies, herpetic ulcers, allergic contact clean clothing and spent hours in front of inoculation by the patient. If left untreated, dermatitis a computer playing computer games. The impetigo can cause glomerulonephritis, patient stated that he dropped out of high although it will not cause rheumatic fever. Resources: school last year. Ecthyma is a variant of impetigo that is 1. Ball, Jane W., G. W. Benedict, Joyce E. Daines, and The mother also stated that the patient more common on distal extremities and Henry M. Seidel. Mosby’s Guide to Physical Examination. 5th ed. St. Louis: Mosby, 2003. 163-224. would threaten to touch them if he didn’t causes punched-out, ulcerated lesions. 2. Braunwald, Eugene, Anthony S. Fauci, J. L. Jameson, get his way. She’d taken the patient to the Stephen L. Hauser, Dennis L. Kasper, and Dan L. Longo, Treatment of both ecthyma and impe- eds. Harrison’s Manual of Medicine. 16th ed. New York: hospital a few days earlier because of her tigo involves the debridement of adherent, McGraw-Hill, 2005. 448-455. concern with his rash. His lack of under- 3. Johnson, Richard A., Dick Suurmond, and Klaus Wolff. crusted areas. The removal of the crusted Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatol- standing of the importance of personal exudate allows better penetration of topical ogy. 5th ed. New York: McGraw-Hill, 2005. 136-137. hygiene combined with the inappropriate 4 Katzung, Bertram G., Susan B. Masters, and Anthony J. antibiotics, such as mupirocin. Mupirocin Trevor. Katzung & Trevor’s Pharmacology. 7th ed. New laughter led to a suspicion of possible is a highly effective topical antibiotic used York: Lange Medical Books/McGraw-Hill, 2005. 424-425. altered mental status along with his poor against the gram-positive bacteria S. aureus hygiene habits. The patient had developed and group A streptococcus, which are the impetigo with cellulitis. He was referred to causative agents of ecthyma and impetigo. counseling and told to bathe regularly. The Mupirocin inhibits the protein synthesis patient was treated with oral cephalosporin of the bacteria by specifically binding to and topical mupirocin. isoleucyl-tRNA synthase. This inhibits the incorporation of isoleucine into bacterial Diagnosis: proteins. Mupirocin is applied three times a day for seven to 10 days. Impetigo with cellulitis Cellulitis is a skin condition caused by the same bacteria, S. aureus and group Discussion: A streptococcus. Cellulitis affects the Impetigo is a superficial infection of the dermis and subcutaneous tissues. The epidermis; it does not spread below the lesions lie flat against the skin and are dermal-epidermal junction. Staphylococcus extremely painful. The epidermis under- aureus is the most common cause of impe- goes epidermal sloughing and superficial tigo, but it can also be caused by group erosion. There is no crusting, oozing, or weeping because the infection is limited 16 IMPETIGO AND POOR HYGIENE
EN COUP DE SABRE: A CASE REPORT AND DISCUSSION
1BVM"BOEFSVE 0.4*** %BOJFM)BOTFO %0 .#" 3ZBO.$BSMTPO %0 4UFWFO,(SFLJO %0 '"0$% *OMSIII, A.T. Still University at KCOM OEZFBS3FTJEFOU 0BLXPPE4PVUITIPSF1SPHSBN .JDIJHBO4UBUF6OJWFSTJUZ 5SFOUPO .* SEZFBS3FTJEFOU 0BLXPPE4PVUITIPSF1SPHSBN .JDIJHBO4UBUF6OJWFSTJUZ 5SFOUPO .* 1SPHSBN%JSFDUPS 0BLXPPE4PVUITIPSF1SPHSBN 8ZBOEPUUF .*
ABSTRACT
En coup de sabre is a type of linear scleroderma that presents on the frontal or frontoparietal scalp. The following is a case of a 40-year-old woman who presented early in the disease process, and we observed a halt in the progression of her disease secondary to institution of early treatment. The clinical presentation, laboratory findings, epidemiology, and treatment options are reviewed.
Case Presentation: moderate deep perivascular infiltrate of lymphocytes and plasma cells. The scar- A 40-year-old Caucasian female ring process is highlighted by diminished presented to the office with complaints van Gieson elastic-fiber staining in the deep of a one-month history of an off-white reticular dermis. to yellow plaque on her frontal scalp with Treatment consisted initially of intral- accompanying hair loss. The lesion was esional glucocorticoid injections of triamci- occasionally pruritic, tender-to-touch, and nolone acetonide 2.5 to 5.0 mg/ml into the accompanied by a pulling sensation on the plaque on the forehead/scalp, along with left side of her forehead and scalp. Several Olux foam (clobetasol propionate) topi- visits later she noted expansion of the cally. When the diagnosis was rendered lesion inferiorly with the development of a and the acuity noted, oral prednisone was depression in her forehead (Figure 1). She instituted in an attempt to halt the progres- Figure 1: Linear scleroderma with did not recall having been bitten by a tick, sion and sclerosis. She was then placed on characteristic linear depression of the had no family history of connective-tissue Methotrexate as a steroid-sparing agent, 15 paramedian forehead disease, and had no pain in her joints. She mg every week, and is being maintained on developed morphea between 1960 and 1993 this regimen to date. She also continues to denied headaches, seizures, and visual in Olmstead County, Minnesota, showed receive intralesional triamcinolone acetonide changes. Medical history is significant only the incidence of en coup de sabre to be injections every three to four weeks. for hypothyroidism. 0.13 cases per 100,000 population.2 Of Physical examination during the initial The condition has remained stable the 82 cases of morphea identified in the visit revealed a healthy, well-appearing without progression of the sclerosis or study, 16 patients had linear scleroderma, middle-aged female. A hypopigmented to worsening of the clinical appearance of the including four with en coup de sabre and yellow sclerotic plaque was present on the depression on her forehead. This case is two with Parry-Romberg syndrome. None left frontal scalp, with overlying alopecia unique in demonstrating how the diagnosis of these patients developed systemic scle- and tenderness to palpation. Several of scleroderma en coup de sabre was made rosis. Progression of linear scleroderma very early on in the progression of the appointments later after workup was to systemic scleroderma has been reported disease. The disease process was halted due commenced, the plaque began to extend in rare cases. Skin softening or disease to early aggressive treatment. The patient is superiorly into the mid scalp and inferiorly resolution occurred in eight of 16 patients very pleased, and we will continue to follow onto the left paramedian forehead with a within five years of diagnosis. Unlike skin and monitor her. linear depression (figure 1). Otherwise, the in localized morphea, skin in linear sclero- face was normal and symmetric. derma may be fixed to underlying tissue. Laboratory analysis showed a positive Discussion Calcinosis may rarely occur. Cutaneous ANA screen, with an ANA titer of 1:640 En coup de sabre is a type of linear changes accompanying the facial hemiat- nucleolar and 1:160 homogenous pattern. scleroderma and is characterized by linear rophy associated with the Parry-Romberg The antibodies to ssDNA were also posi- bands of atrophy and a furrowing of the syndrome may be similar to those found tive. This is typically associated with skin. The extent of atrophy can be exten- in en coup de sabre. Unlike the gradual more extensive involvement of skin and sive, including not only skin and subcu- spontaneous remissions seen in morphea, underlying tissue. All other lab findings, taneous tissue, but also muscle and bone. linear scleroderma tends to have a longer including a CBC, CMP, TSH, anti-dsDNA, It is normally unilateral and typically and occasionally progressive course. Some anti-Smith, and SSA/SSB, were normal. extends paramedially from the forehead authors suggest scleroderma en coup de A punch biopsy measuring 3 mm was into the frontal scalp. Although infrequent, sabre occurs along Blaschko’s lines, which taken from the scalp during the office visit. multiple lesions of en coup de sabre may suggests that it may arise in a mosaic clone It was described as having diminished hair- be found on a single patient. There is a of susceptible cells.3 follicle population with catagen predomi- female preponderance of 3:1, with a higher As with other forms of scleroderma, the nance. There were thickened collagen incidence around menarche, pregnancy, exact etiology of localized scleroderma is bundles in the dermis with sclerotic dermal and menopause.1 Onset is usually during unknown. Hypotheses include microchi- fibrosis surrounding remnant hair folli- the first two decades of life. merism, which leads to a chronic low-grade cles. The pathology report also showed a A retrospective analysis of patients who graft-vs.-host-like disease, or an alteration AANDERUD, HANSEN, CARLSON, GREKIN 19 in antigens caused by ischemic damage.4 Other suggested contributors to the patho- genesis of the disease are environmental exposures, trauma, and Borrelia burgdor- feri infection.5 The vast majority of cases are sporadic. However, a small number of familial localized (linear) scleroderma cases have been reported. No clear HLA associa- tions with localized scleroderma have been established. Many consider localized scle- roderma to be an immunologic disorder, since it is often accompanied by the pres- ence of autoantibodies. Linear morphea is more frequently associated with high ANA titers, in up to 40-80% of patients. Also, single-stranded DNA antibodies are particularly common and specific to linear morphea, and are uncommon with plaque-type morphea. Additional serologic abnormalities include a positive rheuma- toid factor. Eosinophilia may be present, particularly during early active phases, and may correlate with disease activity. A polyclonal IgG and IgM hypergamma- globulinemia may also be present and is found more often with severe cases and with clinical progression.6 Various modalities have proven effec- tive in the treatment of localized scle- roderma. Many of them have yet to be proven in controlled trials. These include topical/intralesional/systemic glucocorti- coids, antimalarials, etretinate, penicillin, D-penicillamine, phenytoin, vitamin E, griseofulvin, retinoids, interferon, calcit- riol, and methotrexate. Surgical excision of stable plaques is also an option. Ultraviolet A (UVA) phototherapy, with and without psoralens, and NB-UVB have both been shown effective in treating localized scle- roderma, including cases of en coup de sabre.7 We have presented a case of en coup de sabre that was successfully halted. The treatment of this disease was simple and efficacious when recognized and initiated early.
References: 1. David J, Wilson J. Scleroderma ‘en coup de sabre.’ Annals of the Rheumatic Diseases 1991;50: 260-262. 2. Peterson LS, et al. The epidemiology of morphea (local- ized scleroderma) in Olmsted County 1960-1993. J Rheu- matol 1997;24:73. 3. Soma Y, Fujimoto M. Frontoparietal scleroderma (en coup de sabre) following Blaschko’s lines. J Am Acad Dermatol 1998;38:366. 4. Amento EP. Immunologic abnormalities in scleroderma. Semin Cutan Med Surg. 1998;17:18. 5. Fujiwara H, et al. Detection of Borrelia burgdorferi DNA (B garinii or B afzelii) in morphea and lichen sclerosus et atrophicus tissues of German and Japanese but not of US patients. Arch Dermatol 1997;133:41. 6. Tuffanelli D. Localized scleroderma. Semin Cutan Med Surg 1998;17:27. 7. Hunzelmann N, et al. Management of localized sclero- derma. Semin Cutan Med Surg 1998;17:34.
20 EN COUP DE SABRE: A CASE REPORT AND DISCUSSION CASE REPORT: GRANULAR PARAKERATOSIS
+POBUIBO4$SBOF %0 '"0$% &SJO(SJGmO #4.4*** 1BUSJDJB)PPE 1"$ ,FMMZ#SJUU 1"$ 8BSSFO8IJUF .% %FSNBUPMPHJTUBU"UMBOUJD%FSNBUPMPHZ"TTPDJBUFT1" 8JMNJOHUPO /$ SEZFBSNFEJDBMTUVEFOUBU1JLFWJMMF$PMMFHF4DIPPMPG0TUFPQBUIJD.FEJDJOF 1JLFWJMMF ,: %FSNBUPMPHZ1IZTJDJBO"TTJTUBOUBU"UMBOUJD%FSNBUPMPHZ"TTPDJBUFT1" 8JMNJOHUPO /$ %FSNBUPMPHZ1IZTJDJBO"TTJTUBOUBU"UMBOUJD%FSNBUPMPHZ"TTPDJBUFT1" 8JMNJOHUPO /$ %FSNBUPQBUIPMPHJTUBU$PBTUBM$BSPMJOB1BUIPMPHZ1" 8JMNJOHUPO /$
ABSTRACT
Granular parakeratosis is a rare disorder characterized by hyperpigmented and hyperkeratotic plaques usually located in cutaneous folds. It is thought to be exacerbated by overuse of topical preparations as well as over-cleaning. We present a 52-year-old black female with axillary granular parakeratosis, along with the condition’s clinical manifestations.
*OUSPEVDUJPO underlying epidermis showed no significant atypia. These features indicated a diagnosis Northcutt et al.2 first described granular of granular parakeratosis. parakeratosis in 1991 as the presence of reddish-brown, hyperkeratotic papillae and Discussion plaques, with a size ranging from 3 to 4 millimeters, located in intertriginous areas. Axillary granular parakeratosis (AGP) The etiology of this condition is unknown, appears as erythematous, hyperpigmented, however; Northcutt postulated that a basic and hyperkeratotic plaques usually located defect existed in the processing of profilag- in the cutaneous folds. It is occasionally grin to filaggrin. Filaggrin’s role in the skin associated with pruritis and has been is to maintain the keratohyaline granules associated with excessive use of topical in the stratum corneum during cornifi- preparations including antiperspirants and Figure 1. An area of hyperkeratosis cation. Metze and Rutten1 later defended deodorants. This condition has also been underneath left axilla this hypothesis. The Ackerman Institute found in individuals who have not used of Dermatopathology in New York, over such products, as well as those with an a five-year period, processed 363,343 occlusive environment. Researchers have slides total, of which 18 were granular tried to link granular parakeratosis to obese parakeratosis (fewer than 1 out of 20,000 individuals, but there have been cases seen specimens), so this condition is said to be in slim patients as well. Due to the abun- extremely rare.3 We are presenting a patient dant postulated causes of AGP, the cause of with axillary granular parakeratosis seen in this skin lesion remains unknown. There our Wilmington, NC, office. have been approximately 40 case reports of this condition in the United States, and Case Report it has no sexual or racial association. Even though axillary granular parakeratosis has In January 2008, a 52-year-old black been reported in children, the majority of female presented complaining of a lesion cases have been reported in adults aged 40 Figure 2. Photo demonstrating in the left axilla. She claimed the area had to 50 years. thickened and parakeratotic corneum been present for one and a half months. From a histopathological point of view, with abundant purplish granules (100x The patient had no major deformities, was AGP demonstrates psoriasiform hyper- magnification) well developed, well groomed, and was in plasia, a thickened stratum corneum with no apparent distress. She denied both exces- retention of keratohyalin granules, and Cryotherapy has not been reported as an sive use of antiperspirants and excessive parakeratosis. Most pathologists report a effective treatment for axillary granular cleaning. She denied any allergies as well as well-developed granular layer and a sparse parakeratosis. any irritation with the rash. Upon physical lymphohistiocytic inflammatory infiltrate. examination, a linear hyperkeratotic area The retained granular layer sometimes Conclusions was seen underneath the left arm extending demonstrates focal vacuolization. A gran- three-quarters of the axilla. This area was ular parakeratosis confined to the follicle We have presented a case of axillary a scaly, raised plaque with a bluish-brown and a dermatophyte-related granular granular parakeratosis arising in a 52-year- discoloration (Fig. 1). No abnormalities parakeratosis have also been described. old black female. We have reviewed the of hair, nails, or teeth were observed. The A KOH preparation can be performed literature with regard to history, physical differential diagnosis included acanthosis in order to distinguish this condition from characteristics, and pathology. This condi- nigricans, linear epidermal nevus, and a a fungal infection. A skin biopsy with tion is considered to be rare; however, we verucca. correlation from the history and physical is feel it is more common than sited in the A biopsy was taken, and the remaining sufficient to diagnose AGP. literature as we have had eight biopsy- lesion was curetted off. The biopsy revealed The treatment regimen of this rare proven cases here in Wilmington, a town of a thickened and parakeratotic corneum condition consists of topical and/or oral fewer than 100,000 people. The patient was with abundant purplish granules. The retinoids, as well as topical corticosteroids. advised to limit use of topical preparations CRANE, GRIFFIN, HOOD, BRITT, WHITE 21 Figure 3. Parakeratotic plaques (200x magnification)
Figures 4a, 4b. One-month follow-up and excessive cleaning to the axilla. No topical preparations were used at this time, as the lesion was removed in its entirety by curettage.
References: 1. Metze D, Rütten A. Granular parakeratosis - a unique acquired disorder of keratinization. J Cutan Pathol. Aug 1999; 26(7):339-52. 2. Northcutt AD, Nelson DM, Tschen JA. Axillary granular parakeratosis. J Am Acad Dermatol. Apr 1991; 24(4):541- 4. 3. Scheinfeld NS, Mones J. Granular parakeratosis: pathologic and clinical correlation of 18 cases of gran- ular parakeratosis. J Am Acad Dermatol. May 2005; 52(5):863-7. [Medline].
22 CASE REPORT: GRANULAR PARAKERATOSIS SCHAMBERG’S DISEASE
3PCFSU"/PSNBO %0 .1) 4UFWFO/PEJOF 0.4*** -BLF&SJF$PMMFHFPG0TUFPQBUIJD.FEJDJOF #SBEFOUPO '-
Report of a Case: that has telangiectasias. Gougerot-Blum disease has lesions of Schamberg’s disease A 71-year-old Caucasian male presented along with lichenoid papules, plaques, and to the office with a complaint of dry, scaly macules. The last pigmented purpuric areas on the palm of his left hand and back dermatosis is Lichen aureus. It has few of his right hand. Both of his legs were patches that are rust colored, purple, or covered in scattered and coalesced brown golden, which arise from the extremities or macules along with a dry, scaly rash that from the trunk. continued from just below the knee all the Stasis dermatitis, on the other hand, is a way to his toes. He said that his skin-color chronic venous insufficiency disease that changes were not itchy, but made him feel results when venous blood fails to return self-conscious, and he had decided not to to the heart. It occurs over a long period wear shorts. He reported that the scaly of time due to venous incompetence of the Figure 1 rash on his legs did itch. lower extremities. The changes that occur The patient stated that the rash started are edema, hyperpigmentation, fibrosis of out as a number of bumps along the mid- the skin and subcutaneous tissue, along calf. The bumps then spread together and with ulceration. Stasis dermatitis occurs down his legs to include the feet and toes. around the lower leg and ankles, with He also said that he had recently noticed scaling and weeping patches. There are the rash spreading up toward his knees. inflammatory papules present with scaly The patient stated that he’d had a heart and crusty erosions. The prevention of attack several years ago and later noticed progression of hyperpigmentation of the the beginnings of this brown color change. lower extremities is accomplished by eleva- What distinguishes this case from stasis tion of the legs, the use of support hose, dermatitis, and did his heart attack play a and mild topical cortisone creams. This role in the development and exacerbation patient’s heart attack likely contributed of the disease? to the addition of stasis dermatitis to his Figure 2 Schamberg’s disease. Diagnosis: Differential Diagnosis: Stasis dermatitis, parapsoriasis, primary amyloidosis, senile Schamberg’s Disease purpura, lichen aureus, Gougerot-Blum disease, Majocchi’s disease. Discussion: Resources: Schamberg’s disease (progressive 1. Ball, Jane W., G. W. Benedict, Joyce E. Daines, and pigmented purpura, or PPP) is a slow, Henry M. Seidel. Mosby’s Guide to Physical Examination. progressive, purpuric dermatosis that is 5th ed. St. Louis: Mosby, 2003. 163-224. 2. Bolognia, Jean L., Joseph L. Jorizzo, and Ronald P. characterized by flat, petechial hemor- Rapini. Dermatology. Vol. 1. London: Mosby, 2003. 361- rhages. This disease is seen in children 363. 3. Gibson, Lawrence. “Schamberg’s Disease: How is It and on the lower legs of older men. Treated?” MayoClinic.com. 3 June-July 2007. Accessed Schamberg’s disease presents as lesions 12 Aug. 2007. http://www.mayoclinic.com/health/scham- bergs-disease/AN01104. that are irregular patches, red and brown 4. Johnson, Richard A., Dick Suurmond, and Klaus Wolff. in color, with superimposed, pinpoint Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatol- ogy. 5th ed. New York: McGraw-Hill, 2005. 136-137. cayenne-pepper macules. The discolor- ation is due to the leakage of blood from small blood vessels near the skin surface. The red lesions are newer hemorrhages, and the older lesions are brown in color. The brown color is due to the hemosid- erin deposits from the degradation of the extravascular erythrocytes. There are typi- cally no symptoms, although some people can experience itching and discomfort. There are three other types of pigmented purpuric dermatoses that are similar to Schamberg’s disease. Majocchi’s disease is an annular from of Schamberg’s disease
NORMAN, NODINE 23 MULTIPLE TRICHOEPITHELIOMAS, CYLINDROMAS, AND SPIRADENOMAS IN BROOKE-SPIEGLER SYNDROME: A UNIQUE CASE OF MALIGNANT TRANSFORMATION AND REVIEW
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
ABSTRACT
Brooke-Spiegler syndrome (BSS) is an autosomal dominantly inherited genodermatosis characterized by the concomitance of multiple trichoepitheliomas, cylindromas, and, rarely, spiradenomas.1 We present a rare case of BSS that demonstrates malignant transformation of trichoepitheliomas into basal-cell carcinomas, and review the theory set forth by Ackerman about the relationship between basal-cell carcinomas and trichoepitheliomas. A novel approach to treatment is presented also, and includes a discussion of genetic counseling, psychological therapy, and routine full-body skin examinations.
Report of a Case features, supported a diagnosis of BSS. cylindromas in a series of patients, which It is interesting to note that our patient suggested the occurrence of the tumors A 69-year-old Caucasian female initially presented with two special features: The within a single genetic entity, namely BSS. presented with a long-standing history of lesions were confined to her face, and she BSS presents most commonly during multiple, painless lesions on her face. She developed malignant degeneration of two the first and second decades of life5,26,27 reported that the lesions had developed trichoepitheliomas (Figs. 2 and 3), which and demonstrates a female predominance during adolescence and, subsequently, are rare findings. (2:1).5 To date, there appears to be no had increased in size and number. She epigenetic modifying factors, such as ethnic could not recall other family members who Discussion background or race, contributing to the were similarly affected, nor did she have disease. Although BSS is often a benign BSS is an autosomal dominantly inher- any children. Her past medical history disorder, it may have an unpredictable ited genodermatosis characterized by the was significant for chronic stable angina, course. Occasionally, de novo malignancies concomitance of multiple trichoepithe- currently treated with nifedipine. No or malignant transformations of existing liomas, cylindromas, and, rarely, spirade- significant family history or social history lesions occur. While there have been no nomas.1 Mutations affecting the CYLD gene was reported, though she did have a drug fatalities reported in the literature, the on chromosome 16q12-q13 cause BSS. A allergy to bacitracin. A review of systems development of any type of malignancy can was negative for preceding illness, recent unique feature of BSS is phenotypic vari- ability,2 and therefore any or all of these be a potentially life-threatening complica- weight loss or constitutional symptoms. lesions may be apparent at presentation, tion. Subsequently, an annual full-body Physical examination revealed a well- though the literature highlights a broad clin- skin examination should be completed, appearing patient with multiple flesh- ical spectrum. For instance, the presence of including inspection of the salivary and colored, smooth, round, papules on the spiradenocylindromas,3,4 trichoblastomas,8 parotid glands. In females, the gynecolo- mid face, ranging in size from 0.5cm to basal-cell carcinomas,9,10 follicular cysts,5-7 gist should be aware of the disease, as a case 1.5cm. Multiple lesions were grouped organoid nevi,5-7 psoriasis,11 and malignant report of invasive ductal breast carcinoma 22 around the nose and the nasolabial folds, degeneration of pre-existing tumors have has been indentified (however, no other and several were present on the ears and been observed.3,11-22, 35,39,40 Several forms cases of breast cancer have been reported eyebrows, bilaterally. The papules were of malignant parotid and salivary gland in association with BSS). Furthermore, non-tender and firm. The remainder of the tumors,15-21 as well as one case of invasive the size and number of lesions in those exam was essentially normal. There was ductal breast carcinoma,22 have also been affected by BSS increase with aging. Over no cervical lymphadenopathy. A clinical described as rare associations. time, the lesions can become progressively diagnosis of trichoepitheliomas was made A number of reports have defined the disfiguring and cause extreme discomfort. at that time. clinical picture of BSS, ultimately shaping In fact, many reports document exten- Over a span of 10 years, the patient our view of the entity as we see it today. sive development of cylindromas on the continued visiting our office for annual The inherited occurrence of cylindromas scalp, coalescing to form unsightly turban 5,26,28,29 total-body skin exams. Twenty-one facial and trichoepitheliomas was recognized in tumours. Severe facial alterations 2 lesions suspicious for skin cancers were the 1800s. Ancell in 1842 first described have also been documented. Infection, removed and sent for biopsy during this a family with inherited multiple scalp anemia secondary to chronic bleeding, and 13 timeframe. The histopathologic results tumors,23 later reviewed by Spiegler in a malodorous smell can also occur. of these biopsies are tabulated in Figure 1. 1897.24 Ancell-Spiegler cylindromas became Trichoepitheliomas, cylindromas, and Several lesions were consistent with basal- the eponym of these tumors, and currently spiradenomas are the primary lesions seen cell carcinoma and were removed with they are called cylindromas. In 1892, in patients with BSS. These skin appendage Mohs’ micrographic surgery, but benign Brooke described the features of inher- tumors are clinically similar, and therefore tumors were not treated. The combined ited trichoepitheliomas.25 Case reports a histological diagnosis is necessary. Both results of the pathologic examinations, postdating these initial findings noted the clinical and histological descriptions of the coupled with the constellation of clinical combination of trichoepitheliomas and lesions are provided here. 24 MULTIPLE TRICHOEPITHELIOMAS, CYLINDROMAS, AND SPIRADENOMAS IN BROOKE-SPIEGLER SYNDROME Figure 1: This table represents the anatomic location and histological diagnosis of each lesion taken from the patient. A diagnosis of BSS was made because of the 4 cases of trichoepitheliomas, 7 cases of cylindromas, and 1 case of spiradenoma. Of note, are the trichoepitheliomas seen on the nose, which demonstrated malignant transformation.
Biopsy Site Histopathologic Diagnosis Left Nasolabial Fold Lateral Trichoepithelioma Left Nasolabial Fold Medial Trichoepithelioma Left Lateral Cheek BCC Left Ear Cylindroma Figure 2: The superior lesion of the left NLF represents a BCC arising Nose BCC arising within Trichoepithelioma within a trichoepithelioma. The lesion directly inferior is a BCC. Left Nasolabial Fold Inferior BCC Left Nasolabial Fold Superior BCC arising within Trichoepithelioma unattached at the epidermis, can sometimes extend into the subcutis, and are formed by Right Medial Ear Cylindroma cords, islands, and/or sheets of cells. Small, Right Lateral Ear Cylindroma dark, basaloid cells with hyperchromatic nuclei and cells with large, pale, vesicular Right Eyebrow Superior BCC and ovoid nuclei are amongst the two types Right Eyebrow Inferior BCC of cells in the nodules. Strands of cells are positive for cytokeratin and carcinoembry- Nasal Tip Inferior Spiradenoma onic antigen.30 Nasal Tip Superior BCC One focus of discussion in the litera- ture surrounds the potential for malig- Left Chin BCC nant transformation of these lesions. Left Temple BCC Spiradenomas progress to malignancy most commonly, with more than 32 cases Right Nose BCC reported.12 About 12 cases of cancerous Right Infraauricular BCC cylindromas have been noted in the liter- ature,13-15,18,31-35 along with four cases of Right Inferior Eyebrow Cylindroma undifferentiated carcinomas3,39 and one Right Superior Eyebrow Cylindroma case of spiradenocarcinoma.40 Finally, malignant parotid gland tumors15-21 and Left Medial Cheek Cylindroma breast masses22 infrequently transform. Left Lateral Cheek Cylindroma One school of thought exists about the possible follicular origins of basal-cell Trichoepitheliomas are rounded, flesh- closely together, often resembling pieces carcinomas. Ackerman et al. postulated colored papules or nodules that are mainly of a jigsaw puzzle. Cytologic examina- that basal-cell carcinomas show follicular located on the nasolabial folds, nose, fore- tion shows two different populations of differentiation and therefore are related 41 head, upper lip, and scalp. Histologically, epithelial cells: smaller ones with little cyto- to trichoblastomas. Furthermore, these lesions characteristically reveal a plasm and a dark-staining nucleus mostly Ackerman uses the term trichoblastoma cribriform pattern of multiple nodules at the periphery of the lobule, and larger liberally in referencing any benign tumor derived from hair germ epithelium. The composed of uniform, basaloid cells, ones with a lighter-staining nucleus in the trichoepitheliomas of BSS would there- frequently with central, keratin-filled center.30 Cutaneous lesions are solitary, fore be considered trichoblastomas. Rarely, cysts, and the prominence of peripheral firm, rubbery nodules with pink, red, or trichoepitheliomas have been transformed palisading. A distinctive feature is the sometimes blue coloring. Cylindromas are into malignant basal-cell carcinomas in papillary-mesenchymal body, which is typically found on the head and neck, but BSS. To our knowledge, there are four essentially a fibroblastic aggregate resem- can also be seen spread diffusely over the 8,42,43 30 cases in the literature, two of which bling an abortive follicular papilla. It is body. The size of lesions is highly variable, have demonstrated aggressive metas- thought that trichoepitheliomas differen- and numerous masses can bunch on, or tases.42,43 Our patient underwent degen- tiate toward or derive from hair structures, completely encompass, the scalp (turban eration of two trichoepitheliomas into 24 particularly the hair bulge. tumors). basal-cell carcinomas, but also had nine The cellular origin of cylindromas also Preferentially, spiradenomas involve the basal-cell carcinomas in close proximity remains unknown because the tumor trunk and extremities, but can develop at to the malignant trichoepitheliomas. The demonstrates immunohistological and other anatomic sites, as was the case with transformations themselves and the close cytomorphological structures of many cell our patient, whose tumor appeared on the anatomical positioning of the transformed lines, though its cellular etiology has been nasal tip. Spiradenomas are usually gray, malignancies to the basal-cell carcinomas most frequently cited as being of apocrine pink, purple, red, or blue nodules of about may provide evidence in support of or eccrine delineation. Histopathology 1 centimeter diameter and seem to have Ackerman’s postulation. reveals multiple lobules of epithelial cells apocrine and trichoepitheliomatous differ- Given the clinical heterogeneity of cuta- that form some tubular structures with entiation. Spiradenomas consist of one or neous lesions seen in BSS, the differential lumina. The lobules contain eosinophilic more large, sharply delineated, basophilic diagnosis may initially appear vast. For globules and are surrounded by eosino- nodules in the dermis, resembling cannon instance, facial adenoma sebaceum, basal- philic membranes. These lobules lie balls or big blue balls. The nodules are cell carcinomas, sarcoidosis, microcytic SAITTA, HUGHES, IOFFE, WAY, MOBINI, BRANCACCIO 25 Figure 3 Basal cell carcinoma arising in association with a trichoepithelioma a. In one area of the specimen, there are aggregates of basaloid cells with formation of keratocysts and multiple papillary mesenchymal bodies. There is a fibroblastic stroma which exhibits clefting between its elements, consistent with a trichoepithelioma. b. In another area, there are aggregates of cells with hyperchromatic nuclei which exhibit peripheral palisading. Several mitotic figures are seen, consistent with a diagnosis of basal cell carcinoma. c. Individual cell necrosis is seen within the islands of basal cell carcinoma. adnexal carcinomas, trichoadenomas, been identified in families exhibiting both Aside from surgical or pharmacological infundibulomas, and basaloid follicular the MFT and the considerably heteroge- interventions, genetic counseling and hamartomas should be in a differential neous BSS phenotypes.6,49,53,54,55 psychological therapy may be discussed for trichoepitheliomas. However, the Finally, other studies have demonstrated with patients. Little attention has been existence of numerous lesions presenting that the clinical features of BSS, MFT, and given to these holistic treatment concepts simultaneously should raise suspicion for FC can be observed concurrently in a single in the literature, despite their clear impor- a genodermatosis or syndrome. With this patient or in multiple patients within a tance. The cosmetic repercussions of BSS notion in mind, multiple trichoepithe- single family.2,5,28,49,56 Taken as a whole, are great, as are the potential psychological liomas may be seen in Rombo syndrome this body of evidence supports the theory sequelae. Thus, involvement of proband and Bazex syndrome. Furthermore, other that this group of genodermatoses repre- family members in genetic counseling and genodermatoses present with multiple sents the phenotypic variability of a single screening for depression are strong recom- skin appendage tumors including familial disease.2,47,48,49 mendations. While we are on the cusp cylindromatosis (FC) and multiple familial The role of mutations to the CYLD gene of more promising treatments, there still trichoepithelioma (MFT). These diseases in producing such diverse phenotypes is remains a dearth of well-tested options for may clinically resemble BSS. Cylindromas still not completely understood; however, patients with BSS. are the only tumors that define FC, and it has been established that CYLD nega- Finally, the metastatic possibility of trichoepitheliomas are the only tumors that tively regulates nuclear factor κB (NF−κB) transformed trichoepitheliomas has been define MFT. In contrast, any or all of these through its interaction with tumor necrosis previously mentioned herein. Normally, lesions may be simultaneously apparent factor receptor associated factor-2 (TRAF- basal-cell carcinomas do not have a high in BSS, which makes the diagnosis diffi- 2),57 TRAF interacting protein (TRIP),58 rate of metastases, though currently metas- 44 cult. In our patient, the diagnosis was and Iκ kinase γ in the NF−κB signaling tases of basal-cell carcinomas arising in clear because she did in fact present with pathway.2,44,47,59,60 While NF−κB activation trichoepitheliomas has been shown in two all three lesion types. It should be stressed has been linked to a variety of neoplasms, out of five cases. To date, reports have not that if patients present with one type of the precise role it plays in adnexal tumori- used this knowledge in shaping a treatment tumor, it is difficult to discern these geno- genesis is still unclear.47 plan. Thus, it is our recommendation that dermatoses initially. There is no established treatment yearly full-body skin exams be an integral Although all of the factors underlying protocol for BSS. Although some lesions component in the care of patients with tumorigenesis in genodermatoses of skin do not require treatment, therapy may be BSS. appendages have yet to be completely eluci- desired to alleviate discomfort/bleeding and dated, recent decades have yielded tremen- for cosmesis. Treatments include surgical References: dous gains in our understanding of the removal, electrocoagulation, dermabra- 1. Kleine-Natrop HE. Simultaneous generalization of benign genetic underpinnings of these syndromes. basalioma of both Spiegler and Brooke types. Arch Clin sion, cryotherapy, trichloroacetic acid, CO2 Exp Dermatol. 1959;209:45-55. In fact, the most recent studies suggest that laser and erbium:YAG laser.26,29,39,45 One 2. Zhang G, Huang Y, Yan K, et al. Diverse phenotype of BSS, FC, and MFT, all of which demon- Brooke-Spiegler syndrome associated with a nonsense review article claims that the best treat- mutation in the CYLD tumor suppressor gene. Ex Der- strate mutations in the CYLD gene, may ment is surgical removal because of low matol. 2006;15:966-970. actually represent phenotypic variations of recurrence rates, but does not provide any 3. Michal M, Lemovec J, Mukensnabl P, et al. Spiradeno- 2,5,6,44,47,49 cylindromas of the skin: tumors with morphological fea- 40 a single disease process. figures. However, small clinical trials tures of spiradenoma and cylindroma in the same lesion: Originally, Biggs et al. used linkage report of 12 cases. Pathol Int. 1999;49:419-425 using CO2 laser and combination CO2 laser 4. Braun-Falco M, Hein R, Ring J. Cylindrospiradenomas analysis to show that predisposition to with erbium:YAG laser demonstrate no in Brooke-Spiegler syndrome. Hautarzt. 2001;21:1021- development of FC was associated with a recurrence for up to two years. Recently, 1025. 47,51 5. Guitierrez P, Eggermann T, Holler D, et al. Phenotype single locus on chromosome 16q12-q13. NF−κB factor inhibitors have been admin- diversity in familial cylindromatosis: a frameshift muta- Further studies utilizing positional cloning 46 tion in the tumor suppressor gene CYLD underlies dif- istered with promising results. These ferent tumors of skin appendages. J Invest Dermatol. and sequence analysis identified LOH pharmacological inhibitors are thought to 2002;119:527-531. germline mutations in the CYLD tumor be especially effective in BSS because the 6. Hu G, Onder M, Gill M, et al. A novel missense mutation 47,52 in CYLD in a family with Brooke-Spiegler syndrome. J suppressor gene in families with FC. genetic disturbance of the disorder results Invest Dermatol. 2003;121:732-734. More recently, CYLD mutations have also 45 7. Scheinfeld N, Hu G, Gill M, et al. Identification of a in an unopposed NF−κB activation. recurrent mutation in the CYLD gene in Brooke-Spiegler 26 MULTIPLE TRICHOEPITHELIOMAS, CYLINDROMAS, AND SPIRADENOMAS IN BROOKE-SPIEGLER SYNDROME syndrome. Clin Exp Dermatol. 2003;28:539-41. with follicular differentiation. New York: Ardor Scribendi; 8 Schulz T, Proske S, Hartschuh W, et al. High-grade 2001:625-1005. trichoblastic carcinoma arising in trichoblastoma. Am J 42. Sau P, Lupton P, Graham H. Trichogerminoma: a report Dermatopathol. 2005;27:9-15. of 14 cases. J Cutan Pathol. 1992;19:357-365. 9. Johnson S, Bennet R. Occurrence of basal cell carci- 43. Regauer S, Beham, Schmid C, et al. Trichoblastic car- noma among multiple trichoepitheliomas. J Am Acad cinoma (“malignant trichoblastoma”) with lymphatic and Dermatol. 1993;28:322-326. hematogenous metastases. Mod Pathol. 2000:13:673- 10. Viksnins P, Berlin A. Follicular atrophoderma and basal 678. cell carcinomas: the Bazex syndrome. Arch Dermatol. 44. Young L, Kellermayer R, Szigeti R, et al. CYLD muta- 1977;113:943-951. tions underlie Brooke-Spiegler, familial cylindromatosis, 11. Kostler E, Schonlebe J, Mentzel T, et al. Psoriasis and and multiple familial trichoepithelioma syndromes. Brooke-Spiegler syndrome with multiple malignancies. 45. Rallan D, Harland C. Brooke-Spiegler syndrome: treat- 12. Ishikawa M, Nakanishi Y, Yamazaki N, et al. Malignant ment with laser ablation. Clin and Exper Dermatol. eccrine spiradenoma: a case report and review of the 2005;30:355-357. literature. Dermatol Surg 2001;27:67-70. 46. Trompouki E, Hatzivassiliou E, Tsichritizi T, et al. CYLD 13. Francesco V, Frattasio A, Pillon B, et al. Carcinosarcoma is a deubiquitinating enzyme that negatively regulates arising in a patient with multiple cylindromas. Am J Der- NF-kB activation by TNFR family members. Nature. matopathol. 2005;27:21-26. 2003;424:793-796. 14. Durani B, Kurzen H, Jaeckel A, et al. Malignant transfor- 47. Lee DA, Grossman ME, Schneiderman P, Celebi JT. mation of multiple dermal cylindromas. Br J Dermatol. Genetics of skin appendage neoplasms and related syn- 2001;145:653-656. dromes. J Med Genet 2005;42:811-819. 15. Antonescu R, Terzakis A. Multiple malignant cylindromas 48. Heinritz W, Grunewald S, Strenge S, Schütz A, Froster of skin in association with basal cell adenocarcinoma with UG, Glander HJ, Paasch U, Simon JC. A case of adenoid cystic features of minor salivary gland. J Cutan Brooke-Spiegler syndrome with a new mutation in the Pathol 1997;24:449-453. CYLD gene. Brit J of Derm 2006;154:992-994. 16. Jungehulsing M, Wagner M, Damm M. Turban tumor 49. Bowen S, Gill M, Lee DA, Fischer G, Geronemus RG, with involvement of the parotid gland. J Laryngol Otol Espinel Vazquez ML, Celebi JT. Mutations in the CYLD 1999;113:779-783. gene in Brook-Spiegler syndrome, familial cylindroma- 17. Hyma B, Scheithauer B, Weiland L, et al. Membranous tosis, and multiple familial trichoepithelioma: lack of basal cell adenoma of the parotid gland: malignant trans- genotype–phenotype correlation. J Invest Dermatol formation in a patient with multiple dermal cylindroma. 2005;124:919-920. Arch Pathol Lab Med. 1988;112:209-211. 50. Fenske C, Banerjee P, Holden C, Carter N. Brooke- 18. Rockerbie N, Solomon A, Woo T, et al. Malignant dermal Spiegler syndrome locus assigned to 16q12-q13. J cylindroma in a patient with multiple dermal cylindromas, Invest Dermatol 2000;?:1057-1058. trichoepitheliomas, and bilateral dermal analogue tumors 51. Biggs PJ, Wooster R, Ford D, Chapman P, Mangion of the parotid gland. Am J Dermatopathol. 1989;11:353- J, Quirk Y, Easton DF, Burn J, Stratton MR. Familial 359. cylindromatosis (turban tumor syndrome) gene localized 19. Alawi M, Hobby J, Lesna M. Familial dermal cylindroma to chromosome 16q12-q13: evidence for its role as a with involvement of the parotid gland. Br J Plast Surg. tumour suppressor gene. Nat Genet 1995;11:441-443. 1982;35:167-170. 52. Bignell GR, Warren W, Seal S, Takahashi M, Rapley E, 20. Ferrandiz C, Campo E, Bauman E. Dermal cylindromas Barfoot R, Green H, Brown C, Biggs PJ, Lakhani SR, (turban tumor) and eccrine spiradenomas in a patient with Jones C, Hansen J, Blair E, Hofmann B, Ouweland A, membranous basal cell adenoma of the parotid gland. J Halley D, Delpech B, Cleveland MG, Leigh I, Leisti J, Cutan Pathol. 1985;12:72-79. Rasmussen S. Identification of the familial cylindroma- 21. Headington J, Batsakis J, Beals T, et al. Membranous tosis tumour-suppressor gene. Nat Genet 2000;25:160- basal cell adenoma of parotid gland, dermal cylindromas, 165. and trichoepitheliomas: comparative histochemistry and 53. Zhang XJ, Liang YH, He PP et al. Identification of the ultrastructure. Cancer. 1977;39:2460-2469. cylindromatosis tumor suppressor gene responsible for 22. Nonaka D, Rosai J, Spagnolo D, et al. Cylindroma of the multiple familial trichoepithelioma. J Invest Dermatol breast of skin adnexal type: a study of 4 cases. Am J 2004;122:658-664. Surg Pathol. 2004;28:1070-1075. 54. Salhi A, Bornholdt D, Oeffner F et al. Multiple familial 23. Ancell H. History of a remarkable case of tumors devel- trichoepithelioma caused by mutations in the cylindroma- oped on the head and face: accompanied with a similar tosis tumor suppressor gene. Cancer Res 2004;64:5113- disease in the abdomen. Medico-Chirurgical Transac- 5117. tions. 1842;25:227-246. 55. Zeng G, Hu L, Huang W et al. CYLD mutation causes 24. Spiegler E. Ueber Endoteliome der Haut. Arch of Derma- multiple familial trichoepithelioma in three Chinese fami- tol Syphiol. 1899;50:163-176. lies. Hum Mutat 2004;23:400. 25. Brooke H. Epithelioma adenoides cysticum. Br J Derma- 56. Gerretsen AL, Beemer FA, Deenstra W, Hennekam tol. 1892;4:296-286. FA, van Vloten WA. Familial cutaneous cylindromas: 26. Martins C, Bartolo E. Brooke-Spiegler syndrome: treat- investigations in five generations of a family. J Am Acad ment of cylindromas with CO2 laser. Dermatol Surg. Dermatol 1995;33:199-206. 2000;26:877-881. 57. Brummelkamp TR, Nijman SM, Dirac AM, Bernards 27.Retamar R, Stengel F, Saadi M, et al. Brooke-Spiegler R. Loss of the cylindromatosis tumor suppressor syndrome: report of four families: treatment with CO2 inhibits apoptosis by activating NF-kappaB. Nature laser. Int J Dermatol. 2007;46:583-586. 2003;424:797-801. 28. Saunders H, Tucker P, Saurine T, Watkins F. Pedigree 58. Regamey A, Hohl D, Liu JW, Roger T, Kogerman P, of multiple benign adnexal tumors of Brooke-Spiegler Toftgard R, Huber M. The tumor suppressor CYLD inter- type. Aust J of Dermatol. 2003;44:144-148. acts with TRIP and regulates negatively nuclear factor 29. Szepietowski J, Wasik F, Szybejko-Machaj G, Bieniek kappaB activation by tumor necrosis factor. J Exp Med A, Schwartz R. Brooke-Spiegler syndrome. JEADV. 2003;198:1959-64. 2001;15:346-349. 59. Trompouki E, Hatzivassiliou E, Tsichritzis T, Farmer 30. Weedon D, Strutton G. In: Weedon D, Strutton G, eds. H, Ashworth A, Mosialos G. CYLD is a deubiquinating Skin pathology. New York: Churchill Livingstone. 2002: enzyme that negatively regulates NF kappaB activation 861,890-892. by TNFR family members. Nature 2003;424:793-6. 31. Gerrestsen A, Van der Putte S, Deenstra W et al. Cuta- 60. Kovalenko A, Christine CB, Cantarella G, Israel A, Wal- neous cylindromas with malignant transformation. Can- lach D, Courtois G. The tumor suppressor CYLD nega- cer. 1993;72:1618-1623. tively regulates NF κB signaling by deubiquitination. 32. Lyon J, Rouillard L. Malignant degeneration of turban Nature 2003;424:801-805. tumors of the scalp. Trans St John’s Hosp. Dermatol Soc. 1961;46:74-77. 33. Tsambaos D, Greither A, Orfanos C. Multiple malignant Spiegler tumors with brachydactyly and racket nails. J Cutan Pathol. 1979;49:31-41. 34. Lotem M, Traftner A, Kahanovich S, et al. Multiple der- mal cylindromas undergoing a malignant transformation. Int J Dermatol. 1992;31:642-644. 35. Beideck M, Kuhn A. Malignant transformation of cutane- ous cylindromas: 2 case reports and a review of the literature. Z Hautkr. 1985;60:73-78. 36. Pizinger K, Michal M. Malignant cylindroma in Brooke- Spiegler syndrome. Dermatology. 2000;201:255-257. 37. Iyer P, Leong A. Malignant dermal cylindromas: do they exist? A morphological and immunohistochemical study and review of the literature. Pathology. 1989;21:269-274. 38. Ayhan M, Adanali G, Senen D, et al. Rarely seen cuta- neous trichoepithelioma. Ann Plast Surg. 2001;47:98-9. 39. Weyers W, Nilles M, Eckert F, et al. Spiradenoma in Brooke-Spiegler syndrome. Am J Dermatopathol. 1993;15:156-161. 40. Kakagia D, Alexiadis G, Kiziridou A, et al. Brooke- Spiegler syndrome with parotid gland involvement. Eur J Dermatopathol. 2004;14:139-141. 41. Ackerman B, Reddy B, Soyer P. Trichoblastic carcinoma. In: Ackerman B, Reddy B, Soyer P, eds. Neoplasms
SAITTA, HUGHES, IOFFE, WAY, MOBINI, BRANCACCIO 27 SPIRADENOCARCINOMA: A CASE REPORT
"NBSB4BZFE %0 '"$0'1 -BZOF%/JTFOCBVN %0 '"0$% 'JSTUZFBS%FSNBUPMPHZ3FTJEFOU $PMVNCJB)PTQJUBM 8FTU1BMN#FBDI '- 1SPHSBN%JSFDUPS $PMVNCJB)PTQJUBM 8FTU1BMN#FBDI '- *TMBOE%FSNBUPMPHZ -BTFSBOE"OUJ"HJOH*OTUJUVUF 1BMN#FBDI '-
ABSTRACT
Spiradenocarcinoma is a rare tumor typically arising from a preexisting spiradenoma.9 Some authors consider it to be of eccrine origin, while others believe it is apocrine.2,11 It is an aggressive, often fatal tumor that frequently presents with metastasis at the time of diagnosis.7,8 This is a case of a 59-year-old female with a changing nodule on the upper extremity.
Case Report may be rendered late in the course as a long-standing stable lesion may be ignored A 59-year-old, African American female by the patient and clinician. Metastasis presented with a changing nodule on her to the regional lymph nodes may occur, left upper arm. The patient was previously and a sentinel lymph node biopsy may evaluated by a plastic surgeon and refused be required.7 Patient mortality has been excision at that time. She was then evalu- reported in up to 20% of cases.8 ated by a dermatologist, and two punch The most common areas of presenta- biopsies (4mm and 5mm) were performed. tion include the trunk and extremities; Routine histology revealed a markedly however, case reports documenting less atypical neoplasm with features of a malig- likely sites have been reported. Russ et al. nant adnexal tumor (Figures 1, 2, 3). The report a case of a spiradenocarcinoma of differential diagnosis included seroma and the scalp, which was treated with MOHS Fig.1: Low Power H&E spiradenoma. micrographic surgery.11 Meyer et al. report a case of an eccrine spiradenocarci- Histology noma of the external auditory canal. And Ribiero-Silva et al. report a case of breast Immunohistochemistry was performed, spiradenocarcinoma.6 revealing positive expression for cytok- Histologically, the tumor displays a carci- eratin 7 throughout the neoplasm and focal nomatous area in combination with benign positivity for epithelial membrane antigen features of spiradenoma.7,8 Spiradenomas (Figures 4, 5). Studies with S-100 protein exhibit two cell populations, which are showed aggregates of cells expressing the often lost with malignant transformation.7,8 antigen, a feature that is typical of spirade- Other distinguishing features of malig- noma (Figure 6). A proliferation marker, nancy include hyperchromasia, an increase Ki-67, was also used and revealed areas of in nuclear to cytoplasmic (N:C) ratio, and high labeling index, usually not evident in 4,6 increased mitotic activity (Ki-67). This Fig. 2: High Power H&E spiradenomas (Figure 7). tumor stains with epithelial markers and Patient follow-up: Unfortunately, the may show positivity with S-100.8 This case patient refused any further work-up or did show S-100 positivity, a typical feature treatment despite being counseled on the of spiradenoma; however, the tumor also dangerous nature of her diagnosis and was showed positive staining with epithelial lost to follow-up. membrane antigen (EMA), which stains adenocarcinomas. There are some reports Discussion that the p53 suppressor oncogene is expressed by the malignant portion of the Spiradenocarcinoma is a rare, aggres- tumor, and p53 immunostaining may be sive adnexal tumor that often arises from 5,9 useful in distinguishing the carcinomatous a long-standing, benign spiradenoma. component of the tumor.2,5 The pathology Less than 30 cases have been docu- in this case did not require further studies mented in the literature, and the earliest with p53 immunostaining, as other markers Fig. 3: H&E, high power showing duct- reported case was published by Dabaska in were positive. 1972.1,2,4,5 Middle age and elderly patients like structures are most commonly affected.8 Patients Summary who develop malignant transformation ties are the most commonly involved from a pre-existing benign neoplasm relay In summary, spiradenocarcinoma is a sites; however, other sites have also been a history of rapid growth of a previously rare, aggressive tumor often evolving reported. Follow-up requires excision of long-standing nodule or plaque. Bleeding from a pre-existing benign lesion. The the lesion and possible sentinel lymph node and ulceration are other common clinical prognosis may be poor, as discovery of the biopsy. 3 findings. Spiradenocarcinoma is a poorly tumor occurs late. The trunk and extremi- differentiated carcinoma, and a diagnosis 28 SPIRADENOCARCINOMA: A CASE REPORT References: 1. Biernat W, Kordek R, Wozniak L. Over-expression of p53 protein as an indicator of the malignant transformation in spiradenoma. Histopathology 1995;26:439-443 2. Biernat W, Wozniak L. Spiradenocarcinoma: A clinoco- pathologic and Immunohistochemical Study of Three Cases. The American Journal of Dermatopathology 16(4): 377-382 3. Bolognia J, Jorizzo J, Rappini R. Dermatology. Mosby, 2007. 1733-1755 4. Dabaska M. Malignant transformation of eccrine spirade- noma. Pol Med J 1972; 11:388-396 5. Delendi M, Puglisi F, Della Mea, Riberti C, Osti M, Parodi PC. Spiradenocarcinoma: morphological and immunohis- tochemical features. Adv Clin Path. 1997 Oct;1(4):287- 291. 6. Elder D, Elenitsas R, Johnson B, Murphy G. Lever’s His- topathology of the Skin. 2005. 903-905. Fig.4: Immunohistochemistry showing 7. Fitzpatrick Fitzpatrick’s Dermatology in General Medicine positive staining with cytokeratin 7 (6th Edition). Freedberg I, Eisen A, Wolff K, Austen KF, Goldsmith L, Katz S, eds. McGraw-Hill, 2003. 8. Granter SR, Seeger K, Calonje E, Busam K, McKee PH. Malignant eccrine spiradenoma (spiradenocarcinoma): a clinicopathologic study of 12 cases. [Journal Article] American Journal of Dermatopathology. 22(2):97-103, 2000 Apr. 9. Meyer TK, Rhee JS, Smith MM, Cruz MJ, Osipov VO. Wackym PA. External auditory canal eccrine spiradeno- carcinoma: a case report and review of literature. Head & Neck. 25(6):505-10, 2003 Jun. 10. Ribeiro-Silva A, Shaletich C, Careta RS, Kazava DK, Siqueira MC, Ponton F. Spiradenocarcinoma of the breast arising in a long-standing spiradenoma. Annals of Diagnostic Pathology. 8(3):162-6, 2004 Jun. 11. Russ BW, Meffert J, Bernert R. Spiradenocarcinoma of the scalp. Cutis. 69(6):455-8, 2002 Jun.
Fig. 5: Immunohistochemistry showing positive focal staining with EMA
Fig. 6 Immunohistochemistry showing aggregates of cells staining positive with S-100 protein
Fig. 7 Immunohistochemistry showing areas of proliferation with Ki-67
SAYED, NISENBAUM 29 A CASE REPORT: OSLER-WEBER-RENDU DISEASE
,SJOB,$IBWEB %0 4IBSJ4QFSMJOH %0 .BSWJO8BUTLZ %0 %FSNBUPMPHZ3FTJEFOU TUZFBS 4U+PIOT&QJTDPQBM)PTQJUBM 'BS3PDLBXBZ /: 1(:'BNJMZQSBDUJDFQSPHSBN 4U+PIOT&QJTDPQBM)PTQJUBM /: 1SPHSBN%JSFDUPS 4U+PIOT&QJTDPQBM)PTQJUBM 'BS3PDLBXBZ /:
ABSTRACT
Osler-Weber-Rendu disease, also referred to as hereditary hemorrhagic telangiectasia (HHT), is an autosomal-dominant disorder characterized by telangiectasis, aneurysms, and arteriovenous malformations. The reported prevalence of this disorder is one to two cases per 100,000 people. The patient’s skin, mucosa, and blood vessels of the lung, liver, and central nervous system can be affected.1 We describe a 62-year-old man who presented with multiple pin-point, non-pulsatile telangiectases on his face, lips, oral cavity, palms and soles. His family history is significant for premature death of his father due to cerebral hemorrhage; his father also suffered recurrent nosebleeds throughout his life. Although our patient was never diagnosed with HHT, based on diagnostic criteria we strongly believe he carries a diagnosis of Osler-Weber-Rendu disease, also known as HHT. Case Report: year of life if associated with congenital pulmonary arteriovenous malformations. A 62-year-old Caucasian man presented It has a wide range of prevalence, as many with a complaint of “multiple red dots” on as one to two cases in per 100, 000 people his face (Fig. 1), tongue (Fig. 2), palms (Fig. in the United States, with an increased inci- 3) and soles for over 30 years. On further dence of one in 16,500 in Vermont , one in questioning, he admitted having frequent 5,000 in Europe, one in 8,000 in Japan , and nose bleeds, more than six times a year. His one in 1,330 in Afro-Caribbean residents of father also suffered from recurrent nose Curacao and Bonaire.1 bleeds, and he died of a cerebral hemor- The diagnosis of HHT is based on the rhage at the age of 58 years. On physical following four criteria, with three criteria exam, he was found to have multiple pin- making a definite diagnosis and two point, non-pulsatile telangiectases on his criteria a possible diagnosis.2 The criteria Fig.1 Telangiectasia on face face (Fig. 1), lips, oral cavity (Fig. 2), palms include: spontaneous or recurrent nose- (Fig. 3) and soles. Laboratory examination bleeds; multiple telangiectases on the lips, results included: hemoglobin 12.8 g/dl and oral cavity, fingers and nose; presence of hematocrit 34%; white-blood-cell count, internal lesions such as pulmonary, hepatic, platelet count, sedimentation, serum elec- spinal or cerebral AVMs or gastrointestinal trolyte levels, liver function and coagulation telangiectasia; and a first-degree relative tests were within normal levels, and a hepa- with HHT according to these criteria.2 titis panel was negative. Upper gastrointes- Epistaxis is the most common manifesta- tinal endoscopy, pulmonary bronchoscopy, tion and occurs in 90% of affected patients, abdominal ultrasonography as well as brain with blood transfusions required in 10-30 CT and MRI revealed normal findings. % of patients.2 Recurrent, painless gastro- intestinal bleeding occurs in 10-40% of Discussion: patients in the fourth or fifth decade of life.2 Telangiectases occur throughout the Fig.2 Telangiectasia on tongue and lips Osler-Weber-Rendu disease was first gastrointestinal tract, more commonly in recognized in the 19th century with the stomach or duodenum than the colon.2 abnormal vascular structures causing Telangiectasia of the skin and buccal bleeding from the nose and gastrointestinal mucosa occurs in 75% of patients after the tract. Rendu, Osler, Weber and Hanes later age of 20 and increases in number and size described it, and Hanes suggested the name with age.2 Telangiectases often occur one hereditary hemorrhagic telangiectasia year after the first episode of epistaxis and (HHT). Abnormal vessels, particularly are rarely seen before puberty. arteriovenous malformations (AVMs) of Pulmonary AVMs are present in 15-20% the pulmonary, hepatic and cerebral circu- of patients with HHT.3 They are thin- lations, were described with HHT in the walled, abnormal vessels that provide a 1940s.1 direct communication between the venous Hereditary hemorrhagic telangiectasia and arterial circulation, leading to right- is comprised of epistaxis, gastrointestinal to-left shunts, hypoxemia, and secondary Fig. 3 Telangiectasia on palm bleeding and iron-deficiency anemia asso- polycythemia.3 Dyspnea is a common ciated with characteristic telangiectases 1 complaint in those with pulmonary AVM and migraine headaches. of the lips, oral mucosa and fingertips. and may be due to high-output heart Symptoms typically present by the third 3 Eight to 12% of patients have neuro- failure. Other symptoms of pulmonary logical involvement with cerebral or decade of life, with recurrent epistaxis AVM include hemoptysis from telangi- developing prior to the second decade. spinal-cord telangiectases, cerebral AVMs, ectasia of the trachea or bronchi, which aneurysms or cavernous angiomas.4 This HHT may be diagnosed within the first may occur in the third or fourth decade,
30 A CASE REPORT: OSLER-WEBER-RENDU DISEASE can lead to headache, seizure, and isch- that is generally avoided. Treatment for 2. Shovlin CL, Guttmacher AE, Buscarini E, et al. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu- 4 emia. Untreated patients have a 2% risk epistaxis is generally reserved for those Osler-Weber syndrome). Am J Med Genet 2000; 91(1): of stroke and a 1% risk of brain abscess.4 patients experiencing massive hemor- 66-7 3. Kjeldsen AD, Oxhoj H, Andersen PE. Pulmonary arterio- Hepatic involvement occurs in up to 30% rhages or having daily episodes of epistaxis. venous malformations: screening procedures and pulmo- of patients, with portal hypertension, Treatments include arterial ligation, septo- nary angiography in patients with hereditary hemorrhagic telangiectasia. Chest 1999 Aug; 116(2): 432-9 biliary disease, right upper-quadrant pain, dermoplasty and, in severe cases, unilateral 4. Kikuchi K, Kowada M, Sasajima H. Vascular malforma- and cirrhosis. or bilateral surgical closure of the nostril tions of the brain in hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber disease). Surg Neurol 1994 May; Physical examination is characteristic for or nasal-septum using skin grafts from the 41(5): 374-80 lower trunk.6 Treatment of telangiectasic 5. Gu Y, Jin P, Zhang L, et al. Functional analysis of muta- telangiectases on the skin, oral and nasal tions in the kinase domain of the TGF-beta receptor ALK1 mucosa, conjunctiva, trunk, forearms, skin lesions includes laser ablation by pulse reveals different mechanisms for induction of hereditary 1 dye laser.7 hemorrhagic telangiectasia. Blood 2006 Mar 1; 107(5): hands and fingers. Skin lesions begin as 1951-4 punctate, non-pulsatile vascular papules Short-term control of gastrointestinal 6. Haitjema T, Westermann CJ, Overtoom TT, et al. Heredi- tary hemorrhagic telangiectasia (Osler-Weber-Rendu dis- or dark red lines. Rarely, skin lesions bleeding may include the use of endoscopic ease): new insights in pathogenesis, complications, and are pulsatile, star-shaped and 1-3 mm in ablation of lesions, although results are not treatment. Arch Intern Med 1996 Apr 8; 156(7): 714-9 6 7. Harries PG, Brockbank MJ, Shakespeare PG, Carruth diameter. All of the mucus membranes are as good as in the non-HHT population. JA. Treatment of hereditary haemorrhagic telangiecta- invariably involved. Recurrent epistaxis Iron-deficiency anemia is treated with oral sia by the pulsed dye laser. J Laryngol Otol 1997 Nov; leads to fatigue and anemia, while pulmo- iron supplementation. Pulmonary AVMs 111(11): 1038-41 nary AVM leads to fistulae, dyspnea, should be treated with embolotherapy, cyanosis and clubbing of the fingers.3 while cerebral AVMs should be treated with HHT subtype 1 (HHT1) is caused by embolectomy, surgical removal or stereot- a mutation on chromosome 9, endoglin; actic radiotherapy.6 Liver transplantation HHT2 is caused by a chromosome 12, is the treatment of choice if medical treat- activin receptor-like kinase 1 (ALK-1) ment fails for hepatic AVMs.6 mutation.5 Endoglin and ALK-1 encode Hormonal therapy, including the use of proteins that are expressed on vascular estrogen, tamoxifen, danazol, octreotide, endothelial cells. ALK-1 is a transforming desmopressin, aminocaproic acid and growth factor (TGF) beta type 1 receptor, tranexamic acid, has been shown to be and endoglin associates with different beneficial in the treatment of recurrent signaling receptors and can modify TGF-1 bleeding secondary to gastrointestinal and beta signaling. Abnormal vessels in HHT nasopharyngeal AV malformations.6 Oral develop because of aberrant TGF-beta contraceptives have been shown to be more signaling during some stage in vascular effective than estrogen alone for mucosal development.5 bleeding.6 There are no widely available lab studies Pregnancy has an associated risk poten- to confirm the diagnosis, but there are a tial in women with HHT, but the majority few that suggest the diagnosis of HHT. of pregnancies are uneventful. Many Complete blood count may show decreased anesthetists will not perform an epidural hemoglobin with an iron-deficiency analgesia in women with HHT since anemia, thrombocytopenia and poly- 1-2% of patients with HHT have spinal cythemia due to chronic hypoxemia.2,6 AVMs. Some studies have also shown that Urine and stool should be evaluated for epistaxis and telangiectases may worsen hematuria and melana.6 An arterial blood throughout pregnancy. Pulmonary AVMs gas (ABG) will show a low pO2 if there is will enlarge during pregnancy, so women a right-to-left shunt. The hyperoxic test with HHT should be screened for pulmo- with the ABG confirms the diagnosis of nary AVM before pregnancy. Any hemop- a pulmonary AVM. In another test, the tysis during pregnancy is considered a patient is put on 100% oxygen and the arte- medical emergency and requires prompt rial partial pressure of oxygen is measured. hospitalization.6 Normally, with 100% oxygen, the partial Most patients with HHT have a favorable pressure should rise significantly, but in the prognosis, with the prognosis depending presence of a shunt it only rises minimally.3 on the degree of systemic involvement. MRI is the best noninvasive imaging Only 10% of patients die from complica- study to view the extent of pulmonary tions. Patients with HHT should be care- and central nervous system AVMs. Chest fully monitored by their physician and radiography may show a peripheral, non- specialists according to the organ system calcified coin lesion attached by vascular involved. strands to the hilus.3 Colonoscopy shows In summary, since our patient meets telangiectases as small, well-defined lesions three out of four criteria to make a diag- surrounded by an anemic halo.1 Although nosis of HHT, which includes recurrent the diagnosis is made on clinical findings, nosebleeds; multiple telangiectasias on the a skin punch biopsy may be helpful in the lips, oral cavity, face and palms; and a first- diagnosis. Dilated capillaries and new degree relative with possible diagnosis of vessel formation in the dermal upper hori- HHT, in our experience he carries the defi- zontal plexus are the classic features.6 nite diagnosis of HHT. One-third of cases of HHT are mild, one-third moderate, and one-third severe. References: 6 Mild cases may need no treatment. 1. Peery WH. Clinical spectrum of hereditary hemorrhagic Cauterization may damage the nasal telangiectasis (Osler- Weber-Rendu disease). Am J Med mucosa, leading to vascular re-growth, so 1987;82:989 -997 CHAVDA, SPERLING, WATSKY 31 TREATMENT OF LICHEN AMYLOIDOSIS WITH THALIDOMIDE – A CASE REPORT
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
ABSTRACT
Amyloidosis is caused by the deposition of amyloid, a proteinaceous fibril material. Lichen amyloidosis is the most common presentation of primary cutaneous amyloidosis. Clinical presentation involves discrete red-brown pruritic papules, sometimes with keratotic scale, that coalesce into reticulated plaques. We present a case of 75-year-old woman with a 10-year history of a pruritic rash on her trunk and extensor surfaces of her extremities. Examination showed hyperpigmented papules coalescing into plaques covering her trunk, and reticulated plaques along her extremities. Biopsy demonstrated eosinophilic aggregates of amorphous material, and crystal violet stained focally positive for amyloid. After failing other regimens, the patient was started on thalidomide in addition to triamcinolone cream. After three months of treatment, the patient reported less pruritus, and examination showed a less extensive area of involvement. Thalidomide may have promise in the treatment of cutaneous amyloidosis. In our patient, treatment was well tolerated, and there was improvement in cutaneous findings.
*OUSPEVDUJPO amyloid deposits are thought to be derived amorphous material in the superficial from degenerated keratin peptides of portion of the dermis, with cleft formation Amyloidosis is a depositional disorder, apoptotic keratinocytes, transformed into and pigment in the dermal macrophages. classified as a systemic or cutaneous disease, amyloid fibrils by dermal macrophages Additionally, the crystal violet stain was and is caused by the deposition of amyloid, and fibroblast.5,16-17 Treatment is primarily focally positive for amyloid. A complete a proteinaceous fibril material. The symptomatic, with a target goal of control- blood count, complete metabolic panel, primary cutaneous forms are subdivided ling pruritus. Overall, treatment of lichen thyroid stimulating hormone and chest into macular amyloidosis, lichen amyloi- amyloidosis is challenging and often X-ray were within normal limits. dosis (papular) and nodular amyloidosis.1 unsatisfactory. The patient failed a course of Atarax Lichen amyloidosis is the most common Typical histology shows acanthosis, (hydroxyzine) 25mg daily and triamcino- presentation of primary cutaneous amyloi- hyperkeratosis, and amyloid deposits in lone 0.1% cream. She was subsequently dosis (PCA), comprising 67% of the diag- the papillary dermis that may displace the started on thalidomide 100mg daily in nosed cases.2 Clinical presentation involves elongated rete ridges laterally. Pigment addition to the triamcinolone 0.1% cream. discrete red-brown pruritic papules, some- incontinence within melanophages and After three months of treatment, the patient times with keratotic scale, that coalesce into a sparse perivascular lymphohistiocytic reported less pruritus, and physical exami- reticulated plaques, mostly presenting on infiltrate are seen as a reticulated pattern. nation showed the area of involvement to the extensor surfaces of the lower legs and On hematoxylin and eosin stained sections, be less extensive (Figure 2). The patient’s arms.3-5 This condition is most prevalent in homogenous, hyaline, and eosinophilic thalidomide was decreased to 50mg daily, middle-aged people of Chinese descent and deposits are seen. Special stains such as but the patient was subsequently lost to with skin phototypes III and IV.6-13 While crystal violet and Congo red have been follow-up. in most cases it is idiopathic, the condi- shown to stain best for lichen amyloidosis. Upon further contact, months following tion has been associated with numerous her previous visit, the patient reported 6-13 connective-tissue diseases. It is also Case Report discontinuing the thalidomide and, within 14 more common in females than in males. days, a worsening of her cutaneous find- Other associations with primary cuta- A 75-year-old woman of Indian descent ings and pruritus. She returned and was neous amyloidosis include: pachyonychia presented with a 10-year history of a restarted on therapy. At the time of her congenital, dyskeratosis congenital, familial pruritic rash on her trunk and extensor return, the lichenoid component was less palmoplantar keratoderma, scleroderma, surfaces of her extremities. She had an evident, with flattening of the lesions SLE, dermatomyositis, primary biliary initial biopsy that was uninformative. She (Figure 2). cirrhosis, and Sipple syndrome (MEN 2a). was treated unsuccessfully in the past with The differential diagnosis for lichen topical steroids and UVB. Discussion amyloidosis includes hypertrophic lichen Examination showed hyperpigmented planus, lichen simplex chronicus, and papules coalescing into plaques covering The treatment of cutaneous amyloidosis papular mucinosis, making diagnosis chal- her back and upper chest, and reticu- is often challenging. Reducing skin fric- lenging for healthcare providers. The exact lated plaques along the extensor surfaces tion -- breaking the rubbing/scratching etiology of amyloid deposition is unknown, of her arms and legs (Figure 1). The cycle -- is paramount.15 Occlusion plays a but the favored theory is that epidermal patient denied systemic symptoms such role in penetration for topical treatments trauma induced by chronic scratching and as neuropathy, and her vital signs were and in blocking trauma. Though the bulk rubbing results in keratinocyte degradation within normal limits. Repeated biopsies of evidence and treatment experience is and formation of amyloid.15 Cutaneous demonstrated eosinophilic aggregates of with topical steroids, calcipotriol oint- 32 TREATMENT OF LICHEN AMYLOIDOSIS WITH THALIDOMIDE – A CASE REPORT 6. Gertz MA, Kyle RA. Secondary systemic amyloidosis: Response and survival in 64 patients. Medicine 1991; 70: Table 1 246-256 7. Gillmore JD, Lovat LB, Persey MR, et al. Amyloid load 5IBMJEPNJEF*OEJDBUJPOTBOE$POUSBJOEJDBUJPOT and clinical outcome in AA amyloidosis in relation to cir- culating concentration of serum amyloid A protein. Lancet 2001; 358: 24-29 8. Joss N, McLaughlin K, Simpson K, Boulton-Jones JM. '%""11307&%*/%*$"5*0/4 Presentation, survival and prognostic markers in AA amy- loidosis. Q J Med 2000; 93: 535-542 Erythema Nodosum Leprosum 9. Lachmann HJ, Goodman HJ, Gilbertson JA, et al. Natural history and outcome in systemic AA amyloidosis. N Engl Multiple Myeloma (in conjunction with dexamethasone) J Med 2007; 356: 2361-2371 10. Leong YO, Tay CH, Fo J. Lichen amyloidosus in Singa- pore. Int J Dermatol 1971; 10: 156-158 0''-"#&-64&4 $0/53"*/%*$"5*0/4 11. Qui BS, Li ZX, Li CH, et al. Primary cutaneous amyloido- sis. Chin Med J (Engl) 1983; 96: 185-200 Prurigo Nodularis Preexisting hepatic or renal disease 12. Simms, RW, Prout, MN, Cohen, AS. The epidemiology of AL and AA amyloidosis. Baillieres Clin Rheumatol 1994; Chron’s Disease Pregnancy 8: 627-634 13. Wong CK. Lichen amyloidosus: a relatively common Uremic Pruritus History of neuritis disorder in Taiwan. Arch Dermatol 1974; 110: 438-440 14. Goller MM, Cohen PR, Duvic M. Lichen amyloidosis pre- Behcet’s disease Congestive Heart Failure senting as a popular pruritus syndrome in Human Immu- Cutaneous lupus erythematosus Hypothyroidism nodeficiency Virus infected man. Dermatology 1997; 104: 62-64 Porphyria cutanea tarda Constipation 15. Wong C, Lin C. Friction amyloidosis. Int J Dermatol 1988; 27: 302-307 Rheumatoid arthritis Venous Thromboembolism 16. Chang Y, Wong C, Chow K, Tsai C. Apoptosis in primary Lichen planus cutaneous amyloidosis. Br J Dermatol 1999; 140: 210- 215 Palmoplantar pustulosis 17. Kumakiri M, Hashimoto K. Histogenesis of primary local- ized cutaneous amyloidosis. J Invest Dermatol 1979; 73: Postherpetic neuralgia 150-162 18. Khoo BP, Tay YK, Goh CL. Calcipotriol ointment vs. Erosive lichen planus betamethasone 17-valerate ointment in the treatment of lichen amyloidosis. International Journal of Dermatology 1999; 38: 539-541 ment and topical 0.1% tacrolimus have mide to be more harmful than placebo and 19. Wolkenstein P, Latajet J, Roujeau JC, et al. Randomized comparison of thalidomide versus placebo in toxic epider- been found to be equally effective in small was shown to increase mortality compared mal necrolysis. Lancet 1998; 352: 1586-1589 trials.3 Other reported treatments include with the placebo group.19 20. Radomsky CL, Levine N. Thalidomide. Derm Clin 2001; 19: 87-103 topical DMSO, UVB, PUVA, dermabrasion, The exact mechanisms of action of 21. Campbell P, Murdock C. Cardiac amyloidosis – sus- double frequency Nd:YAG laser, surgical tained clinical and free light chain response to low dose thalidomide are unknown; however, it is thalidomide and corticosteroids. Intern Med J 2006; 36: debridement, oral retinoids, keratinolytics, thought to be a sedative and have anti- 137-139 and cyclophosphamide.4-5,18 Unfortunately, 22. Oh IY, Kim HK, Kim YJ, et al. An intriguing case of pri- inflammatory and anti-malignancy mary amyloidosis with cardiac involvement: Symptomatic these treatments are partially effective at effects. The sedative effects have been and echocardiographic improvement with thalidomide best. demonstrated in activation of the sleep treatment. Int J Cardiol 2006; 113: 141-143 Thalidomide was introduced into center of the brain.20 Thalidomide’s anti- Western Europe in the late 1950s as a inflammatory effects include decreasing “sleeping agent” with negligible adverse the T-helper/T-suppressor ratio, inhibiting effects. However, this drug never obtained polymorphonuclear leukocyte chemotaxis popular appeal in the United States and and decreasing TNF-α production.20 was never FDA approved in the American Improvement was seen in two case market due to reports of its association reports of systemic amyloidosis with with fetal limb defects (phocomelia) and cardiac involvement. In both cases, the other internal fetal deformities. In 1961, patients were treated with thalidomide and the drug was rapidly withdrawn from the dexamethasone at doses of 100mg daily, world market due to its teratogenicity. subsequently increased to 200-300mg daily, However, thalidomide’s exile was short- with clinical improvement and few side lived. In 1965, thalidomide’s resurgence effects.21-22 as the treatment of choice for erythema Thalidomide may have promise in the nodosum leprosum (ENL) brought this treatment of cutaneous amyloidosis. In drug back on the market as a therapeutic our patient, treatment was well tolerated alternative. In 1997, the FDA granted with no reported side effects; however, thalidomide “approvable” status for the further studies are warranted to evaluate treatment of ENL, opening the door to the effectiveness and side-effect profile of its off-label indication for other diseases thalidomide in treating cutaneous forms of (Table 1). The United States instituted a amyloidosis. program called the System for Thalidomide Education Prescribing Safety (S.T.E.P.S) to References: prevent adverse events like teratogenicity. 1. Looi LM. Primary Localised Cutaneous Amyloidosis in In dermatology, thalidomide treat- Malaysians. Aust J Derm 1991; 32: 39-44 2. Wang WJ, Chang YT, Huang CY, Lee DD. Clinical and ment has been used successfully in condi- histopathological characteristics of primary cutaneous tions like sarcoidosis, lupus erythematous amyloidosis in 794 Chinese patients. Zhonghua Yi Xue Za Zhi (Taipei) 2001; 64: 101-107 profundus, porphyria cutanea tarda and 3. Castanedo-Cazares JP, Lepe V, Moncada B. Lichen pemphigoid, to name a few. It should be amyloidosis improved by 0.1% topical tacrolimus. Derma- tology 2002; 205: 420-421 noted that not all inflammatory cutaneous 4. Jin AG, Por A, Wee LK, et al. Comparative study of pho- diseases improve with the use of thalido- totherapy vs. photochemotherapy vs. topical steroids in the treatment of primary cutaneous lichen amyloidosis. mide. A clinical trial evaluating the use Photodermatology, Photoimmunology, and Photomedi- of thalidomide in the treatment of toxic cine 2001; 17: 42-43 5. Liu HT. Treatment of lichen amyloidosis and dissemi- epidermal necrolysis (TEN) found thalido- nated superficial porokeratosis with frequency-doubled Q-switched Nd:YAG laser. Derm Surg 2000; 26: 958-962 GUEVARA, ZELL, WONGKITTIROCH, SACKHEIM, KERDEL, GLICK 33 LEPROSY: CASE REPORT AND REVIEW OF LITERATURE
1SFUIJ4VOEBSBN.PIJQ %0 %BOJFMMF%FHFOOBSP %0 #SBEMFZ(MJDL %0 .1) '"0$% TUZFBSEFSNBUPMPHZSFTJEFOU 8FMMJOHUPO3FHJPOBM.FEJDBM$FOUFS-&$0. OEZFBSGBNJMZQSBDUJDFSFTJEFOU 8FMMJOHUPO3FHJPOBM.FEJDBM$FOUFS-&$0. 1SPHSBNEJSFDUPS 8FMMJOHUPO3FHJPOBM.FEJDBM$FOUFS-&$0.
Case Presentation disease.7 The main mode of disease trans- mission is via nasal secretions.6 A 17-year-old Hispanic male was referred to our clinic, by the Florida &QJEFNJPMPHZ Department of Juvenile Justice, with an eight-month history of a generalized “rash.” In 1991, the World Health Organization The patient stated it had started on his passed a resolution to eliminate leprosy abdomen and spread to his back and face. as a public health problem by 2000. The He had associated symptoms of pruritus WHO’s definition of elimination is a prev- and numbness within the skin lesions. The alence rate of less than one case per 10,000 patient had been treated with one course persons in all endemic countries. Brazil, of Medrol Dosepak eight months prior India, Madagascar, Mozambique and Nepal and had started on prednisone 10 mg/day are the five countries in which elimination Figure 1 two weeks prior to our evaluation, with still has not been achieved. In 2006, there no changes in his symptoms. He denied were approximately 259,000 new cases; any recent illnesses or travel outside the when leprosy was at its peak in 1998, there United States. He was up to date on all of were 804,000 cases.1, 2 Approximately 85% his immunizations. of new cases in the United States are among On physical exam, the patient had immigrants, and the rest are from exposure numerous indurated, annular, polycyclic, to infected armadillos, overseas travel or erythematous plaques and patches with close contact with an infected patient. central clearing on his face, back and abdomen (Fig. 1, 2, 3). He had associated symptoms of numbness and decreased Classification sensation to light touch within the lesions. Differential diagnosis included leprosy Leprosy has a broad spectrum of clinical or Hansen’s disease, granuloma annu- presentations. The Ridley and Jopling lare, sarcoidosis, SCLE, plaque psoriasis, system helps to classify leprosy based on syphilis and leishmaniasis. Punch biopsies clinical, histologic, and bacterial presen- of lesions on the abdomen and mid-back tations (see Table 1). The classifications were obtained and sent for H&E, Fite, are: Tuberculoid (TT), Borderline tuber- PAS, Giemsa and Steiner stains. Biopsies culoid (BT), Borderline borderline (BB), revealed nodular, pandermal, histiocyte- Borderline lepromatous (BL), Lepromatous rich granulomatous dermatitis involving (LL), and Indeterminate (I). Borderline neurovascular bundles (Fig 4). Fite stains disease is unstable and may move from the TT→LL pole during the course of the showed bacilli in red in only one section 7 (Fig 5, marked by arrow). PAS, Giemsa disease. Cell-mediated immunity is highest Figure 2 and Steiner stains were negative for fungi, in tuberculoid form and lowest in leproma- parasites and spirochetes. The working tous form. or form giant nerve “abscesses”.6 Nerve diagnosis of leprosy, borderline tuberculoid involvement is asymmetric, localized to type, was made based on clinical history Tuberculoid Leprosy (TT) the skin lesions, and leads to changes in the and biopsy results. muscle groups served, such as atrophy and Tuberculoid lesions are either solitary or wasting, early in the course of the disease.7 *OUSPEVDUJPO few in number (often fewer than five). The typical lesions are large, sharply defined, Borderline Leprosy dry, scaly, hairless, reddish-brownish Leprosy is an ancient disease, dating Borderline tuberculoid (BT) – BT lesions back to 600 B.C. In 1873, Hansen identi- plaques with elevated borders and flattened are similar to TT except they are smaller in fied Mycobacterium leprae as the causative atrophic centers. They are asymmetrically size and increased in number. Small satellite agent of leprosy, hence it is also known distributed on the trunk or limbs. Patients lesions around larger macules are common, as Hansen’s disease. Leprosy is a chronic afflicted with the tuberculoid type have 8 infection that primarily affects the skin, a high cell-mediated immunity, which is and nerves are less enlarged than in TT. peripheral nerves and nasal mucosa. M. reflected clinically as the paucibacillary Borderline borderline (BB) – BB cuta- leprae, a gram positive, intracellular acid- form of leprosy.8 The lesions are character- neous lesions are made up of numerous, fast bacillus, has an incubation period of istically anhidrotic and either anesthetic or erythematous, irregular plaques five years for paucibacillary and 20 years hypesthetic, and the surrounding superfi- surrounded by satellite lesions. Anesthesia in multibacillary cases before signs of overt cial, peripheral nerves are enlarged, tender within lesions is moderate. Lesions may 34 LEPROSY: CASE REPORT AND REVIEW OF LITERATURE Table 1 Ridley and Jopling Classification )PTU3FTJTUBODF -FTJPOT1SFTFOU 0SHBOJTNTJO5JTTVF Tuberculoid (TT) High Very Few (1-3) 0 or Paucibacillary Borderline tuberculoid (BT) Unstable Few 1+ or Multibacillary Borderline (BB) Unstable Few or many and asymmetrical 2+ or Multibacillary Borderline lepromatous (BT) Unstable Many 3+ or Multibacillary Lepromatous (LL) None Numerous and symmetrical 4+ or Multibacillary Adapted from Andrews *Paucibacillary = No bacilli present; Multibacillary = One or more bacilli present
Table 2 4VNNBSZPG5SFBUNFOU3FDPNNFOEBUJPOTGPS1BVDJCBDJMMBSZ '%" 8)0 Dapsone 100 mg PO daily 100 mg PO daily Rifampin 600 mg PO monthly 600 mg PO monthly (supervised) (supervised) Length of Treatment 6 months 6 months
Table 3 4VNNBSZPG5SFBUNFOU3FDPNNFOEBUJPOTGPS.VMUJCBDJMMBSZ '%" 8)0 Dapsone 100 mg PO daily 100 mg PO daily Rifampin 600 mg PO daily 600 mg PO monthly (supervised) Figure 3 Clofazimine 50 mg PO daily 300 mg PO monthly (supervised) and 50 mg PO daily Length of Treatment 2 years 2 years remain in this stage, improve or worsen in be visualized. There are abundant bacilli the course of the disease.8 Histopathology visualized on Fite stains. Borderline lepromatous (BL) – BL lesions Punch biopsies should be performed are similar to LL and consist of numerous, of most active lesions and should include symmetrically distributed macules, papules Leprosy Reactions subcutaneous tissue. M. leprae is best seen and nodules. Anesthesia is often absent by using Fite-Faraco stain; however, immu- There are two major types of leprosy within the lesions.8 nofluorescent techniques or PCR can also reactions, and they maybe triggered by Lepromatous Leprosy (LL) be used.7 multiple drug treatment of the disease, vaccinations, pregnancy and stress. Lepromatous lesions are generalized Tuberculoid lesions consist of non- caseating granulomas, which are made However, treatment should not be stopped macules, papules, plaques or nodules that 11 of epithelioid cells, Langhans giant cells, in the presence of either reaction. are symmetrically distributed. There is Type 1 reaction occurs in borderline little or no loss of sensation, and there are and lymphocytes. They may extend into the epidermis, leaving no Grenz zone, and disease as a result of interaction between no signs of anhidrosis. These patients have patients’ cell-mediated immunity and M. poor cell-mediated immunity and therefore into the peripheral nerves. Dermal nerves demonstrate edema and fibrosis that can leprae antigen, a type of delayed hyper- have a multibacillary type of leprosy. Nerve sensitivity reaction. Clinical signs include involvement occurs later in the disease in be visualized with S100 stain. Bacilli are few in number and mostly found in edema, ulceration and nerve damage. the form of neuropathy that causes skin It is usually managed with bed rest and wounds, clawing and contractures of digits, nerves, subepidermal zone and arrector pili muscles.6 NSAIDS. If there are signs of nerve and blindness, which lead to physical damage, then oral prednisone is initiated 7 Lepromatous granulomas are composed disabilities. Other clinical features include and then tapered once symptoms resolve.11 madarosis or loss of eyebrows and diffuse of lipid- and bacilli-laden histiocytes called Type 2 reaction, also known as erythema infiltration of the face, giving a leonine lepra or Virchow cells. Lesions are local- nodosum leprosum (ENL), is an immune- appearance.9 ized in the dermis, and a Grenz zone may SUNDARAM-MOHIP, DEGENNARO, GLICK 35 lary treatment; and dapsone 100 mg daily, rifampin 600 mg PO monthly supervised, and clofazimine 50 mg PO daily and 300 mg PO monthly under supervision for two years for multibacillary10 (see Tables 2 and 3). Resistance to MDT has not yet been established, but there are relapses. The relapse rate varies based on paucibacillary or multibacillary type, just over 1% and just under 1% respectively.10 If relapses occur, it is recommended that the prior Figure 4 treatment is reinitiated unless the form has changed. For those patients with the multi- bacillary form who relapse, in addition to the two-year regimen it is also recom- mended to consider dapsone indefinitely to prevent further relapses. Outcome Our patient was immediately started on prednisone 20 mg a day, rifampin 300 mg twice a day and triamcinolone 0.1% cream twice a day pending biopsy results. The patient followed up in two weeks with marked improvement of his lesions and symptom of numbness. The patient was Figure 5 started on standard multi-drug therapy for paucibacillary leprosy, which included rifampin 600 mg PO monthly and dapsone complex-mediated disease that occurs 100 mg PO daily. The patient was moving in borderline or lepromatous disease. to a new city and was scheduled to follow Unlike type 1 reaction, where there are up at National Hansen’s Disease clinic no systemic signs of illness, type 2 reac- in his area. He has yet to experience any tion presents with fever, myalgias and arth- leprosy reactions. ralgias. Patients have multiorgan disease with conjunctivitis, synovitis, nephritis and orchitis, accompanied by tender erythema- References: tous nodules on extremities. Thalidomide 1. Global leprosy situation. Wkly Epidemiol Rec 2007; 11 82:226 is the treatment of choice for ENL. 2. WHO Leprosy Fact Sheet, October 2005 3. Hansen’s Disease (Leprosy) Technical Information. Coor- dinating Center for Infectious Diseases/Division of Bacte- Treatment rial and Mycotic Diseases. Oct. 2005 4. Progress towards leprosy elimination. Wkly Epidemiol Rec 1998; 73:153 Early detection and treatment with 5. Moet FJ, Pahan D, Schuring RP, et al. Physical distance, multi-drug therapy (MDT) are the most genetic relationship, age and leprosy classification are independent risk factors for leprosy in contacts of patients important steps in preventing deformity with leprosy. J Infect Dis 2006; 193:346 and disability associated with leprosy. The 6. Skin Pathology, page 629 7. James W, Berger T, Elston D. Andrews Diseases of the treatment protocols for leprosy are based Skin. Clinical Dermatology 10th Edition. Canada: Saun- on the number of skin lesions and bacilli ders Elsevier, 2006 8. Freedberg, Irwin M, Ed. Fitzpatrick’s Dermatology in Gen- present. The paucibacillary treatment is eral Medicine 6th Edition. McGraw-Hill Professional, May given to those who have five or fewer skin 2003 9. Singh N, et al. An evaluation of the S-100 stain in the lesions without detectable bacilli, whereas histological diagnosis of tuberculoid leprosy and other the multibacillary treatment is given to granulomatous dermatoses. Int J Leprosy and Other Mycobacterial Diseases. 1994 Jun; 62(2): 263-7 those who have six or more skin lesions 10. WHO Study Group. Chemotherapy of Leprosy. WHO and may have detectable bacilli. The first, Teach Rep Ser No 847, Geneva, WHO, 1994. 11. Moschella SL. An update on diagnosis and treatment of FDA-approved treatment protocol includes leprosy. J Am Acad Dermatol 2004; 51:417. dapsone 100 mg PO daily and rifampin 600 mg PO once a month (observed) for six months for paucibacillary disease, and dapsone 100 mg PO daily, rifampin 600 mg PO daily and clofazimine 50 mg PO daily for two years multibacillary disease. The second, WHO protocol includes a single dose of rifampin 600 mg, ofloxacin 400 mg, and minocycline 100 mg (also called ROM) for single-lesion paucibacillary treatment; dapsone 100 mg PO daily and rifampin 600 mg PO monthly under supervision for six months for standard paucibacil-
36 LEPROSY: CASE REPORT AND REVIEW OF LITERATURE © 2008 Medicis, The Dermatology Company ZNA 08-029 07/30/09 JAOCD Members of the AOCD may advertise "position available"
This is a free service for all active members of the AOCD. A 3" column black and white ad will be provided in the journal as a free service. If members wish to use a larger space, they may do so. The cost for this advertising is:
Black and White - 1/4 page-$125, 1/2 page-$200, full page-$350
Full 4 color ad - 1/4 page-$275, 1/2 page-$350, full page-$500
Resident members may run a 3" column black and white ad stating their desired professional position.
These ads must be submitted as an e-mail attachment and sent to [email protected]. Any photos to be included in an active member's ad, must be in a .pdf format.
38 A NEW TREATMENT FOR EYELID LAXITY
+POBUIBO4$SBOF %0 '"0$% &SJO(SJGmO #4.4*** 1BUSJDJB)PPE 1"$ ,FMMZ#SJUU 1"$ %FSNBUPMPHJTUBU"UMBOUJD%FSNBUPMPHZ"TTPDJBUFT1" 8JMNJOHUPO /$ SEZFBSNFEJDBMTUVEFOUBU1JLFWJMMF$PMMFHF4DIPPMPG0TUFPQBUIJD.FEJDJOF 1JLFWJMMF ,: %FSNBUPMPHZQIZTJDJBOBTTJTUBOUBU"UMBOUJD%FSNBUPMPHZ"TTPDJBUFT1" 8JMNJOHUPO /$ %FSNBUPMPHZQIZTJDJBOBTTJTUBOUBU"UMBOUJD%FSNBUPMPHZ"TTPDJBUFT1" 8JMNJOHUPO /$ 8FIBWFOPBGmMJBUJPOXJUI&MMNBOPSBOZPGUIFPUIFSQSPEVDUTMJTUFEIFSF
ABSTRACT
Baggy eye lids and skin laxity of the eye lids are common complaints that we encounter in the dermatology office. For 10 years we have used treatment by electric cautery to tighten the skin and allow patients to avoid blepharoplasty surgery. This treatment does not replace blepharoplasty in patients with significant infra-orbital fat pads, but it is an excellent option for many patients.
*OUSPEVDUJPO Many patients complain about wrinkled, sagging skin or bags under the eyes. We are presenting a non-invasive technique to tighten the skin under the eyes. We have been utilizing this technique, which involves using an electric cautery to tighten skin, for more than 10 years. In this case we used an Ellman Surgitron FFPF. We also perform treatments with a Bovie AARON 900 high-frequency desiccator and a Con Med hyfrecator. The cautery is applied at Figure 1 Figure 3 low intensity, usually at a setting between 1 and 2. We use a “hemo” or “cut and coag” setting on the Ellman. On other cautery units, we always stay away from straight “cut” settings. We do not use any anesthetic. The elec- trode is lightly touched to multiple spots on the eyelid, treating approximately 20 to 30 spots per lower eyelid. See example with red dots representing where we would touch the electrode for a brief instant (with actual patients we do not mark the spots). We watch to see just a slight skin discolor- ation, contracture, or skin sloughing in the Figure 2 Figure 4 spot touched. Following the procedure, polysporin is applied under the eyes bilater- ally. This treatment is performed bi-weekly lifting and tightening of the under-eye skin. contracting of the collagen fibrils. The for a total of eight to 10 treatments. The patient elected to use the Ellman ablative cutaneous injury induces a healing electrocautery to tighten her eyelids. We response, resulting in the deposition of a Case Report treated the lower lids every two weeks new skin matrix with improved charac- for a series of 10 treatments. The patient teristics.1 During this healing process, skin A 53-year-old Caucasian female commented on her fourth treatment that rejuvenation probably occurs by a prolif- presented complaining of bags under the she felt her lower eyelids were close to 100 eration of fibroblast activity, the action of eyes. She previously had used topical over- percent improved. By the sixth treatment, inflammatory mediators, and a deposi- the-counter cosmetic products. Upon patient stated she was “extremely happy,” tion of new collagen and other dermal- physical examination, under-eye baggi- and by the last treatment she commented matrix proteins. In short, heating results ness, laxity, and rhytides were noted. The that her eyelids “looked fabulous.” in collagen remodeling and a subdermal area underneath the eyes also appeared injury, leading to an inflammatory process slightly hyper-pigmented, with no scarring Discussion and remodeling. or deformities. We discussed possible treat- ment options including topical retinoid eye It is postulated that the radio frequency Conclusion creams, applying the electric cautery for heats the collagen and causes tightening. skin tightening, and bilateral lower bleph- In addition to heat, cauterizing may result The Ellman Surgitron offers a great aroplasty. We explained that the results in micro scarring, which potentially could option for non-invasive treatment of of electro cautery would not be equal to play a role in skin tightening. The heating under-eye laxity. Results will vary from surgical procedures but would offer some of the collagen below the epidermis causes patient to patient, but we tell our patients CRANE, GRIFFIN, HOOD, BRITT 39 Figure 5 to expect around 30 percent improvement. During and for three months after the treatment, the patient is advised to avoid sun exposure. There may be some scabbing and redness of the under-eye area for a week or so after each treatment. Applying polysporin twice a day for seven days will help prevent infection and assist with healing. This is a great treatment option for patients who are looking to avoid blepharo- plasty surgery and still obtain significant improvement.
Reference: 1. Narins, David J, Narins, Rhoda S. Non-surgical radio frequency facelift. Journal of Drugs in Dermatology. Oct 2003.
40 A NEW TREATMENT FOR EYELID LAXITY NEUTROPHILIC ECCRINE HIDRADENITIS: EXPANDING THE CLINICAL SPECTRUM IN NON-CHEMOTHERAPY PATIENTS "$"4&3&10350'/&)*/"$)*-%8*5)4&*;63&4 "/%"3&7*&80'5)&-*5&3"563&
Amy Basile, MPH,1.FISWBTI)BHIJHIJ .% 2 Soheil Simzar, MD,3 Noah Craft, MD, PhD,44IJ,BVOH1FOH .% 1BVM,4IJUBCBUB .%6 1UIZFBSNFEJDBMTUVEFOU 8FTUFSO6OJWFSTJUZPG)FBMUI4DJFODFT $PMMFHFPG0TUFPQBUIJD.FEJDJOFPGUIF1BDJmD 1PNPOB $" OEZFBSQBUIPMPHZSFTJEFOU )BSCPS6$-".FEJDBM$FOUFS 5PSSBODF $" 3OEZFBSEFSNBUPMPHZSFTJEFOU )BSCPS6$-".FEJDBM$FOUFS 5PSSBODF $" 4"TTPDJBUF1SPHSBN%JSFDUPS )BSCPS6$-".FEJDBM$FOUFS%JWJTJPOPG%FSNBUPMPHZ 5PSSBODF $" 5%JSFDUPSPG1BUIPMPHZ )BSCPS6$-".FEJDBM$FOUFS 5PSSBODF $" 6%JSFDUPSPG%FSNBUPQBUIPMPHZ )BSCPS6$-".FEJDBM$FOUFS %BWJE(FGGFO4DIPPMPG.FEJDJOFBU6$-" 5PSSBODF $" DPSSFTQPOEJOHBVUIPS
ABSTRACT
Neutrophilic eccrine hidradenitis (NEH) is a self-limited inflammatory dermatosis usually associated with chemotherapeutic agents, manifesting as erythematous eruptions on the trunk and extremities. Since its first description in 1982, a form of NEH referred to as idiopathic palmoplantar hidradenitis (IPH) has been reported in healthy children and is identified for its specific location on the body. More recently, a subset of cases associated with microorganisms and viral illness has been identified in literature. NEH without underlying malignancy or palmoplantar distribution is exceedingly rare. We describe a child with neutrophilic eccrine hidradenitis who presented with erythematous plaques that developed on the upper extremities in the second week after new onset of generalized seizures. Histopathologic findings show characteristic features of neutrophilic eccrine hidradenitis as well as squamous syringometaplasia occurring without associated chemotherapy or microorganism. A review of the literature, highlighting unusual case presentations of NEH, is further discussed.
*OUSPEVDUJPO neutrophilic eccrine hidradenitis fall under the subcategory of dermal type without Neutrophilic eccrine hidradenitis (NEH) vasculitis. Finally, small vessel vasculitis is a neutrophilic dermatosis affecting the and erythema elevatum et diutinum are eccrine glands and was initially described examples of the third subcategory, dermal in patients with acute myelogenous type with vasculitis.7 leukemia (AML) receiving chemotherapy.1,2 NEH is one of the least common of all The condition is usually self-limited, the known neutrophilic dermatosis. A total resolving in 1-3 weeks with no scarring of 79 cases of NEH have been reported in following discontinuation of the offending literature since 1982. Of these cases, only agent. NEH manifests clinically as nonspe- 13 have been reported in healthy patients. cific cutaneous lesions on the extremities NEH in a child without underlying malig- which are typically tender, erythematous nancy or palmoplantar distribution is Figure 1. Umbilicated pink papules on or purpuric macules, papules, nodules, or exceedingly rare. Unusual presentations patient’s arm plaques. Fever can often accompany NEH of this rare disease raise questions about although many patients are neutropenic.3 causality and may result in unnecessary stranded DNA and Herpes Simplex Virus Anatomical locations besides the distal tests and delayed resolution. Further PCR were negative. Nasopharyngeal extremities are distinctly unusual and have evaluation of unusual presentations of swab cultures and stool cultures were included the face,4, 5 trunk, or proximal NEH may lead to a better understanding negative. Titers of Anti –EBV antibodies extremities. Rarely, NEH presents in a of the etiology and pathology of disease. were reported as IgG= 1:160 (reference generalized distribution.6 A diagnosis of We present an unusual case of NEH in a 14 range:<1:10)and IgM <1:20 (reference NEH can be confirmed with a skin biopsy year old girl with new onset seizures. range:<1:20). Computerized tomography showing characteristic pathologic changes, scanning and magnetic resonance imaging specifically neutrophils infiltrating eccrine Case Report of the head revealed no significant abnor- glands. With prolonged lesions, squamous malities, including no evidence of multiple syringometaplasia may supervene atop the A 14 year-old girl with no significant sclerosis. On hospital day 14 she developed inflammatory changes. prior medical history presented to the umbilicated pink papules on her bilat- NEH falls under a broad category hospital emergency department with new eral wrists, right forearm, and mid lower of dermatological diseases referred to as onset of generalized seizures and altered back ranging in size from 3 mm to 6 mm. neutrophilic dermatoses. Bolognia et al., mental status with a week-long history The lesions appeared in various stages of describes neutrophilic dermatoses as a of myalgia and headaches. Her vital healing, some with crusts (Fig1). At that heterogeneous set of cutaneous diseases signs were normal. No focal neurolog- time, there were no other skin findings. with similar histopathology and thera- ical problem was identified. The patient 4 mm punch biopsy of the skin revealed peutic options. Neutrophilic infiltrate experienced between 5 and 13 seizures a features of neutrophilic eccrine hidradenitis without associated infectious disease is day for the first week of hospitalization (Fig 2), with a dense neutrophilic infiltrate the histopathologic finding.7 Neutrophilic which were controlled with Valproate, within and around the eccrine coils, with dermatoses are further grouped as having Dilantin, and Levetiracetam. Her altered associated necrosis of the sweat coils and epidermal involvement or dermal involve- mental status persisted until hospital day squamous syringometaplasia. ment with or without vasculitis. The 12 when she began following commands. No vasculitis was observed. No micro- epidermal category includes conditions Electroencephalogram showed severe organisms were noted with special stains such as pustular psoriasis and keratoderma generalized encephalopathy with nonspe- including PAS, Gomori-Methenamine blennorhagicum. Sweet’s syndrome, Behcet cific findings. Cerebrospinal fluid analysis silver, tissue Gram stain, and Ziehl-Nielsen disease, pyoderma gangrenosum and was unremarkable. Serology for anti-double stain for AFB. Tissue cultures of lesion BASILE, HAGHIGHI, SIMZAR, CRAFT, PENG, SHITABATA 41 Figure 2. Scanning magnification shows a dense infiltrate of neutrophils and lymphocytes in the upper dermis and within the eccrine secretory coils (hematoxylin-eosin stain). A. Foci of squamous syringometaplasia with focal necrosis of epithelial cells in the sweat ducts (magnification 200x) B. Neutrophilic infiltration with micro abscess formation in the loose connective tissue and fat surrounding the eccrine coils (magnification 200x) Section: Magnification 20x for Varicella-Zoster virus and fungus associated with NEH. What remains tory role, is an important factor in the were negative. An immunohistochemical consistent in all of the hypotheses is etiology of some forms of NEH. There stain with EBV LMP1 (Latent membrane that NEH represents an altered inflam- are approximately two to four million protein 1) antigen was negative. The lesions matory reaction to nonspecific stimuli or eccrine glands on every person and are resolved spontaneously after 2 weeks and chemotherapeutic agents requiring both found almost universally throughout the the patient remained free of any seizures. a triggering agent and an altered immune skin but concentrated in various areas.19 response.8 The most common theory For example, the palms and soles have the -JUFSBUVSF3FWJFX suggests that NEH represents direct damage greatest number of eccrine glands, followed and inflammation to the eccrine duct from by the head, trunk and then extremities in Using Pubmed, a systematic review of the drug agent.1,9 Others suggest that NEH decreasing order.19 This pattern of density the literature utilizing the search terms is a paraneoplastic syndrome10, or that it corresponds to the most common locations neutrophilic eccrine hidradenitis and develops from leukemic precursors which for NEH lesions, that is, the extremities, the eccrine hidradenitis, from 1982 to 2007, differentiate following chemotherapy.11 face, and the trunk. Normal physiological was conducted. In total, 79 cases of NEH Supporting the theory that an offending processes occurring in the eccrine ducts were identified from the PubMed search. agent induces an inflammatory reaction include the concentration and excretion of Idiopathic palmoplantar hidradenitis and within the eccrine ducts is the propensity certain drugs. As reviewed by Wenzel and plantar hidradenitis were also searched to for NEH to spontaneously resolve when Horn (2000), drugs including ethanol20, further include all types of NEH. A total the medication is discontinued. The recur- amphetamines21, cocaine22, nicotine23, and of 65 cases of IPH were identified in the rence of disease can be seen when the same ciprofloxacin24 have been studied, while literature since the first case was published chemotherapeutic agent is once again many others have been attributed to eccrine in 1948. 19 administered.2 Contributing to the theory disorders such as NEH. Discussion that chemotherapy incites the lesions is a Other diseases associated with study by Templeton et al, in which injec- NEH The discovery of NEH in patients under- tions of bleomycin into the skin of healthy going chemotherapeutic treatment for volunteers led to the development of NEH A variety of medical conditions, in addi- acute myelogenous leukemia (AML) lead and syringosquamous metaplasia (SSM) tion to malignant hemopathies, have been 12 investigators to first hypothesize that the within 24 hours. identified in patients diagnosed with NEH. condition develops from a toxic drug reac- Although most lesions resolve sponta- The most commonly reported condition tion in the sweat glands.1, 3 Since the first neously, reports demonstrating the need is Behcets disease (BD)15, 25, 26, a neutro- published cases of NEH, multiple types of for a short trial of dapsone or colchicine philic dermatosis characterized by systemic malignances and chemotherapeutic agents have also been described in literature.13, 14 inflammation and mucocutaneous lesions. have been reported with this condition These treatments are particularly useful in In one case, NEH was thought to represent (Table 1). The association of NEH with NEH diagnosed late, in cases of comorbid a form of neutrophil mediated cutaneous malignant hemopathies remains strong disease including Behcet’s15, or in patients lesions in BD.26 In another case, the patient although it is not an exclusive feature of who must continue chemotherapy.13 was found to have oral apthosis, anterior the disease. Non-chemotherapeutic Occasionally, corticosteroids or NSAIDS uveitis and a positive pathergy test in addi- medications such as acetaminophen and have been used, usually for the treatment tion to pruritic papules on her arms and Granulocyte Colony Stimulating Factor of concurrent pain or fever, and seem to legs confirmed to be NEH. She responded (GCSF), as well as medical conditions such shorten the course of the lesions.13,16-18 well to 100mg dapsone daily and had no as Behcets and lupus erythematosus have Fortunately, once the lesions have resolved recurrence over 9 months.15 Other diseases subsequently been reported with NEH. A there are enough dermal eccrine remnants reported in association with NEH include list of the various medical conditions and to regenerate without scarring.3 a patient with systemic lupus erythema- medications reported in association with The presumed target of NEH is the tosis (SLE) undergoing cyclophosphamide NEH are listed in Table 1. eccrine duct, a thermoregulatory sweat therapy27 and a patient being treated Although the clinical picture of NEH gland that responds to increased body with methotrexate for actinic reticuloid continues to expand over time, the patho- temperature by secretion of water on syndrome.28 The etiologic association with genesis of the disease remains elusive. the skin surface.19 The eccrine duct also NEH is unclear. Multiple hypotheses exist in order to excretes waste products, which although Patients with malignant hemopathies account for the range of clinical scenarios minor compared to the thermoregula- but without concurrent chemotherapy 42 NEUTROPHILIC ECCRINE HIDRADENITIS: EXPANDING THE CLINICAL SPECTRUM IN NON-CHEMOTHERAPY PATIENTS in two weeks.33 G-CSF is proposed to cause NEH by stimulation of neutrophilic Table 1 precursors and accumulation of neutro- "EBQUFEGSPN#BDINFZFSBOE"SBDUJOHJ phils in the dermis through chemotaxis.33 Interestingly, G-CSF has also been reported Chemotherapeutic agents Malignancies to cause other neutrophilic dermatoses 5-Fluorouracil AML including Sweet’s syndrome and pyoderma 6-Thioguanine NSCLC gangrenosum.34-36 Bleomycin Ovarian Cancer Two reports indicate acetaminophen Chlorambucil CML in the development of NEH. In one case Cisplatin CLL the patient developed NEH while taking Cyclophosphamide Hodgkin’s only acetaminophen. The patient had no Cytarabine Testicular Cancer other underlying disease or malignancy.37 Dactinomycin Non Hodgkin’s Lymphoma Another case of NEH is described in a 8 Daunorubicine Wilms’ Tumor 68 year old female with untreated CLL. Administration of acetaminophen was the Decarbazine Lung Cancer causative link upon retrospective review Etoposide Breast Cancer of her medical file. Within 30 minutes Imatinib mesylate Osteosarcoma of taking acetaminophen periorbital, Lomustin violaceous patches appeared and were Methotrexate Microorganisms confirmed to be NEH. The patient was Mitoxantrone Enterobacter treated with methyprednisolone 80mg/day Topotecan Serratia and the lesions resolved within 1 week.8 Vinblastine Streptococcus The latter case represents both, an unusual Vincristine Staphylococcus presentation and causative agent; the pres- Zidovudine Nocardia ence of CLL adds evidence to the theory Rocky Mountain Spotted Fever that an underlying immune dysfunction may contribute to NEH without regard to 0UIFS.FEJDBUJPOT the type of systemic medication. G-CSF Viral infections Acetaminophen HIV Infectious agents associated with HSV NEH CMV Eccrine ducts have been described as EBV resistant to microbes but the mechanism Hepatitis C by which the sweat glands protect the body from invading organisms is not well 0UIFSDPOEJUJPOT known. Research suggests that there are Actinic Reticuloid Syndrome high levels of IgA in the sweat glands38 and Behcet’s that these immunoglobulins are inhibitory 39 Bullous Pemphigoid to bacterial growth. Recently, an anti- Lupus microbial peptide called “cathelicidin” has been found to be secreted by sweat glands, perhaps contributing to its innate defense have also been reported with NEH. In in the body. These symptoms are thought against microbes.40 Despite the aforemen- these cases, NEH has been proposed to to be the result of cytokines or hormones tioned defense mechanisms, adding to represent a paraneoplastic syndrome. In released from tumor cells rather than origi- the spectrum of NEH are reported cases five patients, NEH was reported as the nating directly from cancer cells. These associated with microorganisms including heralding symptom prior to the develop- reports of paraneoplastic syndrome, in Streptococcus41, Nocardia42, Enterobacter42, ment of AML or CML; none of the patients addition to the known association between 43, Serratia44, 45, Staphylococcus42, gram had recently undergone chemotherapy. In NEH and malignancies, lend further positive cocci46, Rocky Mountain Spotted one case, the patient was previously diag- support to continually evaluate patients for Fever (RMSF)47 and coagulase negative nosed with chronic myelogenous leukemia signs of malignancy. staphylococcus.48 and developed NEH six months after his Other medications associated In one case of NEH, skin biopsy cultures final round of chemotherapy, just prior to revealed Serratia marcescens and the patient 29 with NEH a relapse of CML . Lesions associated with had multiple recurrences of disease.44 With chemotherapy have been reported to begin NEH has also been reported in asso- each recurrence the patient’s symptoms on average 10 days after initiation of the ciation with other medications, including resolved with a short course of antibiotics. agent3, 19; if chemotherapy was the inciting G-CSF and acetaminophen. G-CSF is a In a recent case series of 10 children with agent, this case would represent a delayed haematopoietic growth factor which stimu- NEH, biopsies from two infants with response. lates the differentiation of neutrophils in classic symptoms of NEH grew coagulase The other four cases describe NEH as bone marrow, and is often used in patients negative staphylococcus.48 The patient’s the first indication of new onset leukemia; with bone marrow toxicity following symptoms consisted of multiple papules after the onset of NEH, three patients chemotherapy.33 A 40 year old male with and nodules of the limbs which resolved subsequently developed AML10, 30, 31 and leukemia was given two treatments with within three weeks.48 One case of NEH was one patient developed CML32. All of the G-CSF over a period of months; following reported in a 15 year old boy with Rocky patients’ symptoms resolved spontaneously the second course he developed a purple Mountain Spotted Fever (RMSF); the boy’s after approximately 3 weeks. A paraneo- plaque on his leg. Biopsy evaluation iden- skin lesions showed signs of both NEH plastic syndrome is defined by a symptom tified the lesion as NEH. After discontinu- and leukocytoclastic vasculitis.47 In each or disease caused by the presence of cancer ation of the G-CSF the lesion disappeared of the reported cases of infectious NEH, BASILE, HAGHIGHI, SIMZAR, CRAFT, PENG, SHITABATA 43 the microorganism is either cultured from tion that syringometaplasia is typically not the cutaneous eruption of ESSM is more a skin biopsy44, 48 or directly observed in seen in later stages of disease. likely to be found centrally on the body the inflamed eccrine ducts.46 Additionally, Amongst the reports of idiopathic (trunk, abdomen, neck) rather than on a short course of antibiotics successfully plantar hidradenitis, suggested etiologies the extremities as in NEH. Investigators resolves the cutaneous rash whereas in include history of exposure to damp, cold have suggested that NEH represents the aseptic cases of NEH the lesions generally footwear63 as well as trauma or excessive inflammatory stage of the disease while resolve spontaneously over time. activity.64 Simon et al explains that trauma ESSM represents the noninflammatory NEH has also been described in patients to the extremities may rupture palmo- or late stage of disease.75 Alternatively, the with viral infections including HIV9,49-51, plantar eccrine glands, release inflamma- lack of inflammatory infiltrate, i.e. neutro- HSV52, and hepatitis C53. One HIV patient tory cytokines and cause an accumulation phils, in ESSM may implicate a direct toxic with NEH was being treated with stavu- of neutrophils leading to the develop- effect of the chemotherapeutic agent or dine, a reverse transcriptase inhibitor9; ment of the tender lesions.16 After rest viral infection on the sweat gland.73, 76 The a second HIV patient was being treated or avoidance of wet footwear, the lesions current patient presents with features of for non-Hodgkin’s lymphoma and subse- resolve spontaneously. Only a few cases both NEH and ESSM including central quently developed NEH49; and a third reported the use of steroids and NSAIDs and peripheral clinical lesions, as well as HIV patient was taking no medications.49 as treatment, leading to a resolution of histological evidence of a neutrophilic Consistent with current hypotheses, an disease in 1 – 2 weeks.64, 65 IPH has been infiltrate in addition to syringosquamous offending organism such as a microor- reported to have such a classical clinical metaplasia. The question remains why ganism or virus may cause direct cellular presentation that histological evaluation is some patients develop neutrophilic eccrine damage or an inflammatory reaction in the unnecessary, however if symptoms persist hidradenitis with squamous metaplasia and eccrine ducts.9 Supporting the theory that beyond 1-2 weeks histological evaluation others develop eccrine syringosquamous virus’ can play a role in eccrine pathology is recommended to rule out other disease.16 metaplasia. Given the similarities between is a recent investigation of hepatitis C Particularly in children, the avoidance of the two conditions, further evaluation of virus which has been found to replicate in unnecessary diagnostic tests, antibiotics or ESSM may help to elucidate the patho- eccrine duct cells as well as healthy kerati- steroid treatments may be significant. logical mechanism of disease in NEH. nocytes, and can be excreted into sweat.54 NEH in healthy adults or in children Other unusual presentations of Additionally, the same researchers found without a palmoplantar distribution is NEH that in non-hairy plantar skin the human extremely rare. A handful of NEH cases papillomavirus63 targets both keratinocytes in healthy adults have been reported8,37,66,67, There has been one case report of IPH and eccrine ducts.54 There exists no data including the two cases suggesting the presenting in pustular form.77 Annular regarding a possible relationship between role of acetaminophen in the etiology of plaque presentations of NEH have been Epstein-Barr virus (EBV) and neutrophilic disease.8,37 In a case series of 10 children, reported on multiple occasions78,79; one eccrine hidradenitis as it was a diagnostic 8 of the children are described as having case of annular NEH was reported on a consideration in the currently described NEH with no associated chemotherapy, patient’s hands. 80 NEH appearing as facial patient. EBV has on rare occassions been malignancy, or microorganism. The lesions plaques has also been identified81, 82, one implicated in several cutaneous diseases in these cases were distributed primarily of which presented as bilaterally swollen including erythema multiforme55, cuta- over the lower limbs and resolved spon- ears4. NEH mimicking other diseases has neous amyloidosis56, hydroa vacciniforme57, taneously after three weeks.48 Another also been reported including facial cellulitis oral hair leukoplakia58, and lymphoprolif- case of NEH was described in a neonate 83 and orbital cellulitis.5 Finally, a serpen- erative disorders59, 60, particularly amongst also suffering with neonatal onset multi- tine supravenous eruption was reported at transplant patients.61 Contrary to the organ inflammatory disease (NOMID).68 the chemotherapy injection site on the arm current case, the EBV infection was detect- Revealing the etiology in these patients of a child being treated for a malignancy.84 able in all of the skin lesions in these cases. presents a challenge to clinicians and high- Further investigation of the infectious lights the necessity to evaluate nuances in Summary causes of NEH, particularly in the immu- unusual cases as the search for the patho- nocompromised, may help to redefine this genesis of disease continues. Our case is distinctly unusual, occurring neutrophillic dermatosis. in an immunocompetent patient with no Syringosquamous metaplasia history of an underlying blood dyscrasia NEH in healthy patients Eccrine syringosquamous metaplasia or chemotherapy. Furthermore, the wrists, An offending agent or organism is not (ESSM) is a distinct dermatologic condition arms, and back are unusual locations for always identifiable in cases of NEH and considered to fall within histopathologic NEH to manifest. The patient’s altered these patients are considered to be other- spectrum of NEH. Squamous metaplasia mental status and elevated viral titers to wise healthy. The prevailing form of NEH is the defining histopathologic feature of Epstein-Barr virus suggest a possible viral found in healthy children presents in a ESSM and is also a feature described in etiology for these clinical and histopatho- palmoplantar distribution and has there- the later stages of NEH. Eccrine syringo- logic changes. Although an immunohis- fore been identified as idiopathic palmo- metaplasia is similar to NEH in both its tochemical stain to Epstein-Barr virus plantar hidradenitis (IPH). Approximately etiology and histology. Similar to NEH, LMP1 was negative in our patient, this 65 cases of IPH have been reported in liter- it is often found in patients undergoing does not exclude the possibility that the ature since it was first described in 1994.62 chemotherapy for malignancies69,70,71 and virus may have facilitated an inflammatory The general presentation of this disease has been described in association with cytotoxic response. New onset seizures is tender nodules on the hands or soles of viral illnesses such as CMV and HIV.52,72- requiring a daily dose of multiple anti- the feet, in a patient with no malignancy 75 ESSM is characterized by squamous epileptic medications, which preceded or chemotherapy. An increased density of metaplasia of the epithelial cells lining the symptom onset by two weeks, suggests a eccrine ducts on the palms and soles may sweat ducts and it can mimic squamous possible medication etiology. However, explain the propensity for this anatomical cell carcinoma because of the presence of this etiology is unlikely since the signs distribution.19 Similar to NEH, the condi- islands of squamous epithelium as well as and symptoms resolved while the anti- tion is self limited within a few days or necrosis of the ductal epithelium.75 seizure medications were still administered. weeks of onset. Histologically, IPH shares ESSM is distinct from NEH in its sparsity Further research is needed to investigate the same features of NEH with the excep- of neutrophillic infiltrates. Additionally, the underlying mechanisms to explain
44 NEUTROPHILIC ECCRINE HIDRADENITIS: EXPANDING THE CLINICAL SPECTRUM IN NON-CHEMOTHERAPY PATIENTS patient with Behcet’s disease. Cutis. Aug 2001;68(2):107- 57. Iwatsuki K, Ohtsuka M, Harada H, Han G, Kaneko F. these histopathologic changes. 111. Clinicopathologic manifestations of Epstein-Barr virus- In conclusion, this case report and 27. Lienesch DW, Mutasim DF, Singh RR. Neutrophilic associated cutaneous lymphoproliferative disorders. Arch eccrine hidradenitis mimicking cutaneous vasculitis in a Dermatol. Sep 1997;133(9):1081-1086. review examines the expanding clinical lupus patient: a complication of cyclophosphamide. Lupus. 58. Ikediobi NI, Tyring SK. Cutaneous manifestations 2003;12(9):707-709. of Epstein-Barr virus infection. Dermatol Clin. Apr profile for NEH. Avoidance of unneces- 28. Tojo M, Iwatsuki K, Furukawa H, Takahashi M, Kaneko F. 2002;20(2):283-289. sary tests and treatments in patients with Neutrophilic eccrine hidradenitis in actinic reticuloid syn- 59. Cho KH, Lee SH, Kim CW, et al. Epstein-Barr virus-asso- drome. Eur J Dermatol. Mar-Apr 2002;12(2):198-200. ciated lymphoproliferative lesions presenting as a hydroa NEH is critical as most cases resolve spon- 29. Saada V, Aractingi S, Leblond V, Marinho E, Frances C, vacciniforme-like eruption: an analysis of six cases. Br J taneously upon removal of the offending Chosidow O. [Neutrophilic eccrine hidradenitis associated Dermatol. Aug 2004;151(2):372-380. with relapse of acute myeloblastic leukemia]. Ann Derma- 60. Cho KH, Kim CW, Kwon OS, et al. Epstein-Barr virus- agent or after treatment for a specific infec- tol Venereol. Jul 1998;125(6-7):420- 422. associated lymphoproliferative eruption with progression to 30. Yasukawa K, Kato N, Aikawa K, Kodama K, Hamasaka A, large granular lymphocytic leukaemia. Br J Dermatol. Sep tious organism. Various anatomical loca- Hata H. Neutrophilic eccrine hidradenitis with scleroder- 1997;137(3):426-430. tions, diseases and medications continue moid change heralding the relapse of acute myelogenous 61. Snavely NR, Sonabend M, Rosen T. Posttransplant leukemia: is this a paraneoplastic phenomenon? Derma- Epstein-Barr virus related lymphoproliferative disorder to broaden the clinical picture associated tology. 2007;215(3):261-264. with a primary cutaneous presentation. Dermatol Online J. 31. Roustan G, Salas C, Cabrera R, Simon A. Neutrophilic 2007;13(4):7. with NEH. A characteristic histopatho- eccrine hidradenitis unassociated with chemotherapy in a 62. Stahr BJ, Cooper PH, Caputo RV. Idiopathic plantar logic finding in an unusual clinical setting patient with acute myelogenous leukemia. Int J Dermatol. hidradenitis: a neutrophilic eccrine hidradenitis occurring Feb 2001;40(2):144-147. primarily in children. J Cutan Pathol. Aug 1994;21(4):289- should alert the clinician to consider NEH 32. Gomez Vazquez M, Peteiro C, Toribio J. Neutrophilic 296. in the clinical differential diagnosis. eccrine hidradenitis heralding the onset of chronic myel- 63. Naimer SA, Zvulunov A, Ben-Amitai D, Landau M. Plantar ogenous leukaemia. J Eur Acad Dermatol Venereol. May hidradenitis in children induced by exposure to wet foot- 2003;17(3):328-330. wear. Pediatr Emerg Care. Jun 2000;16(3):182-183. 19 33. Bachmeyer C, Chaibi P, Aractingi S. Neutrophilic eccrine 64. Ben-Amitai D, Hodak E, Landau M, Metzker A, Feinmesser References: hidradenitis induced by granulocyte colonystimulating fac- M, David M. Idiopathic palmoplantar eccrine hidradenitis in tor. Br J Dermatol. Aug 1998;139(2):354-355. children. Eur J Pediatr. Mar 2001;160(3):189-191. 1. Harrist TJ, Fine JD, Berman RS, Murphy GF, Mihm 34. Ross HJ, Moy LA, Kaplan R, Figlin RA. Bullous pyoderma 65. Bartolo E, Anes I, Capitao-Mor M, Brandao FM. Idiopathic MC, Jr. Neutrophilic eccrine hidradenitis. A distinctive gangrenosum after granulocyte colonystimulating factor plantar hidradenitis. J Eur Acad Dermatol Venereol. May type of neutrophilic dermatosis associated with myelog- treatment. Cancer. Jul 15 1991;68(2):441-443. 1998;10(3):257-261. enous leukemia and chemotherapy. Arch Dermatol. Apr 35. Park JW, Mehrotra B, Barnett BO, Baron AD, Venook 66. Manganoni AM, Facchetti F, Gavazzoni R, Marocolo D, 1982;118(4):263-266. AP. The Sweet syndrome during therapy with granulo- De Panfilis G. Neutrophilic eccrine hidradenitis in a healthy 2. Flynn TC, Harrist TJ, Murphy GF, Loss RW, Moschella SL. cyte colony-stimulating factor. Ann Intern Med. Jun 15 women. Dermatology. 1994;189(2):211-212. Neutrophilic eccrine hidradenitis: a distinctive rash associ- 1992;116(12 Pt 1):996-998. 67. Morice A, Penven K, Comoz F, Cribier B, Dompmartin ated with cytarabine therapy and acute leukemia. J Am 36. Richard MA, Grob JJ, Laurans R, et al. Sweet’s syndrome A, Leroy D. [Neutrophilic eccrine hidradenitis in a healthy Acad Dermatol. Oct 1984;11(4 Pt 1):584-590. induced by granulocyte colony-stimulating factor in a patient]. Ann Dermatol Venereol. Aug-Sep 2005;132(8-9 3. Bachmeyer C, Aractingi S. Neutrophilic eccrine hidradeni- woman with congenital neutropenia. J Am Acad Dermatol. Pt 1):686-688. tis. Clin Dermatol. May-Jun 2000;18(3):319-330. Oct 1996;35(4):629-631. 68. Huttenlocher A, Frieden IJ, Emery H. Neonatal onset 4. Ostlere LS, Wells J, Stevens HP, Prentice G, Rustin MH. 37. Kuttner BJ, Kurban RS. Neutrophilic eccrine hidradenitis multisystem inflammatory disease. J Rheumatol. Jun Neutrophilic eccrine hidradenitis with an unusual presenta- in the absence of an underlying malignancy. Cutis. Jun 1995;22(6):1171-1173. tion. Br J Dermatol. Jun 1993;128(6):696-698. 1988;41(6):403-405. 69. Valks R, Fraga J, Porras-Luque J, Figuera A, Garcia-Diez 5. Bardenstein DS, Haluschak J, Gerson S, Zaim MT. Neu- 38. Okada T, Konishi H, Ito M, Nagura H, Asai J. Identification A, Fernandez-Herrera J. Chemotherapy-induced eccrine trophilic eccrine hidradenitis simulating orbital cellulitis. of secretory immunoglobulin A in human sweat and sweat squamous syringometaplasia. A distinctive eruption in Arch Ophthalmol. Nov 1994;112(11):1460-1463. glands. J Invest Dermatol. May 1988;90(5):648-651. patients receiving hematopoietic progenitor cells. Arch 6. Wong GC, Lee LH, Chong YY. A case report of neutro- 39. Stephens S, Dolby JM, Montreuil J, Spik G. Differences Dermatol. Jul 1997;133(7):873-878. philic eccrine hidradenitis in a patient receiving chemo- in inhibition of the growth of commensal and enteropatho- 70. Karam A, Metges JP, Labat JP, Leroy JP, Guillet G. therapy for acute myeloid leukaemia. Ann Acad Med genic strains of Escherichia coli by lactotransferrin and Squamous syringometaplasia associated with docetaxel. Singapore. Nov 1998;27(6):860-863. secretory immunoglobulin A isolated from human milk. Br J Dermatol. Mar 2002;146(3):524-525. 7. Moschella SL, Davis MDP. Neutrophilic Dermatoses. In: Immunology. Nov 1980;41(3):597-603. 71. Wong P, Bangert JL, Levine N. A papulovesicular eruption Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 2nd 40. Murakami M, Ohtake T, Dorschner RA, Schittek B, Garbe in a man receiving chemotherapy for metastatic melanoma. Ed. ed: Mosby Elsevier; 2008. C, Gallo RL. Cathelicidin anti-microbial peptide expression Squamous syringometaplasia (squamous metaplasia) of 8. F ELS, Ammoury A, Chababi M, Dhaybi R, Bazex J. Neu- in sweat, an innate defense system for the skin. J Invest the eccrine glands. Arch Dermatol. Feb 1993;129(2):232- trophilic eccrine hidradenitis to acetaminophen. J Eur Acad Dermatol. Nov 2002;119(5):1090- 1095. 233, 235-236. Dermatol Venereol. Nov 2006;20(10):1338-1340. 41. Takai T, Matsunaga A. A case of neutrophilic eccrine 72. Munoz E, Valks R, Fernandez-Herrera J, Fraga J. Her- 9. Krischer J, Rutschmann O, Roten SV, Harms M, Saurat hidradenitis associated with streptococcal infectious endo- petic syringitis associated with eccrine squamous syringo- JH, Pechere M. Neutrophil eccrine hidradenitis in a patient carditis. Dermatology. 2006;212(2):203-205. metaplasia in HIV-positive patients. J Cutan Pathol. Aug with AIDS. J Dermatol. Mar 1998;25(3):199-200. 42. Antonovich DD, Berke A, Grant-Kels JM, Fung M. Infec- 1997;24(7):425-428. 10. Pierson JC, Helm TN, Taylor JS, Elston DM, Tuthill RJ. tious eccrine hidradenitis caused by Nocardia. J Am Acad 73. Hurt MA, Halvorson RD, Petr FC, Jr., Cooper JT, Jr., Neutrophilic eccrine hidradenitis heralding the onset Dermatol. Feb 2004;50(2):315-318.18 Friedman DJ. Eccrine squamous syringometaplasia. A of acute myelogenous leukemia. Arch Dermatol. Jun 43. Allegue F, Soria C, Rocamora A, et al. Neutrophilic eccrine cutaneous sweat gland reaction in the histologic spectrum 1993;129(6):791-792. hidradenitis in two neutropenic patients. J Am Acad Der- of ‘chemotherapy-associated eccrine hidradenitis’ and 11. Aractingi S, Mallet V, Pinquier L, et al. Neutrophilic der- matol. Dec 1990;23(6 Pt 1):1110-1113. ‘neutrophilic eccrine hidradenitis’. Arch Dermatol. Jan matoses during granulocytopenia. Arch Dermatol. Oct 44. Combemale P, Faisant M, Azoulay-Petit C, Dupin M, 1990;126(1):73-77. 1995;131(10):1141-1145. Kanitakis J. Neutrophilic eccrine hidradenitis secondary 74. Chetty R, Bramdev A, Govender D. Cytomegalovirus- 12. Templeton SF, Solomon AR, Swerlick RA. Intradermal to infection with Serratia marcescens. Br J Dermatol. Apr induced syringosquamous metaplasia. Am J Dermato- bleomycin injections into normal human skin. A histopatho- 2000;142(4):784-788. pathol. Oct 1999;21(5):487-490. logic and immunopathologic study. Arch Dermatol. May 45. Moreno A, Barnadas MA, Ravella A, de Moragas JM. 75. El Darouti MA, Marzouk SA, El Hadidi HA, Sobhi RM. 1994;130(5):577-583. Infectious eccrine hidradenitis in a patient undergoing Eccrine syringosquamous metaplasia. Int J Dermatol. Dec 13. Shear NH, Knowles SR, Shapiro L, Poldre P. Dapsone in hemodialysis. Arch Dermatol. Sep 1985;121(9):1106- 2001;40(12):777-781. prevention of recurrent neutrophilic eccrine hidradenitis. J 1107. 76. Greenbaum BH, Heymann WR, Reid CS, Travis SF, Don- Am Acad Dermatol. Nov 1996;35(5 Pt 2):819-822. 46. Oono T, Matsuura H, Morizane S, Yamasaki O, Iwatsuki aldson MH. Chemotherapy-associated eccrine hidradeni- 14. Belot V, Perrinaud A, Corven C, de Muret A, Lorette G, K. A case of infectious eccrine hidradenitis. J Dermatol. tis: neutrophilic eccrine hidradenitis reevaluated: the role of Machet L. [Adult idiopathic neutrophilic eccrine hidradenitis Feb 2006;33(2):142-145. neutrophilic infiltration. Med Pediatr Oncol. 1988;16(5):351- treated with colchicine]. Presse Med. Oct 2006;35(10 Pt 47. Kao GF, Evancho CD, Ioffe O, Lowitt MH, Dumler JS. Cuta- 355. 1):1475-1478. neous histopathology of Rocky Mountain spotted fever. J 77. Hernandez-Martin A, Pinedo F, Perez-Lescure J. Pustular 15. Nijsten TE, Meuleman L, Lambert J. Chronic pruritic Cutan Pathol. Nov 1997;24(10):604-610. idiopathic recurrent palmoplantar hidradenitis: an unusual neutrophilic eccrine hidradenitis in a patient with Behcet’s 48. Shih IH, Huang YH, Yang CH, Yang LC, Hong HS. Child- clinical feature. J Am Acad Dermatol. Nov 2002;47(5 disease. Br J Dermatol. Oct 2002;147(4):797-800. hood neutrophilic eccrine hidradenitis: a clinicopathologic Suppl):S263-265. 16. Simon M, Jr., Cremer H, von den Driesch P. Idiopathic and immunohistochemical study of 10 patients. J Am Acad 78. Headley CM, Ioffreda MD, Zaenglein AL. Neutrophilic recurrent palmoplantar hidradenitis in children. Report Dermatol. Jun 2005;52(6):963-966. eccrine hidradenitis: a case report of an unusual annular of 22 cases. Arch Dermatol. Jan 1998;134(1):76-79. 49. Bachmeyer C, Reygagne P, Aractingi S. Recurrent neu- presentation. Cutis. Feb 2005;75(2):93-97. 17. Bernstein EF, Spielvogel RL, Topolsky DL. Recurrent trophilic eccrine hidradenitis in an HIV-1-infected patient. 79. Scherbenske JM, Benson PM, Lupton GP. Asymptomatic neutrophilic eccrine hidradenitis. Br J Dermatol. Nov Dermatology. 2000;200(4):328-330. erythematous papules in a leukemic patient.Neutrophilic 1992;127(5):529-533. 50. Sevila A, Morell A, Banuls J, Silvestre JF, Betlloch I. Neu- eccrine hidradenitis. Arch Dermatol. Apr 1990;126(4):528- 18. Nikkels AF, Hansen I, Collignon J, Fassotte MF, Fillet trophilic eccrine hidradenitis in an HIV-infected patient. Int 529, 531-522. G, Pierard GE. Neutrophilic eccrine hidradenitis. A case J Dermatol. Sep 1996;35(9):651-652. 80. Scong VY, Appell ML, Sanders DY, Omura EF. Annular report. Acta Clin Belg. 1993;48(6):397-400. 51. Smith KJ, Skelton HG, 3rd, James WD, Holland TT, plaques on the dorsa of the hands. Neutrophilic eccrine 19. Wenzel FG, Horn TD. Nonneoplastic disorders of the Lupton GP, Angritt P. Neutrophilic eccrine hidradenitis in hidradenitis. Arch Dermatol. Sep 1991;127(9):1398-1399, eccrine glands. J Am Acad Dermatol. Jan 1998;38(1):1-17; HIV-infected patients. Armed Forces Retrovirus Research 1400-1392. quiz 18-20. Group. J Am Acad Dermatol. Nov 1990;23(5 Pt 1):945- 81. Crawford GH, Chu AY, Halpern M, James WD. Ery- 20. Phillips M, McAloon MH. A sweat-patch test for alcohol 947. thematous facial plaques in a patient with leukemia. consumption: evaluation in continuous and episodic drink- 52. Dauden E, Porras JI, Buezo GF, Garcia-Diez A. Eccrine Neutrophilic eccrine hidradenitis. Arch Dermatol. Apr ers. Alcohol Clin Exp Res. Oct 1980;4(4):391-395. squamous syringometaplasia and cytomegalovirus. Am J 2003;139(4):531-536. 21. Vree TB, Muskens AT, van Rossum JM. Excretion of Dermatopathol. Dec 2000;22(6):559-561. 82. Keane FM, Munn SE, Buckley DA, Hopster D, Mufti amphetamines in human sweat. Arch Int Pharmacodyn 53. Crowson AN, Nuovo G, Ferri C, Magro CM. The dermato- GJ, du Vivier AW. Neutrophilic eccrine hidradenitis Ther. Oct 1972;199(2):311-317. 17 pathologic manifestations of hepatitis C infection: a clinical, in two neutropaenic patients. Clin Exp Dermatol. Mar 22. Cone EJ, Hillsgrove MJ, Jenkins AJ, Keenan RM, Darwin histological, and molecular assessment of 35 cases. Hum 2001;26(2):162-165. WD. Sweat testing for heroin, cocaine, and metabolites. J Pathol. Jun 2003;34(6):573- 579. 83. Srivastava M, Scharf S, Meehan SA, Polsky D. Neutro- Anal Toxicol. Oct 1994;18(6):298-305. 54. Ortiz-Movilla N, Lazaro P, Rodriguez-Inigo E, et al. Hepa- philic eccrine hidradenitis masquerading as facial celluli- 23. Balabanova S, Buhler G, Schneider E, Boschek HJ, Sch- titis C virus replicates in sweat glands and is released into tis. J Am Acad Dermatol. Apr 2007;56(4):693-696. 20 neitler H. [Nicotine excretion by the apocrine and eccrine sweat in patients with chronic hepatitis C. J Med Virol. Dec 84. Marcoux D, Anex R, Russo P. Persistent serpentine sweat in smokers and passive smokers]. Hautarzt. Feb 2002;68(4):529-536. supravenous hyperpigmented eruption as an adverse 1992;43(2):73-76. 55. Drago F, Romagnoli M, Loi A, Rebora A. Epstein-Barr reaction to chemotherapy combining actinomycin and 24. Hoiby N, Johansen HK. Ciprofloxacin in sweat and antibi- virus-related persistent erythema multiforme in chronic vincristine. J Am Acad Dermatol. Sep 2000;43(3):540- otic resistance. The Copenhagen Study Group on Antibiot- fatigue syndrome. Arch Dermatol. Feb 1992;128(2):217- 546. ics in Sweat. Lancet. Nov 4 1995;346(8984):1235. 222. 25. Mercader-Garcia P, Vilata-Corell JJ, Pardo-Sanchez J, 56. Drago F, Ranieri E, Pastorino A, Casazza S, Crovato Fortea-Baixauli JM. Neutrophilic eccrine hidradenitis in F, Rebora A. Epstein-Barr virus-related primary cutane- a patient with Behcet’s disease. Acta Derm Venereol. ous amyloidosis. Successful treatment with acyclovir and 2003;83(5):395-396. interferon-alpha. Br J Dermatol. Jan 1996;134(1):170-174. 26. Bilic M, Mutasim DF. Neutrophilic eccrine hidradenitis in a BASILE, HAGHIGHI, SIMZAR, CRAFT, PENG, SHITABATA 45 PSEUDOMONAS FOLLICULITIS AFTER SWIMMING IN A POND: A UNIQUE CASE REPORT AND REVIEW
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
*OUSPEVDUJPO burn,” and prevented her from being able to sleep. She also reported having a low- Pseudomonas folliculitis (PF) has been grade fever and generalized achiness. She well documented and reported in random was current on her immunizations. No outbreaks since the early 1970s. Although one else in her family had any lesions, and generally associated with recreational use they all denied any recent travel or hot tub/ of hot tubs and whirlpools, outbreaks have whirlpool use. been reported after exposure to saunas, The patient’s past medical and surgical swimming pools, bathing facilities, water history was unremarkable, and she had slides and diving suits, and there has been no known drug allergies. Her review at least one reported outbreak after indus- of systems was negative except for the trial exposure to water used in a cardboard presenting complaint. 1 manufacturing plant. Pseudomonas aerugi- On physical exam, she had hundreds nosa has a ubiquitous distribution in soil of 1 to 3mm erythematous papules and and water and is not considered normal pustules distributed most densely in areas skin flora. PF outbreaks have been reported along where the elastic bands from her in the United States, Canada, Europe bathing suit had been, specifically her waist and Japan. P. aeruginosa serotype O:11 line, panty line, and bra line (Images 1,2). is most commonly associated with folli- Some of the papules were also scattered on culitis outbreaks, but other serotypes have her back, abdomen and proximal extremi- 2 been reported. Since 1971, the Centers ties. Most of the lesions were centered for Disease Control and Prevention (CDC) on a follicle. No lymphadenopathy was Figure 1 and the U.S. Environmental Protection appreciated. Agency have surveilled and reported on A presumptive diagnosis of swimmer’s waterborne diseases and outbreaks associ- itch (cercarial dermatitis) was made based ated with recreational water use (natural on the history of swimming in a fresh water and treated).3 To our knowledge, this is pond. The physical exam was not entirely the first reported case of PF associated with consistent with this diagnosis since she had swimming in a freshwater pond. a heavy concentration of lesions in areas The skin manifestations of PF include that had been covered by her swimsuit. We an erythematous, papulopustular rash that ordered a Gram stain from a scraping of is often pruritic and/or painful. Lesions one of the lesions; however, the specimen appear 24 to 48 hours after exposure to was mishandled so we did not get these contaminated water. The rash can have results. We decided to treat the patient a generalized distribution but is most symptomatically, and reserve biopsy concentrated around areas of tight-fitting for a future visit if she did not respond clothing. Associated symptoms may be adequately. present and include fever, muscle aches, To investigate the possibility of a bacte- fatigue and earache. Most cases are mild rial folliculitis, a bacterial culture was and self-limiting, with symptoms resolving obtained from a pustule on the patient’s spontaneously over seven to15 days. back. Also, because she was having systemic symptoms of fatigue and low-grade fevers, Case Report we obtained a complete blood count with differential. An 11-year-old Caucasian female from Figure 2 North Texas presented to the Dermatology Since the patient had been vaccinated Institute in August complaining of a rash against measles and chicken pox, we did of two days duration that first began one not believe these were the etiology of her with a short course of tapering oral steroid, day after swimming in a pond behind rash; but to rule out an atypical presenta- since the rash was affecting her and her her house. She first noticed the “bumps” tion of a herpes virus, a Tzanck smear was parents’ sleep. We prescribed an oral anti- around her waist and buttocks. The bumps made from the scraping of a pustule. histamine, hydroxyzine, as needed for were extremely itchy, “felt like a bad sun We elected to treat her severe itching itching. She was given a sample of a topical 46 PSEUDOMONAS FOLLICULITIS AFTER SWIMMING IN A POND: A UNIQUE CASE REPORT AND REVIEW later, the patient stated she was feeling syndrome, pseudomonas infection of much better and had less itching. She the palms and soles is attributed to skin had only needed a few of the “itch pills.” abrasions secondary to gritty, abrasive Upon inspection, most of the papules had linings of pools and wet decks.7,8 These cleared, and she just had some residual post cases present with painful, erythematous inflammatory hyperpigmentation (Images palmar and plantar nodules. Other cases of 3-5). No pustules or open areas could be pseudomonas folliculitis have been docu- found. The bacterial culture that was taken mented after wax epilation. four days earlier showed a heavy growth Our original diagnosis of cercarial of Pseudomonas aeruginosa. Her CBC dermatitis in this patient was clinically was within normal limits, and the Tzanck based on history, her presenting symptoms smear was non-diagnostic. A diagnosis of of tender, pruritic papules, and the strong Pseudomonas folliculitis was made. association of cercarial dermatitis with Based on the fact that there were no swimming in warm, shallow, freshwater signs of a persistent, active infection, and ponds and lakes. While the rashes may be a review of the literature, we decided not similar in appearance and share identical to start antibiotic therapy. The patient was symptoms, the distribution of the rash may instructed to finish her oral steroids and help distinguish between the two. Cercarial only use the topical steroid and oral anti- dermatitis usually affects areas of skin not histamine if needed for itching. She was to covered by clothing, whereas pseudomonas return to the clinic in two weeks. folliculitis most commonly affects areas that are covered. As is the case with many Figure 3 Eight days after her initial visit, the patient’s mother called, stating the patient conditions, there may be overlap between had “a few new bumps” on her waist line. the two. We believe this case demonstrates She was prescribed Silvadene (silver sulfa- that pseudomonas folliculitis is not limited diazine) cream and told to come back into to hot tubs and pools, and that history of the office if fever developed or the rash swimming in a freshwater pond should not spread. Otherwise, she was to keep her discourage a diagnosis of pseudomonas next follow-up appointment in 10 days. folliculitis when considering a diagnosis of Over the next few days, we were informed cercarial dermatitis. that the pruritis had resolved and she had no new papules or pustules. $MJOJDBM'FBUVSFT Discussion The rash of pseudomonas folliculitis will appear, on average, 48 hours after expo- In the United States from 1971 to 2000, sure to contaminated water, with a range a total of 259 outbreaks of waterborne of eight hours to five days.2,9 It begins as disease involving over 21,000 cases were a pruritic, erythematous, follicular and reported in association with recreational papular dermatitis with a characteristic water use.4 Pseudomonas was responsible distribution. It quickly progresses to a for 31% of cases from treated water, as tender and pruritic, papulopustular rash. compared to less than 1% from untreated The rash will be worst on areas of skin water. The reported illnesses included occluded by tight-fitting swimming suits. dermatitis, otitis externa and conjuncti- The head and face are usually spared, vitis. Pseudomonas folliculitis was associ- with the waist, buttocks, back and axilla Figure 4 ated most frequently with whirlpool baths, being most commonly affected. Although hot tubs and swimming pools. The most this distribution is characteristic, it is not commonly cited reason for Pseudomonas unique to pseudomonas folliculitis. outbreaks was improper maintenance of Other symptoms are uncommon but pH and chlorination in pool water, with include fever, lymphadenopathy, malaise, heavy swimmer burden and contamination otalgia, conjunctivitis, pharyngitis and as contributing factors. myalgias. These symptoms do not neces- Pseudomonas aeruginosa is a ubiquitous, sarily indicate bacteremia or systemic gram-negative, motile bacillus. Its ther- spread. The eruption clears usually within mophilic properties allow it to survive the seven to 15 days, but some patients may warm temperatures of hot tubs and whirl- experience recurrent crops of lesions for pools. Its pathogenesis in dermatitis is up to three months. It is unlikely that the thought to occur, in part, from superhydra- infection is spread from person to person; tion of the stratum corneum, promoting however, multiple members within a family Figure 5 colonization and follicular invasion.5 This may develop folliculitis concomitantly is supported by observations that frequent if the source of infection is within the steroid, Olux-E Foam (clobetasol propi- and extended use of whirlpools may be home.10 onate 0.05%), to apply once or twice daily risk factors.2 Occlusion likely promotes Diagnosis is generally made by history to affected areas as needed. Antibiotics invasion as well. The rash is typically most of hot tub or whirlpool exposure and were deferred pending bacterial cultures dense under areas occluded by bathing supported by physical exam. Under Wood’s suits or diving suits.2,6 Showering after lamp, a pale, green fluorescence may be and sensitivity. She was further instructed swimming does not seem to be protec- appreciated.11 It is not uncommon for to dispose of the swimsuit. tive. In a clinically distinct but related bacterial cultures from pustules to be nega- At her follow-up appointment four days syndrome, pseudomonas hot hand-foot tive. The CBC may show an elevated white HATTER, MILLER, WAY 47 blood cell count with a rise in neutrophils. patient presents with pustules. Although Histopathology demonstrates perifollicular, PF is usually mild and self-limited, prompt perivascular and perieccrine neutrophil recognition can help guide appropriate infiltration with edema of the interfolli- management. cular papillary dermis.8,10 References: Differential Diagnosis 1 Hewitt D, Weeks D, Millner G, Huss G. Indus- trial pseudomonas folliculitis. Am J Industrial Med The differential diagnosis for PF 2006;49(11):895-99. 2. Ratnam S, Hogin K, March S, Butler R. Whirlpool asso- includes staphylococcal infection, cercarial ciated folliculitis caused by pseudomonas aeruginosa: dermatitis, seabather’s eruption, scabies, Report of an outbreak and review. J Clin Microbiol 10 1986;23(3):655-59. and insect bites. Furthermore, the rash 3. Dziuban E, Liang J, Craun G, Hill V, Yu P, Painter J, has been confused with herpes simplex, Moore M, Calderon R, Roy S, Beach M. Surveillance for 2 waterborne disease and outbreaks associated with recre- chicken pox and contact dermatitis. In ational water- US, 2003-2004. In: CDC Surveillance Sum- at least one outbreak of pseudomonas hot maries, December 22, 2006. MMWR 2006;55(ss12)1-24. 4. Craun G, Calderon R, Craun M. Outbreaks associated hand-foot syndrome, the palmoplantar with recreational water in the United States. Int J Environ lesions led physicians to consider menin- Health Res 2005;15(4):243-62. 5. Hojyo-Tamoka M, Marples R, Kligman A. Pseudomo- gococcemia, Rocky Mountain spotted fever nas infection in superhydrated skin. Arch Dermatol and idiopathic palmoplantar hidradenitis.8 1973;107:723-27. 6. Saltzer K, Schutzer P, Weinberg J, Tangoren I, Spiers E. Swimmer’s itch, or cercarial dermatitis, Diving suit dermatitis: a manifestation of pseudomonas may occur on exposure to fresh or salt folliculitis. Cutis 1997;59(5):245-46. 7. Fiorillo L, Zucker M, Sawyer D, Lin A. The pseudomonas water. It is very pruritic and tends to cause hot-foot syndrome. N Engl J Med 2001;345(5):335-38. erythematous papules on body parts that 8. Yue Y, Cheng A, Wang L, Dumne W, Bayliss S. Hot tub folliculitis or hot hand-foot syndrome caused by were exposed to the water. Bacterial folli- pseudomonas aeruginosa. J Am Acad Dermatol July culitis can present as follicularly centered 2007, article in press. 9. Gustafson T, Band J, Hutcheson R, Schaffner W. papules and pustules with varying degrees Pseudomonas folliculitis: an outbreak and review. Rev of pruritis. Potential causes of bacte- Infect Dis 1983;5:1-8. 10. Zichi L, Asta G, Nato G. Pseudomonas aeruginosa rial folliculitis include Staphylococcus, folliculitis after shower/bath exposure. Int J Dermatol Streptococcus and Pseudomonas, as well as 2000;39(4):270-73. 11. Amichai B, Finkelstein E, Halevy S. Early detection of many others. Seabather’s eruption usually pseudomonas infection using a wood’s lamp. Clin Exp begins after bathing in the Atlantic Ocean; Dermatol 1994;19(5):449. 12 .Habif T. Clinical Dermatology. 4th edition. Mosby, it is caused by larvae that become trapped 2004:290. under the bathing suit and release their 13. Odem R, James W, Berger T. Andrew’s Diseases of the Skin: Clinical Dermatology. 9th edition. W.B. Saunders toxin because of external pressure. These Company, 2000:332. lesions tend to affect the buttocks, waist 14. Berger T, Kaveh S, Becker D, Hoffman J. Cutaneous manifestations of pseudomonas infections in AIDS. J Am and bra area. Viral exanthems can present Acad Dermatol 1995;32(2 Pt 1):279-80. as widespread erythematous papules, most 15. El Baze P, Thyss A, Caldani C, Juhlin L, Schneider M, Ortonne JP. Pseudomonas aeruginosa O-11 folliculitis. specifically varicella or measles. Development into ecthyma gangrenosum in immunosup- pressed patients. Arch Dermatol 1985;121(7):873-76. Management The infection of PF is generally mild and self-limited, demonstrating spon- taneous involution without medical therapy. However, a 5% acetic acid wet compress applied for 20 minutes two to four times per day and/or silver sulfadi- azine cream may be helpful.12 In patients who fail topical treatment, have severe or prolonged cases, or have fever and consti- tutional symptoms, a third generation oral cephalosporin or a fluoroquinolone may be used.12,13 A more aggressive approach would be necessary in immunosuppressed patients, including those with AIDS. In the immunosuppressed patient, PF can progress to cellulitis, panniculitis and/or ecthyma gangrenosum.14,15 Conclusion We described an isolated case of PF asso- ciated with swimming in a North Texas pond. While PF is generally associated with swimming in pools and hot tubs or other chemically treated waters, we do not believe a history of only non-treated water exposure should discourage this diagnosis. We also believe that a bacterial culture and sensitivity should be obtained anytime a
48 PSEUDOMONAS FOLLICULITIS AFTER SWIMMING IN A POND: A UNIQUE CASE REPORT AND REVIEW 5IF0OMZ'%""QQSPWFE#SBOEFE0SBM5IFSBQZGPS3PTBDFB
5.
03"$&")"4/0#3"/%&%03(&/&3*$#*0&26*7"-&/5p
0SBDFBJTJOEJDBUFEGPSUIFUSFBUNFOUPGPOMZJOnBNNBUPSZ MFTJPOT QBQVMFTBOEQVTUVMFT PGSPTBDFBJOBEVMUQBUJFOUT p1MFBTFTFFUIFGVMMQSFTDSJCJOHJOGPSNBUJPO 3FGFSFODF*.4)FBMUI /BUJPOBM%JTFBTFBOE5IFSBQFVUJD *OEFY $VTUPN3FQPSU 6OPSUIPEPYZDZDMJOFBOEi"OUJJOnBNNBUPSZ/PUBOUJNJDSPCJBMw BSFUSBEFNBSLT BOE0SBDFBBOE(BMEFSNBBSFSFHJTUFSFE USBEFNBSLT PG(BMEFSNB-BCPSBUPSJFT -1 ª (BMEFSNB-BCPSBUPSJFT -103"
'PSNPSFJOGPSNBUJPO WJTJUXXXPSBDFBDPN
4BGFUZ$POTJEFSBUJPOT *ODMJOJDBMUSJBMT UIFNPTUDPNNPOBEWFSTFFWFOUTSFQPSUFE PCTFSWFEJODMJOJDBMUSJBMT 0SBDFBQBUJFOUTTIPVMENJOJNJ[F XFSFHBTUSPJOUFTUJOBMVQTFUT OBTPQIBSZOHJUJTQBJOBOEOBTBM PSBWPJEFYQPTVSFUPOBUVSBMPSBSUJm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eep out of reach of children. MICROBIOLOGY The plasma concentrations of doxycycline achieved with ORACEA during administration (see DOSAGE AND ¥ ADMINISTRATION) are less than the concentration required to treat bacterial diseases. In vivo microbiological studies utilizing a similar drug exposure for up to 18 months demonstrated no detectable long-term effects on bacterial flora of the oral cavity, skin, intestinal tract, and vagina. Carcinogenesis, Mutagenesis, Impairment of Fertility: Doxycycline was assessed for potential to induce carcinogenesis in a study in which the compound was administered to Sprague-Dawley rats by gavage at Brief Summary of Full Prescribing Information dosages of 20, 75, and 200 mg/kg/day for two years. An increased incidence of uterine polyps was observed INDICATIONS AND USAGE in female rats that received 200 mg/kg/day, a dosage that resulted in a systemic exposure to doxycycline ORACEA is indicated for the treatment of only inflammatory lesions (papules and pustules) of rosacea in approximately 12.2 times that observed in female humans who use ORACEA (exposure comparison based upon adult patients. area under the curve (AUC) values). No impact upon tumor incidence was observed in male rats at 200 mg/kg/ The dosage of ORACEA differs from that of doxycycline used to treat infections. To reduce the development day, or in either gender at the other dosages studied. Evidence of oncogenic activity was obtained in studies with of resistant bacteria as well as to maintain the effectiveness of other antibacterial drugs, ORACEA should be related compounds, i.e., oxytetracycline (adrenal and pituitary tumors) and minocycline (thyroid tumors). used only as indicated. Doxycycline demonstrated no potential to cause genetic toxicity in an in vitro point mutation study with CLINICAL PHARMACOLOGY mammalian cells (CHO/HGPRT forward mutation assay) or in an in vivo micronucleus assay conducted in CD-1 mice. However, data from an in vitro assay with CHO cells for potential to cause chromosomal aberrations Pharmacokinetics suggest that doxycycline is a weak clastogen. ORACEA capsules are not bioequivalent to other doxycycline products. Oral administration of doxycycline to male and female Sprague-Dawley rats adversely affected fertility and CONTRAINDICATIONS reproductive performance, as evidenced by increased time for mating to occur, reduced sperm motility, velocity, This drug is contraindicated in persons who have shown hypersensitivity to doxycycline or any of the other and concentration, abnormal sperm morphology, and increased pre-and post-implantation losses. Doxycycline tetracyclines. induced reproductive toxicity at all dosages that were examined in this study, as even the lowest dosage WARNINGS tested (50 mg/kg/day) induced a statistically significant reduction in sperm velocity. Note that 50 mg/kg/day is Teratogenic effects: 1) Doxycycline, like other tetracycline-class antibiotics, can cause fetal harm approximately 3.6 times the amount of doxycycline contained in the recommended daily dose of ORACEA for a when administered to a pregnant woman. If any tetracycline is used during pregnancy or if the 60-kg human when compared on the basis of AUC estimates. Although doxycycline impairs the fertility of rats patient becomes pregnant while taking these drugs, the patient should be informed of the potential when administered at sufficient dosage, the effect of ORACEA on human fertility is unknown. hazard to the fetus and treatment stopped immediately. Pregnancy: Teratogenic Effects: Pregnancy Category D. (see WARNINGS section). Results from animal ORACEA should not be used during pregnancy (see PRECAUTIONS: Pregnancy). studies indicate that doxycycline crosses the placenta and is found in fetal tissues. 2) The use of drugs of the tetracycline class during tooth development (last half of pregnancy, Nonteratogenic effects: (see WARNINGS section). infancy, and childhood up to the age of 8 years) may cause permanent discoloration of the teeth Labor and Delivery: The effect of tetracyclines on labor and delivery is unknown. (yellow-gray-brown). This adverse reaction is more common during long-term use of the drug but has been Nursing Mothers: Tetracyclines are excreted in human milk. Because of the potential for serious adverse reactions observed following repeated short-term courses. Enamel hypoplasia has also been reported. Tetracycline drugs, therefore, should not be used during tooth development unless other drugs are not likely to in infants from doxycycline, ORACEA should not be used in mothers who breastfeed. (see WARNINGS section). be effective or are contraindicated. Pediatric Use: ORACEA should not be used in infants and children less than 8 years of age (see WARNINGS 3) All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate section). ORACEA has not been studied in children of any age with regard to safety or efficacy, therefore use has been observed in premature human infants given oral tetracycline in doses of 25 mg/kg every 6 hours. in children is not recommended. This reaction was shown to be reversible when the drug was discontinued. ADVERSE REACTIONS Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can Adverse Reactions in Clinical Trials of ORACEA: In controlled clinical trials of adult patients with mild to cause retardation of skeletal development on the developing fetus. Evidence of embryotoxicity has been noted moderate rosacea, 537 patients received ORACEA or placebo over a 16-week period. The most frequent in animals treated early in pregnancy (see PRECAUTIONS: Pregnancy section). adverse reactions occurring in these studies are listed in the table below. Gastrointestinal effects: Pseudomembranous colitis has been reported with nearly all antibacterial agents and may range from mild to life-threatening. Therefore, it is important to consider this diagnosis Incidence (%) of Selected Adverse Reactions in Clinical Trials of ORACEA (n=269) vs. Placebo (n=268) in patients who present with diarrhea subsequent to the administration of antibacterial agents. ORACEA Placebo Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Nasopharyngitis 13 (4.8) 9 (3.4) Studies indicate that a toxin produced by Clostridium difficile is a primary cause of “antibiotic-associated colitis”. Pharyngolaryngeal Pain 3 (1.1) 2 (0.7) If a diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild Sinusitis 7 (2.6) 2 (0.7) cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and Nasal Congestion 4 (1.5) 2 (0.7) treatment with an antibacterial drug clinically effective against Clostridium difficile colitis. Fungal Infection 5 (1.9) 1 (0.4) Metabolic effects: The anti-anabolic action of the tetracyclines may cause an increase in BUN. While this Influenza 5 (1.9) 3 (1.1) is not a problem in those with normal renal function, in patients with significantly impaired function, higher Diarrhea 12 (4.5) 7 (2.6) serum levels of tetracycline-class antibiotics may lead to azotemia, hyperphosphatemia, and acidosis. If renal impairment exists, even usual oral or parenteral doses may lead to excessive systemic accumulations of the Abdominal Pain Upper 5 (1.9) 1 (0.4) drug and possible liver toxicity. Under such conditions, lower than usual total doses are indicated, and if therapy Abdominal Distention 3 (1.1) 1 (0.4) is prolonged, serum level determinations of the drug may be advisable. Abdominal Pain 3 (1.1) 1 (0.4) Photosensitivity: Photosensitivity manifested by an exaggerated sunburn reaction has been observed in Stomach Discomfort 3 (1.1) 2 (0.7) some individuals taking tetracyclines. Although this was not observed during the duration of the clinical studies with ORACEA, patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or Note: Percentages based on total number of study participants in each treatment group. UVA/B treatment) while using ORACEA. If patients need to be outdoors while using ORACEA, they should Adverse Reactions for Tetracyclines: The following adverse reactions have been observed in patients wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures receiving tetracyclines at higher, antimicrobial doses: with their physician. Gastrointestinal: anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, and inflammatory PRECAUTIONS lesions (with vaginal candidiasis) in the anogenital region. Hepatotoxicity has been reported rarely. Rare instances General: Safety of ORACEA beyond 9 months has not been established. of esophagitis and esophageal ulcerations have been reported in patients receiving the capsule forms of the As with other antibiotic preparations, use of ORACEA may result in overgrowth of non-susceptible micro- drugs in the tetracycline class. Most of the patients experiencing esophagitis and/or esophageal ulceration took organisms, including fungi. If superinfection occurs, ORACEA should be discontinued and appropriate therapy their medication immediately before lying down. (see DOSAGE AND ADMINISTRATION section). instituted. Although not observed in clinical trials with ORACEA, the use of tetracyclines may increase the Skin: maculopapular and erythematous rashes. Exfoliative dermatitis has been reported but is uncommon. incidence of vaginal candidiasis. Photosensitivity is discussed above. (see WARNINGS section). ORACEA should be used with caution in patients with a history of or predisposition to candidiasis overgrowth. Renal toxicity: Rise in BUN has been reported and is apparently dose-related.(see WARNINGS section). Bacterial resistance to tetracyclines may develop in patients using ORACEA. Because of the potential for drug- Hypersensitivity reactions: urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness, resistant bacteria to develop during the use of ORACEA, it should be used only as indicated. pericarditis, and exacerbation of systemic lupus erythematosus. Autoimmune Syndromes: Tetracyclines have been associated with the development of autoimmune Blood: Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have been reported. syndromes. Symptoms may be manifested by fever, rash, arthralgia, and malaise. In symptomatic patients, liver function tests, ANA, CBC, and other appropriate tests should be performed to evaluate the patients. Use OVERDOSAGE of all tetracycline-class drugs should be discontinued immediately. In case of overdosage, discontinue medication, treat symptomatically, and institute supportive measures. Dialysis does not alter serum half-life and thus would not be of benefit in treating cases of overdose. Tissue Hyperpigmentation: Tetracycline class antibiotics are known to cause hyperpigmentation. Tetracycline therapy may induce hyperpigmentation in many organs, including nails, bone, skin, eyes, thyroid, visceral DOSAGE AND ADMINISTRATION tissue, oral cavity (teeth, mucosa, alveolar bone), sclerae and heart valves. Skin and oral pigmentation has THE DOSAGE OF ORACEA DIFFERS FROM THAT OF DOXYCYCLINE USED TO TREAT INFECTIONS. been reported to occur independently of time or amount of drug administration, whereas other pigmentation EXCEEDING THE RECOMMENDED DOSAGE MAY RESULT IN AN INCREASED INCIDENCE OF SIDE has been reported to occur upon prolonged administration. Skin pigmentation includes diffuse pigmentation EFFECTS INCLUDING THE DEVELOPMENT OF RESISTANT MICROORGANISMS. as well as over sites of scars or injury. One ORACEA Capsule (40 mg) should be taken once daily in the morning on an empty stomach, preferably at Pseudotumor cerebri: Bulging fontanels in infants and benign intracranial hypertension in adults have least one hour prior to or two hours after meals. been reported in individuals receiving tetracyclines. These conditions disappeared when the drug was Efficacy beyond 16 weeks and safety beyond 9 months have not been established. discontinued. Administration of adequate amounts of fluid along with the capsules is recommended to wash down the Laboratory Tests: Periodic laboratory evaluations of organ systems, including hematopoietic, renal and hepatic capsule to reduce the risk of esophageal irritation and ulceration. (see ADVERSE REACTIONS section). studies should be performed. Appropriate tests for autoimmune syndromes should be performed as indicated. Drug Interactions: 1. Because tetracyclines have been shown to depress plasma prothrombin activity, HOW SUPPLIED patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. ORACEA (beige opaque capsule printed with CGPI 40) containing doxycycline, USP in an amount equivalent to 2. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid 40 mg of anhydrous doxycycline. Bottle of 30 (NDC 64682-009-01). giving tetracycline-class drugs in conjunction with penicillin. 3. The concurrent use of tetracycline and Storage: All products are to be stored at controlled room temperatures of 15°C-30°C (59°F-86°F) and methoxyflurane has been reported to result in fatal renal toxicity. 4. Absorption of tetracyclines is impaired by dispensed in tight, light-resistant containers (USP). Keep out of reach of children. bismuth subsalicylate, proton pump inhibitors, antacids containing aluminum, calcium or magnesium and iron- Patent Information: U.S. Patents 5,789,395; 5,919,775; 7,232,572; 7,211,267 and patents pending. containing preparations. 5. Doxycycline may interfere with the effectiveness of low dose oral contraceptives. To ORACEA is a registered trademark of CollaGenex Pharmaceuticals, Inc. avoid contraceptive failure, females are advised to use a second form of contraceptive during treatment with doxycycline. 6. There have been reports of pseudotumor cerebri (benign intracranial hypertension) associated Manufactured by: Marketed by: with the concomitant use of isotretinoin and tetracyclines. Since both oral retinoids, including isotretinoin CardinalHealth Galderma Laboratories, L.P. and acitretin, and the tetracyclines, primarily minocycline, can cause increased intracranial pressure, the Winchester, KY 40391 Fort Worth, TX 76177 concurrent use of an oral retinoid and a tetracycline should be avoided. 7961-01 BPI 06/08 VARICELLA- ZOSTER VASCULITIS PRESENTING AS ECTHYMATOUS ULCERS
4UFQIFO"4XJUMZL .% +POBUIBO-$MFBWFS .4*7 .JDIBFM#.PSHBO .% $MJOJDBM"TTJTUBOU1SPGFTTPS %FSNBUPMPHZ 6OJWFSTJUZPG4PVUI'MPSJEB$PMMFHFPG.FEJDJOF UIZFBSNFEJDBMTUVEFOU ,JSLTWJMMF$PMMFHFPG0TUFPQBUIJD.FEJDJOF 1SPGFTTPSPG1BUIPMPHZ %FQBSUNFOUPG1BUIPMPHZ 6OJWFSTJUZPG4PVUI'MPSJEB$PMMFHFPG.FEJDJOF
ABSTRACT
Uncommon presentations of varicella zoster virus (VZV) are difficult to recognize and are often misdiagnosed. Herein, we describe a 71-year-old, immuno-competent male who presented with three circumscribed papules with central eschar and surrounding erythema. Upon histological examination, pronounced infiltrate of neutrophils and accompanying fibrin thrombi were visualized. Positive staining for VZV in-situ was localized to the vascular endothelia nuclei. A diagnosis of necrotizing leukocytoclastic vasculitis was rendered secondary to VZV. This report underscores the importance of clinico-pathologic correlation and should alert the reader to the varied clinical and pathologic presentations potentially encountered in VZV.
*OUSPEVDUJPO remaining titers, including herpes simplex virus 1 and 2 and other lab work, were Cutaneous eruptions caused by Varicella- normal. zoster virus (VZV) are relatively common, Microscopic examination revealed and in the average patient population, epidermal ulceration (Figure 1) with characteristic clinical findings can lead superficial dermal coagulative necrosis to a correct diagnosis. Varicella zoster, a (Figure 2). The dermal vessels contained a member of the herpes virus family, is a pronounced infiltrate of neutrophils, both common eruption conventionally char- intact and fragmented, with accompanying acterized by painful macules and papules fibrin thrombi (Figure 2-3). VZV in-situ that progress to vesicles and then to ulcers. hybridization showed positive staining These lesions manifest themselves in localized to the vascular endothelia nuclei. specific dermatomes.1 A prodromal period A diagnosis of VZV with leukocytoclastic often occurs, presenting as severe pain, vasculitis was rendered. paraesthesia or pruritus. Less commonly, the vesicular stage is circumvented, instead Discussion initially manifesting as a papular eruption, Figure 1. Two of the well bullae, or hyperkeratotic lesions. Herein, we Immunosuppressed patients (particularly circumscribed ulcers with central report a case of a previously documented HIV+ patients or individuals with hemato- black eschar and surrounding presentation of VZV as an ecthymatous logic disease) are most likely to present erythema. (4mm and 6mm). eruption with histologic features of leuko- with atypical clinical findings in cutaneous cytoclastic vasculitis. VZV.2,3,4 Unusual presentations may mimic is a routine accompaniment of cytomega- a cutaneous lymphoma, pseudolym- lovirus infection, it is exceptional for such Presentation of Case: phoma,2,3,4,5 or in one of several guises of changes to appear in conjunction with the cutaneous vasculitis. The most common other herpes virus agents, including HSV A 71-year-old, previously healthy male histologic types include leukocytoclastic, or VZV infection. presented with complaints of a “rash” on lymphocytic or granulomatous vasculitis. Lymphocytic vasculitis may be seen in his right leg that developed precipitously Leukocytoclastic vasculitis may be primary conjunction with reactivation of the virus. two weeks prior. The patient denied any (i.e. caused by the herpes virus itself) or Less commonly, granulomatous vasculitis insect bites, itching, burning or oozing represent a reactive process.2 Erhard et al6 may be seen with lymphocytic vascu- from the affected areas. Physical exam described the only other similar clinical litis.7,8 The granulomatous inflammation revealed three ulcers located on the right presentation of a painless skin eruption may be seen within the blood vessels or anterior thigh ranging from 3-6mm in size. consisting of ecthymatous nodules that the surrounding dermis, and rarely may The well-circumscribed papules consisted failed to form vesicles throughout the produce an interstitial pattern reminiscent of a central black eschar with surrounding disease process. The patient was immu- 9 erythema (Figure 1). A punch biopsy and nosuppressed, receiving treatment with of granuloma annulare. Cerebral vasculitis, the following serologies were performed: systemic chemotherapeutic agents for Stage although rare, has been described in asso- complete blood count, complete metabolic IV cutaneous T-cell lymphoma. Biopsies ciation with VZV, detectable by polymerase panel, C-reactive protein and herpesvirus 1 in this case similarly revealed a lack of chain reaction in the affected vessels as and 2, along with Varicella-zoster virus and epidermal involvement, with endothe- well as concomitant clinical findings such mycoplasma pneumonia antibody titers, lial changes of vasculitis and viral cyto- as a classic herpes zoster elsewhere on the 10,11 rheumatoid factor, anti-nuclear antibody, pathic effects confirmed by polymerase body. anti-phospholipid antibodies, Sjogren chain reaction (PCR) testing. Erhard et In cases of ecthymatous eruption with syndrome antigen A/Sjogren syndrome B, al. hypothesized that upon re-activation histologic features of leukocytoclastic vasc- complement studies, rapid plasma reagin, with VZV, epidermal invasion and/or folli- ulitis, VZV should be suspected, particu- hepatitis panel and serum protein elec- cular involvement was circumvented by the larly among the immunosuppressed, where trophoresis. The Varicella-zoster IgG and close proximity of dermal nerves to blood VZV can present in a variety of guises. IgM (1:1200) titers were positive. All of the vessels. Although endothelial involvement Although our patient was not immunosup- SWITLYK, CLEAVER, MORGAN 51 Figure 2. Hematoxylin and eosin stain on low power. nCentral epidermal ulceration.
Figure 3. Hematoxylin and eosin stain on high power. Polymorphnuclear infiltrate of fragmented neutrophils along the vessel wall with fibrin thrombi. pressed, the serologic studies and nuclear hybridization results aided in the correct diagnosis, establishing the importance of such studies in confirming a diagnosis.
References: 1. Anderson W, Safdar A. Varicella Zoster Virus: Emedicine http://www.emedicine.com/med/topic2361.htm. Accessed August 9, 2007. 2. Leinweber B, Kerl H, Cerroni L. Histopathologic Features of Cutaneous Herpes Virus Infections (Herpes Simplex, Herpes Varicella/Zoster): A Broad Spectrum of Presenta- tions with Common Pseudolymphomatous Aspects. Am J Surg Path. 2006;30:50-58. 3. Roo E, Villegas C, Lopez-Bran E, Jimenez E, Valle P, Sanchez-Yuz E. Post-Zoster cutaneous pseudolym- phoma. Arch Dermatol. 1994;130:971-4. 4. Wolf HH, Wendt V, Winzer M. Cutaneous pseudolym- phoma at the site of prior herpes zoster eruption. Arc Dermatol Res. 1987;279:S52-4. 5. Sanchez JL, Mendez JA, Palacio R. Cutaneous pseudo- lymphoma at the site of resolving herpes zoster. Arch Dermatol. 1981;117:377. 6. Erhard H, Runger TM, Kreienkamp M, Muller J, Muller- Hermelink HK, Brocker EB. Atypical varicella-zoster virus infection in an immunocompromised patient: result of a virus-induced vasculitis. J Am Acad Dermatol. 1995;32:908-911. 7. Gesierich A, Krahl D, Weiss H, Brocker EB, Rose C. Granulomatous dermatitis following herpes zoster with detection of varicella zoster virus DNA. J Ger Soc Der- matol, 2004;2:770-772. 8. Langenberg A, Yen TS, LeBoit PE. Granulomatous vasculitis occurring after cutaneous herpes zoster despite absence of viral genome. J Am Acad of Dermatol. 1991;24:429-433. 9. Uhoda I, Pierard-Franchimont C, Pierard GE. Varicella- zoster virus vasculitis: a case of recurrent varicella with- out epidermal involvement. Dermatol. 2000;200:173-175. 10. Outteryck O, Senechal O, Berteloot D, Delande I, Mounier-Vehier F. Cerebral vasculitis second- ary to Varicella-Zoster virus infection. Rev Neurolog. 2005;161:836-839. 11. Jain R, Deveikis J, Hickenbottom S, Mukherji SK. Vari- cella-zoster vasculitis presenting with intracranial hemor- rhage. Am J Neuroradiol. 2003;24:971-974.
52 VARICELLA- ZOSTER VASCULITIS PRESENTING AS ECTHYMATOUS ULCERS WAARDENBURG SYNDROME: A CASE PRESENTATION
+BNFT+#SJMFZ +S %0 %BWJE#,FTTMFS %0 .BSWJO48BUTLZ %0 SEZFBS%FSNBUPMPHZ3FTJEFOU 4U+PIOT&QJTDPQBM)PTQJUBMo4PVUI4IPSF 'BS3PDLBXBZ /FX:PSL .BTTBQFRVB%FSNBUPMPHZ .BTTBQFRVB /FX:PSL %FSNBUPMPHZ3FTJEFODZ1SPHSBN%JSFDUPS 4U+PIOT&QJTDPQBM)PTQJUBMo4PVUI4IPSF 'BS3PDLBXBZ /FX:PSL
ABSTRACT
Waardenburg syndrome (WS) is a rare, inherited disorder of neural crest cell development that was first described in1947 by Dr. Petrus Johannes Waardenburg, a Dutch ophthalmologist. It is an auditory-pigmentary syndrome caused by a defect in neural crest cell migration and melanin synthesis. WS is the most common form of inherited congenital deafness worldwide. In this paper, a case report of WS will be presented. Also, we will discuss the prevalence, clinical findings, diagnostic criteria, inheritance patterns, pathophysiology, and prognosis of WS in order to raise awareness and provide a better understanding of this rare genodermatosis.
Case Presentation family pedigree (Figure 5) and the clinical findings and criteria set forth for WS as discussed below (Table 1). History A 53-year-old Caucasian male with a Discussion past medical history significant for hypertension, hypertriglyceridemia, and Background piebaldism presented with the complaint of WS is a rare, inherited disorder of non-healing, red, scaly patches of skin on neural crest cell development with almost his arms and face for several months dura- complete penetrance but variable expres- tion. His medications included amlodipine, sivity.1 It is characterized by deafness in gemfibrozil, and aspirin. He had no known association with pigmentary anomalies of medication allergies. His family history the skin, hair, and eyes, as well as some- was significant for a son, mother, and aunt times other neural-crest-derived tissue Figure 1 with white forelocks of hair resembling defects. It has also been referred to as Van his own (Figure 1), a sister with a white der Hoeve-Halbertsma-Gualdi syndrome, forelock and deafness since birth, and his Ptosis-Epicanthus syndrome, and Mende maternal grandmother with a white fore- syndrome. lock and hearing loss. The first documented description of Physical Exam WS was in 1947 by Dr. Petrus Johannes Waardenburg, a Dutch ophthalmologist. On physical exam, erythematous, scaly He reported a patient having hearing loss, papules were found scattered on the face dystopia canthorum, and retinal pigmen- and forearms. These were clinically diag- tary differences. In 1951, the syndrome nosed as actinic keratoses, and subsequently was formally named after Dr. Waardenburg treated with liquid nitrogen cryotherapy. subsequent to him identifying many other More interestingly, our patient was noted patients with similar signs and symptoms, to have a white forelock of hair on the as well as describing six characteristic frontal scalp, present since birth according features. Figure 2 to the patient, as well as pigmentary incon- The six characteristic features first tinence of many terminal hairs on his described by Dr. Waardenburg include: 1) arms, legs, and abdomen, with underlying dystopia canthorum – lateral displacement subtypes of WS, classified by phenotype leukoderma. He was previously diagnosed of the medial canthi in addition to dystopia and clinical findings, mode of inheritance, in childhood with piebaldism based on of the lacrimal puncta; 2) broad and high and gene mutations (Table 2). The most these findings. However, in addition to nasal root; 3) synophrys – hypertrichosis of common forms of WS include types 1 and the above, he also had bilateral segmental the medial part of the eyebrows; 4) partial 2, while types 3 and 4 are rare. heterochromia irides, a broad nasal root or total heterochromia iridis; 5) white WS can be inherited in an autosomal- with mild synophrys, and extensive leuko- forelock; and 6) congenital sensorineural dominant (AD) or autosomal-recessive derma of his arms, legs, and abdomen, hearing loss.2 Today, these findings are (AR) fashion, with the latter being less giving an overall “dappled” appearance to most closely associated with WS type 1. common. It is frequently apparent at birth his skin (see Figures 1-4). and is the most common form of inherited Due to the additional physical find- Epidemiology congenital deafness worldwide.4 Affected ings and abnormalities, the previous The prevalence of WS is estimated to individuals have a higher risk for neural- diagnosis of piebaldism was questioned. be one in 42,000 worldwide, with men tube defects, cleft lip and palate, limb Subsequently, we diagnosed our patient and women being equally affected. WS is abnormalities, and Hirschsprung disease, with Waardenburg syndrome (WS), auto- responsible for 2-5% of all cases of congen- also known as congenital aganglionic somal-dominant type 1, established by his ital deafness.3 Today, there are four known megacolon. BRILEY, KESSLER, MARVIN S. WATSKY 53 complete heterochromia iridis, partial Table 1 or segmental heterochromia iridis, or Major Criteria Minor Criteria hypoplastic blue iridis. A white forelock and a broad and high nasal root are also Congenital sensorineural hearing loss Congenital leukoderma commonly seen in those affected with WS. Pigmentary disturbances of the iris – Medial eyebrow flare (Synophrys) Dystopia canthorum is found in WS types complete, partial or segmental 1, 3, and 4, and is present when the calcu- heterochromia iridis; hypoplastic lated W index exceeds 1.95 in the formula W index = X + Y + a/b (Figure 6). blue iridis Other clinical findings in WS include: White forelock Broad and high nasal root multiple nevi, eyebrow anomalies, cleft Dystopia canthorum Hypoplasia of alae nasi lip and palate, receding chin, Sprengel’s shoulder (congenital upward scapular 8 index > 1.95 displacement), spina bifida, syndactyly Affected first-degree relative Premature graying of hair (WS type 3), hypoplasia or contractures of the limbs (WS type 3), and Hirschsprung disease (WS type 4). Table 2 Differential Diagnosis 5ZQF %JTUJOHVJTIJOH'FBUVSFT *OIFSJUBODF (FOF%FGFDU Because WS consists of auditory and pigmentary abnormalities, the differential WS1 Dystopia canthorum AD PAX3 (2q35-q37) diagnosis varies widely and includes any W index > 1.95 syndrome with either auditory or pigmen- Hearing loss (~25%)9 tary abnormalities, or both. The differential diagnosis includes diseases such as: Tietz WS2 No dystopia canthorum AD; AR MITF (3p14.1-p12.3) syndrome, Ziprkowski-Margolis syndrome, Hearing loss (~50%)9 SLUG (AR) (8q11.21) Woolf’s syndrome, Fisch’s syndrome, WS3 WS 1 + musculoskeletal AD PAX3 (2q35-q37) Rozycki’s syndrome, ocular albinism with (Klein- defects (upper limb) sensorineural deafness, piebaldism, and nonsyndromic sensorineural hearing loss Waardenburg) hypoplasia (Table 3). WS4 WS 1 + Hirschsprung’s AR > AD EDN3 (20q13.2-q13.3) Pathophysiology (Shah- disease = congenital EDNRB (13q22) Waardenburg) aganglionic megacolon SOX10 (22q13) WS is an auditory-pigmentary syndrome caused by a defect in neural crest cell migration, melanocyte differentiation, and melanin synthesis. The physical absence of melanocytes from the skin, hair and Table 3 eyes and stria vascularis of the cochlea is 4ZOESPNF $MJOJDBM'JOEJOHT responsible for the expressed phenotype of WS.7 To date, there are six known gene Tietz Syndrome Albinism and deafness mutations in WS, all of which are critical Ziprkowski-Margolis Syndrome Deaf-mutism, heterochromic irides, for the development and migration of and piebaldism (XLR) neural crest cells, in particular melanocytes (Table 2). Woolf’s Syndrome Piebaldism and deafness Microphthalmia transcription factor Fisch’s Syndrome Deafness, premature graying, and (MITF) is a leucine zipper transcription partial heterochromia iridis factor that transactivates the gene tyro- sinase, a key enzyme for melanogenesis. Rozycki’s Syndrome Leukoderma, congenital deafness, MITF is critically involved in melanocyte muscle wasting, and achalasia differentiation. Defects in MITF lead to absence of melanocytes affecting pigmen- Piebaldism Leukoderma and poliosis with tation of the hair, skin and eyes and stria mutation in C-KIT gene vascularis of the cochlea.8 MITF gene mutations are seen in WS type 2, where there is a higher incidence of hearing loss Diagnosis the criteria for WS type 1 in addition to as compared to WS type 1 due to the stria other neural-crest defects specific for each vascularis being affected (Table 2).9 In 1992, the Waardenburg Syndrome type. WS type 3, also known as Klein- Paired box gene 3 (PAX3) encodes for Consortium proposed diagnostic criteria Waardenburg syndrome, has musculoskel- DNA-binding transcription factors and for WS type 1 based on specific clinical etal defects, such as upper limb hypoplasia, 5 is defined by a paired homeodomain findings. Individuals with two major, as its distinct feature. And WS type 4, also transcription factor. PAX3 transactivates or one major plus two minor criteria are known as Shah-Waardenburg syndrome, the MITF promoter, thereby indirectly considered to be affected with WS type has Hirschsprung disease as its distinct regulating MITF. PAX3 defects result in 1 (Table 1). In 1995, Liu et al. defined feature. WS type 2 as those individuals having craniofacial and skeletal malformations.10 two major criteria without dystopia Clinical Findings Mutations in PAX3 result in WS types 1 6 and 3. canthorum. Clinical findings in WS include pigmen- WS types 3 and 4 are diagnosed using tary disturbances of the iris that include SRY-related HMG-box gene 10 (SOX10) belongs to the high-mobility group (HMG) 54 WAARDENBURG SYNDROME: A CASE PRESENTATION box super-family of DNA-binding proteins. subtle but pertinent clinical findings. This SOX10 is expressed in the formation of case presentation serves to bring greater the peripheral nervous system, and can awareness and a better understanding of be detected in the enteric ganglia. SOX10 WS, a rare genodermatosis, in order to aid works in synergy with PAX3 to activate in accurate diagnosis, appropriate genetic MITF.11 SOX10 gene mutations result in counseling and testing, and early interven- WS type 4, where Hirschsprung disease is tion strategies. seen. Snail homolog 2 (SNAI2 or SLUG) is References: a zinc finger transcription factor that is a 1. Waardenburg PJ. A new syndrome combining develop- downstream target of MITF and a marker mental anomalies of the eyelids, eyebrows and nose root with pigmentary defects of the iris and head hair and with for neural crest cells. SLUG gene muta- congenital deafness. Am J Hum Genet 1951; 3:195-253. tions result in WS type 2, where dystopia 2. Tagra S, Talwar AK, Walia RS, Sidhu P. Waardenburg Figure 3 Syndrome. Indian J Dermatolo Venereol Leprol 2006; canthorum is absent. 72:326-326. Endothelin 3 (EDN3) and endothelin 3. Nayak CD, Isaacson G. Worldwide distribution of Waardenburg syndrome. Ann Otol Rhinol Laryngol 2003; receptor type B (EDNRB) are endothelium- 112:817-20. derived vasoactive peptides that interact 4. Groundfast KM, Siparshy N, Chuong D. Genetics and molecular Biology of Deafness. Otolaryngol Clin North together and are essential for develop- Am 2000; 33:1367-1394. ment of neural-crest-derived cell lineages 5. Farrer LA, Grundfast KM, Amos J, Arnos KS, Asher JH Jr, Beighton P, et al. Waardenburg syndrome (WS) type such as melanocytes and enteric neurons. 1 is caused by defects at multiple loci, one of which is Mutations in EDN3 and EDNRB result in near ALPP on chromosome 2: First report of the WS Consortium. Am J Hum Genet 1992; 50:902-13. WS type 4, where Hirschsprung disease is 6. Liu XZ, Newton VE, Read AP. Waardenburg syndrome seen. type II: phenotypic findings and diagnostic criteria. Am J Med Genet 1995 Jan 2; 55(1):95-100. 7. Fish C. Deafness as part of a hereditary syndrome. J Prognosis, Prevention, and Laryngol Otol 1959; 73:353-62. 8. Waardenburg PJ. A new syndrome combining develop- Treatment mental anomalies of the eyelids, eyebrows and nose root with pigmentary defects of the iris and head hair and with Figure 4 The prognosis of WS depends on the congenital deafness. Am J Hum Genet 1951; 3:195-253. subtype, with subtypes 3 and 4 being more 9. Liu XZ, Newton VE, Read AP. Hearing loss and pigmen- tary disturbances in Waardenburg’s syndrome with refer- severe in phenotype. Nonetheless, those ences to WS type II. J Laryngol Otol 1995; 109:96-100. affected with WS generally have a normal 10. Tagra S, Talwar AK, Walia RS, Sidhu P. Waardenburg Syndrome. Indian J Dermatolo Venereol Leprol 2006; lifespan and normal intelligence with the 72:326-326. appropriate interventions, such as: newborn 11. Nayak CD, Isaacson G. Worldwide distribution of Waardenburg syndrome. Ann Otol Rhinol Laryngol 2003; screening for hearing loss, hearing aids, 112:817-20. cochlear implants, special diets and medica- 12. Groundfast KM, Siparshy N, Chuong D. Genetics and molecular Biology of Deafness. Otolaryngol Clin North tions for proper gastrointestinal motility Am 2000; 33:1367-1394. (WS type 4), and durable medical equip- 13. Farrer LA, Grundfast KM, Amos J, Arnos KS, Asher JH Jr, Beighton P, et al. Waardenburg syndrome (WS) type ment for proper ambulation and daily-func- 1 is caused by defects at multiple loci, one of which is tioning activities (WS type 3). near ALPP on chromosome 2: First report of the WS Consortium. Am J Hum Genet 1992; 50:902-13. However, there is an increased risk of 14. Liu XZ, Newton VE, Read AP. Waardenburg syndrome alveolar rhabdomyosarcomas with PAX3 type II: phenotypic findings and diagnostic criteria. Am J Med Genet 1995 Jan 2; 55(1):95-100. gene mutations found in WS types 1 and 3. It is prudent to offer genetic testing and counseling for families affected with WS because most cases are AD in nature. In Figure 5 addition, folic acid supplementation has been recommended for women of child- bearing age with WS, especially WS type 1, due to the increased incidence of neural- tube defects in offspring. Conclusion WS is a rare, inherited disorder of neural crest cell development characterized by deafness in conjunction with pigmen- tary abnormalities, and sometimes other neural-crest-derived tissue defects. Though Figure 6 penetrance is nearly 100%, there is a wide W index = X + Y + a/b degree of expressivity among those indi- where X = (2a – 0.2119c – 3.909) / c viduals affected. However, WS remains the where Y = (2a – 0.2479b – 3.909) / c most common form of inherited congenital a = inner canthal distance in deafness worldwide. millimeters b = interpupillary distance in This case presentation serves as a millimeters reminder that diagnoses, just as disease c = outer canthal distance in processes, can be dynamic and ever millimeters changing with increasing knowledge. Our patient was originally diagnosed with piebaldism, but later was found to meet the criteria for WS based on family history and BRILEY, KESSLER, MARVIN S. WATSKY 55 CASE REPORT: HYPERPROLIFERATIVE HSV INFECTIONS IN HIV PATIENTS
3PCFSU"/PSNBO %0 .1) -BOB)BMBCJ .4*7 /PWB4PVUIFBTUFSO6OJWFSTJUZ 'PSU-BVEFSEBMF '-
A 48-year-old African American male the most significant causes of opportu- the chronic nature of this disease in HIV with HIV/AIDS presented to the clinic nistic infections in patients with HIV. As patients and the increasing resistance to for evaluation and treatment of a rapidly opposed to the self-limiting herpetic infec- acyclovir, it is necessary for the physician progressing lesion on his right tricep. He tions in immunocompetent individuals, to be thorough in the diagnostic workup stated that it began as a very small lesion the lesions of herpes simplex in patients of this disease. Physicians must be aware but got progressively larger over the course with HIV/AIDS are often irregular in shape that multiple biopsies and cultures may of a two-month period. He reported and do not resolve readily. Lesions can be necessary to come to a final diagnosis. continued, serous drainage, which had become chronic and progress to epidermal Sensitivity testing and a more aggressive increased in the past week. The patient necrosis and painful ulcerations.2 Often, the approach to medical and surgical therapy stated the triamcinolone cream prescribed cutaneous manifestations in these immu- may be necessary to assist in care and treat- by his primary care physician worsened nocompromised patients can be tissue ment of this disease. his condition. In addition, over the past destructive and large.3 They can present few weeks he noticed two similar, smaller atypically and are frequently confused with References: 4 lesions both on his right buttocks and pyoderma and other diseases. Examples 1. Fangman W, Myers S, Rao C. Hypertrophic herpes sim- perirectally. of the various clinical presentations include plex virus in HIV patients. Journal of Drugs in Dermatol- ogy 2003 Apr; 2(2):198-201. Past medical history was remarkable for a crusty appearance, an ulcerous-vegetating 2. Garman M, Tyring S. The cutaneous manifestations of a diagnosis of HIV 10 years prior (CD4 45, appearance, a verrucous appearance, or an HIV infection. Dermatologic Clinics. 2002 Apr; 20(2):193- 208 viral load undetectable), as well as depres- extensively erosive appearance. As a result 3. Georgiev, Vassil. Opportunistic infections: Treatment and sion. His antiretroviral regimen consisted of this atypical presentation, the diagnosis Prophylaxis. Humana Press 2003. 4. Trope B, Lenzi M. AIDS and HIV infections: uncommon of Videx, Kaletra, and Truvada. His other can be difficult, and patients are often presentations. Clinics in Dermatology. 2005 Nov-Dec medications included Dapsone 50mg daily treated unsuccessfully with several antibi- (23); 572-580. and acyclovir 800mg twice daily, which otics before HSV is eventually diagnosed.4 he admitted to taking only sporadically The pathogenesis of the proliferative over a one-year period secondary to nature of HSV lesions in HIV is unclear financial difficulties. His drug-allergy and controversial. Some theories include history was negative. Family history was that the HSV presentations seen in HIV noncontributory. patients are a result of overproduction of Physical exam of the posterior aspect of tumor necrosis factor and the recruitment the right distal arm revealed an ulcerated, of T cells and cytokines, combined with the vegetating 4.5 x 5cm plaque with yellow increased duration of the disease course.1 exudates and hemorrhagic crusting. In addition, the tendency for HIV patients At the time of presentation, a shave to heal more slowly and experience more biopsy was performed, and the patient was frequent reactivation of the virus may also 3 treated empirically with Ciprofloxacin and be contributory. Bactroban ointment. The patient returned Further, atypical presentations of the for follow-up one week later with clinical herpes simplex virus seem to be more improvement. A lesional skin biopsy was common in patients who have already obtained and found to be consistent with a started prophylactic acyclovir. The inci- herpes simplex virus infection. The patient dence of acyclovir-resistant infection in was then treated with Famciclovir 500mg HIV-positive patients is approximately twice daily. After several weeks of therapy, 5%.3 Acyclovir resistance has made treating no significant clinical improvement was HSV infections in HIV patients signifi- noted. A repeat biopsy was performed cantly more challenging for physicians. due to the concern of neoplastic transfor- Higher doses may be required, suscepti- mation. GMS, AFB, Fite stain, and tissue bility testing may be necessary, and there gram stains were found to be negative for may be a need to make use of second- and microorganisms. Multinucleated giant third-line antiviral drugs. If the HSV lesion cells, as well as immunohistological studies, does not respond to acyclovir in five to 10 confirmed the diagnosis of HSV. Surgical days, then resistance can be suspected.1 options were discussed, and the patient Intravenous Foscarnet is the most effective agreed to wide excision of the lesion. The drug used for treating acyclovir-resistant buttocks lesions were also biopsied and herpes simplex lesions, but it is limited by reported as herpes simplex infections. its substantial, renal-toxic side effects.2 Discussion Summary Herpes virus infections frequently have Taking into consideration the vari- cutaneous manifestations and are one of ability of presentations of HSV lesions,
56 CASE REPORT: HYPERPROLIFERATIVE HSV INFECTIONS IN HIV PATIENTS CLASSIC PRESENTATION OF NEVOID BASAL CELL CARCINOMA SYNDROME IN A 49-YEAR-OLD FEMALE: A CASE PRESENTATION AND REVIEW
+BDPC8JMMJBN8BUUFST 0.4*** .FMJOEB(SFFOmFME %0 5IJSEZFBS0TUFPQBUIJD.FEJDBM4UVEFOU (FPSHJB$BNQVTPGUIF1IJMBEFMQIJB$PMMFHFPG0TUFPQBUIJD.FEJDJOF 4VXBOFF (FPSHJB **Clinical Assistant Professor GA-PCOM, Private Practice, Albany Dermatology Clinic, Albany, Georgia
ABSTRACT
We present a 49-year-old patient who demonstrated plantar-palmar pitting as well as widespread basal-cell carcinoma lesions classically seen in nevoid basal-cell carcinoma syndrome (NBCCS). We present clinical findings and her response to trichloroacetic acid, and we review current literature for other physical manifestations of the disease as well as comparisons of various treatments.
These treatments include Mohs surgery, INF/immunoglobulins, curettage with and without electrodessication, CO2 laser resurfacing, cryosurgery, and both trichloroacetic acid and 5% fluorouracil topical applications.
*OUSPEVDUJPO multiple and recurrent KCOTs, with subse- quent extreme craniofacial disfigurement, Since the skin is the organ most as well as the characteristic cutaneous commonly affected by neoplasms,1 it BCCs on the body and palmar-plantar stands to reason that key cutaneous disor- pitting as seen in Figures 1 through 4. The ders and diseases be paid special attention patient’s mother, however, was affected only and periodically reviewed, especially those by the cutaneous neoplasms. Our patient with classic and easily recognizable presen- has two sisters, one 42 years old and the tations. The following article serves as a other 46, both of whom are also NBCCS review for the condition known as nevoid patients. The younger sister has a history basal-cell carcinoma syndrome (NBCCS). of a solitary KCOT and recurrent history It has been well documented that NBCCS, of BCCs. The older sister has a history of also known as Gorlin-Goltz syndrome and multiple and recurrent keratocystic odon- Figure 1 basal-cell nevus syndrome, is a disorder togenic tumors with only occasional BCCs. characterized by an autosomal-dominant Generally speaking, patients are affected pattern of inheritance. The classic mani- primarily by either the cutaneous mani- festation consists of keratocystic odonto- festation of NBCCS or the oral manifesta- genic tumors (KCOT), multiple basal-cell tions, as opposed to both.5 Our patient carcinomas (BCC) arising throughout has a son in his mid-twenties who was first the skin, and a multitude of consistently diagnosed with NBCCS at the age of six. documented musculoskeletal abnormali- He reportedly was affected exclusively by ties (Table 1).1,2,3 The BCCs resulting from KCOTs, which necessitated a string of inva- the disease are common in areas unexposed sive oral procedures. The KCOTs present in to the sun, and they most commonly affect the son displaced at least one tooth into the the face, neck, back, thorax, abdomen and child’s orbit, though with removal of the extremities, in that order.2 cyst and with braces it was brought back The genetic mutations or deletions into the oropharynx proper. Much like the Figure 2 leading to NBCCS are located on chro- cases previously reported, the occurrence of mosome 9q22.3, which codes for the new KCOTs subsided as he approached the 5-9 PTCH gene, a gene that interacts with end of his third decade. This family holds the hedgehog set of genes involved in true to the generalization that complica- tions within NBCCS families are relatively the segmentation and development of 5 the limbs and other anatomical struc- similar throughout generations. tures.1 Regardless of the initial origin of Our patient, much like her mother, BCCs, sporadic or hereditary, the histo- was affected only by the cutaneous mani- logic presentation and pathologic course festations of the disease, demonstrating are indistinguishable.4 The incidence of the classic palmar-plantar pitting seen NBCCS is approximately one per 56,000.5 in anywhere from half to three-quarters of patients5,6,8 (Figures 1-4). She also had Case Presentation multiple BCCs over her body surface, classically in areas unexposed to the Figure 3 Our patient is a 49-year-old Caucasian sun3 (Figures 5-10). Interestingly, these palmar-plantar pits, as well as the KCOTs female with a familial history of NBCCS. the patient felt Differin cream was ineffec- She was first diagnosed with NBCCS at the that commonly develop in these patients, tive at preventing recurrent BCC lesions. age of 11. Both her mother and maternal are unlikely to transform into malignant grandmother were known NBCCS patients. lesions.5 Acitretin was discontinued primarily due The patient’s grandmother was the first Initially, the patient was treated with to the patient’s complaint of xerostomia, known family member to have the disease. 0.1% Differin cream at night along with a known side effect of retinoids. Other The grandmother reportedly manifested the systemic retinoid acitretin. Over time, treatments attempted before reaching WATTERS, GREENFIELD 57 Table 1 .VTDVMPTLFMFUBMBOEPUIFSQIZTJDBMNBMGPSNBUJPOT BTTPDJBUFEXJUI/#$$4
NVTDVMPTLFMFUBMNBMGPSNBUJPOT abnormal cutaneous frontal/temporal bossing10 manifestations prognathism3 facial milia2,3,6 cardiac fibroma5 comedonal lesions3 keratocystic odontogenic epidermal cysts3 tumors1-3,7,8,10 fibromas3,5 Figure 4 bifid/splayed ribs3,7,10 lipomas3 kyphoscoliosis2,3,7,10 café au lait spots3 cervical/thoracic vertebral numerous pigmented nevi2,3 anomalies3,7,10 hypertrophic ectopic spina bifida3,7,10 calcification3,5,10 marfanoid syndrome3 palmar/plantar pits1,3,6 pectus excavatum3,7 pectus carinatum3 misc. other manifestations shortened 4th metacarpals3 ovarian fibromas3,5,10 hypogonadism3,10 neurologic/brain manifestations cryptorchidism3,7,10 mental retardation3,7,8,10 testicular agenesis3 Figure 5 schizophrenia7 adrenal cortical adenoma3 EEC abnormalities3 Hodgkin’s lymphoma5 corpus callosum agenesis2,3 dural/falx/tentorial calcification3,7,10 craniofacial malformations seizures3,5 hypertelorism7,10 congenital hydrocephalus3 ophthalmic abnormalities5,7,10 nerve deafness3 dystophia canthorum3,10 medulloblastoma3,5 strabismus5,7 glaucoma3 colombas of retina/iris3,10 cleft lip7 Figure 6 her current prophylactic management Discussion KCOTs (up to 90.5%), and the fact that in consisted of topical 5-fluorouracil (5-FU), one study, 8% of all 83 patients presenting topical retinoids, cryosurgery, and surgical As previously stated, there can be with any number of KCOTs were found excision (Figures 5-10). This patient’s numerous findings in NBCCS patients, to have NBCCS, highlights the need for current prophylactic maintenance consists the most recognizable of which are wide- close monitoring of patients with these oral 5,6,8,9 primarily of 50-70% trichloroacetic acid spread BCCs and KCOTs. The triad of lesions. Consultation with the patient’s primary dentist is also warranted, as often- chemical peels every five to six weeks. This BCCs, KCOTs, and dural calcifications were times a dentist or other oral health care treatment has proven effective and has concomitantly found in the majority of patients (70.6%) in one 2007 study, making professional is first to discover the signs resulted in fewer tolerance complaints from of NBCCS. In one 2007 study,9 24 percent the patient. Though the exact number of these findings together highly suggestive of NBCCS.8 Ocular abnormalities present of patients were diagnosed with NBCCS lesions before prophylactic treatment and in more than one-quarter of patients, and as an incidental finding upon presentation after treatment have not been tabulated, it ovarian fibromas/calcifications present in to an oral health clinic. For those patients is our and the patient’s rough approxima- who presented to a dental clinic in this almost one-quarter of female patients with same study, approximately 75% of patients tion that new lesions have been reduced NBCCS.5 Recurrent BCCs, with or without reported the vague symptoms of swelling, by 75% or more with the current treat- palmar-plantar pitting, is highly suggestive ment. While the literature on the utiliza- pain, or discharge of the oropharynx.9 of NBCCS. Patients with recurrent KCOTs may find tion and effectiveness of trichloroacetic A patient presenting to a dermatology acid chemical peels for the treatment of some solace in the fact that the incidence of office may not be innately inclined to KCOTs drops off after puberty, though any BCCs in NBCCS is sparse, it has been an report elements of his or her oral and cran- patient with NBCCS has an increasing risk effective prophylactic treatment, signifi- iofacial medical history. Should there be for the development of an initial KCOT as cantly reducing new BCC lesions in our any question of NBCCS or a history of he or she ages.5 Patients can be assured that patient and in the 10 patients with primary recurrent BCCs, questioning the patient while the oral neoplasms have potential to BCCs who had a mean follow-up of over directly about his or her dental health be disfiguring if not treated early, there is 26 years as reviewed by Hantash et al. (see could prove pertinent. The high incidence little or no concern for malignant trans- Table 2).20 of patients with NBCCS presenting with formation of the cysts.5 Any patient who 58 CLASSIC PRESENTATION OF NEVOID BASAL CELL CARCINOMA SYNDROME IN A 49-YEAR-OLD FEMALE patients with medulloblastomas, suggesting patients.4 Mohs surgery has also proven this group has a predilection for developing highly effective in the treatment of patients mental retardation. Any NBCCS patient with established histories of recurring has a 5% lifetime risk for developing a BCCs, with subsequent recurrence rates medulloblastoma.5 of 4% after surgery (patients numbered As with any inheritable genetic disorder, 1,484).14 Regardless of whether the lesions genetic counseling should be discussed were primary or recurrent, Mohs surgery with NBCCS patients. The primary focus had an overall recurrence rate of less than should center on the fact that a child with 3% in an Australian study of more than one parent known to have NBCCS has a 3,000 patients.14 Surgical procedures on any 50% chance of developing NBCCS in his NBCCS patient should be limited, as these or her lifetime, and the complications of patients will be treated for recurrent BCCs Figure 7 NBCCS tend to be similar within families, throughout their lives (for an example of as already discussed.5 Patients who ulti- a primarily surgical approach to the initial mately choose to have children should be treatment of NBCCS in a 32-year-old reminded of the importance of regular female, read the article by Doctoroff et checkups and sun protection. al.).15 Intravenous interferon and immu- 5SFBUNFOUBOE1SFWFOUJPO noglobulin agents may also be used off- label in the management of BCCs, with In the review of current literature, it is complete responses commonly greater than apparent there are many approaches for 60% and reportedly as high as 100% (see the long-term treatment and management Smith et al. for more detailed informa- of NBCCS, though there seem to be few tion and summary of multiple studies).16 reports of trichloroacetic acid used prophy- And, of course, imiquimod 5% cream may lactically. The treatment regime chosen for also be used open-label in the treatment Figure 8 any particular patient will be highly depen- of BCC, with similar success to the topical dent upon physician knowledge, skill and interferon agents.15,17,18 A 64% confirmed comfort, available options, cost and insur- histopathological clearance of BCCs ance coverage of specific treatment options, was reported in one 2007 study utilizing and the individual desires of the patient. 5% imiquimod cream.18 One case study Treatment will be lifelong; therefore, any reported successful prophylactic treatment treatment should have the patient’s full of a 25-month-old with the combination support so that compliance is not an issue. treatment of 5% 5-FU cream and 0.1% If we look at the treatment etiology of topical tretinoin cream.19 NBCCS as no different than the treatment Anatomic location is always an impor- etiology of spontaneous BCCs unrelated tant factor in choosing any form of derma- to NBCCS, as their histologic appearance tological treatment, and this is no different and pathologic progression are essentially for patients with NBCCS. The literature the same,4,11 then differing therapies can be on the specific use of trichloroacetic Figure 9 assessed. Recurrence at a site of a previous acid chemical peels for the prophylactic BCC is considered to result from incom- treatment specifically of BCC is sparse. plete removal of the initial neoplasm. However, one randomized, prospective In the case of sporadic BCCs, methods five-year study comparing the incidence that produce lower recurrence rates are of non-melanoma skin cancers (NMSC) considered more successful at fully excising between controls and three different treat- or otherwise completely resolving the ment modalities, including topical 5-FU, neoplasms. In comparing these therapies, 30% topical trichloroacetic acid, and CO2 however, it is important to remember laser resurfacing, determined all three were that recurrent BCCs are to be expected in equally effective, but the application of 30% NBCCS regardless of the chosen therapy. trichloroacetic acid once a month had the In treating BCCs curettage alone has lowest NMSC incidence per patient years as reportedly been similarly effective to compared to the other two modalities20 (see curettage with electrodesiccation,2 with Table 2). The authors also reported patients Figure 10 curettage alone having the advantage of preferring chemical peels to 5% 5-FU due being less likely to cause hypertrophic scar- to the once-a-month application, reduced is newly diagnosed with NBCCS should ring (see Table 2). In the non-randomized cutaneous irritation, and rapid recovery 20 be advised to seek regular dental checkups, clinical trial of 204 patients in the paper times. Both the trichloroacetic acid group especially prepubescent children. by Rodriguez-Vigil et al., a recurrence rate and the 5% 5-FU group had only a single as low as 1.2% at five years for patients incidence of squamous-cell carcinoma Additional concerns in newly diagnosed treated with curettage and electrodesicca- (SCC), and neither group had any incidents pediatric cases of NBCCS include brain 20 tion was reported. It is important to note, of primary BCC. The CO2 laser group, tumors such as glioblastoma multiforme, though, that in this achievement of such however, developed three primary BCCs in meningioma, and medulloblastoma a low recurrence rate, all patients studied three different patients.20 multiforme, and mental retardation. were treated by the same physician, who Doctoroff et al. chose to use combination Most of these tumors are expected to had over 30 years experience.13 therapy in a 32-year-old female NBCCS manifest within the first two years of life, Mohs surgery achieved recurrence rates patient presenting with approximately 45 though.3,5,7,8,10 Evans et al. (1993) reported 15 as low as 1.4% at five years for primary BCCs lesions on her face. Full-face CO2 mental retardation only in the cases of BCCs in a study of over 1,800 Australian laser resurfacing was chosen as her primary WATTERS, GREENFIELD 59 Table 2 0WFSWJFXBOEDPNQBSJTPOPGWBSJPVTUSFBUNFOUTJOTFMFDUFETUVEJFTGPS#$$MFTJPOT
5Y0QUJPOT 3FDVSSFODF3BUFT "EWBOUBHFT %JTBEWBOUBHFT USFBUFE Df_jjli^\ip`e(²9::(+ (%+ 7,pij c`kkc\jZXii`e^# jfd\n_Xk`emXj`m\# 5(#/'' _`^_jlZZ\jjiXk\ \og\ej`m\#gk]\Xij Df_jjli^\ip`egkjn`k_)' +%' 7,pij c`kkc\jZXii`e^# jfd\n_Xk`emXj`m\# (#+/+ i\Zlii\ek9:: _`^_jlZZ\jjiXk\ \og\ej`m\#gk]\Xij @E=&`ddlef^cfYlc`ej(,$(/ β_`^_cpmXi`XYc\ efjZXii`e^#\Xjpkf _`^_cp\og\ej`m\#c\jj βj\\ X[d`e`jk\i#gkZfdgc`XeZ\ \]]\Zk`m\&i\c`XYc\ jkl[`\j(,$(/ ZfdgXi\[kffk_\id\k_f[j :li\kkX^\n`k_<;(* (%) 7,pij c`kkc\jZXii`e^# jZXii`e^gfk\ek`Xc )'+ `e\og\ej`m\ nfij\k_Xekfg`ZXcko :li\kkX^\"&$<;() *$(/%/ 7,pij `e\og\ej`m\#\Xjpkf mXi`XYc\i\jgfej\& α-#0.( d\Xe3/%( g\i]fid i\Zlii\eZ\iXk\j :ipfjli^\ip), (%) 7,pij `e\og\ej`m\#\Xjp c`d`k\[jkl[`\j χ,,) X[d`e`jkiXk`fe#c`kkc\&ef kfgifm\\]]\Zk`m\e\jj jZXii`e^ *' ki`Z_cfifXZ\k`ZXZ`[)' !'%'+ )' `e\og\ej`m\#\Xjp cXZbjcXi^\jZXc\jkl[`\j (' j`e^c\ki\Xkd\ek d\Xegkp\Xijkf X[d`e`jkiXk`fe#_`^_gk kf[\k\id`e\\]]\Zk`m\e\jj# ]fccfn$lg4)-%(' Zfdgc`XeZ\#c`kkc\&efjZXii`e^ `ejliXeZ\Zfm\iX^\ , ]clfifliXZ`cZi\Xd)' !'%)( )' _`^_cp\]]\Zk`m\#c`kkc\ `ejliXeZ\Zfm\iX^\# / 9`;o*n\\bj d\Xegk$p\Xijkf &efjZXii`e^#\Xjp \og\ej`m\ ]fccfn$lg4)*%/* kfX[d`e`jk\i )' )' (,#)($)* :F)cXj\ii\jli]XZ`e^ !'%(, fk_\ijkl[`\j \og\ej`m\#`emXj`m\#dXp - [flYc\gXjj d\Xegk$p\XijXk hl\jk`fe\]]\Zk`m\e\jj XZklXccp`eZi\Xj\9:: ]fccfn$lg4)'%*. i\Zlii\eZ\iXk\j
ED – electrodesiccation α10 independent studies with varying skill levels over several decades βincompatibility of studies does not allow for simplification to fit into table χnumber of BCC lesions treated, not actual patients *P value <0.001 treatment modality for these lesions.15 after the procedure, excluding Fulton et al., applied chemicals that are activated by While she had complete facial re-epithe- which does state a moisturizer with SPF-34 light to kill superficial tissues. Its success in lization at one month, at two months was used post-resurfacing.5,21-24 Fulton et al. the treatment of BCCs has been variable, two BCCs developed on her face (subse- theorized the ineffectiveness of laser resur- and there is a trend toward more effective quently treated with Mohs surgery), and facing may be attributable in part to its treatments for superficial lesions.26-29 The four additional BCC neoplasms developed precise nature of penetration, which does cosmetic outcome with the use of photody- at 10 months (also subsequently treated not penetrate any deeper at pre-malignant namic therapy has generally been described with Mohs surgery).15 In another paper sites, which generally have greater depth as good to excellent.26-29 by Iyer et al. in 2004, 23 patients treated than surrounding tissue.23 Though not referenced here, both topical with multiple-pass UlraPulse CO2 laser Cryosurgery can also be highly effective and systemic retinoids may be used in the resurfacing had a BCC recurrence rate of in the treatment of BCCs, provided proper management of NBCCS patients.30 The 3.2% (two patients) within 36 months.21 selection of candidates and adequate proce- side effects of retinoids should, of course, Additional studies question the effective- dures are undertaken. In the treatment of be discussed with patients ahead of time. ness and utility of CO2 laser resurfacing in one series of 552 BCC lesions, Kuflick had a They commonly include: cheilitis, dry the treatment of BCCs,22 some reporting recurrence rate as low as 1.2% at five years.25 mucosa, xerosis, retinoid-induced derma- rapid development of NMSC after laser In the treatment of over 4,400 NMSC titis, enhanced granulation tissue, body resurfacing,15,22,23 while still others are lesions, of which nearly 4,000 were BCCs, stiffness, and hyperlipidemia. Retinoids are inconclusive or supportive.21,24 It should be Kuflick reported a total cure rate of 98.6%.25 not generally considered to be a primary noted that most of the studies discussing The success of his treatments is likely due to treatment for NBCCS, but they may have laser resurfacing hold little or no discus- his strict implementation of technique. significant adjunctive benefits.30-33 In one sion of sunscreen utilization by the patients Photodynamic therapy uses topically twin study from 1989, with one twin on
60 CLASSIC PRESENTATION OF NEVOID BASAL CELL CARCINOMA SYNDROME IN A 49-YEAR-OLD FEMALE 0.4 mg/kg/day of isotretinoin and the Table 2, trichloroacetic acid has the lowest use them as a first-line treatment when other on 0.2 mg/kg/day, the higher-dose recurrence rate for the treatment of BCCs; compared to the alternatives.15-18 twin demonstrated four times fewer BCCs however, the largest limitation is the small Mohs surgery has a great deal of data compared to the lower-dose twin.30 number of patients, just 10, treated in supporting it as an effective treatment with Ultraviolet light protection is especially this manner. The benefits of choosing a low recurrence rates of primary BCCs. important in these patients and should not regime of trichloroacetic acid is its easy However, due to the nature of continued be undervalued for the prevention of BCCs. application, infrequent application (in BCC lesions expected in NBCCS, relying One 2005 study demonstrated that NBCCS our case, every six to eight weeks), little to solely on Mohs surgery for long-term treat- cells are more sensitive to UVB than no scarring as a result of treatment, and ment seems a poor choice despite good controls, though their response to UVC compliance outside the office visit is not an expected cosmetic outcomes for single was essentially the same as controls.11,34 issue. The drawbacks to trichloroacetic acid surgeries. Additionally, Mohs surgery is chemical peels as treatments for BCC are not readily available in many areas and is Summary of Table 2 cost, which may not be covered by insur- much more expensive than other treat- ance; and while there are limited studies ment choices that have good results. What Table 2 summarizes the benefits and proving trichloroacetic acid as highly effec- Mohs surgery has over most of the other consequences, in very general terms, of the tive in treating primary BCCs, there are treatment modalities is large-scale studies different treatments discussed in regard no large-scale studies supporting its use in proving its effectiveness in the treatment of to managing BCC lesions. Some of these BCC caused by NBCCS. primary BCCs. studies address the management of BCCs in Curettage with electrodesiccation (ED) NBCCS patients, while others only address and cryosurgery have recurrence rates Conclusion the treatment of BCCs from non-hered- as low as 1.2% in the treatment of BCC itary causes. We are allowed to compare lesions at five years.13,25 Both are inexpen- More data is needed before trichlo- these two different BCC etiologies only sive and easy to administer and generally roacetic acid and other topically applied because their histopathologic progression cause minimal or no scarring.13,25 Studies medical treatments can be conclusively and description is indistinguishable from proving the effectiveness of using cryosur- determined to be beneficial in the treat- one another.4 We were unable to find any gery alone as treatment for BCC lesions are ment of BCCs in NBCCS. However, there large-scale comparative studies specifically limited.25 Both treatments can be consid- is enough evidence to support the use of addressing the use of trichloroacetic acid ered in treating NBCCS patients, but it some of these treatments in the manage- chemical peels in managing BCC lesions in must be remembered that any NBCCS ment of NBCCS. Which modality is chosen NBCCS patients. The only other discussion patient will have recurrent BCC lesions will be determined by the clinician’s we found concerning trichloroacetic acid throughout his or her lifetime, and as such experience and skill, the patient’s insur- chemical peels specifically in the manage- even a small potential for scarring can have ance coverage, local availability, and the ment of BCC lesions in NBCCS patients significant cosmetic consequences over patient’s acceptance of various cosmetic was a case reporting of a 76-year-old time. Curettage with or without ED can outcomes. It was our decision to treat our woman by the Japanese authors Kaminaka have recurrence rates as little as 3.0% or patient with a once-a-month, topical treat- et al. from the Department of Dermatology as high as almost 20%, with a mean of ment of trichloroacetic acid. In our case of Wakayama Medical University in Japan.35 approximately 8.0% at five years.12 The data the concentration used to treat our patient This patient presented to the authors with used to generate this information comes was considerably higher than in previous multiple BCC lesions ranging from 3-50 from a review of literature over the course studies already mentioned. The patient was mm in diameter.35 She was treated three of several decades from 10 different studies started at a lower concentration of trichlo- times in one month using a combination in which the skill level of the physicians roacetic acid and gradually titrated up to of 60% trichloroacetic acid and phenol involved is highly variable. As such it is higher concentrations (50-70%) as toler- chemical peels.35 She was followed up at difficult to accurately interpret whether ated. Given our success in the prophylactic one-year with complete resolution.35 At two curettage alone should be the sole treat- prevention of hereditary BCCs and the years, additional biopsies from previous ment choice as there is a high degree of apparent success of other authors in the BCC sites demonstrated no recurrence.35 variability in outcomes.12 treatment of primary BCC lesions using However, as promising as these result Five percent 5-FU cream, double-pass the application of trichloroacetic acid once might sound, the diagnosis of NBCCS in a month, or every six to eight weeks, we CO2 laser resurfacing, and INF/immuno- this patient was based on skin biopsies and globulins may also be used as treatment suggest trichloroacetic acid chemical peels the concomitant presence of dural calcifica- options. Both 5-FU cream and CO laser be considered in the management of all 35 2 tions confirmed by X-ray only. There was resurfacing have recurrence rates of less NBCCS patients afflicted with the cuta- no family history with this patient, which is than 0.21%, but the small number of neous manifestations of the disease. rarely the case with NBCCS as it is a geneti- patients treated with these methods cally inheritable disorder, and the authors in this review does not allow these two References: failed to report when the BCC lesions first treatments to be considered conclusively 35 1. Grulio R, editor. Robbins and Cotran: Pathologic Basis of began to arise. The fact that there were no effective. 5-FU has the benefit of being Disease, 7th ed. Philadelphia: Elsiever Saunders; 2005. new BCC lesions reported in the two-year 2. Gorlin RJ, Goltz RW. Multiple nevoid basal-cell epithe- easy to administer and results in essentially lioma, jaw cysts and bifid rib: a syndrome. New England interim without continued therapy makes it no scarring. While CO laser resurfacing Journal of Medicine 1960;262(18):908-12. highly doubtable that this patient suffered 2 3. Hurwitz S, MD. Clinical Pediatric Dermatology: A Text- seemingly has a low recurrence rate, it is book of Skin Disorders of Childhood and Adolescence, from NBCCS. Her age alone can easily also a much more invasive and expensive 2nd ed. W.B. Saunders Company. Philadelphia, PA. account for both the multiple BCC lesions 1993. modality that some studies suggest may 4. Ling et al. PATCHED and p53 gene alterations in and dural calcification, both of which are actually increase the recurrence rate of sporadic and hereditary basal cell cancer. Oncogene much more common in the elderly. We 15,20-23 2001;20:7770-8. BCCs. INF and immunoglobulins 5. Evans DGR, Ladusans EJ, Rimmer S, Burnell LD, Thak- would like to have more data supporting may be easy to administer and result in ker N, Farndon PA. Complications of the naevoid basal the use of trichloroacetic acid chemical cell carcinoma syndrome: results of a population based little scaring, but their clinical outcome is study. Journal of Medical Genetics 1993;30:460-4. peels for both treatment and prophylaxis also highly variable, and the medication is 6. Crean SJ. Gorlin’s Syndrome: main features and of BCCs in NBCCS, but studies and case recent advances. British Journal of Hospital Medicine expensive. While INF and immunoglob- 1996;56(8):392-7. reports on the subject are sparse. ulins are not ruled out in the treatment 7. Fernandez et al. Odontogenic tumors: a study of 340 Compared to the raw data presented in cases in a Brazilian population. J Oral Pathol Med of BCCs in NBCCS, it is questionable to 2005;34(10)-583-7.
WATTERS, GREENFIELD 61 8. Friedrich RE. Diagnosis and treatment of patients with nevoid basal cell carcinoma syndrome [Gorlin-Goltz Syn- drome (GGS)]. Anticancer Research 2007;27:17838. 9. Habibi A et al. Keratocystic odontogenic tumor: a 10-year retrospective study of 83 cases in an Iranian population. J of Oral Science. 2007;49(3)229-35. 10. Lo Muzio et al. Nevoid basal cell carcinoma syndrome. Clinical findings in 37 Italian affected individuals. Clin Genet 1999;55(1):34-40. 11. Applegate et al. Hypersensitivity of skin fibroblasts from basal cell nevus syndrome patients to killing by ultra- violet B but not ultraviolet C radiation. Cancer Research 1990;50:637-41. 12. Barlow et al. Treatment of basal cell carcinoma with curettage alone. J of the American Academy of Dermatol- ogy 2006;54:1039-45. 13. Rodriquez-Vigil T et al. Recurrence rates of primary basal cell carcinoma in facial risk areas treated with curettage and electrodesiccation. J of the American Academy of Dermatology 2007;56:91-5. 14. Leibovitch et al. Basal cell carcinoma treated with Mohs surgery in Australia. II. Outcome at 5-year follow up. J of the American Academy of Dermatology 2005;53:452-7. 15. Doctoroff et al. Full-face carbon dioxide laser resurfac- ing in the management of a patient with the nevoid basal cell carcinoma syndrome. Dermatologic Surgery 2003;29:1236-40. 16. Smith et al. Off-label uses of biologics in dermatology: interferon and intravenous immunoglobulin (Part 1 of 2). J of the American Academy of Dermatology 2007;56: e1-54. 17. Blasi MA, Giammaria D, Balestrazzi E. Immunotherapy with imiquimod 5% cream for eyelid nodular basal cell carcinoma. American J of Ophthalmology 2005;140;1136- 9. 18. Eigentler et al. A phase III, randomized, open label study to evaluate the safety and efficacy of imiquimod 5% cream applied thrice weekly for 8 to 12 weeks in the treatment of low-risk nodular basal cell carcinoma. J of the American Academy of Dermatology 2007;57:616-21. 19. Strange PR, Lang Jr. PG. Long-term management of basal cell nevus syndrome with topical tretinoin and 5-fluorouracil. J of the American Academy of Dermatol- ogy 1992;27:842-5. 20. Hantash et al. Facial resurfacing for nonmelanoma skin cancer prophylaxis. Arch of American Derm 2006;142:976-82. 21. Iyer et al. Treatment of basal cell carcinoma with pulsed carbon dioxide laser: a retrospective analysis. Derm Surg 2004;30:1214-8. 22. Stratigos et al. Rapid development of nonmelanoma skin cancer after CO2 laser resurfacing. Arch of Derm 2002 ;138;696-7. 23.Fulton et al. Disappointing results following resurfacing of facial skin with CO2 lasers for prophylaxis of keratosis and cancers. Dermatol Surg 2000;26:93-4. 24. Massey et al. A case reporting of laser resurfacing as a skin cancer prophylaxis. Derm Surg 1999:25;513-516. 25. Kuflick E. Cryosurgery for skin cancer: 30-year experi- ence and cure rates. Derm Surg 2004;30:297-300. 26. Chapas AM, Gilchrest BA. Broad area photodynamic therapy for treatment of multiple basal cell carcinomas in a patient with nevoid basal cell carcinoma syndrome. J Drugs Dermatol 2006:5;3-5. 27. Itkin A, Gilchrest BA. delta-Aminolevulinic acid and blue light photodynamic therapy for treatment of multiple basal cell carcinomas in two patients with nevoid basal cell car- cinoma syndrome. Derm Surg 2004;7:1054-61. 28. Kopera et al. Different treatment modalities for the man- agement of a patient with the nevoid basal cell carci- noma syndrome. J of the American Academy of Derm 1996;34;937-9. 29. Madan et al. Nodular basal cell carcinoma in Gorlin’s syn- drome treated with systemic photodynamic therapy and interstitial optical fiber diffuser laser. J of the Academy of Derm 2006:55;586-9. 30. Goldenberg et al. Effectiveness of isotretinoin in prevent- ing the appearance of basal cell carcinomas in basal cell nevus syndrome. J of the American Academy of Derm 1989;21: 144-145. 31. Cristofolini et al. Aromatic retinoid in chemoprevention of the progression of nevoid basal cell carcinoma syndrome. J of Derm Surg and Onc 1984:10:778-81. 32. Hodak et al. Etretinate treatment of the nevoid basal cell carcinoma syndrome. Inter Journal of Derm 1987;26:606- 9. 33. Peck et al. Chemoprevention of basal cell carcinoma with isotretinoin. J of the American Academy of Derm 1982;6:815-23. 34. Nishigori et al. Impaired removal of 8-hydroxydeox- yguanosine induced in naevoid basal cell carcinoma syndrome cells. British J of Derm 2005;153:52-56. 35. Kaminaka et al. Nevoid basal cell carcinoma syndrome treated with trichloroacetic acid and phenol peeling. J of Derm 2007;34:841-43.
62 CLASSIC PRESENTATION OF NEVOID BASAL CELL CARCINOMA SYNDROME IN A 49-YEAR-OLD FEMALE Members of the AOCD may advertise "position available"
This is a free service for all active members of the AOCD. A 3" column black and white ad will be provided in the journal as a free service. If members wish to use a larger space, they may do so. The cost for this advertising is:
Black and White - 1/4 page-$125, 1/2 page-$200, full page-$350
Full 4 color ad - 1/4 page-$275, 1/2 page-$350, full page-$500
Resident members may run a 3" column black and white ad stating their desired professional position.
These ads must be submitted as an e-mail attachment and sent to [email protected]. Any photos to be included in an active member's ad, must be in a .pdf format.
63 A 58-YEAR-OLD FEMALE WITH A HISTORY OF RENAL TRANSPLANT AND MULTIPLE NON-MELANOMA SKIN CANCERS, RECENTLY DIAGNOSED WITH MERKEL-CELL CARCINOMA
#SJBO",PQJU[LJ %0 ,JNCBMM84JMWFSUPO %0 4FDPOEZFBS3FTJEFOU (FOFTZT3FHJPOBM.FEJDBM$FOUFS (SBOE#MBOD .* .JDIJHBO4UBUF6OJWFSTJUZ4UBUFXJEF$BNQVT4ZTUFN 1SPHSBN%JSFDUPS (FOFTZT3FHJPOBM.FEJDBM$FOUFS (SBOE#MBOD .* .JDIJHBO4UBUF6OJWFSTJUZ4UBUFXJEF$BNQVT4ZTUFN
ABSTRACT
Solid-organ transplant recipients comprise a growing population at high risk for cutaneous neoplasms resulting in significant morbidity and mortality. Non-melanoma skin cancer accounts for 90% of all skin cancer in transplant patients, with squamous-cell carcinoma being the most common by far, occurring 65 times more frequently than basal cell and 10 times more frequently than in the general population. Other types of skin cancers such as Merkel cell, AFX, angiosarcoma, verrucous carcinoma, and CTCL are thought to have a higher incidence as well, although the actual numbers are not known because the data is based solely on anecdotal reports. These skin cancers are more aggressive in transplant patients, with a higher frequency of local recurrence, metastasis, and mortality. We present a case of a 58-year-old female with a history of multiple SCCs and a recent diagnosis of Merkel-cell carcinoma as well as a literature review of squamous-cell carcinoma in transplant patients.
)JTUPSZBOE$MJOJDBM movable and does not appear fixed to any underlying structures (Figure 2). Presentation: Lymphatic exam failed to reveal any We present the case of a 58-year-old adenopathy. female who first presented to our office two years ago with multiple actinic keratosis on Dermatohistopathology: her extremities, some of them thickened Many biopsies of her extremities have with cutaneous horns, and some lesions been performed over the two years we have suspicious for Bowen’s disease. She has been following her, and they have revealed a history of renal transplant in 2000 for numerous occurrences of squamous-cell focal segmental glomerulosclerosis, and her carcinoma in situ. She did have one inci- medications include cyclosporine150mg dence of a well-differentiated, invasive Figure 1: Erythematous, hyperkeratotic qd, mycophenolate mofetil 500mg bid, squamous-cell carcinoma as well. and prednisone 5mg qd. She has blond plaque on sun-exposed surface The lesion from her hand shows irregular hair, blue eyes, and a prior history of sun consistent with SCC. sheets and cords of hyperchromatic cells exposure but no previous diagnosis of within the dermis. The cells have relatively skin cancer. She has been in good health uniform size, round to ovoid in shape, otherwise, and her past medical history with scant cytoplasm and fine dusky chro- includes controlled hypertension and matin. Mitotic figures are quite abundant. hyperparathyroidism. Her graft status has Immunohistochemical stains are positive been excellent, with a stable creatine and for pancytokeratin and synaptophysin, and regular follow-up with her nephrologist show perinuclear, globular-appearing dot- and transplant surgeon. like positivity with Cytokeratin 20. This The patient follows up on a regular basis is consistent with Merkel-cell carcinoma with our office, every two to three months, (Figures 3, 4, 5, 6). for surveillance and treatment and has done so for the past two years, often with 5IFSBQZBOE$PVSTF a clinical presentation similar to the one Figure 2: Nodule of right hand, painless and freely mobile. described above. Recently she presented The patient’s therapy for her actinic with a different-appearing lesion involving keratoses, squamous-cell carcinoma in situ, the dorsal web space of the right hand, and invasive SCC has been largely surgical, which is described in greater detail below. with electrodessication and curettage, exci- coverage. The sentinel lymph node study sion, and cryosurgery (for AKs). In total, was negative, and she is continuing to Physical Exam: she has had approximately 40 cancerous progress in her recovery. and pre-cancerous lesions removed by our There are multiple erythematous, hyper- office. She had been on topical 5-FU prior Discussion: keratotic lesions involving the sun-exposed to her presentation to our office, and the surfaces of her extremities, some of which large surface area of damaged skin limited Solid-organ transplant recipients (OTRs) have cutaneous horns (Figure 1). There is the tolerability. We will likely proceed comprise a growing population at high a field effect of sun damaged skin involving with long-term systemic retinoid therapy risk for cutaneous neoplasms resulting in the sun-exposed surfaces of her integu- pending approval from her nephrologist. significant morbidity and mortality. There ment. She also has multiple well-healed Upon the diagnosis of the Merkel cell, were 25,000 solid-organ transplantations surgical scars from previous excisions. she was sent to the Merkel-cell clinic at performed in the United States in 2003,1 The nodule of her right hand measures University of Michigan, where she under- and this number continues to increase as 1.6cm and involves the dorsal web space went successful, wide local excision of techniques are refined and postoperative of the 2nd and 3rd metacarpal. It is freely the lesion with split-thickness skin-graft management improves. Non-melanoma
64 A 58-YEAR-OLD FEMALE WITH A HISTORY OF RENAL TRANSPLANT AND MULTIPLE NON-MELANOMA SKIN CANCERS, RECENTLY DIAGNOSED WITH MERKEL-CELL CARCINOMA skin cancer (NMSC) accounts for 90% of photosensitizer offers an advantage over all skin cancer in transplant recipients.2 5-aminolevulinate in that it has enhanced There is an inversion of the normal basal- lipophilicity and thus greater skin penetra- cell carcinoma (BCC) to squamous-cell tion, and greater specificity for neoplastic carcinoma (SCC) ratio, which is four to cells.9 one in non-immunosuppressed patients.1 A transplant patient who has greater In transplant recipients, SCC occurs 65 than five NMSCs in one year should be times as frequently as in the general popu- evaluated for prophylactic systemic retin- lation, and BCC is increased by a factor of oids.2 Kovach et al. (2005) looked at nine 10.3 The cumulative incidence increases trials with original data and showed that with number of years post-transplantation, eight of nine of these studies revealed a from 7% after one year of immunosup- decreased incidence of NMSCs in response Figure 3: H&E 10x showing irregular pression, to 45% after 11 years, to 70% to oral retinoids. Optimal dosing and indi- sheets of uniform blue cells within the after 20 years as shown in an Australian cations for initiation of systemic retinoid dermis that contain scant cytoplasm study.4 These squamous-cell carcinomas therapy was not conclusive from the data.1 and fine dusky chromatin. There is are more aggressive, with a high frequency It is thought that retinoids act in the overlying SCC in situ. of local recurrence (13.4%) during the first chemoprevention of NMSCs by immu- six months after excision, and lymph node nomodulation, induction of apoptosis, metastasis (7%) during the second year effects on cell-cycle control, influences on after excision.5 SCC is a significant source multiple transcription factors, inhibition of mortality, with 5.2% of OTRs in one of ornithine decarboxylase, alteration of series dying from skin cancer, 63% of which gap-junction intercellular communication, were SCC.1 There is also a suspected role and effects on keratinocyte differentiation for HPV, specifically types 5 and 8, in the and patterns of keratinocyte expression.1 development of SCC in transplant recipi- There is loss of efficacy soon after discon- ents as it is found at a higher frequency in tinuing therapy, and a rebound effect in this population.6 which patients may experience an increase Risk factors associated with the develop- in the number of skin cancers has also been ment of NMSC in transplant recipients observed.2 Chemoprevention using retin- include increased age, exposure to ultravi- oids can be problematic due to the need for Figure 4: H&E 40x of epidermis olet radiation, increased amount of immu- long-term therapy. Side effects are compa- showing full-thickness keratinocyte nosuppression, Fitzpatrick skin types I-III, rable to non-immunosuppressed patients atypia with atypical mitoses. prior history of AKs, NMSC, or melanoma, and include mucocutaneous dryness, mild and HPV infection. Heart transplants have hair loss, elevations of cholesterol and the highest risk of NMSC, followed by triglycerides, and musculoskeletal symp- kidney and then liver.2 toms. It is important to note that there Other types of skin cancer are also at were no reported cases where graft failure an increased risk. There is a 3.8- to 5-fold was thought to be influenced by retinoid increased incidence of de novo melanoma therapy. after transplantation.7 Kaposi’s sarcoma has Other potential chemopreventative been shown to have an 84-fold increased agents include difluoromethylornithine incidence in OTRs.3 Merkel-cell carcinoma (DFMO) and cyclo-oxygenase-2 (COX-2) also appears to be more common, as well inhibitors, although controlled clinical-trial as atypical fibroxanthoma, angiosarcoma, data is lacking.1 The medications 5-fluo- verrucous carcinoma, leiomyosarcoma, rouracil, cisplatin, bleomycin, doxorubicin, and cutaneous T-cell lymphoma.2 No and methotrexate all show activity against large-scale studies have been performed on NMSC, but data on their use has been Figure 5: H&E 40x showing cords of atypical small blue cells with minimal these diseases, thus the actual incidence is limited to treatment of existing aggres- cytoplasm within the dermis. unknown because the data is based solely sive or metastatic disease rather than for on anecdotal reports.2 prophylaxis in OTRs. Resveratrol, perillyl The most important elements in the alcohol, green and black tea polyphe- preventive management of skin cancer in nols, and black tea theaflavins have been transplant patients are patient education, suggested to have chemopreventative rigorous sun protection, and a multidisci- activities, but there is little in vivo data on plinary approach to patient care. their use in prevention or management of 1 Application of prophylactic topical retin- NMSC. oids or episodic 5-FU may be warranted Merkel-cell carcinoma is a rare skin in patients who develop multiple AKs or neoplasm originally described by Toker NMSC. Five percent imiquimod cream in 1972. It is an aggressive tumor charac- appears safe on skin surfaces up to 60cm2 terized by frequent relapse and an overall in renal transplant patients, and a small mortality rate of 35%.12 There have been study of 14 patients suggested a possible between 500 and 1,000 reported cases in reduction in SCC.8 Dragieva et al (2004) the literature, and it is thought that trans- Figure 6: CK20 positivity at 40x showed some efficacy using photodynamic plant patients are at increased risk because showing characteristic paranuclear of immunosuppression. A study of Merkel dot-staining pattern. therapy in immunosuppressed patients, although lower cure rates were reported cell in 41 transplant patients showed that in the OTRs compared to the immuno- compared to non-immunosuppressed competent controls. It is thought that patients, many were younger (29% < age using methyl aminolevulinate as a topical 50), 68% had nodal disease present at diag- KOPITZKI, SILVERTON 65 nosis (30% in non-immunosuppressed), and consequently 60% died of their disease (35% in non-immunosuppressed).13,14 Treatment in transplant patients is no different than in the general population and depends on the stage of the disease. This includes wide surgical excision, MOHS surgery, sentinel lymph node biopsy, radical lymph node dissection, radiation therapy, and chemotherapy.14 In summary, there is a large and ever- increasing population of solid-organ transplant patients who are on chronic immunosuppression. Skin cancer, espe- cially squamous-cell carcinoma, is more frequent, more aggressive, and has higher rates of metastasis in this population. There should be a low threshold for biopsy of suspicious lesions. Early and aggres- sive surveillance and treatment is needed, as is vigorous sun protection and patient education. This can be optimized using a multidisciplinary approach utilizing dermatologists, dermasurgeons, trans- plant teams, nephrology, cardiology, and hepatology.
References: 1. Kovach BT, Sams HH, Stasko T. Systemic strategies for chemoprevention of skin cancers in transplant recipients. Clin Transplant 2005: 19: 726-734. 2. Traywick T, O’Reilly F. Management of skin cancer in solid organ transplant recipients. Dermatologic Therapy 2005: 18: 12-18. 3. Hartevelt MM, Bavinck JN, Koote AM, Vermeer BJ, Vandenbroucke JP. Incidence of skin cancer after renal transplantation in the Netherlands. Transplantation 1990: 49: 506-509. 4. Bavinck JN, Hardie DR, Green A et al. The risk of skin cancer in renal transplant recipients in Queensland, Australia. A follow up study. Transplantation 1996: 61: 715-21. 5. Carucci JA, Martinez JC, Zeitouni N, et al. In transit metastasis from primary cutaneous squamous cell carci- noma in organ transplant recipients and nonimmunosup- pressed patients: clinical characteristics, management and outcome in a series of 21 patients. Derm Surg 2004: 30(4): 651-655. 6. Stockfleth E, Nindl I, Sterry W, Ulrich C, Schmook T, Meyer T. Human papillomavirus in transplant- associated skin cancers. Dermatol Surg 2004: 30: 604 7. Penn I. Malignant melanoma in organ allograft recipients. Transplantation 1996: 61: 274-278. 8. Brown V, Atkins M, Ghali L, Cerio R, Harwood C, Proby C. Safety and efficacy of 5% Imiquimod cream for the treatment of skin dysplasia in high-risk renal transplant recipients. Arch Dermatol 2005: 141: 985-993 9. Christian H, Pavel S, Stender I, Wensveen C. Topical photodynamic therapy for prevention of new skin lesions in renal transplant recipients. Acta Derm Venereol 2006: 86: 25-28. 10. Lebwohl M, Tannis C, Carrasco D. Acitretin suppression of squamous cell carcinoma: case report and literature review. Journal of Dermatological Treatment 2003: 14: 3-6 11. Wright T, Spencer J, Flowers F. Chemoprevention of nonmelanoma skin cancer. JAAD 2006: 54(6): 933-946. 12. Urbatsch A, Sams W, Urist M, Sturdivant R. Merkel cell carcinoma occurring in renal transplant patients. JAAD 1999: 41: 289-91. 13. Veness M. Merkel cell carcinoma: An overview on man- agement. Australian Journal of Dermatology 2006: 47: 160-65 14. Penn I, First R. Merkel’s cell carcinoma in organ recipi- ents: report of 41 cases. Transplantation 1999: 68: 1717- 1721.
66 A 58-YEAR-OLD FEMALE WITH A HISTORY OF RENAL TRANSPLANT AND MULTIPLE NON-MELANOMA SKIN CANCERS, RECENTLY DIAGNOSED WITH MERKEL-CELL CARCINOMA One less battle in the fight against acne Answer irritation with hydration —Duac® Care System (CS)
Irritating acne treatments can Duac® CS is designed to Patients agree, DUAC Topical Gel discourage compliance1 minimize irritation4,5 delivers impressive results7
Increasing irritation correlates with increasing DUAC® Topical Gel is unique acne Significant improvement in acne grade transepidermal water loss (TEWL)2 medication because it contains 1% began as early as week 1 (P=.013) and dimethicone and 4% glycerin continued throughout the study (Pb.038) Poor compliance has been reported to be the most common cause of nonresponse With its unique hydrating vehicle, DUAC At 12 weeks, ~90% of patients using DUAC to acne medication3 Topical Gel significantly reduces TEWL Topical Gel (n=65) agreed with physician (P=.0193)6 assessment that their acne was improved
DUAC Topical Gel is indicated for the topical treatment of inflammatory acne vulgaris. References: 1. Tanghetti EA. The building blocks to better acne treatment. Skin Aging. 2005;13(8):74-77. http://www.skinandaging.com/article/4494. Accessed September 27, 2007. 2. Wu Y, Wang X, Zhou Y, et al. Correlation between stinging, TEWL and capacitance. Important Safety Information Skin Res Technol. 2003;9(2):90-93. 3. Zaghloul SS, Cunliffe WJ, Goodfield MJD. Objective assessment of compliance with treatments in acne. Br J Dermatol. 2005;152(5):1015-1021. DUAC Topical Gel is contraindicated in patients who have shown hypersensitivity 4. Del Rosso JQ. The role of the vehicle in combination acne therapy. Cutis. 2005;76(suppl 2):15-18. 5. Fagundes DS, Fraser JM, Klauda HC. Difference in the irritation potential and to any of its components or lincomycin, and in those with a history of regional enteritis, cosmetic acceptability of two combination topical acne gels—combined results of two ulcerative colitis, or antibiotic-associated colitis. comparative studies. Todays Ther Trends. 2003;21:269-275. 6. Data on file, Stiefel Laboratories, Inc. 7. Langner A, Chu A, Goulden V, Ambroziak M. A randomized, single-blind Diarrhea, bloody diarrhea, and colitis have been reported with the use of topical clindamycin. comparison of topical clindamycin + benzoyl peroxide and adapalene in the treatment of mild Discontinuation is recommended if significant diarrhea develops. to moderate facial acne vulgaris. Br J Dermatol. 2008;158(1):122-129. Side effects may include erythema, peeling, burning, and dryness. © 2008 Stiefel Laboratories, Inc. DTG-28-2008-USA US Patent No. 5466446. Patents Pending. Please see brief summary of prescribing information on the following page. DUAC, STIEFEL, and STIEFEL and the “S” logo are registered trademarks of Stiefel Laboratories, Inc. www.stiefel.com
UNILATERAL GENERALIZED MORPHEA: A CASE REPORT
#SFUU##FOEFS %0 .BVSFFO$MJGGFM %0 +PIO1VJ .% .JDIBFM+.BIPO %0 '"0$% $IJFG3FTJEFOU 10)#()$POTPSUJVN 1POUJBD .* "UUFOEJOH%FSNBUPMPHJTU 1POUJBD0TUFPQBUIJD)PTQJUBM 1POUJBD .* %FSNBUPQBUIPMPHJTU )JMCSJDI%FSNBUPQBUIPMPHZ-BCPSBUPSZ (BSEFO$JUZ .* 1SPHSBN%JSFDUPS 10)#()$POTPSUJVN 1POUJBD .*
ABSTRACT
Morphea is a type of cutaneous sclerosis that does not show systemic involvement. There are many variants of this condition, including localized, generalized, bullous, linear, guttate, deep and keloidal. In this article, we describe a case of an 11-year-old female who presented with a unilateral, generalized form of morphea. Laboratory workup was positive for mildly elevated cholesterol and triglyceride levels. She was treated with topical therapy only and has seen improvement of her lesions over eight months.
*OUSPEVDUJPO Physical exam revealed a healthy appearing, mildly overweight young female Morphea is the term used to describe in no distress. Numerous violaceous the clinical entity that presents as an patches and plaques with very slightly erythematous-to-violaceous patch or erythematous borders were noted on her plaque that evolves into a firm, indurated right upper extremity, right chest and lesion. Histologically, morphea can closely abdomen, right lower extremity, right groin mimic lesions of systemic sclerosis (scle- and right lower back and buttock. Her roderma), but can be differentiated by face, scalp, palms and soles and left side of certain features upon examination. The her body were spared. There was a sharp presence of Raynaud’s phenomenon, digital cutoff at the midline between involved sclerosis and internal organ involvement, skin and non-involved skin (Figs. 1-3). namely pulmonary or GI tract, in systemic Scattered plaques on her right abdomen Figure 1 sclerosis helps to make the clinical differ- and right volar forearm showed moderate entiation from morphea. In addition to induration; the other areas were atrophic. the classical plaque-type morphea, other No incidence of telangiectasia, dilated nail variations exist. Some of these variations fold capillary loops, digital sclerosis or include linear, guttate, generalized, deep or Raynaud’s phenomenon was noted. Full subcutaneous, superficial, keloidal, bullous range of motion of all extremities without and sclerodermoid inflammatory disor- discomfort was demonstrated. ders. In this paper, we describe a case of A 4 mm punch biopsy was taken from unilateral generalized morphea in a healthy an indurated area on her right abdomen. Caucasian adolescent. Histological examination revealed a deep perivascular and interstitial mixed-cell Case Report infiltrate of lymphocytes and plasma cells concentrated in the lower two-thirds of An 11-year-old Caucasian female Figure 2 the dermis and subcutaneous fat. Dermal presented to the outpatient resident derma- edema was noted, as well as a subtle altera- tology clinic with her mother for a chief tion in collagen bundles (Figs. 4-5). A complaint of purple spots on her body. Verhoeff van Gieson stain showed pres- She stated that the spots had been present for approximately five years and had been ervation of elastic fibers and accentuated previously diagnosed as “bruises” and the subtle sclerosis of the lower dermal “birthmarks.” She denied any symptoms of collagen bundles (Fig 6). pain or pruritus in the lesions, but revealed Laboratory workup revealed normal that new lesions were still appearing over chemistries and normal hematology. recent months. Her past medical history Calcium level was 10.7 mg/dl (range: was only significant for recently (within 9.0-10.6), and lipid levels were moderately the previous year) diagnosed hyperlipi- elevated: total cholesterol 231 mg/dl (range: demia, which she has been on lovastatin for 0-199), LDL 155 mg/dl (range: 0-99), trig- three months, and multiple upper respira- lycerides 204 mg/dl (range: 40-149) and Figure 3 tory infections as a young child requiring HDL 36 mg/dl (range: 40-59). Antinuclear a tonsil and adenoidectomy and place- antibody (ANA) was negative (<1:40), most indurated lesions. This treatment ment of tympanostomy tubes. She denied as was the Scl-70 antibody. Erythrocyte was gradually reduced to a mid-potency any symptoms of dysphagia, Raynaud’s sedimentation rate was 13 mm/hr (range: corticosteroid ointment and finally to a phenomenon or restriction of motion 0-20). combination of tacrolimus 0.1% ointment (she plays softball in a league without any Treatment with super-high potency at bedtime and calcipotriene 0.005% cream limitations). corticosteroid ointment was started on the in the morning. Due to the mostly asymp- BENDER, CLIFFEL, PUI, MAHON 69 tomatic nature of the problem, systemic are symptomatic, impair motor function options such as prednisolone, PUVA and or involve areas that are important for methotrexate were withheld at the time. everyday functioning, systemic treatment Since being on topical therapy, the patient is warranted. Current systemic treatments has not seen any new lesions, and her that have showed promise include: metho- previous lesions have become much less trexate,10 pulsed dose IV prednisolone,4 indurated. She is being followed by her UVA phototherapy, penicillin antibiotics/ pediatrician for her hyperlipidemia. penicillaminex11 and physical therapy. In summary, we have presented a case of Discussion unilateral generalized morphea in a child as an unusual variant of localized sclero- Morphea is a relatively uncommon derma. Due to the relatively asymptom- condition, affecting approximately 27 per atic nature of our patient’s disease, local Figure 4 million persons annually, with women topical therapy was initiated with accept- representing the majority of cases (almost able results. The finding of hypertriglyc- 1 3:1 over men). Children under the age of eridemia and hypercholesterolemia has not 18 are commonly affected, with the local- been previously reported as a co-existing ized plaque and linear types being the most morbidity with generalized morphea as was 2 common variants reported. Generalized seen in our patient. Whether or not this is morphea, especially in a unilateral distribu- simply a coincidence or a marker of an 1 tion, is a rarely reported entity. Naga et al. increased systemic inflammatory response reported the first case of unilateral general- needs to be determined, and further inves- ized morphea in a 6-year-old Japanese boy tigation is warranted. in 2002.3 Their patient showed involve- ment of the right side of his body with References: indurated plaques, but no evidence of 1. Peterson LS, Nelson AM, Su WP, et al. The epidemiology systemic involvement. Laboratory evalua- of morphea (localized scleroderma) in Olmsted County Figure 5 tion was positive for a mildly elevated ANA 1960-1993. J Rheumatol 1997; 24:73-80. 2. Vancheeswaran R, Black CM, David J, et al. Childhood titer (1:320) and a positive anti-SS DNA; onset scleroderma: is it different from adult-onset dis- all other labs were within normal limits. ease. Arthritis Rheum 1996;39:1041-9. 3. Nagai Y, Hattori T, Ishikawa O. Unilateral Generalized Topical steroid therapy was initiated, and Morphea in Childhood. J Dermatol 2002;29:435-38. softening of the lesions was noted over a 4. Appelhans C, Breuckmann F, Gambichler T, Brockmeyer H, Altmeyer P, Kreuter A. Unilateral generalized morphea period of 10 months. is a rare variant of localized scleroderma. Eur J Med Res Appelhans et al. published a case series 2006;11:152-56. 5. Falanga V, Medsger TA Jr., Reichlin M. Antinuclear anti- of four patients with unilateral general- body and anti single-stranded DNA antibodies in morphea ized morphea.4 In their article, they detail and generalized morphea. Arch Dermatol 1987;123:350- 53. four cases, all women between the ages of 6. Cunningham B, Londells I, Langman C, Sailer D, Paller 14 and 38 with a history of long-standing A. Topical calcipotriene for morphea/linear scleroderma. J Am Acad Dermatol 1998;39:211-215. disease. In each case, lesions had been 7. Mancuso G, Berdondini RM. Localized scleroderma: present for more than five years; in one response to occlusive treatment with tacrolimus ointment. Br J Dermatol 2005;152:180-2. patient, lesions began at the age of four. 8. Kreuter A, Hyun J, Stucker M, Sommer A, Altmeyer P, Figure 6 Key characteristics of each case included: Gambichler T. A randomized controlled study of low dose UVA-1, medium dose UVA-1 and narrowband UVB pho- right-side only involvement in three of totherapy in the treatment of localized scleroderma. J Am four cases (the other case showed left-side Acad Dermatol 2006;54-440-47. 9. Morison W. Psoralen UVA therapy for linear and general- involvement), significant elevation of ANA ized morphea. J Am Acad Dermatol 1997;37:657-59. titers in all patients, and varying degrees of 10. Obadiah J, Moore T, Sigfried E. Methotrexate for the treatment of pediatric localized scleroderma. J Am Acad sclerosis and contractures affecting range Dermatol 2007;56:AB64. of motion. As treatment for these more 11. Falanga V, Medsger TA Jr. D-penicillamine in the treatment of localized scleroderma. Arch Dermatol severely affected patients, the authors used 1990;126:609-12. a combination of pulsed dose IV predniso- lone, low-dose methotrexate and UVA1. The etiology of the unilateral nature of these lesions is still undetermined. Current theories include: a developmental anomaly showing a Blaschkoid distribution, or inflammatory involvement along a nerve segment.3,4 Serum tests that are commonly elevated in generalized morphea include ANA and anti-SS DNA, with the latter being more indicative of severe disease.5 Treatment of generalized morphea is dependent on the severity of symptoms. Asymptomatic, non-disabling lesions can be treated conservatively: topical corticos- teroids, calcipotriene cream/ointment,6 calcineurin inhibitors,7 PUVA/UVA1/ NB-UVB light therapy,8 ,9 or simple “active non-intervention,” as many cases are known to resolve spontaneously. When lesions
70 UNILATERAL GENERALIZED MORPHEA: A CASE REPORT URTICARIA IN EASTERN SAUDI ARABIA
0NBS."MBLMPCZ .% "TTPDJBUF1SPGFTTPS $POTVMUBOU%FSNBUPMPHJTUBOE$IBJSNBO %FQBSUNFOUPG%FSNBUPMPHZ ,JOH'BIE)PTQJUBMPGUIF6OJWFSTJUZ $PMMFHFPG.FEJDJOF ,JOH'BJTBM6OJWFSTJUZ %BNNBN 4BVEJ"SBCJB
Correspondence of the Author: King Fahd Hospital of the University P.O. Box 40130, Al-Khobar 31952, Saudi Arabia. 5FMFQIPOFOPt.PCJMF Email address: [email protected]
ABSTRACT
Objective: To study the pattern of urticaria in Eastern Saudi Arabia Method: The data of patients clinically diagnosed as urticaria seen in the Dermatology Clinic, King Fahd Hospital of the University (KFHU), Al-Khobar, between January and December 2005, was analyzed using SPSS package program. Results: 51 patients (28 males, 23 females; ages between 3 and 60 years) were seen with an occurrence rate of 43%. The male:female ratio was 1.2:1. The clinical pattern of urticaria was as follows: chronic idiopathic 16 (31.4%), chronic with identifiable/ detectable causes 10 (19.6%), physical 12 (23.5%), acute with detectable cause 8 (15.7%), acute idiopathic 4 (7.8%), other urticaria disorders 21 (41.2%) patients. Conclusion: Urticaria is not uncommon in Saudi Arabia. A high consanguinity rate among parents may account for the increased frequency of allergic disease in our patients. A possible etiology was identified in 35.3% of our cases and suggests thorough history and physical examination supported by investigation for causes of chronic urticaria. Key words: Urticaria, Saudi Arabia, angioedema, consanguinity, investigation
*OUSPEVDUJPO vessel walls. The triggering factors for such The obtained data was collected in a data allergic reactions may be food, food addi- entry form and statistically evaluated using Urticaria is a cutaneous vascular reac- tives, drugs, infections, etc. Sometimes the Statistical Package for Social Sciences tion characterized clinically by the appear- urticaria may not be related to allergy, (SPSS), version 11.5. ance of evanescent itching wheals. It but rather to a direct effect of the agents, presents as erythematous, elevated, edema- causing release of histamine from the mast Results tous plaques surrounded by flares. Each cells, e.g. plants (nettles and strawber- new lesion usually lasts for a few hours, ries), animals (caterpillars, jellyfish and Of 1,188 new patients seen in the but not more than 24 hours. It may be lobsters), chemicals (cinnamic aldehyde, Dermatology Clinic of the KFHU, replaced by new crops of similar eruptions dimethylsulfoxide [DMSO]) and medica- Al-Khobar, during the study period, 51 had recurring for a few days, weeks, months tions (aspirin, morphine, codeine, poly- a confirmed diagnosis of one of the clinical and even years. Subcutaneous and mucosal myxin, etc.).2-4 Urticaria may also appear types of urticaria, giving an occurrence rate swelling, particularly involving the lips, as an associated or a preceding symptom of 43% in new dermatology patients in one eyelids, hands and feet, may accompany the of a systemic disease, including autoim- year. cutaneous findings. In severe urticaria, the mune diseases (Hashimoto’s thyroiditis, Twenty-eight (54.9%) were males and 23 affected person may complain of abdom- systemic lupus erythematosus, scleroderma, (45.1%) females, giving a male to female inal pain and respiratory distress due to the dermatomyositis and rheumatoid arthritis), ratio of 1.2:1. Forty (78.4%) were Saudi involvement of mucous membranes of the thyroid disease, malignancies (reticuloses nationals, and 11 were non-Saudis (21.6%). gastrointestinal and respiratory tract.1,2 and lymphomas) and some rare urticarial The age at onset ranged between 3 and 60 Urticaria has diverse clinical presenta- syndromes (Muckle-Wells syndrome and years, with an average age of 27.3 years at tions and causes, and it can be broadly clas- Schnitzler syndrome).3, 5 onset. Consanguinity among the parents of sified as spontaneous urticaria and physical The aim of this study is to document the patients was observed in 20 (39.20%). urticaria. Spontaneous urticaria may the pattern of urticaria in Eastern Saudi Nine of 51 patients (17.6%) had a posi- present as acute, where the wheals recur Arabia. tive family history of atopic dermatitis daily for a few days or weeks but not more or other allergic diseases (Table 1). These than six weeks, or as chronic when the .FUIPET findings were based on detailed history wheals persist beyond six weeks. Physical and physical examination supported by urticaria may be due to exposure to cold, All patients with the diagnosis of urti- laboratory investigations when needed. Of heat or sun, or due to trauma (delayed caria and/or angioedema who attended the the acute urticaria with identified causes, pressure, vibrations and dermographism). outpatient department of Dermatology in five patients history alone was enough to There may be other unclassified variants Clinic at King Fahd Hospital of the identify the cause, while in three patients, like aquagenic urticaria, contact urticaria, University (KFHU), Al-Khobar, between laboratory investigations were needed. cholinergic urticaria and exercise-induced January and December 2005, were included. Only three patients with chronic urticaria urticaria.2-7 Patients’ medical record numbers were were diagnosed based on history alone. Regarding the pathophysiology, urticaria obtained from the logbook of patients. The clinical types of urticaria are shown may be mediated by type-I allergy reac- Additional data, including gender, nation- in Table 2; chronic idiopathic urticaria was tions, IgE reactions, and type-III allergic ality, marital status, types of urticaria, found in 16 patients (31.4%). Repeated reactions, where immune complexes (IgG, onset of disease and family history, were investigations did not reveal any obvious IgM and antigens) are deposited into blood also retrieved from their medical records. cause or specific allergen. Acute Idiopathic ALAKLOBY 71 because of patients’ and physicians’ fears, Table 1 extensive and costly investigations are still 19-24 %FNPHSBQIJDGFBUVSFTPGVSUJDBSJBJO&BTUFSO4BVEJ"SBCJB recommended by some investigators. Kozel25 found that in 86% of chronic urti- J EldY\if]GXk`\ekj DXc\j =\dXc\j JXl[`j Efe$JXl[`j (jk[\^i\\ )e[[\^i\\ EfkI\cXk\[ Gfj`k`m\ E\^Xk`m\ study by Zuberbier et al.28 confirmed the ,( )/ )* +' (( (- + *( 0 +) role of aromatic compounds of food as ,+%0 +,%( ./%+ )(%- *(%+ .%/ -'%/ (.%- /)%+ an eliciting factor of pseudoallergic reac- tions in chronic urticaria. Parasitic infesta- urticaria was found in four patients (7.8%). sants. Eleven patients did not receive any tion was detected in 3.9% of our patients. Detailed history, physical exam and investi- treatment. Parasitic infestation is a relatively rare cause of urticaria in developed countries, e.g. in gations did not reveal any obvious cause or 13,16 specific allergens. Chronic urticaria with a Northern European countries. The role Discussion of Helicobacter pylori as a possible cause detectable cause was found in 10 patients of chronic urticaria has been confirmed (19.6%). The details of the causes were as Although urticaria is a very common in some studies.29-31 The association of follows: three due to food allergens; one dermatosis that can affect 15%-20% of 2,7 thyroid autoantibodies with chronic urti- with Hashimoto’s thyroiditis; one due to the population at some time in life, to caria has also been documented by some inspired airborne allergens; two due to the best of author’s knowledge there are investigators.32-34 intestinal parasites (positive stools for ova very few reported studies in the literature and parasites); one with internal malig- from the Middle East. In this study, there Idiopathic urticaria may be due to some nancy; and two with chronic peptic ulcer was a slight male preponderance (1.2:1). unknown abnormality, which can be modi- disease with positive Helicobacter pylori. However, in some studies, a significantly fied by numerous other factors including allergy.2,4 The relevance of anti-Fc-εRI-α Acute urticaria with a detectable cause higher prevalence of urticaria has been reported in females.8-10 This might be autoantibodies in the pathophysiology of was found in eight patients (15.7%), 35-37 related to the male/female proportion in some urticaria cases has been studied. with details as follows: three due to drugs These antibodies could be found in idio- [Penicillin 1 and Nonsteroidal anti-inflam- the general population. In Saudi Arabia, there are quite a few male expatriates pathic chronic urticaria patients as well matory drugs (NSAIDs) 2]; two due to as in patients with pseudoallergy to food food allergens (one to nuts, one to eggs); without their families, which might have influenced the ratio. whose symptoms cleared on elimination two due to viral infections (hepatitis B and of the causative diet. These autoanti- In this study, chronic urticaria is more acute respiratory viral infection); and one bodies have been shown to cross-link the frequent (26, 51%) than acute urticaria due to bacterial infection (β-hemolytic unoccupied IgE-receptors.38,39 Possible (12, 23.5%). In comparison, reports in the streptococcal tonsillitis). Angioedema was explanations for these findings have been literature range from 16%-84%.10-11 This found in 21 patients (41.2%). In most suggested by Zuberbier and Maurer.3 First, is probably because patients with hives of of the cases, 18 out of 21, angioedema the Fc-εRI-α autoantibodies are not of acute urticaria not associated with anaphy- presented as an associated symptom of pathophysiological relevance in all patients urticaria, while in three out of 21, angioe- laxis may not go to the physician, as has 12 with urticaria, and second, asynergism dema occurred as an isolated finding. been suggested by Beltrani. between the autoantibodies and the elic- Other urticaria disorders were found in The causative factors of acute urticaria iting stimuli, e.g. food, is necessary for 21 patients (41.2%), with the following were found in 15.7% of patients, including: the appearance of clinical symptoms in clinical types: physical urticaria in the form acute viral infections (hepatitis B and some patients.3 Histamine-releasing IgG of dermographism in 17 (33.3%), with respiratory viral infection), hypersensitivity autoantibodies to a subunit of IgE recep- 11 of those on top of urticaria and six as to drugs (penicillin and NSAIDs), food tors may be found in the circulation of isolated findings; cholinergic urticaria in allergy (eggs and nuts), and acute bacte- some patients with chronic idiopathic urti- two patients; and aquagenic urticaria in rial infection (β-hemolytic streptococcal caria.2,4,36 About 30%-40% of patients with two patients. tonsillitis). These possible causative agents idiopathic chronic urticaria have clinically Besides the classical features of urticaria, have been reported among causes of acute relevant functional autoantibodies to the the following findings were encountered: urticaria.13 Beltran12 found that the cause high-affinity IgE receptor (Fc-εRI-α) on co-existing allergic diseases were present in of acute urticaria is identified by history in basophils and mast cells; less commonly 16 patients (31.4.0%), including: bronchial the majority of patients. In one study, 63% (about 10%), patients have anti-IgE.40 This asthma in three patients, allergic rhinitis of patients were suspected to have food subgroup of chronic urticaria is known in 10, atopic dermatitis in two, and hay etiology, but with thorough investigation, as autoimmune urticaria. These patients fever in one. There was elevated IgE in 19 food was found to be the causative agent present with highly symptomatic, severe, patients (37.25%), dyspnea and wheezing for acute urticaria in only one out of 109.14 continuous urticaria associated with in five (9.8%), and arthralgia and/or joint Chronic urticaria with detectable causes systemic symptoms, but without any swelling in five (9.8%). was found in 10 patients (19.6%) (three known cause or physical triggers. A majority of the treated patients (25, based on history and seven based on inves- Physical urticaria in the form of dermog- 49%) responded well to H1-antihistmines tigations). This is in agreement with other raphism was found in 17 patients (33.3%). alone or in combination with H2-blockers. studies, which concluded that success of Of these, six (11.8%) patients had dermog- Those who did not respond well even to detecting a causative factor for chronic urti- raphism as an isolated finding, corre- combination therapy (15 patients, 29.4%) caria does not exceed 5%-20%, even with sponding to reports in the literature of needed various alternative therapies, such the performance of repeated episodes of about 6.2%-10.7%.3,5,10 Co-existing allergic as systemic steroids and immunosuppres- sophisticated investigations.2,4,15-18 However, disease in the form of atopy were found in 72 URTICARIA IN EASTERN SAUDI ARABIA Table 2 $MJOJDBMGJOEJOHTPGVSUJDBSJBJO&BTUFSO4BVEJ"SBCJB TYPES OF URTICARIA :_ife`Z :_ife`Z 8Zlk\ 8Zlk\ 8e^`f\[\dX `[`fgXk_`Z Lik`ZXi`Xn`k_ @[`fgXk_`Z Lik`ZXi`Xn`k_ N`k_flk Fk_\ilik`ZXi`X[`jfi[\ij Lik`ZXi`X! `[\ek`]`\[ZXlj\ Lik`ZXi`X [\k\ZkXYc\ZXlj\Ö lik`ZXi`X EldY\if] GXk`\ekj :_fc`e\i^`Z 8hlX^\e`Z ;\idf^iXg_`jd ,( (- (' + / * lik`ZXi`X lik`ZXi`X N`k_flklik`ZXi`X *(%+ (0%- .%/ (,%. ,%0 ) ) - *%0 *%0 ((%/ * 8 with dermographism and 15 with angioedema † 3 with dermographism and 2 with angioedema ‡ one with angioedema 16 patients (31.4%). Buss41 found 23% of investigations for every patient with acute 25. Kozel MM, Moein MC, Mekkes JR, et al. Evaluation of a clinical guideline for the diagnoses of physical and his patients with history of atopy, which urticaria, unless it is associated with serious chronic urticaria and angioedema. Acta Derm Venereol. corresponds to the prevalence of atopic systemic manifestations. 2002; 82(4): 270-4. 26. Zuberbier T, Chantraine-Hess S, Hartmann K, et al. disease in general population. Elevated Pseudoallergen-free diet in the treatment of chronic urti- IgE was found in 19 patients (37.25%) caria - a prospective study. Acta Derm Venereol 1995; References: 75: 484-487. and most of them had acute urticaria. 1. James WD, Berger TG, Elston DM. Andrew’s diseases of 27. Pigatto PD, Valsecchi RH. Chronic urticaria: a mystery. This is less than what has been reported the skin, 10th edition; Saunders Elsevier 2006;149-155.. Allergy 2000; 55: 306-308. 10,42 2. Thabif TB. Urticaria in Clinical Dermatology, 3rd edition 28. Zuberbier T, Pfrommer C, Specht K, et al. Aromatic com- by others. The high consanguineous 1995: 122-147. ponents of food as novel eliciting factors of pseudoaller- rate (39.2%) and family history of allergic 3. Zuberbier T, Maurer M. Urticaria: Current Opinions about gic reactions in chronic urticaria. J Allergy Clin Immunol Etiology, Diagnosis and Therapy. Acta Derm Venereol 2002; 109: 348-349. diseases might have contributed to high 2007; 87: 196-205. 29. Gaig P, Garcia-Ortega P, Enrique E, et al. Efficacy of the rate of coexisting atopic diseases (31.4%). 4. R. Hein. Chronic urticaria: Impact of Allergic Inflamma- eradication of Helicobacter pylori infection in patients with tion. Allergy 2002. 57: Suppl. 76; 10-24. chronic urticaria. A placebo-controlled double blind study. In all guidelines, intense and costly 5. Soter NA. Acute and Chronic Urticaria and Angioedema. Allergol Immunopathol (Madr) 2002; 30: 255-258. general-screening programs for urticaria J Am Acad Dermatol 1991; 25: 146-154. 30. Federman DG, Kirsner RS, Moriarty JP, Concato J. The 6. Rook A, et al. Urticaria in Textbook of Dermatology, 4th effect of antibiotic therapy for patients infected with Heli- are discouraged. It has been reported that Edition, Vol 2. 1987: 1099-1108. cobacter pylori who have chronic urticaria. J Am Acad acute allergic urticaria is significantly asso- 7. Sheldon JM, et al. The vexing urticaria problem: present Dermatol 2003; 49: 861-864. concepts of etiology and management. J Allergy 1954; 31. Wedi B, Kapp A. Helicobacter pylori infection in skin dis- ciated with atopic/allergic disease, and that 25(6):525-560. eases: a critical appraisal. Am J Clin Dermatol 2002; 3: these patients have a higher incidence of 8. Gaig P, et al. Epidemiology of Urticaria in Spain. J Inves- 273-282. tig Allergol Clin Immunol 2004; 4 (3): 214-220. 32. Leznoff A, Josse RG, Denberg J, et al. Association of developing one type of urticaria than do 9. Dibbern DA, Dreskin SC. Urticaria and angi chronic urticaria and angioedema with thyroid autoimmu- normal persons.2,4,43 oedema: an overview. Immunol Allergy Clin North Am nity. Arch Dermatol 1983; 119: 636-640. 2004; 24: 141-162. 33. Rumbyrt JS, Schocket AL. Chronic urticaria and thyroid In one retrospective study of urticaria 10. Buss YA, Garrelfs UC, Stitcherling M. Chronic urticaria – disease. Immunol Allergy Clin North Am 2004; 24: 215- which clinical parameters are pathogenetically relevant? 223. and angioedema, 49% of patients had both A retrospective investigation of 339 patients. JDDG. 34. Leznoff A, Sussman GL. Syndrome of idiopathic chronic conditions at the same time, while 40% had 2007; 5: 22-29. urticaria and angioedema with thyroid autoimmunity: a 11. Humphreys F, Hunter JAA. The characteristics of urticaria study of 90 patients. J Allergy Clin Immunol 1989; 84: urticaria alone and 11% had angioedema in 390 patients. BR J Derm. 1998; 42: 366-375. 66-71. 10 alone. 12. Beltrani VS. An overview of chronic urticaria. Clin Rev 35. Hide M, Francis DM, Grattan CEH, et al. Autoantibodies Allergy Immunol. 2002 Oct; 23(2): 147-69. against the high-affinity IgE receptor as a cause of his- Regarding guidelines for the diagnosis of 13. Kemp SF, Lockey RF, Wolf BL, et al. Anaphylaxis. A tamine release in chronic urticaria. N Engl J Med 1993; chronic urticaria, angioedema and physical review of 266 cases. Arch Intern Med 1995; 155: 1749- 328: 1599-1604. 36. Fiebiger E, Hammerschmid F, Atingl G, et al. Anti-FcεRI-α 44 1754. urticaria, a systemic review by Kozel et al 14. Zuberbier T, Ifflander J, Semmler C, Czarnetzki BM. autoantibodies in autoimmune-mediated disorders. Iden- concluded that 10 studies emphasized the Acute Urticaria - clinical aspects and therapeutic respon- tification of a structure-function relationship. J Clin Invest siveness. Acta Derm Venereol 1996; 76: 295-297. 1998; 101: 243-251. importance of history in the diagnosis, 13 15. Champion RH, Roberts SOB, Carpenter RH, Roger JG. 37. Staubach P, Onnen K, Vonend A, et al. Autologous whole studies stated that routine laboratory tests Urticaria and angioedema; a review of 544 patients. Br J blood injections to patients with chronic urticaria and a Dermatol 1969; 81: 588-597. positive autologous serum skin test: a placebo-controlled are of little value, and seven studies stated 16. Mekkes JR, van der Schaar WW, Bos JD. Anamnese trial. Dermatology 2006; 212: 150-159. that laboratory tests are only useful if based en diagnostiek van chronische urticaria. Ned Tijdschr 38. Stadler BM, Pachlopnik J. Vogel M, et al. Conditional Geneeskd 1986; 130: 1801-1805. autoantibodies in urticaria patients: a unifying hypothesis. on history. Five studies stated that routine 17. Jacobson MKW, Branco LB, Nelson HS. Laboratory tests J Invest Dermatol Symp Proc 2001; 6: 150-152. laboratory screening could be useful. in chronic urticaria. JAMA 1980; 243: 1644-1646. 39. Horn MP, Pachlopnik JM, Vogel M, et al. Conditional 18. Champion RH. Urticaria: then and now. Br J Dermatol autoimmunity mediated by human natural anti-Fc(epsilon) 1988; 119: 427-436. RIalpha autoantibodies? FASEB J 2001; 15: 2268-2274. 19. Bressler RB, Sowell K, Huston DP. Therapy of chronic 40. Tong LJ, Balakrishnan G, Kochan JP, et al. Assess- Conclusion idiopathic urticaria with nifedipine: demonstration and ment of autoimmunity in patients with chronic urticaria. J beneficial effect in a double-blinded, placebo-controlled, Allergy Clin Immunol 1997; 99: 461-465. This study shows that urticaria in not crossover trial. J Allergy Clin Immunol 1989; 83: 756-763. 41. Rajka G. Essential Aspects of Atopic Dermatitis. Springer- 20. Claveau J, Lavoie A, Brunet C, Bedard PM, Hebert Verlag, Berlin. 1989. uncommon in Saudi Arabia and has a J. Chronic idiopathic urticaria: possible contribution of 42. Grattan CEH, Wallingtin TB, Warin RP, Kennedy CTC, et marginal male preponderance. The high histamine-releasing factor to pathogenesis. J Allergy Clin al. A serological mediator in chronic idiopathic urticaria – Immunol 1993; 92: 132-137. a clinical immunological and histological evaluation. Br J consanguinity among the parents of our 21. Kaeser P, Revelly ML, Frei PC. Prevalence of IgE anti- Derm 1989; 114: 583-590. patients may account for an increased bodies specific for food allergens in patients with chronic 43. Soter NA, Wasserman SI. Urticaria and Angioedema: A urticaria of unexplained etiology. Allergy 1994; 49: 626- Consideration of Pathogenesis and Clinical Manifesta- frequency of allergic diseases in our 629. tion. Int J Dermatol 1979; 18: 517-523. patients. A possible cause of urticaria 22. Kaplan AP. Urticaria and angioedema, In: Middleton 44. Kozel MMA, Bossuyt PMM, Mekkes JR, Bos JD. Labora- E, Reed CE, Ellis EF, Adkinson NF, Yuginger JW, eds. tory tests and identified diagnoses in patients with physi- was found in 35.3% of our patients. This Allergy Principles and Practice. 3rd ed. 1988: 1377-1401. cal and chronic urticaria and angioedema: a systemic suggests that the search for a cause of 23. Armenaka M, Lehach J, Rosenstreich DL. Successful review. J Am Acad Dermatol 2003; 28(3): 409-416. management of chronic urticaria. Clin Rev Allergy 1992; urticaria may be beneficial after detailed 10: 371-389. history and physical examination. However, 24. Kaplan A, Buckley RH, Mathews KP. Allergic skin disor- it is unnecessary to do costly and invasive ders. JAMA 1987; 20: 2905-2909. ALAKLOBY 73 ECCRINE NEVUS WITH MUCINOUS DEPOSITION: A CASE REPORT $ISJTUPQIFS8FZFS %0 .PMMZ,BUIMFFO4NJUI .% +PBO5BNCVSSP %0 '"0$% TUZFBS3FTJEFOU /PSUIFBTU3FHJPOBM.FEJDBM$FOUFS ,JSLTWJMMF .0 %FSNBUPMPHZ &BTUFSO7JSHJOJB.FEJDBM4DIPPM /PSGPML 7" 1SPHSBN%JSFDUPS 3JDINPOE)FJHIUT.FEJDBM$FOUFS 3JDINPOE)FJHIUT 0) ABSTRACT Eccrine nevus is a rare lesion, with the mucinous variant only being reported in five previous individuals. The mucinous variant has shown a female predominance (4:1) and various ages of onset, from infancy (3 mo) to middle age (46 yr). Four of the lesions were reported on extremities, while the other was on the buttock. We report a case of mucinous eccrine nevus that occurred on the left lower trunk in an 18-month-old African American female. Of the five previous cases of mucinous eccrine nevus reported, two were associated with hyperhydrosis. We report the third case of mucinous eccrine nevus that presented with hyperhidrosis. Case Report difficult to differentiate histologically from eccrine nevus include eccrine angioma- A healthy 18-month-old African tous hamartoma, in which capillaries are a American female with a past medical predominate component within the lesion, history for sickle-cell trait presented with and sudoriparous angioma, in which the a 1.5 cm x1.0 cm, light brown patch located capillaries predominate with dilated, not on her left lower back. Her parents noticed hyperplastic ducts.7 the lesion at birth, and report that it has Recently, a variant of eccrine nevus was increased in size. The baby appeared to described by Romar and Taira (1994).8 have no discomfort associated with the They described a tender, erythematous lesion. The parents reported seeing a nodule 1 cm in diameter on the right recurrent clear fluid over the lesion that lower extremity of a 47-year-old female. would reappear after being wiped dry. A punch biopsy was taken, and histology Fig. 1 - Punch biopsy showing groups A 4 mm punch biopsy of the lesion was showed mucinous stroma surrounding a of eccrine glands within the deep performed and submitted for pathology proliferation of benign eccrine glands.8 dermis. The glands are mildly dilated, with a clinical differential diagnosis of They termed the variant “mucinous eccrine and are surrounded by mucin and benign adnexal tumor vs. plexiform neuro- nevus” (MEN).8 Since then, four other connective tissue. No inflammatory fibroma. Histology of the lesion showed reports of MEN have been published. infiltrate is noted. (4X) a normal epidermis. Within the dermis In 2003, Llombert et al. described two were increased numbers of eccrine glands, brown nodules, 1 cm in diameter, on the occasionally dilated eccrine glands, and buttock of a two-year-old female. They ducts surrounded by mucin. first occurred at three months of age.9 The lesions were without associated pain Discussion or hyperhidrosis.9 In 2004, Park et al. described a firm, tender, erythematous, Eccrine nevus is a rare lesion with less 2.5 cm x 1.5 cm patch on the dorsum of then 20 cases reported, first named by the left fourth toe of a 46-year-old man, 1,2 Pippione et al. Eccrine nevus typically which had been present for one month.10 presents as a plaque or patch of hyper- This lesion was without hyperhidrosis.10 hidrosis on an extremity, most often the In 2006, Espana et al. described several forearm, although it can also occur on brown, irregular, 1 cm to 1.5 cm nodules 2,3,4 the trunk or back. It most commonly following the lines of Blaschko on the left Fig. 2 - Colloidal iron stain. Note prominent mucin deposition occurs in childhood, with several reports buttock and on the leg of a 32-year-old surrounding the eccrine ducts. (4X) of a congenital lesion. These lesions have female, present since age 12.11 These lesions also been reported to occur up to age 79, increased in size and number from their 2,4 with no gender predilection. Although original presentation, and were noted to be tailored to a patient’s symptoms. In not commonly seen in association with a be pruritic with increased areas of hyper- most reports of eccrine nevus, pain is rarely particular syndrome, one case occurred in hidrosis.11 Also in 2006, Man et al. reported present, and hyperhidrosis is variable.2 5 a patient with trisomy 21. The histology the latest case of MEN, in an 18-year-old Instances in which treatment for these of an eccrine nevus shows an increase in female in whom it had been present for 17 symptoms was requested, total excision of the number and/or size of normal eccrine years. The lesion was a 4 cm x 3 cm, well- the lesion was the most common successful glands. Eccrine nevus is one of five demarcated plaque on the distal left foot therapy.13 Other reported therapies for different eccrine subtypes that have been associated with hyperhidrosis.12 See Table hyperhidrosis include: topical aluminum described. The others include: eccrine 1 for a summary of these cases. chloride or anticholinergics, injections angiomatous hamartoma, eccrine-centered of botulinum toxin (BOTOX), systemic nevus, eccrine syringofibroadenoma, and Treatment treatment with antidepressants containing porokeratotic eccrine ostial and dermal anticholinergic properties, as well as clon- 6 duct nevus. Two lesions that may be Treatment options are varied and should azepam and clonidine.2,14,15,16 74 ECCRINE NEVUS WITH MUCINOUS DEPOSITION: A CASE REPORT Table 1 1BUJFOUTVNNBSZGPSNVDJOPVTFDDSJOFOFWVT "HFPGPOTFU 4FY -PDBUJPOMFTJPOT 1BJO )ZQFSIJESPTJT 5SFBUNFOU 45 yo, F RLE* / 1 yes no unknown 3 mo, F Buttock / 2 no no none 46 yo, M L 4th toe / 1 yes no none 12 yo, F L buttock, leg / no yes unknown multiple 1 yo, F L distal Foot / 1 no yes excision w/ medical therapy Birth, F L lower back / 1 no yes excision *Right lower extremity To date, there are no reports of malignant transformation of eccrine nevi. Recently, a report of eccrine angiomatous hamartoma was reported to have spontaneous regres- sion.17 Due to its benign nature, patients may elect conservative treatment of their lesions unless symptomatic. The parents of our patient plan to have the lesion excised due to the complications of hyperhidrosis. References: 1. Pippione M, Depaoli MA, Sartoris S. Naevus eccrine. Dermatologica 1976; 152:40-6. 2. Kawaoka JC, Gray J, Schappell D, Robinson-Boston L. Eccrine nevus. J Am Acad Dermatology 2004 Aug; 51: 301-4. 3. Mayou SC, Black MM, Russell Jones R. Sudoriferous hamartoma. Clinical Exp Dermatology 1988; 13:107-8. 4. Ruiz de Erenchun F, Vazquez-Doval FJ, Contreras Mejuto F, Quintanilla E. Localized unilateral hyper- hidrosis: eccrine nevus. J Am Acad Dermatology 1992; 27:115-6. 5. Vazquez MR, Gomez de la Fuente E, Fernandez JG, Martin FJ, Estebaranz JL, Moraleda FP. Eccrine Naevus: case report and literature review. Acta Derm Venereol 2002;82:154-6. 6. Sassmannshausen J, Bogomilsky J, Chaffins M. Poro- keratotic eccrine ostial and dermal duct nevus: a case report and review of the literature. J Am Acad Dermatol- ogy 2000 Aug; 43(pt 2):364-7. 7. Pelle MT, Pride HB, Tyler WB. Eccrine angiomatous hamartoma. J Am Acad Dermatology 2002 Sep; 47:429- 35. 8. Romar JC, Taira JW. Mucinous eccrine nevus. Cutis 1994; 53:259-61. 9. Llombert B, Molina I, Monteagudo C, et al. Mucinous eccrine nevus: an unusual lesion in a child. Pediatric Dermatology 2003; 20:137-9. 10. Park HS, Lee UH, Choi JC, Chun DK. Mucinous eccrine nevus. J Dermatology 2004; 31: 687-9. 11. Espana A, Marquina M, Idoate MA. Extensive mucinous eccrine naevus following the lines of Blaschko: a new type of eccrine naevus. Br J Dermatology 2006 May; 154(5): 1004-6. 12. Man XY, Cai SQ, Zhang AH, Zheng M. Mucinous eccrine naevus presenting with hyperhidrosis: a case report. Acta Derm Venereol 2006;86(6):554-5. 13. Martnelli PT, Tschen JA. Eccrine angiomatous hamar- toma: a case report and review of the literature. Cutis 2003 Jun; 71:449-55. 14. Jung WK, Lee JS, Jung MJ, Whang KW, Kim YK. A case of eccrine nevus. Ann Dermatology 1995;7:270-2. 15. Takase Y, Tsushimi K, Yamamoto K, Fukusako T, Mori- matsu M. Unilateral localized hyperhidrosis responding to treatment with clonazepam. Br J Dermatology 1992; 126:416. 16. Kuritzky A, Hering R, Goldhammer G, Bechar M. Clo- nidine treatment in paroxysmal localized hyperhidrosis. Arch Neurology 1984;41:1210-1. 17. Tay YK, Sim CS. Eccrine angiomatous hamartoma asso- ciated with spontaneous regression. Pediatric Dermatol- ogy. 2006 Sept-Oct; 23(5):516-517 WEYER, SMITH, TAMBURRO 75 CASE REPORT: MILIARIA CRYSTALLINA TREATED WITH BOTOX® BOTULISM TOXIN TYPE A +POBUIBO4$SBOF %0 '"0$% &SJO(SJGmO #4 .4*** 1BUSJDJB)PPE 1"$ ,FMMZ#SJUU 1"$ 8BSSFO8IJUF .% $SBJH8FCC 1"$ %FSNBUPMPHJTUBU"UMBOUJD%FSNBUPMPHZ"TTPDJBUFT1" 8JMNJOHUPO /$ SEZFBSNFEJDBMTUVEFOUBU1JLFWJMMF$PMMFHF4DIPPMPG0TUFPQBUIJD.FEJDJOF 1JLFWJMMF ,: %FSNBUPMPHZQIZTJDJBOBTTJTUBOUBU"UMBOUJD%FSNBUPMPHZ"TTPDJBUFT1" 8JMNJOHUPO /$ %FSNBUPMPHZQIZTJDJBOBTTJTUBOUBU"UMBOUJD%FSNBUPMPHZ"TTPDJBUFT1" 8JMNJOHUPO /$ %FSNBUPQBUIPMPHJTUBU$PBTUBM$BSPMJOB1BUIPMPHZ1" 8JMNJOHUPO /$ 1IZTJDJBOBTTJTUBOUBU8JMNJOHUPO)FBMUI"TTPDJBUFT 8JMNJOHUPO / ABSTRACT Miliaria is a unique skin condition brought on by occlusions of eccrine ducts. It is divided into three categories depending on the level of obstruction. These three subtypes are discussed below. We are presenting a case report of a 32-year-old man with miliaria on both cheeks. This condition was exacerbated when he perspired. His formation of miliaria was so frequent and severe that he was ready to move to Alaska from Wilmington, N.C., so as to stay in a cool environment. *OUSPEVDUJPO bilaterally (Figure 1 and Figure 2). A 3 mm papillary dermis, generating a substantial, punch biopsy was taken of the right cheek. periductal lymphocytic infiltrate and spon- There are three types of miliaria: miliaria While waiting for the biopsy results we giosis of the intra-epidermal duct. rubra, crystallina, and profunda. The advised the patient to avoid hot tubs and Normal skin flora such as Staph epider- etiology of this rash is an obstruction of saunas, and to try to stay cool at night. midis and Staph aureus are thought to play the eccrine duct, triggered by environ- The patient was prescribed Differin gel to a role in the pathogenesis of the condition. ments of high heat and humidity. The three apply every night and Azelex cream to use It has been shown that people with miliaria subtypes of this condition differ on where every morning. This topical treatment did have three times as many bacteria per unit the obstruction occurs at the level of the not help. The pathology report demon- of skin versus normal subjects.1 A hyper- eccrine duct. Miliaria rubra, referred to as strated some obstruction of the parracrine keratotic plug can be found upon biopsy, a “heat rash,” produces extremely pruritic, duct with little lymphocytic infiltrate in occluding an eccrine duct. This is thought erythematous papules and is occluded at the dermis and epidermis. These results led to be a late change in the disorder, not the the level of the intraepidermal eccrine duct. us to the diagnosis of miliaria crystallina. causing agent. Miliaria crystallina is mostly This produces leakage of sweat around the The absolute cure for this skin condition found in neonates but, as in the above case, duct and the release of local inflamma- is to cease sweating. We therefore decided can be found in adults as well. Worldwide, tory mediators. Miliaria profunda appears to begin injections with Botox®. Using a miliaria is most common in tropical envi- as subtle, asymptomatic, flesh-colored dilution of 2.2 cc of normal saline per 100 ronments, especially among people who papules and is due to an occlusion at the unit vial, we began injecting Botox® intra- recently moved to such environments from dermal-epidermal junction. The crystallina dermal about his cheeks and forehead. We more temperate zones. Miliaria has been subtype is a result of a more superficial used two units per site and spaced the sites a significant problem for American and occlusion and appears as clear vesicles. This at about 1 cm intervals. This relieved the European military personnel who serve in condition is usually present in newborn miliaria, and he now does very well with Southeast Asia and the Pacific. This skin infants but can also present in adults. We injecting Botox® every six months. condition occurs in individuals of all races, are reporting miliaria crytallina in an adult and no sex preference is seen. male. Discussion Upon physical exam, miliaria crystallina Case Report Miliaria crystallina is very common in appears as clear, superficial lesions 1 to newborn babies who are “bundled” up a 2 millimeters in diameter. These lesions A 32-year-old Caucasian male presented large part of the time or who live in warm occur in clusters and usually do not possess complaining of “bumps” that occur when environments. The conditions of high any surrounding erythema. he sweats a lot or is out in the sun, present heat and humidity lead to occlusion of the In infants, lesions tend to occur on the for a year and a half. He explains they have eccrine ducts. Occlusion of the skin due head, neck, and upper part of the trunk. been getting worse. At his job, when he to clothing and bandages can also lead to In adults, they usually occur on the trunk. works in the operating room, the mask miliaria. Miliaria crystallina is a blockage Lesions rupture easily and resolve with and O.R. lights seem to cause the rash to at the superficial level of the duct, the superficial branny desquamation. This flare up. The patient stated he can even jog stratum corneum. At this superficial point, skin condition is thought to primarily in place and numerous of these “bumps” few inflammatory mediators are present, occur in neonates due to their imma- show up on his cheeks. He found this to be and the rash can be asymptomatic but still ture eccrine glands, which easily rupture. a huge blow to his self esteem. He found unsightly to the patient. In contrast, in The rupture leads to the occlusion of that people were often starring at him. miliaria rubra, the leakage of sweat into the duct and the appearance of miliaria. Upon physical examination, the patient the subcorneal layers produces spongiotic Pseudohypoaldosteronism has also been had no major deformities and was well vesicles, along with a chronic periductal, linked to miliaria due to the mineralcor- developed and groomed. He had no short- inflammatory cell infiltrate in the papillary ticoid resistance. This resistance leads to ness of breath and was alert and oriented. dermis and lower epidermis; and miliaria excess salt loss through the sweat ducts and Vesicular areas were noted upon the cheek profunda results in sweat escaping into the is associated with repeat bouts of miliaria. 76 CASE REPORT: MILIARIA CRYSTALLINA TREATED WITH BOTOX® BOTULISM TOXIN TYPE A Figure 1. Vesicular eruptions on left cheek Figure 2. Vesicular eruptions on right cheek Candidiasis, herpes simplex, and folli- culitis are all in the possible differential. History and physical examination are suffi- cient for diagnosing miliaria, but a biopsy can confirm the diagnosis, especially in an adult case. Conclusion We have presented an unusual case of miliaria crystallina arising on the face of a 32-year-old Caucasian male. We have reviewed the literature with regard to history and physical and pathological traits. Treatment is usually not needed due to the fact that this condition is asymptom- atic and self limiting. However, we treated our patient with Botox® injections, as we would with a hyperhidrosis patient. After his first treatment, the patient reported an 80 percent improvement in symptoms. Therefore, we have continued to manage this patient with Botox® to limit his sweating and thus limit miliaria crystalline. References: 1. Feng E, Janniger CK: Miliaria. Cutis 1995 Apr; 55(4): 213-6[Medline]. 2. Wenzel FG, Horn TD: Nonneoplastic disorders of the eccrine glands. J Am Acad Dermatol 1998 Jan; 38(1): 1-17 CRANE, GRIFFIN, HOOD, BRITT, WHITE, WEBB 77 78 The 2009 South Beach Symposium Faculty to include: Join us in Miami Beach... (Partial List) Symposium Chair Mark S. Nestor, MD, PhD Session Directors Brian Berman, MD, PhD James Q. Del Rosso, DO Zoe D. Draelos, MD Michael H. Gold, MD Gary D. Monheit, MD Distinguished Faculty ™ Glynis R. Ablon, MD Brian Berman, MD, PhD South Beach Clinical Dermatology Symposium Diane S. Berson, MD David E. Cohen, MD South Beach Aesthetics Symposium Joel L. Cohen, MD James Q. Del Rosso, DO FEBRUARY 12–16, 2009 Zoe D. Draelos, MD Loews Miami Beach Hotel • Miami, Florida Steven Fagien, MD Patricia K. Farris, MD Featuring three non-overlapping CME tracks: Roy G. Geronemus, MD Clinical Dermatology Symposium Michael H. Gold, MD February 12, 13 and 15 C. William Hanke, MD Michael Kane, MD The South Beach Clinical Dermatology Symposium will host the world’s top medical Bruce E. Katz, MD and surgical dermatology faculty to cover topics ranging from advances in clinical and Mark G. Lebwohl, MD therapeutic dermatology, photodynamic therapy, immune response modifiers, biologic Stephen H. Mandy, MD therapies for psoriasis, wound care management, acne, rosacea, psoriasis and much more. Gary D. Monheit, MD Mark S. Nestor, MD, PhD Aesthetic Dermatology Symposium David M. Pariser, MD Feb ruary 12, 14 and 15 Harold S. Rabinovitz, MD The South Beach Aesthetic Symposium will present new innovations in aesthetic Kent B. Remington, MD procedures and technologies and feature the world leaders in cosmetic and aesthetic Marta I. Rendon, MD dermatology. It will offer multiple live patient demonstration and certification workshops on Darrell S. Rigel, MD new fillers and new filler applications, botulinum toxin-type A, demonstrations of new laser, Eva C. Ritvo, MD light and radiofrequency devices. Lawrence A. Schachner, MD James M. Spencer, MD Practice Management Symposium Nowell Solish, MD February 16 only Neil A. Swanson, MD Guy F. Webster, MD, PhD The South Beach Practice Management Symposium will include an interactive session on Susan H. Weinkle, MD how patients view dermatologists, financial benchmarks, elements to improve both clinical Robert A. Weiss, MD and cosmetic practice, EMR and imaging solutions and risk management strategies. Registration includes clinical, aesthetic and practice management symposium. Register NOW More than 40 hours of AMA & AAD Category 1 for Maximum Savings! CME Credit offered! www.southbeachsymposium.org Hosted by the Florida Society of Dermatology and Dermatologic Surgery Jointly Sponsored by Creative Educational Concepts, Inc. and SBS Medical Education, LLC 2009 South Beach Symposium™ Registration February 12–16, 2009•Loews Miami Beach Hotel, Miami, FL 1 First Name Middle Initial Last Name Affiliation HOTEL INFORMATION Hotel reservations are on a first come, first serve basis. Book your rooms early and guarantee your spot in the HOST Hotel! Hotels Mailing Address are based on availability on the date the request form is received. Should the host hotel be sold out for the dates requested, your room City State or Province Zip Country reservations will automatically be confirmed in the next available hotel. Phone Emergency Contact/Phone DEADLINE DATE January 9, 2009 - Any reservation received after this date cannot be Email Fax assured of hotel availability or the group rate and will be accepted on Check all that apply: a space-available basis. MD DO PhD RN NP PA ARNP PharmD Other HOST HOTEL—Loews Miami Beach Hotel Medical Specialty Room Rate—$339 single/double $PMMJOT"WFOVFt.JBNJ#FBDI 'MPSJEB General Registration 2 Please check your appropriate fee. Registration fees include all lectures, course OVERFLOW HOTEL—Royal Palm Hotel materials, and two tickets to all meeting events.* Room Rate—$359/single, $389/double plus a $19/night resort fee $PMMJOT"WFOVFt.JBNJ#FBDI 'MPSJEB Before 12/31 After 12/31 Room Type (indicate quantity needed) Physician Registration $995 $1,095 ______single (1 Bed) ______double (2 Beds) One administrative office staff per registered Physician can attend Monday’s sessions free– Arrival Date:______Departure Date:______Additional staff will be charged No. of Adults in Room:______No. of Children:______Special Needs/Requests:______ARNP’s, PA’s and Medical Staff $995 $1095 Administrative Office Staff I will not require a sleeping room Monday lectures and exhibit hall only $499 $599 HOTEL DEPOSIT A credit card guarantee of one night’s room and tax is required as Dermatology Resident $0 $0 deposit. The deposit is refundable if cancellation is received 72 hours prior to arrival. A fee of $50 will be charged in the event of an early departure. Registration Total $_____ $_____ VISA Master Card AMEX Guests & Social Events Credit Card # ______3 * One guest badge included in registration fee. Please enter your complimentary guest’s name below, plus any additional tickets needed for the South Beach Gala. Exp Date ______Security Code ______Signature ______Guest name(s) Name on Card ______x $0 $0 NO reservation will be confirmed without a deposit. ______x $80 $_____ CHANGE POLICY: Any changes made to a reservation after the initial ______x $80 $_____ confirmation is subject to a $25 administrative fee. NOTE: All changes and cancellations must be done in writing to SBS. Social Events and Guest Total $_____ Combined Total Sections 2 & 3 $_____ Registration: Meeting Registration Payment Registration and payment must be received no later than 4 January 9, 2009. After this date a syllabus and name badge VISA Master Card AMEX Check cannot be guaranteed-so register TODAY! Make checks payable to: SBS Medical Education Cancellation: Credit Card # A written notice of cancellation must be received no later than January 9, 2009 and a $250 cancellation fee will apply. No refunds will Exp. Date Security Code be given after this date. Signature ADA Compliance: Name on Card Attendees who need additional reasonable accommodations or who have special needs should contact the SBS at 904-309-6262. Three Convenient Ways To Register: Mail: Fax: South Beach Symposium Website: 904-998-0855 6816 Southpoint Pkwy., Suite 1000 www.southbeachsymposium.org Jacksonville, FL 32216 ISDS Any questions regarding this meeting please call 904-309-6262