Journal of the

American Osteopathic College of Dermatology

SPONSORS: Volume 11, Number 1

July 2008www.aocd.org

Journal of the

American Osteopathic College of Dermatology

JAOCDFounding Sponsor

EditorsJay S. Gottlieb, D.O., F.O.C.O.O.

Stanley E. Skopit, D.O., F.A.O.C.D.

James Q. Del Rosso, D.O., F.A.O.C.D.

Editorial Review BoardRonald Miller, D.O.

Eugene Conte, D.O.

Evangelos Poulos, M.D.

Stephen Purcell, D.O.

Darrel Rigel, M.D.

Robert Schwarze, D.O.

Andrew Hanly, M.D.

Michael Scott, D.O.

Cindy Hoffman, D.O.

Charles Hughes, D.O.

Bill Way, D.O.

Daniel Hurd, D.O.

Mark Lebwohl, M.D.

Edward Yob, D.O.

Jere Mammino, D.O.

Schield M. Wikas, D.O.

Iqbal A. Bukhari, M.D.

2007-2008 OfficersPresident: Jay Gottlieb, DOPresident Elect: Donald Tillman, DOFirst Vice President: Marc Epstein, DOSecond Vice President: Leslie Kramer, DOThird Vice President: Bradley Glick, DOSecretary-Treasurer: Jere Mammino, DO (2007-2010)Immediate Past President: Bill Way, DOTrustees: James Towry, DO (2006-2008)Mark Kuriata, DO (2007-2010)Karen Neubauer, DO (2006-2008)David Grice, DO (2007-2010)

Journal of the American Osteopathic College of Dermatology

Sponsors:Global Pathology Laboratory

Stiefel Laboratories

Medicis

Galderma

Printed by: Stoyles Graphics Services, Mason City, IA 50401Proofreading: Julia Layton, Freelance Proofreading and EditingJournal of the American Osteopathic College of Dermatology

Letter from the JAOCD Editors .....................................................................................................................................................................4Letter from the President ...............................................................................................................................................................................5Primary Cutaneous Marginal Zone B-cell Lymphoma: Case Report and Review .....................................................................................6 Holly Kanavy, DO, David B. Kessler, DO, FAOCDLeishmaniasis – Case Report with Current Diagnostic and Treatment Strategies ...................................................................................11 Joseph Schneider, DO, Rick Seiger, DO, Michael Mahon, DOSporotrichoid Mycobacterium Marinum Infection: Case report and review of the Literature ..............................................................17 John G. Stoner Jr., DO, Thomas D. Griffin MD Spiradenocarcinoma: A Case Report ..........................................................................................................................................................19 Amara Sayed, DO, FACOFP, Layne D. Nisenbaum, DO, FAOCDKID Syndrome: A Case Report and Review................................................................................................................................................21 Roger S. Sica, DO, Richard A. Miller, DO, FAOCDCarotenoderma Associated with Red Palm Oil Consumption ..................................................................................................................26 Valerie A. Nozad, DO, Mary K. McGonagle, DO, Stephen M. Purcell DO, FAOCDNew Technologies for Early Detection of Melanoma: Update & Progress - 2007 ....................................................................................28 Kevin T. Belasco, DO, MS, Richard Miller, DO, FAOCDIdiopathic Complex Aphthous Stomatitis: A Case Report and Review of the Literature ........................................................................33 Bradley G. Neuenschwander, DO, Michael J. Mahon, DO, FAOCDAcquired Perforating Dermatosis: A Case Report and Brief Review .........................................................................................................35 Cory Trickett, DO, Oliver Wisco, DO, Daryl Hodson, MD, FAADMorphea: Case Report and Review of the Literature ................................................................................................................................37 Allison Schwedelson, DO, Stanley Skopit, DO, FAOCDLichen Planus Actinicus: A Case Presentation and Review of the Literature ...........................................................................................39 Jessica Flowers, DO, Patrick Keehan, DO, Bill Way, DO, FAOCDExtrafacial Granuloma Faciale ....................................................................................................................................................................42

John P. Minni, DO, Dana L. Haake, MS3, Jeffrey Martin, DO, Mark C. George, PA-C, Evangelos G. Poulos, MD, Layne D. Nisenbaum, DO

Pediatric Genital Warts—Case Study and Review .....................................................................................................................................44 Robert A. Norman, DO, MPH, Steven Nodine, OMS IIIHypohidrotic Ectodermal Dysplasia: A Case Presentation ........................................................................................................................47 Todd Kreitzer, DO, RPh, Neil Korman, MD, PhD, Joan Tamburro, DO, FAOCDCase Series: N-palmitoylethanolamide Cream (PEA or Mimyx®) used as an adjunct to prevent inverse psoriasis flare frequency .....49 Marcus B. Goodman, DO, Merrick D. Elias, DO, Stanley Skopit, DO, FAOCDA Case Presentation of Nephrogenic Fibrosing Dermopathy ...................................................................................................................51

Kelly Anne Truesdale, Melinda F. Greenfield, DO, Chris Bass, PA, Kevin Bush, PA, R. Wesley Wetherington, MDMycobacterium chelonae infection following a full thickness skin graft: A Case report and Review of Literature ...............................54 Lela Lankerani, DO, J. Greg Brady, DO, Stephen Purcell, DOCutaneous Manifestation of Metastatic Prostate Cancer ...........................................................................................................................58 Joseph S. Machuzak, DO, Megan G. Machuzak, DO, Stephen E. Kessler, DOBioscreen: An Innovative Approach to a Common Disease ......................................................................................................................60 Ryan M. Carlson, DO, Michelle Bruner, DO, Steven K. Grekin, DO, FAOCDWells’ Syndrome: Eosinophilic cellulitis secondary to infliximab infusion therapy ................................................................................63 Chad R. Peterson DO, Don A. Anderson DO, FAOCD, FASMS

CONTENTS

VOLUME 11, NUMBER 1 JULY 2008

AOCDJOURNAL OF THE

AMERICAN OSTEOPATHIC COLLEGE OF DERMATOLOGY

LETTER FROM THE EDITORS

4 LETTER FROM THE EDITORS

JAY S. GOTTLIEB, D.O. STANLEY E. SKOPIT, D.O. JAMES Q. DELROSSO, D.O.

Welcome to the 11th issue of the JAOCD! This has been an exciting year for the AOCD and for the JAOCD. We believe that both people and organizations have two options:

Option 1: Green and GrowingOption 2: Ripe and Rotten

Both the AOCD and the JAOCD remain very vibrant and growing forces within the osteopathic medical profession. Our leadership, members, residents and student members keep us in the ‘Green and Growing’ phase. We should always focus on what we can do to improve ourselves, our prac-tices, our organization and of course the JAOCD.

The EEC has recognized that the JAOCD is an integral part of our organization. Being a training orga-nization, the JAOCD gives our residents and our members a chance and a means to share exciting clinical cases and research with each other. Residents are excited to see their hard work published.

Is the JAOCD a perfect journal? Our answer is ‘not yet’. Will the JAOCD become a perfect journal? Maybe and maybe not, but we are committed to ‘CANEI’, that is Constant and Never Ending Improvement. Nobody can ask more from us personally or professionally then to do the best we can, from where we are, with what we have.

We hope that you enjoy this issue of the JAOCD. We are committed to making the JAOCD a great journal that can represent the AOCD.

We are thankful to have Global Pathology Laboratory, Medicis-The Dermatology Company, Stiefel Laboratory and Galderma as sponsors of the JAOCD. They continue their commitment to the dermatology profession and support the AOCD in all of its endeavors.

Jay S. Gottlieb, D.O., F.A.O.C.D, F.O.C.O.O. (Editor) Stanley E. Skopit, D.O., F.A.O.C.D. (Editor)James Q. DelRosso, D.O., F.A.O.C.D. (Associate Editor)

LETTER FROM THE PRESIDENT OF THE AOCD

LETTER FROM THE PRESIDENT 5

Dear Fellow & Resident AOCD members,

I just read an article in the Dermatology Times, where the writer discussed the pros and cons of training primary care physicians to act a ‘skin specialists’. These primary care physicians would spend a period of time (much shorter then a standard residency in dermatology) with a board certified dermatologist. They would then be given a certificate to practice as a ‘skin specialist’. This is one of the ways that has been proposed to answer the shortage of dermatology care in our country. I ponder what has driven the public and the medical sector to even consider something as ludicrous as this.

I agree that in certain areas of this country there is a shortage of dermatology care. I also agree that it takes longer to see a dermatologist for a suspicious nevus then it does to get cosmetic Botox treatments in many areas. I see non-dermatologist physicians practicing cosmetic dermatology and offering Botox, lasers, fillers and tightening procedures.I also see many dermatologists limiting there practices to cosmetic dermatology. There are physicians that think that nurse practitioners and physician assistants should be able to run a dermatology office and see patients without a dermatologist present for supervision. I know that the reimbursements for medical treatments and procedures continues to decline while the costs of running a medical practice seem to be escalating at a faster and faster pace.

Since the cost of a gallon of gasoline has now officially gone over $4 a gallon, taxicab drivers have been given permission to add a surcharge to each ride. The surcharge is allowed to go up as the price of gasoline goes up. But physicians are being forced to accept the same type of financial squeeze that even a taxi driver is not expected to swallow.

Yes, these are trying times for our profession. When I was an otolaryngologist, the chairman of my ENT department always told me “be able to perform good ear surgery, there is no competition for ear surgery and patients will then come to you for all of the services that you offer”.

I guess my advice to the residents and members of our profession is do ‘good dermatology’ because there is no real competition for medical dermatology. And if you practice good medical dermatology, your patients will come to you for all of their cosmetic skin care needs if you offer those services.

I am enjoying my year as president of the AOCD. Dr. Don Tillman is planning a fantastic annual meeting in Las Vegas. I hope to see all of you in Las Vegas in October and I am looking forward to seeing all of you at the Presidential Banquet on Monday, October 27th.

Fraternally Yours,

Jay

Jay Gottlieb, DO, FAOCD, FOCOO

JAY GOTTLIEB, D.O., F.A.O.C.D., F.O.C.O.O., PRESIDENT

6 PRIMARY CUTANEOUS MARGINAL ZONE B-CELL LYMPHOMA: CASE REPORT AND REVIEW

Case ReportA 76-year-old male was referred by his

primary care physician for evaluation of a lump on his right medial thigh. The lesion was reported as being asymptomatic and painless and had been present for at least two years with gradual enlargement. Upon review of systems, the patient denied any constitutional symptoms, including weight loss, weakness, fever, and night sweats.

His past medical history was significant for coronary artery disease, for which he had undergone a double coronary artery bypass five years before. He had hyperten-sion and BPH. The patient also reported undergoing surgery for colon cancer two years prior. He did not receive postop-erative therapy and reported being disease free. His medications included Toprol XL, Amitriptyline, Finasteride, and Flomax. He had no known allergies and no family history of cancer. He had a 40 pack-year history of cigarette smoking and had quit 20 years ago. He did not drink alcohol, and he was retired after working various jobs including truck driver and warehouse manager.

On physical examination there was a solitary, non-tender, well-circumscribed 5.5cm x 5.5cm red plaque of the right medial thigh. The plaque was indurated with a slightly scaly, peau d’orange surface and a halo of erythema. There was no significant enlargement of inguinal or any other lymph nodes appreciated.

A punch biopsy was performed, which revealed an extensive infiltrate of mononu-clear cells within the superficial and deep dermis, including small round lympho-cytes, plasma cells, and occasional centro-cyte-like cells. Immunohistochemistry stains for CD3, CD43, and CD45RO deco-rated a small number of cells within the

infiltrate. Immunostains for CD20 and CD79 alpha decorated the majority of cells in the infiltrate. Immunostains for CD5, CD10, CD23, CD30, and cyclin D1 were negative.

The patient was referred to a surgical oncologist for resection of the lesion. He also saw a medical oncologist for a full evaluation of the extent of his disease. Included in his bloodwork was a complete blood count with differential, a general chemistry panel, serum protein electro-phoresis, immunoglobulin levels, and a hepatitis panel. The only abnormal finding was an elevated IgM level of 707mg/dL (normal range 40-230mg/dL). Additional evaluation to rule out cutaneous involve-ment of a systemic lymphoma included CT scan of the chest, abdomen, and pelvis, and PET/CT scan from skull base to thigh. No evidence of systemic lymphoma was discovered. Bone marrow aspiration and biopsy was nondiagnostic, and cytoge-netic studies revealed no chromosomal abnormality. A period of observation was chosen as the initial management strategy, the other option being a course of local radiation therapy.

PCBCLPrimary cutaneous B-cell lymphoma

is defined as a malignant proliferation of B-cells that originates in the skin with no evidence of extracutaneous involvement at presentation and for six months following a complete staging examination.

Both the World Health Organization (WHO) and the European Organization for Research and Treatment of Cancer (EORTC) have provided systems of clas-sification for the subtypes of PCBCL, and recently these two systems have merged to provide a new system, called the

WHO-EORTC classification. It categorizes the primary cutaneous B-cell lymphomas into four subtypes: 1) marginal zone B-cell lymphoma, 2) follicle center lymphoma, 3) diffuse large B-cell lymphoma, leg type, and 4) diffuse large cell lymphoma, other.1

Primary cutaneous marginal zone B-cell lymphoma (PCMZL) represents 2 to 16 percent of all cutaneous lymphomas.2 It is a low-grade, slow-growing lymphoma characterized by clonal proliferation of small B-cells. Included in this category are those diseases formerly classified by EORTC as immunocytoma and cutaneous plasmacytoma. PCMZL is considered

Holly Kanavy, DO,* David B. Kessler, DO, FAOCD***Intern, North Shore University Hospital, Plainview, New York**Attending Dermatology Physician, New York, New York

PRIMARY CUTANEOUS MARGINAL ZONE B-CELL LYMPHOMA: CASE REPORT AND REVIEW

ABSTRACT

Primary cutaneous marginal zone B-cell lymphoma (PCMZL) is classified as one of the major types of cutaneous B-cell lymphoma, according to the recently revised classification by the World Health Organization - European Organization for Research and Treatment of Cancer. It is a low-grade, slow-growing lymphoma with an excellent prognosis. It tends to present in the fifth or sixth decade of life. Clinically, patients tend to present with solitary or clustered reddish papules, nodules, and plaques. A number of possible etiologies have been proposed, including Borrelia burgdorferi infection, underlying reactive lymphoid hyperplasia, and several autoimmune conditions. Histopathologically, the characteristic findings consist of nodular or diffuse infiltration of the dermis and subcutaneous fat, with sparing of the epidermis. The infiltrate consists mainly of monocytoid B-cells, which stain strongly positive for CD20 and CD79a. Once the diagnosis of PCMZL is made, patients must undergo a complete staging workup to be evaluated for an underlying lymphoma. Radiation therapy and surgical excision have proven to be highly successful treatments for these patients, with a five-year survival of 98 to 100 percent.

Figure 1: Gross

Figure 2: Gross, close-up

part of the group of mucosa-associated lymphoid tissue (MALT) lymphomas, also known as extranodal MZL, and in fact was once referred to as SALT (skin-associated lymphoid tissue) lymphoma.3

The disease tends to present in the fifth or sixth decade of life, although cases have been reported in patients as young as seventeen. There has been demonstrated a slight preponderance of men over women.4 The typical clinical presentation of PCMZL consists of asymptomatic, localized, deep red or brownish infiltrated papules, plaques, or nodules, ranging from 0.2cm to 9cm. They are frequently surrounded by diffuse or annular erythema. They may sometimes present with “gray follicular dots” visible within the plaque.7 These lesions appear most commonly on the trunk and extremities.1,4 They may be solitary or, more frequently, multifocal and regionally clustered. The presence of disseminated lesions suggests secondary spread to the skin from another MALT primary site.

There are no known risk factors or inheritance patterns elucidated for the development of primary cutaneous B-cell lymphomas; however, there appears to exist a combination of etiological factors that contribute to its pathogenesis. There has been a reported association of PCMZL with Borrelia burgdorferi infection, which is associated with Lyme disease.6,7 In fact, B. burgdorferi-specific DNA sequences have been demonstrated in some patients with PCBCL from European geographical areas that have endemic Borrelia infection. There was also a case reported by Bogle et al. in 2005 that described a patient with high Borrelia titers in whom a complete remission was induced and maintained with doxycycline and ampicillin regimens.7 Involvement of B. burgdorferi infection in the United States, however, seems to be quite rare. This association has not been observed with Asian cases, either.7,8 There also exists the theory that PCBCL may arise from an underlying reactive lymphoid hyperplasia. This is a reactive lymphocytic proliferation caused by a variety of anti-genic stimuli, including tattoo pigments,9

recurrent herpes simplex virus type 1 infection,10 and influenza and hepatitis A vaccination.11, 12 Secondary marginal zone lymphomas may occur in association with autoimmune diseases including Sjogren’s syndrome, serum paraproteinemia, epidermolysis bullosa acquisita, idiopathic thrombocytopenic purpura, autoimmune thyroid disease, rheumatoid arthritis, type 2 diabetes mellitus, ulcerative colitis, chronic Epstein-Barr virus infection, and hepatitis C infection.21,22

Molecular analysis of PCMZL has demonstrated an increasing number of translocations. Some of these include t(14;18)(q32;q21), involving the IGH gene (immunoglobulin heavy chain locus) on chromosome 14 and the MALT1 gene on chromosome 18; and t(3;14)(p14.1;q32), involving IGH and FOXP1 genes. It has also been observed that trisomy 3 and/or 18 coexists in some of these patients.13,14

Histopathologically, there typically exists diffuse or nodular perivascular or peri-adnexal infiltrates throughout the dermis and subcutaneous fat, with the epidermis almost always being spared. Cytologically, the infiltrates consist mostly of small, round, monocytoid B-cells surrounding reactive lymphoid follicles. The marginal zone cells appear as small to medium sized cells with irregular nuclei, inconspicuous nucleoli, and abundant pale cytoplasm. There are also scattered, solitary, blast-like cells resembling centroblasts or immuno-blasts, as well as plasma cells. The plasma cells are often found at the periphery of infiltrates and in the superficial dermis. Reactive T-cells as well as eosinophils may also be observed. PAS-positive intranuclear or intracytoplasmic inclusions may also be present. This is a distinct feature of immunocytomas known as Dutcher bodies, which are thought to represent deposits of immunoglobulin.3,4,15,20

The centrocyte-like and monocy-toid B-cells are positive for B-cell asso-ciated CD20 and CD79a markers and are CD5, CD10, and CD23 negative. Immunohistochemical staining may also reveal some admixed CD3 and CD43 positive reactive T-cells.7,16,20 The cells are

also bcl-2 positive and bcl-6 negative, a feature that helps to distinguish them from primary cutaneous follicular lymphomas (bcl-2 negative) and cutaneous lymphoid hy perplas ia (pseudolymphomas) . 17 Monotypic cytoplasmic immunoglob-ulin light-chain staining patterns with a predominance of kappa over lambda light chains is seen in the plasma cells.1,4,7,20 Aberrant nuclear expression of bcl-10 has been reported frequently in PCMZL and is often associated with locally aggressive tumors.8,20

Patients must undergo a complete staging work-up at the time of diagnosis of any PCBCL, and these lesions should be considered as secondary to a systemic lymphoma until proven otherwise. The work-up must include a complete history and physical examination as well as CT scan of the chest, abdomen, and pelvis. Serum chemistries, complete blood count, and lactate dehydrogenase (LDH) should be performed.23 Patients should also undergo nuclear imaging with either a positron emission tomography (PET) scan or gallium scan. It should be kept in mind, however, that PET has a high false-negative rate in marginal zone lymphomas, and gallium has a high false-negative rate in low-grade lymphoma. A bone marrow biopsy and aspirate is also recommended.

Radiation therapy and/or surgical excision have shown to be successful for patients with PCMZL with a solitary lesion or few lesions. It is recommended that patients who show clinical evidence of Lyme disease be treated with systemic antibiotics.18 In patients that present with multifocal skin lesions, intra-lesional or subcutaneous administration of interferon-alpha or oral chlorambucil may induce complete remission in 50% of patients. Rituximab (anti-CD20 antibody) may also be effective in these patients; however, relapses are common.19 Lesions that are small and superficial may be treated with topical or intra-lesional steroids.2

The lesions of PCMZL tend to be recur-rent in nature.1 In a study by Hoefnagel et al. published in 2005, 48% of patients experienced relapses.2 These relapses were

KANAVY, KESSLER 7

Figure 3: H&E, low-power magnification, showing diffuse monomorphous, lymphoplasmacytoid infiltrate with sparing of the epidermis

Figure 4: H&E, higher-power magnification, displaying the typical small, round lymphocytes

Figure 5: CD79 alpha stain with strong, diffuse immunohistochemical reactivity

8 PRIMARY CUTANEOUS MARGINAL ZONE B-CELL LYMPHOMA: CASE REPORT AND REVIEW

observed more frequently in patients who presented with multifocal skin lesions than in those who presented with solitary lesions. Some relapses have also been reported to spontaneously resolve.1 Dissemination to extracutaneous sites is quite rare, and the estimated five-year survival is 98 to 100 percent.5

References1 Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC

classification for cutaneous lymphomas. Blood 2005; 105:3768-3785.

2 Hoefnagel JJ, Vermeer MH, Jansen PM, et al. Primary cutaneous marginal zone B-cell lymphoma: clinical and therapeutic features of 50 patients. Arch Dermatol 2005; 141:1139-1145.

3 Santucci M, Pimpinelli N, Arganini L. Primary cutaneous B-cell lymphoma: a unique type of low grade lymphoma. Cancer 1991; 67: 2311-26.

4 Cerroni L, Signoretti S, Hofler G, et al. Primary cutaneous marginal zone B-cell lymphoma: a recently described entity of low-grade malignant cutaneous B-cell lymphoma. Am J Surg Pathol. 1997; 21: 1307-1315

5 Fink-Puches R, Zenahlik P, Back et al. Primary cutane-ous lymphomas: applicability of current classification schemes (EORTC, WHO) based on clinicopathologic fea-tures observed in a large group of patients. Blood 2002; 99: 800-5.

6 Cerroni L, Zochling N, Putz B, Kerl H. Infection by Borre-lia burgdorferi and cutaneous B-cell lymphoma. J Cutan Pathol. 1997; 24:457-461.

7 Bogle MA, Riddle CC, Triana EM, et al. Primary cutane-ous B-cell lymphoma. J Am Acad Dermatol 2005; 53: 479-484.

8 Li C, Inagaki H, Kuo TT, Huo S, Okabe M, Eimoto T. Primary cutaneous marginal zone B-cell lymphoma: a molecular and clinicopathologic study of 24 Asian cases. Am J Surg Pathol. 2003; 27: 1061-1069.

9 Sangueza OP, Yadav S, White CR, et al. Evolution of B-cell lymphoma from pseudolymphoma. Am J Dermato-pathol 1992; 14:408-413.

10 Zendri E, Venturi C, Ricci R, et al. Primary cutaneous plasmacytoma: a role for a triggering stimulus? Clin Exp Dermatol 2005; 30: 229-231.

11 May SA, Netto G, Domiati-Saad R, Kasper R. Cutaneous lymphoid hyperplasia and marginal zone B-cell lym-phoma following vaccination. J Am Acad Dermatol 2005; 53:512-516.

12 Willemze, Rein. Primary cutaneous B-cell lymphoma: classification and treatment. Curr Opin Oncol 18:425-431.

13 Streubel B, Lamprecht A, Dierlamm J, et al. T(14;18)(q32;q21) involving IGH and MALT1 is a frequent chro-mosomal aberration in MALT lymphoma. Blood. 2003; 101:2335-2339.

14 Streubel B, Vinatzer U, Lamprecht A, Raderer M, Chott A. T(3;14)(p14.1;932) involving IGH and FOXP1 is a novel recurrent chromosomal aberration in MALT lymphoma. Leukemia. 2005 Feb 10; ?????.

15 Schmid U, Eckert F, Griesser H, et al. Cutaneous follicu-lar lymphoid hyperplasia with monotypic plasma cells. A clinicopathologic study of 18 patients. Am J Surg Pathol. 1995; 19:12-20.

16 LeBoit PE, McNutt NS, Reed JA, et al. Primary Cutane-ous immunocytoma: A B-cell lymphoma that can easily be mistaken for cutaneous lymphoid hyperplasia. Am J Surg Pathol 18:969-978, 1994.

17 Hoefnagel JJ, Vermeer MH, Jansen PM, et al. Bcl-2, Bcl-6 and CD10 expression in cutaneous B-cell lym-phoma: further support for a follicle center origin and differential diagnostic significance. Br J Dermatol. 2003; 149: 1183-1191.

18 Zenahlik P, Pink-Fuches R, Kapp KS, Kerl H, Cerroni L. Therapy of primary cutaneous B-cell lymphomas. Hau-tarzt. 2000; 51: 19-24.

19 Soda R, Costanzo A, Cantonetti M, Orlandi A, Bianchi L, Chimenti S. Systemic therapy of primary cutaneous B-cell lymphoma, marginal zone type, with rituximab, a chimeric anti CD20 monoclonal antibody. Acta Derm Venereol. 2001; 81:207-208

20 Cho-Vega JH, Vega F, Rassidiakis G, Medeiros LJ. Pri-mary cutaneous marginal zone B-cell lymphoma. Am J Clin Pathol. 2006; 125(Suppl 1): S38-S49.

21 Magro CM, Porcu P, Ahmad N, et al. Cutaneous immu-nocytoma: a clinical, histologic, and phenotypic study of 11 cases. Appl Immunohistochem Mol Morphol. 2004; 12:216-224.

22 Rijlaarsdam JU, Van der Putte SCJ, Berti E, et al. Cuta-neous immunocytomas: a clinicopathologic study of 26 cases. Histopathol 1993; 23:117-125.

23 Burg G, Kempf W, Haeffner AC, et al. Cutaneous Lym-phomas. Curr Probl Dermatol. 1997; 9: 137-204.

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Case ReportA 5-year-old boy presented with a

three-month history of a slowly enlarging growth on the left cheek, right upper lip, and left lower vermilion border (Figure 1). The boy spoke no English, and the father had limited understanding of the English language. They denied any other skin problems, fever, weight loss, or recent illness. The patient did admit that the lesions were sometimes itchy. Past medical and surgical histories were negative, he was on no medications, and he had no allergies. Physical exam revealed three well demarcated, erythematous plaques with adherent yellowish crust. The largest lesion on the left cheek measured 2cm x 2cm. The other two lesions were 5mm and 3mm, respectively.

The working diagnosis was impetigo, and the patient was given amoxicillin PO and topical Bactroban with instructions to treat the nares as well. A bacterial culture was obtained for culture and sensitivity.

At two-week follow-up, the lesions were essentially the same, except the crust had been traumatically ripped off the larger lesion during play, revealing a shallow atro-phic center that accentuated the raised, rolled border (Figure 2). The bacterial culture grew only normal flora. A more thorough history was obtained through an interpreter and revealed the boy had just moved from Yemen approximately three months ago and had the lesions (although much smaller) at the time of immigration. Considering the morphology of the lesions and recent habitance in an area endemic for Leishmania, cutaneous leishmaniasis became a high consideration. A 4mm punch biopsy was obtained, and the patient was placed on topical sertaconazole cream

under occlusion. The results of the biopsy were consistent with cutaneous leishma-niasis. Treatment options were discussed, and cryotherapy was initiated to both lesions. Pediatric infectious disease was consulted to work up a vague history of “a white blood cell problem” and because one lesion was in close proximity to the lip. Another punch biopsy was performed and sent to the CDC for PCR analysis; however, the CDC was unable to type the species, possibly due to prior cryotherapy and use of sertaconazole cream. Three sessions of cryotherapy were performed, two weeks apart, in addition to applica-tion of sertaconazole cream under occlu-sion, with steady decrease in the size of the lesions. The patient was lost to follow-up, but a phone conversation with the father revealed that the lesions had completely healed about three months post diagnosis, with minimal scarring.

BackgroundLeishmaniasis is caused by protozoal

species of the genus Leishmania in the family Trypanosomidae. The vector is generally the sand fly, and reported possible reservoirs include the gerbil and the sloth. The extracellular form of leishmaniasis is a promastigote, and once inside the host, it proliferates as an amastigote within the cells of the monocyte macrophage line. The infection has been reported on all continents, but it is endemic in tropical and subtropical countries. There are around two million cases reported worldwide each year. Currently, the largest worldwide focus of cutaneous leishmaniasis (CL) is in Kabul City, Afghanistan, with an estimated 67,500 cases.1

From 2002 through 2004, the CDC

reported 522 cases in servicemen and women stationed in Iraq, Afghanistan and Kuwait.2 In the Middle East, the infec-tion (Old World leishmaniasis) is gener-ally regarded as purely cutaneous. In the Americas, the infection (New World leish-maniasis) may be cutaneous, mucocuta-neous, or visceral. A syndrome unique to Ethiopia and Kenya occurs in patients with an absence of specific cell-mediated immu-nity and manifests as diffuse cutaneous leishmaniasis, which is often refractory to therapy. Terminology of the lesions differs geographically according to terrestrial and cutaneous locations. Old World leish-

Joseph Schneider, DO,* Rick Seiger, DO,** Michael Mahon, DO****3rd year dermatology resident, Michigan State University, Botsford General Hospital, Farmington Hills, MI**Assistant clinical professor of dermatology, Pontiac Osteopathic Hospital, Pontiac, MI***Program director of dermatology, Michigan State University, Botsford General Hospital and Pontiac Osteopathic Hospital, Farmington Hills, MI

LEISHMANIASIS – CASE REPORT WITH CURRENT DIAGNOSTIC AND TREATMENT STRATEGIES

ABSTRACT

Leishmaniasis is a parasitic disease of various leishmania protozoan species. It is transmitted by the bite of an infected sand fly. Two major types of infection occur and are divided by region: the mostly cutaneous disease of Old World leishmaniasis, and the more invasive New World leishmaniasis. Generally, the disease is self-limited if the patient has an effective immune system. In healthy individuals, the lesions spontaneously regress over several months, often leaving an atrophic scar. Since lesions occur on exposed surfaces such as the face, significant disfigurement may occur. There are certain conditions under which the disease may be more serious, or life threatening. Mucocutaneous disease may cause horrible disfigurement to the central face; and visceral disease, especially in immunodeficient hosts, may cause death. The current standard of care is pentavalent antimony, a metal with significant adverse side effects. There are many other treatment options available: local surgical, topical and intralesional therapy; systemic oral and intravenous therapy; and immunotherapy. Immunizations to specific species of leishmania have been developed, but each infers immunity only to one species so they may not be cost effective at this time.

Figure 1

Figure 2

SCHNEIDER, SEIGER, MAHON 11

12 LEISHMANIASIS – CASE REPORT WITH CURRENT DIAGNOSTIC AND TREATMENT STRATEGIES

maniasis is known as the Baghdad boil, Oriental sore, Biskra button, Delhi boil, Aleppo boil, Kandahar sore, and Lahore sore. New World CL has been referenced to as uta, pian bois, bay sore, and forest yaws. Espundia is the term used when there is major involvement of the nasal mucosa. If on the ear, the term chiclero’s ulcer is used (Tables I, II).

Visceral leishmaniasis involves the inva-sion of the internal organs, particularly the reticuloendothelial system. This systemic disease is entitled Kala-azar, which is Hindi for “black poison,” due to the irregular darkening of patients’ hands, feet, face and abdomen. It is the second-largest parasitic killer in the world (second to malaria), responsible for an estimated half-million deaths worldwide each year. Endemic areas for visceral leishmaniasis are in Bangladesh, Brazil, India, Nepal, and Sudan, accounting for 90% of all cases.3 This disease affects the poorest areas and is considered by many to be a neglected disease due to the lack of resources amongst those most affected, and pharmaceutical companies’ reticence to manufacture anything but “blockbuster” drugs. There is growing concern about HIV and leishmaniasis co-infection, which has a much higher morbidity than either infection alone.4

Most cases of leishmaniasis are self-limited cutaneous disease, consisting of a slowly enlarging papule that ulcerates. Lesions are often seen on the exposed skin of children. They may appear as plaques with a rolled border. The lesion is generally single, but may be few in number. They heal over the course of six to 12 months, with scarring. Some cultural regions prac-tice inoculation of children’s legs to prevent scarring in a cosmetically sensitive area while providing species-specific immunity.

There is a several-month period between initial infection and clinical presentation. With endemic areas in parts of the Middle East, where a large number of United States soldiers are currently deployed, as well as in Mexico and South America, where vacation travel and emigration is increasing, it is likely that many vacationers, immigrants, and service men and women will present in U.S. clinics with leishmania infection. The purpose of this article is to review the current strategies in diagnosis and treat-ment for leishmaniasis, with emphasis on cutaneous leishmaniasis (CL).

Diagnosis:Diagnosis may be made by several

methods. In endemic areas, the disease has been mainly diagnosed clinically. Due to high levels of resistance, the CDC now recommends that all disease be specifically typed.

Touch preparation: Scrape the involved skin at the border of a lesion with a blade, and rub a glass slide on the lesion. It is

recommended that at least five slides be obtained and stained with Giemsa or H&E.

Aspiration: Using a small gauge needle, aspirate the lesion and place the fluid on glass slides as with the touch preparation.

Biopsy: It is recommended that the center of the lesion be biopsied and Giemsa stain be used, followed by interpretation by an experienced dermatopathologist. A 100X oil immersion or greater must be used to visualize the amastigotes. A sample should be sent to the CDC, or other appro-priate department of defense beneficiary, for PCR and to type the specific species, as this may change the treatment regimen.

Culture: Obtain a specimen asepti-cally as with touch preparation. Use NNN (Novy-Nicolle-McNeal) culture medium. This method has moderate-to-poor growth and does not type the species unless further analysis of the culture, such as PCR, is performed.

Leishmanin (Montenegro) test: This is a delayed-type hypersensitivity reaction much like the tuberculin skin test. Killed promastigotes are injected into the skin intradermally and read 72 hours later. This test may not be performed on patients with immunodeficiency, and has a negative result in patients with visceral or diffuse cutaneous disease. It does not differentiate between species.

PCR: This is the gold standard of diag-nosis in the United States, as it is highly specific (100%) and sensitive (87%), and it differentiates the specific species for proper treatment and documentation.5

It is recommended by the CDC that in suspected or confirmed cases of leishmani-asis, clinicians should contact the Infectious Disease Service of either Walter Reed Army Medical Center (District of Columbia), telephone 202-782-1663/8691, or Brooke Army Medical Center (San Antonio, Texas), telephone 210-916-5554/1286. Diagnostic support can be obtained by contacting the director of the leishmaniasis diagnostic laboratory at Walter Reed Army Institute of Research (Silver Spring, Maryland), tele-phone 301-319-9956. These institutions will supply antimony if indicated.

Treatment OptionsThere is no clear consensus on treat-

ment of CL, due to a number of factors. In the endemic areas where most cases of CL are seen, the diagnosis is generally clinical; therefore, the subtype of Leishmania has rarely been proven prior to treatment. Of the 522 cases reported by the Department of Defense (DOD), 176 were typed to species, and all were typed as Leishmania major (L. major). Cutaneous disease is generally self-limited, making assessments of whether clearance of the disease is due to efficacy or to spontaneous resolution difficult. Nearly 25 compounds have been

reported to have antileishmanial effects.6 The current recommended regimens have been described as having no sound basis in therapeutics and toxicity, and the “classic” treatment with pentavalent antimony has been described as “the best drugs of a bad bunch” due to its toxicity and high number of treatment failures.7 Antimony has been proven to be cleared faster in children than in adults, decreasing the efficacy in those most commonly infected.17 Furthermore, specific treatment regimens according to age of the patient, stage of the disease, and location of lesions have not been clearly elucidated. More than 17 treatments were seen in the review of literature, mostly case reports or small case series.

Systemic Therapy

Antimony:Antimony is the 51st element in the

periodic table, also known as stibis (Sb). It is a metal in group Vb of the periodic system, just below arsenic, with which it shares several chemical and toxicological properties.8 Antimony was used in ancient Egyptian times as a cosmetic due to its brilliant orange color, as well as a medi-cine for various skin infections and fever. Early preparations were in the trivalent form, and they had significant power to kill amastigotes of Leishmania; unfortu-nately, they had significant power to kill humans as well. In the 1930s, a pentavalent preparation was introduced, which had less toxicity. The major toxicity is cardiac, resulting in bradycardia or other arrhyth-mias. Toxicity is dose related, acutely as well as cumulatively, and also includes myalgia, joint stiffness, malaise, anorexia, nausea, and headache. One publication reported rates of elevated pancreatic and hepatic enzymes to be 80%.9 Other rarely reported adverse events include hematuria, myoglobinurea, renal tubular acidosis,10 thrombocytopenia,11 and pancreatitis.12

The Walter Reed Army Medical Center reports the most common side effects to be chemical pancreatitis, myalgia, rash, and elevated transaminases.13

Sodium stibogluconate (Solustibosan) was discovered in 1937 by Kikuth and Schmidt to be effective in treating leish-maniasis. 14 The medications used today include sodium stibogluconate (Pentostam®) and N-methylglucamine antimoniate (Glucantime®); they are currently considered the only first-line medication and the “standard of care” for leishmaniasis. The CDC recommends 20 mg/kg/day of pentavalent antimony for all forms of leishmaniasis, without an upper limit on the daily dose, as opposed to prior treatment regimens of 10 mg/kg/day. They believe this higher dose is more efficacious and is not substantially more toxic than regimens with lower daily doses. Cutaneous leishmaniasis should

be treated for 20 days, and visceral and mucosal leishmaniasis for 28 days.15 The WHO recommends the dosage for CL to be 20mg/kg/day to a maximum of 600 mg IM daily for 10 to 14 days. A repeat course may be performed in two weeks if disease is resistant.16

Pentostam is available through the Walter Reed Army Medical Center. The mechanism of action is unclear, but it has been shown that pentavalent antimony forms mono- and bis-adducts with adenine and guanine ribonucleosides, suggesting that ribonucleosides may be a target for this class of medications.17 The efficacy of antimonials seems to depend on an effec-tive immune response.18 The cure rates have been reported at 70% to 100%;19,20,21 however, a recent article from the CDC reports increasing resistance and a much lower response rate.22

Antifungals:Drugs in the imidazole class, such as

ketoconazole, miconazole and fluconazole, have shown some promise in the treat-ment of CL.23 Most studies using this class of antifungals are individual reports or case series.24,25,26 Fluconazole 5 mg/kg/day orally for 10 days was successful in one case of an 11-year-old girl with disseminated L. major.27 The largest study evaluating itraconazole was shown to have a 59% complete response rate in a study of 131 patients after three weeks of 7 mg/kg.28

This response rate was only slightly higher than the placebo clearance rate of 44.3%. Another large study evaluated fluconazole 200mg QD for six weeks. It reported a response rate of 59% versus the placebo group clearance rate of 22%, with minimal toxicity.29 Although generally quite toler-able, gastrointestinal side effects do occur, and there have been some reports of hepa-totoxicity.30 Other authors have raised the question of whether responses to antifun-gals reported in the literature are due to the drugs or to spontaneous healing.31

Amphotericin B (AmB) is a polyene antibiotic produced by Streptomyces species. It selectively binds to the parasite membrane ergosterol, but also, to a lesser extent, to human cholesterol. AmB has been used effectively in the treatment of mucocutaneous leishmaniasis.32 Although Leishmania species have not been shown to have acquired any resistance to ampho-tericin since its discovery in 1956, the side effects have limited its use. It has been called “shake and bake” due to the common side effects of shaking, chills and fever. It is also nicknamed “Amphoterrible” due to renal, hematologic, and gastrointestinal toxicity. Other toxicity includes phlebitis, hypotension, hypokalemia, and hypomag-nesemia. The maximal dose of AmB for human use is 1.5 mg/kg, which sometimes is not sufficient for cure. Recently, a more tolerable form, liposomal amphotericin B

(AmBisome), has been evaluated for treat-ment of L. braziliensis when given IV 3mg/kg for five days with a sixth dose on day 10, with a side effect profile much more trac-table than amphotericin B deoxycholate33 or sodium stibogluconate.34

Metronidazole has had mixed reports of efficacy.35, 36

Pentamidine:Pentamidine works by damaging

the kinetoplast DNA-mitochondria complex. An aerosolized form is a well-tolerated primary prophylaxis regimen for Pneumocystis carinii pneumonia (PCP) in patients infected with human immu-nodeficiency virus (HIV). Pentamidine isethionate has been shown to have anti-protazoal properties at 4 mg/kg given by slow IV infusion or deep intramuscular injection. It has been used widely in the past for treatment of trypanosoma and babesia, with less use in leishmaniasis. A few small studies have shown benefit at 2 mg/kg IV infusion every other day for four to seven doses.37, 38 One large study comparing pentamidine with meglumine antimoniate (Glucantime) in treating L. braziliensis showed a poor cure rate of 35% compared to 78% with antimony. Both regimens were equally tolerable.39 Some reported toxicity includes sterile abscesses at injection site, hypoglycemia, nephro-toxicity, and orthostatic hypotension. It is has been considered an option for resistant cases of cutaneous leishmaniasis.xl

Hexadecylphosphocholine:Hexadecylphosphocholine (Miltefosine)

is an alkylphosphocholine, originally developed for the treatment of cancer. The mechanism of action is most likely based on interference with the synthesis and degradation of parasitic membrane lipids.41 Miltefosine was most extensively studied for the treatment of visceral leishmaniasis in 1998 by Indian researches for Old World disease, and Colombian researchers for New World disease in 1999. Both studies showed 90% to 100% clearance rates with a dose of 2.5 mg/kg/day orally for 28 days. About half of the patients had mild gastro-intestinal side effects, and 10% to 20% developed elevation in transaminase and creatinine levels.42

Dapsone:Dapsone is a sulfone drug whose mecha-

nism of action is unclear. It is known to exert effects on neutrophils in inflamma-tory conditions and on folic acid in the treatment of leprosy.43 Dapsone has been shown, in a fairly large study, to be effica-cious in treating leishmaniasis at a dose of 100 mg PO BID for six weeks, with little toxicity.44

Azithromycin:One study of 20 patients with New

World cutaneous leishmaniasis were put

in different treatment groups receiving azithromycin at doses of 500 mg PO per day for three, five and 10 days and of 1,000 mg for two days. Overall, there was a cure rate of 85%.45 Two other studies have not been able to duplicate this success.46, 47

Allopurinol:Systemic allopurinol has been used in the

veterinary community for years in treating canine and feline leishmaniasis; however, studies on humans are sparse. One study of 18 patients showed a 67% cure rate with a regimen of 1,250 mg of allopurinol ribo-side (AR) four times daily for 28 days.48

Other systemic treatments:Successful use of oral rifampicin,49

nifurtimox,50 zinc sulfate,51 and granulo-cyte-macrophage colony-stimulating factor (GM-CSF)52,53 have been reported, but none are considered more than experimental at this time. Chloroquine has been shown not to be efficacious in the treatment of various species of leishmaniasis infection.54

Local TherapyLocal therapy has the advantages of

decreased cost, ease of treatment, and less systemic side effects and toxicity. The main disadvantage is the inability to treat visceral and mucocutaneous disease. There have been many reports of successful treatment of localized disease with local therapy. Therapies include physical methods, intralesional infiltration, and topical treat-ment, as well as combinations of local and systemic therapy. The WHO has made the following recommendations regarding local therapy: 1) The patient must not have dissemination to local lymph nodes; 2) the therapeutic measure used must ensure that most of the organisms are eradicated; and 3) local therapy should be easier to employ and less toxic than systemic therapy.

Physical methods:It is reported that in early times, a sharp,

spoon-like curette was used in treating leishmaniasis.55 Curetting is not recom-mended, however, due to the chance of causing lymphatic dissemination. Excision with flaps or grafts, when necessary, has been employed for smaller infections, with good results.56

Thermal therapy: It has been shown that leishmaniasis

species are temperature sensitive, and both heat and cold can destroy the amastigotes.

Heat therapy is currently used by United States Army medical centers and is recog-nized by the FDA, WHO, and CDC as a potential treatment. The Army medical center at Fort Campbell reports excellent results with the ThermoMed device when used on local, cutaneous disease. With the area anesthetized with lidocaine, the device heats the affected tissue between

SCHNEIDER, SEIGER, MAHON 13

14 LEISHMANIASIS – CASE REPORT WITH CURRENT DIAGNOSTIC AND TREATMENT STRATEGIES

two prongs to 50° C. Painless edema and bullae occur and last approximately one week. This treatment was reported as safe and well tolerated, with excellent results in 26 soldiers.57 Other authors have reported success rates of 90% in treating New World disease with heat therapy.58

Seven of eight cases of diffuse cutaneous disease were treated successfully with 39° to 41° heat for a cumulative 20 hours with a hot-water pad. The authors concluded that the failure in one patient was probably due to a strain resistant to this method.59 Indeed, it does appear that different strains of leishmaniasis respond differently to heat therapy. New World disease has been shown to be thermosensitive at a tempera-ture of 37° C, while L. tropica may not respond to temperature quite as well.60

It has also been shown in vivo that L. braziliensis panamensis may have increased infectivity with higher temperature.61

Cryotherapy has been shown to have a cure rate between 40% and 78%.62,63,64 One study at the low end of the cure rate reported using one treatment with a cryomachine for 60 seconds. At the high end of the cure rate, the lesions were treated with multiple freeze-thaw cycles of 15 to 30 seconds freeze with one-minute of thaw in between.

Intralesional TherapySeveral authors have reported high

success rates with intralesional therapy of CL with antimony. 65, 66 This method is considered first-line treatment in many areas. including Brazil and Turkey. It has the advantages of delivering a first-line medi-cation in lower total doses for decreased toxicity. In fact, researchers have found no difference in efficacy of intralesional meglumine antimoniate versus intramus-cular treatment.67 One study cited using 85 mg Stibogluconate/ml, 0.2-1 ml total, with an endpoint of complete blanching of the base of the lesion. Treatment sessions were once weekly up to 20 weeks with a reported cure rate of 97.2%.68

Three small studies using intralesional injections of zinc sulfate 2% found dissimilar results compared to antimony. One study reported similar efficacy to antimony for acute cutaneous leishmaniasis,69 another study reported a high cure rate,70 while another similar-sized study found zinc sulfate to be much less efficacious than antimony.71

Intralesional hypertonic saline was first studied in 1997. Researchers reported a 96% cure rate using hypertonic sodium chloride weekly. Cure took an average of one month.72 Only one other small study was found in the literature using this method, which reported good results with 7% sodium chloride.73

Intralesional imidazole compounds have been studied by one investigator; however, this author was unable to access even the abstract of that study.74

Immunotherapy

There has been some interest in using killed parasites along with antimony for treatment-resistant mucosal leishmani-asis.75 The small studies reported did show benefit, and this may be a good alternative treatment for the more invasive, refractory cases of leishmaniasis.76

Combination Therapy Several combinations of medications,

generally one systemic and one local, have been studied in the treatment of cutaneous and visceral leishmaniasis.

Antimony plus topical human granulo-cyte-macrophage colony-stimulating factor has been evaluated by several authors with consistently improved outcomes over anti-mony alone.77,78,79

Table I - New World Leishmaniasis

Table II - Old World Leishmaniasis

L. donovani{Brazil, Honduras}

L. mexicana{South America}

L. braziliensis{South America}

L. tropica{Urban areas of Middle East, India, central Asia, Afghanistan, and Turkey}

L. tropica major{Rural areas of Middle East, PakistanAfrica, China and India}

L. aethiopica{Ethiopia, Kenya, Uganda, Yemen}

L.d. chagasi

L.d. donovani

L.d. infantum

L.m. amazonensisL.m. garnhamiL.m. mexicanaL.m. pifanoiL.m. venezuelensis

L.b. peruvianaL.b. colombiensisL.b. lainsoni L.b. shawiiL.b. naiffi L.b. braziliensisL.b. guyanensisL.b. panamensis

L. tropica minor

L. killicki

L. tropica major

L. aethiopica

“Kala-azar”

“Chiclero’s ulcer”

“Uta”

“Espundia”“Pian bois”“Espundia”

“Baghdad boil”

“Oriental sore”“Delhi boil”“Aleppo boil”“Kandahar sore”“Lahore sore”

“Biskra button”

High potential for

visceral disease in this

complex

This complex has high

virulence; to be treated

with IV antimony as

first line

Disseminated cutaneous

Disseminated cutaneous

All in this complex have

potential for visceral

disease

Mucocutaneous

Mucocutaneous

Mostly cutaneous,

slow growing, dry

type; potential for

Leishmaniasis recidivans;

potential for Kala-azar

Mostly cutaneous

Mostly cutaneous, fast

growing and ulcerative

with moist exudates;

“wet type”

Mostly cutaneous,

slow growing, dry

type; potential

for disseminated

cutaneous disease or

mucocutaneous disease

Rarely, donovani and

infantum cause Old

World disease

All New World disease

vector is Lutzomyia

sand fly

Amazonensis and

mexicana have

potential for visceral

disease

Guyanensis and

panamensis have

potential for

nodular spread

through lymphatic

sporotrichoid spread

RAll Old World

disease vector

is Phlebotamus

sand fly

Check for secondary

bacterial infections

Systemic antimony in combination with topical imiquimod was shown to have no greater efficacy than antimony alone.80

Liposomal amphotericin plus topical human granulocyte-macrophage colony-stimulating factor was shown to be more effective than liposomal amphotericin alone in treating visceral leishmaniasis.81

Aqueous garlic extract (8 mg/kg/day) has been added to a bivalent DNA vaccine. The researchers found no difference in viral load, but overall survival was increased.82

Immunizations:A synthetic vaccine against the L. mexi-

cana strain has recently been shown to be efficacious in preventing infection.83 Live attenuated vaccines against other species are currently being investigated,84 and a vaccine with the ability to immu-nize against pan-Leishmania species has shown promise in an animal model.85 At this time, however, it appears that mass immunizations in endemic regions are not cost effective.

Conclusion:The rate of leishmaniasis infection

worldwide is well into the millions. With the trend of globalization, the number of U.S. patients diagnosed with leishmaniasis will most likely increase. It is important for physicians in the United States to recognize the disease, be able to make an accurate diagnosis, and implement treat-ment in a timely fashion to prevent exces-sive morbidity associated with this disease. Presented in this article is a case report of cutaneous leishmaniasis successfully treated with cryotherapy and topical sert-aconazole under occlusion. Background of the disease along with current diagnostic and treatment options are also presented.

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45 Prata A, Silva-Vergara ML, Costa L, Rocha A, Krolew-iecki A, Silva JC, de Paula EV, Pimenta FG Jr, Giraldo LE. Efficacy of azithromycin in the treatment of cutane-ous leishmaniasis. Revista Da Sociedade Brasileira de Medicina Tropical. 2003 Jan-Feb. 36(1):65-9.

46 Momeni AZ, Shafiei A, Emamjoeh M, Aminjavaheri M, Momeni A. Azithromycin is not effective in the treatment of old world cutaneous leishmaniasis. European Journal of Dermatology. 2006 Nov-Dec. 16(6):701-2.

47 Daoud S, Boushi L. Azithromycin, ineffective in the treat-ment of old-world cutaneous leishmaniasis. International Journal of Dermatology. Sept 2006 45(9):1126-8.

48 aenz RE, Paz HM, Johnson CM, Marr J, Nelson DJ, Pat-tishall KH, Rogers MD. Treatment of American cutaneous leishmaniasis with orally administered allopurinol riboside. Journal of Infectious Diseases. Jul 1989 160(1):153-8.

49 Joshi RK, Nambiar PM. Dermal leishmaniasis and rifam-picin. International Journal of Dermatology. Nov 1989 28(9):612-4.

50 Guena MFV, Marsden PD, Cuba CC, Barreto AC. Fur-ther trials of nifurtimox in mucocutaneous leishmaniasis. Trans Roy Soc Trop Med Hyg 1981;75:335.

51 Najim RA, Sharquie KE, Farjou IB. Zinc sulphate in the treatment of cutaneous leishmaniasis: an in vitro and ani-mal study. Memorias do Instituto Oswaldo Cruz. Nov-Dec 1998 93(6):831-7.

52 Almeida RP, Brito J, Machado PL, de Jesus AR, Schriefer A, Guimaraes LH, Carvalho EM. Successful treatment of refractory cutaneous leishmaniasis with GM-CSF and antimonials. American Journal of Tropical Medicine & Hygiene. Jul 2005 73(1):79-81.

53 eed SG. Colony-stimulating factors in parasitic diseases. Diagnostic Microbiology & Infectious Disease. Sep-Oct. 1990 13(5):387-9.

54 Dedet JP, Esterre P. Lack of effect of antimalarial prophy-laxis with chloroquine or amodiaquine in cutaneous leish-maniasis in French Guiana. Transactions of the Royal Society of Tropical Medicine & Hygiene. 1986 80(3):490, 1986.

55 Hoare CA. Early discoveries regarding the parasites of oriental sore. Trans Roy Soc Trop Med Hyg 1938;32: 67-92.

56 Azab AS, Kamal MS, El-Hagar MS, Metawaa BA, Hind-way DS. Early surgical treatment of cutaneous leishma-niasis. J Dermatol Surg Oncol 1983;9:1007-12.

57 Willard RJ, Jeffcoat AM, Benson PM, Walsh DS. Cutane-ous leishmaniasis in soldiers from Fort Campbell, Ken-tucky returning from Operation Iraqi Freedom highlights diagnostic and therapeutic options. Journal of the Ameri-can Academy of Dermatology. June 2005 52(6):977-87.

58 Velasco-Castrejon O, Walton BC, Rivas-Sanchez B, Garcia MF, Lazaro GJ, Hobart A, et al. Treatment of cutaneous leishmaniasis with localized current field (radio frequency) in Tabasco, Mexico. Am J Trop Med Hyg. 1997;57:309-312.

59 Neva FA, Petersen EA, Corsey R, Bogaert H, Martinez D. Observations on local heat treatment for cutaneous leishmaniasis. American Journal of Tropical Medicine & Hygiene. Sept 1984 33(5):800-4.

60 Sacks DL, Barral A, Neva FA. Thermosensitivity patterns of Old vs. New World cutaneous strains of Leishmania growing within mouse peritoneal macrophages in vitro. American Journal of Tropical Medicine & Hygiene. Mar 1983 32(2):300-4.

61 Smejkal RM, Wolff R, Olenick JG. Leishmania brazilien-sis panamensis: increased infectivity resulting from heat shock. Experimental Parasitology. Feb 1988 65(1):1-9.

62 Salmanpour R, Razmavar MR, Abtahi N. Comparison of intralesional meglumine antimoniate, cryotherapy and their combination in the treatment of cutaneous leishma-niasis. Int J Dermatol. Sept 2006 45(9):1115-6.

63 Gurei, MS, Tatli N, Ozbilge H, Erel O, Seyrek A, Kocyigit A, Ulukanligil M. Efficacy of cryotherapy and intralesional Pentostam in treatment of cutaneous leishmaniasis. Journal of the Egyptian Society of Parasitology. Apr 2000 30(1):169-76.

64 Al-Majali O, Routh HB, Abuloham O, Bhowmik KR, Muh-sen M, Hebeheba H. A 2-year study of liquid nitrogen therapy in cutaneous leishmaniasis. International Journal of Dermatology. June 1997 36(6):460-2.

65 Barrios LA, Costa JM, Netto EM, Vexenat CO, Cuba CC,

SCHNEIDER, SEIGER, MAHON 15

Marsden PD. Intralesional glucantime in Leishmania bra-ziliensis infections. Transactions of the Royal Society of Tropical Medicine & Hygiene. 1986 80(1):173-4.

66 Oliveira-Neto MP, Schubach A, Mattos M, da Costa SC, Pirmez C. Intralesional therapy of American cutane-ous leishmaniasis with pentavalent antimony in Rio de Janeiro, Brazil - an area of Leishmania (V.) braziliensis transmission. International Journal of Dermatology. June 1997 36(6):463-8.

67 Alkhawajah AM, Larbi E, al-Gindan Y, Abahussein A, Jain S. Treatment of cutaneous leishmaniasis with anti-mony: intramuscular versus intralesional administration. Ann Trop Med Parasitol. 1997 Dec;91(8):899-905.

68 Uzun S, Durdu M, Culha G, Allahverdiyev AM, Memiso-glu HR. Clinical features, epidemiology, and efficacy and safety of intralesional antimony treatment of cutaneous leishmaniasis: recent experience in Turkey. Journal of Parasitology. Aug 2004 90(4):853-9.

69 Iraji F, Vali A, Asilian A, Shahtalebi MA, Momeni AZ. Comparison of intralesionally injected zinc sulfate with meglumine antimoniate in the treatment of acute cutane-ous leishmaniasis. Dermatology. 2004 209(1):46-9.

70 Sharquie KE, Najim RA, Farjou IB. A comparative con-trolled trial of intralesionally-administered zinc sulphate, hypertonic sodium chloride and pentavalent antimony compound against acute cutaneous leishmaniasis. Clini-cal & Experimental Dermatology. Jul 1997 22(4):169-73.

71 Firooz A, Khatami A, Khamesipour A, Nassiri-Kashani M, Behnia F, Nilforoushzadeh M, Pazoki-Toroudi H, Dowlati Y. Intralesional injection of 2% zinc sulfate solution in the treatment of acute old world cutaneous leishmaniasis: a randomized, double-blind, controlled clinical trial. Journal of Drugs in Dermatology. 2005 Jan-Feb 4(1):73-9.

72 Sharquie KE. A new intralesional therapy of cutaneous leishmaniasis with hypertonic sodium chloride solution. Journal of Dermatology. Oct 1995 22(10):732-7.

73 Eissa MM, Soliman AS, Nassar SO. Ultrastructural and immunological features of experimental cutaneous leish-maniasis after treatment with intralesional hypertonic sodium chloride and CO2 laser rays. Journal of the Egyp-tian Society of Parasitology. Apr 2003 33(1):329-52.

74 Al-Waiz M, Sharquie KE, Al-Assir M. Treatment of cuta-neous leishmaniasis by intralesional metronidazole. Saudi Medical Journal. Oct 2004 25(10):1512-3, 2004 [Medline].

75 Jha TK. Drug unresponsiveness & combination therapy for kala-azar. Indian Journal of Medical Research. Mar 2006 123(3):389-98.

76 Badaro R, Lobo I, Munos A, Netto EM, Modabber F, Campos-Neto A, Coler RN, Reed SG. Immunotherapy for drug-refractory mucosal leishmaniasis. Journal of Infec-tious Diseases. Oct 15 2006 194(8):1151-9.

77 Almeida RP. Brito J. Machado PL. DE Jesus AR. Schriefer A. Guimaraes LH. Carvalho EM. Successful treatment of refractory cutaneous leishmaniasis with GM-CSF and antimonials. American Journal of Tropical Medicine & Hygiene. July 2005 73(1):79-81.

78 Almeida RP, Brito J, Machado PL, de Jesus AR, Schriefer A, Guimaraes LH, Carvalho EM. Successful treatment of refractory cutaneous leishmaniasis with GM-CSF and antimonials. American Journal of Tropical Medicine & Hygiene. July 2005 73(1):79-81.

79 Santos JB, de Jesus AR, Machado PR, Magalhaes A, Salgado K, Carvalho EM, Almeida RP. Antimony plus recombinant human granulocyte-macrophage colony-stimulating factor applied topically in low doses enhances healing of cutaneous Leishmaniasis ulcers: a random-ized, double-blind, placebo-controlled study. Journal of Infectious Diseases. Nov 15 2004 190(10):1793-6.

80 Firooz A, Khamesipour A, Ghoorchi MH, Nassiri-Kashani M, Eskandari SE, Khatami A, Hooshmand B. Imiquimod in combination with meglumine antimoniate for cutaneous leishmaniasis: a randomized assessor-blind controlled trial. Archives of Dermatol. Dec 2006 142(12):1575-9.

81 Mastroianni A. Liposomal amphotericin B and rHuGM-CSF for treatment of visceral leishmaniasis in AIDS. Infezioni in Medicina. Sept 2004 12(3):197-204. [Med-line].

82 Gamboa-Leon R, Paraguai de Souza E, Borja-Cabrera GP, Santos FN, Myashiro LM, Pinheiro RO, Dumonteil E, Palatnik-de-Sousa CB. Immunotherapy against vis-ceral leishmaniasis with the nucleoside hydrolase-DNA vaccine of Leishmania donovani. Vaccine. May 29 2006 24(22):4863-73.

83 Rogers ME, Sizova OV, Ferguson MA, Nikolaev AV, Bates PA. Synthetic glycovaccine protects against the bite of leishmania-infected sand flies. Journal of Infec-tious Diseases. Aug 15 2006 194(4):512-8.

84 Selvapandiyan A, Duncan R, Debrabant A, Lee N, Sreeni-vas G, Salotra P, Nakhasi HL. Genetically modified live attenuated parasites as vaccines for leishmaniasis. Indian Journal of Medical Research. Mar 2006 123(3):455-66.

85 Carrillo E, Ahmed S, Goldsmith-Pestana K, Nieto J, Osorio Y, Travi B, Moreno J, McMahon-Pratt D. Immuno-genicity of the P-8 amastigote antigen in the experimental model of canine visceral leishmaniasis. Vaccine. Feb 9 2007 25(8):1534-43.

16 LEISHMANIASIS – CASE REPORT WITH CURRENT DIAGNOSTIC AND TREATMENT STRATEGIES

STONER, GRIFFIN 17

Case ReportA well appearing 49 year old woman, self

described avid gardener; presented with a four week history of sore nodules initially starting on the left hand. She progressed to having more lesions on her hand and multiple red nodules ascending up her arm.

At the time of initial consultation a diag-nosis of sporotrichosis was made and the patient was started on oral itraconazole. A biopsy was performed for routine histo-logical examination and for bacterial and fungal cultures.

The histology on H & E exam showed a deep dermal abscess containing eosino-phils, lymphocytes, and histiocytes. Stains for fungal organisms were negative. Acid fast stains revealed long gram negative nods. Itraconazole was then discontinued and the patient was started on minocycline. After two weeks of therapy the patient showed only minimal improvement. This lack of response prompted a change to a combination of clarithromycin and rifampin. Six weeks following the initial biopsy, the culture grew mycobacterium marinum sensitive to clanthromycin and rifampin, with only intermediate sensitivity to minocycline.

Upon further questioning the patient denied being in a swimming pool or having a fish tank. After 5 months of combination therapy the patient’s lesions slowly resolved. One year later the patient remains lesion free and asymptomatic.

DiscussionMycobacterium marinum is a nontu-

berculous atypical Mycobacterium that is known to cause cutaneous infection. This occurs particularly to wounds exposed to contaminated fresh or salt water. Known originally as swimming pool granuloma, this infection was first described in 1951 after large outbreaks involving swimming pools. However, after widespread pool chlorination in the 1960s most reported

cases were in fisherman and aquarium owners, giving rise to the term fish tank granuloma.1,2 With improper chlorination and the emergence of chlorine-resistant organisms, swimming pool associated infections have reemerged.3

Following entrance into an open wound, M. marinum usually causes a tender erythematous nodule or pustule at the site of inoculation. Although the infection typically occurs on the dominant hand, any extremity may be affected. The average incubation period is approximately two to four weeks, but can last as long as nine months.3,4 In time, the lesion can evolve into a crusted ulcer with an underlying purulent abscess, a verrucous nodule or a plaque. As the infection spreads, multiple nodules can be found following the course of lymphocutaneous drainage. This form of spread is commonly known as sporo-trichoid spread because of its resemblance to the ascending lymphangitis of sporo-trichosis.2,5 The other variant is a nonlym-phocutaneous infection, this pattern is defined by nodules and/or abscesses at sites of prior trauma.6 With deeper infections, tenosynovitis may occur with the possi-bility of progression to septic arthritis and even osteomyelitis.7

A diagnosis of M. marinum skin infection is best established by obtaining at least a 4 mm punch biopsy specimen of the granu-loma. The specimen should be bisected, with one half used for hematoxylin-eosin and acid fast stains, and the other half for inoculation on Lowenstein-Jensen media. The culture specimen should be incubated at 30-33 degrees Celsius for 2 to 5 weeks for optimal growth.8

The histopathological findings in patients with M. marinum infections can range from acute and chronic inflammation to ill-defined suppurative granulomas, which is typical to mycobacterial infections. The granulomas are characterized by clusters of surviving organisms contained within a mixture of surrounding lymphocytes, histiocytes, and neutrophils. The organ-isms, which are scattered and minimal, are

rarely visualized on routine hematoxylin and eosin stain, but are likely to be positive on acid-fast stains such as Ziehl-Neelsen or Fite.9

The increased incidence of non-tubercu-loid mycobacterial diseases has created the need for the development of rapid detec-tion methods.10 This is essential because the clinical manifestations of M. Marinum, in cases where the typical lymphatic spread is observed, can be confused with the sporotrichoid pattern caused by other microorganisms. This includes Sporothrix schenckii, Leishmania brasiliensis and Francisella tularensis.11 Thus, a diag-nostic tool could be extremely useful since conventional cultures often fail to detect M. marinum. Existing models used in the diagnosis of M. marinum are based on PCR and consist of the amplification of sequences that are specific for mycobac-teria. Notably the 16S rRNA12,13 or hsp6514

John G. Stoner Jr., D.O.*, Thomas D. Griffin M.D.***2nd year Family Practice Resident - Heart of Lancaster Regional Medical Center**Associate Clinical Professor Drexel University Department of Dermatology

SPOROTRICHOID MYCOBACTERIUM MARINUM INFECTION: CASE REPORT AND REVIEW OF THE LITERATURE

ABSTRACT

In this paper, we report a patient in whom Mycobacterium marinum infection was diagnosed. Mycobacterium marinum is an atypical mycobacterium known to cause cutaneous infections. There are multiple mycobacterial strains that will cause an infection, in addition to M. Marinum. These skin infections can and will present in different fashions. It is thus beneficial for physicians to understand how to diagnose and treat mycobacterial infections effectively.

Figure 1

Figure 2

genes, followed by restriction enzyme anal-ysis or sequencing of amplicons. 14

A new molecular method was developed by Kox et al.15 It is based on the analysis of PCR products obtained from 16S rDNA with specific oligonucleotide probes in a reverse cross-blot hybridization assay.11 The results of this probe are easily inter-preted and not subject to mistake. In addi-tion, this assay takes into account 13 other clinically relevant species of mycobacte-rium, and allows one to detect mycobac-teria directly on clinical specimens derived from formalin-fixed, paraffin-embedded biopsies.11

Atypical mycobacterial infections of the skin present a therapeutic challenge to dermatologists and other clinicians. No clinical trials exist for the treatment of M. marinum infections because of the small number of patients with the disease. However, Trimethoprim-sulfamethoxazole, minocycline, and clarithromycin are all effective treatments.4 Success with mino-cycline is particularly well-documented in dermatology literature, even in the cases complicated by delayed diagnosis and systemic immunosuppression.10 On the other hand, according to infectious disease literature clarithromycin is favored as a first line treatment.5 Ethambutol and rifampin should be added to resistant strains. This combination of clarithromycin, rifampin and ethambutol has proven to be more effective against M. marinum than any single antibiotic regimen.4 Treatment should be preformed for a minimum of 6 months, or for at least 2 months after the lesions have disappeared; however in patients with disseminated disease, treat-ment for 9 to 12 months is required.4

ConclusionMycobacterial skin infections can be

prevented by wearing gloves while working in fish tanks. Also, immediately cleaning any abrasions or injuries that occur while working in potentially contaminated water can prevent infection with Mycobacterium marinum.5

This case report reminds physicians that mycobacterial infections can present in atypical fashions. Despite the lack of a supporting clinical history this patient

managed to become infected by an atypical mycobacterium. The best ways to assure a correct diagnosis is to biopsy a suspicious lesion and send it for culture, including mycobacterial stains.

References:1. Norden A, Linell F. A new type of pathogenic Mycobacte-

rium. Nature. 1951; 168:826.2. Palenque R. Skin diseases and nontuberculous atypical

mycobacteria. Int J Dermatol. 2000;39:659-666.3. Jernigan JA, Farr BM. Incubation period and sources of

exposure for cutaneous Mycobacterium marinum infec-tions: case report and review of the literature. Clin Infect Dis. 2000;32:439-443.

4. Edelstein H. Mycobacterium marinum skin infections. Report of 31 cases and review of the literature. Arch Intern Med. 1994;154:1359-1364.

5. Lewis FT, Marsh BJ, von Reyn CF. Fish tank exposure and cutaneous infections due to Mycobacterium mari-num: tuberculin skin testing, treatment, and prevention. Clin Infect Dis. 2003;37:390-397.

6. Anaissie EJ, Penzak SR, Dignani MC. The hospital water supply as a source of nosocomial infections. A plea for action. Arch Int Med 2002;162:1483-92

7. Barton A, Berstein RM, Struthers JK, et al. Mycobac-terium marinum infection causing septic arthritis and ostreomyelitis. Br J Rheumatol. 1997;36:1207-1209

8. Belic M, Miljkovic J, Marko P B, Sporotrichoid pre-sentation of Mycobacterium marinum infection of the upper extremity. A case report. Acta Dermatoven APA. 2006;15:135-139

8. Bartralot R, Garcia-Patos V, Sitjas D, et al. Clinical pat-terns of cutaneous nontuberculous mycobacterial infec-tions. Br J Dermatol. 2005;152:727-734

9. Salfinger M, Pfyffer GE, The new diagnostic myco-bacteriology laboratory. Eur J Clin Microbiol Infect Dis 1994;13:961-979

10. Posteraro B, Sanguinetti M, Garcovich A, Ardito F, Zam-petti A, Masucci L,Sbordoni G, Cerimele D, Fadda G, Polymerase chain reaction-reverse cross-blot hybridiza-tion assay in the diagnosis of sporotrichoid Mycobacte-rium marinum infection. Br J Dermatol. 1998;139:872-876

11. Avaniss-Aghajani E, Jones K, Holtzman A et al. Molecu-lar technique for rapid identification of mycobacteria. J Clin Microbiol. 1996;34:98-102

12. Vaneechoutte M, de Beenhouwer H, Clayes G et al. Identification of Mycobacterium species by using ampli-fied ribosomal DNA restriction analysis. J Clin Microbiol 1993;31:2061-2065

13. Telenti A, Marches F, Bald M et al. Rapid identification of mycobacteria to the species level by polymerase chain reaction and restriction enzyme analysis. J Clin Microbiol 1993;31:175-178

14. Kox LFF. Van Leeuwen J. Knijper S et al. PCR assay based on DNA codinf for 16S rRNA for detection and identification of Mycobacteria in clinical samples. J Clin Microbiol Infect Dis 1995;33:3225-3233

15. Janik JP, Bang RH, Palmer CH. Case reports: success-ful treatment of Mycobacterium marinum infection with minocycline after complication of disease by delayed diagnosis and systemic steroids. J Drugs Dermatol. 2005;4:621-624

18 SPOROTRICHOID MYCOBACTERIUM MARINUM INFECTION: CASE REPORT AND REVIEW OF THE LITERATURE

Figure 4

SAYED, NISENBAUM 19

Case PresentationA 59-year-old African American female

presented with a changing nodule on her left upper arm. The patient was previously evaluated by a plastic surgeon and refused excision at that time. She was then evalu-ated by a dermatologist, and two punch biopsies (4mm and 5mm) were performed. Routine histology revealed a markedly atypical neoplasm with features of a malig-nant adnexal tumor (Figures 1, 2, 3). The differential diagnosis included seroma and spiradenoma.

HistologyImmunohistochemistry was performed,

revealing positive expression for cytok-eratin 7 throughout the neoplasm and focal positivity for epithelial membrane antigen (Figures 4, 5). Studies with S-100 protein showed aggregates of cells expressing the antigen, a feature that is typical of spirade-noma (Figure 6). A proliferation marker, Ki-67, was also used and revealed areas of high labeling index, usually not evident in spiradenomas (Figure 7).

Patient follow-up: Unfortunately, the patient refused any further work-up or treatment despite being counseled on the dangerous nature of her diagnosis. She was lost to follow-up.

DiscussionSpiradenocarcinoma is a rare, aggres-

sive, adnexal tumor that often arises from a long-standing, benign spiradenoma.5,9

Fewer than 30 cases have been docu-mented in the literature, and the earliest reported case was published by Dabaska in 1972.1,2,4,5 Middle aged and elderly patients are most commonly affected.8 Patients that develop malignant transformation from a pre-existing benign neoplasm relay a history of rapid growth of a long-standing nodule or plaque. Bleeding and ulceration are other common clinical find-ings.3 Spiradenocarcinoma is a poorly

differentiated carcinoma, and a diagnosis may be rendered late in the course, as a long-standing stable lesion may be ignored by the patient and clinician. Metastasis to the regional lymph nodes may occur, and a sentinel lymph node biopsy may be required.7 Patient mortality has been reported in up to 20% of cases.8

The most common areas of presenta-tion include the trunk and extremities; however, case reports documenting less likely sites have been reported. Russ et al. report a case of a spiradenocarcinoma of the scalp that was treated with MOHS micrographic surgery.11 Meyer et al. report a case of an eccrine spiradenocarcinoma of the external auditory canal,9 and Ribeiro-Silva et al. report a case of breast spiradenocarcinoma.6

Histologically, the tumor displays a carci-nomatous area in combination with benign features of spiradenoma.7,8 Spiradenomas exhibit two cell populations, which are often lost with malignant transformation.7,8 Other distinguishing features of malig-nancy include hyperchromasia, an increase in nuclear to cytoplasmic ratio (N:C), and increased mitotic activity (Ki-67).4,7 This tumor stains with epithelial markers and may show positivity with S-100.8 This case did show S-100 positivity, a typical feature of spiradenoma; however, the tumor also showed positive staining with epithelial membrane antigen (EMA), which stains adenocarcinomas. There are some reports that the p53 suppressor oncogene is expressed by the malignant portion of the tumor, and p53 immunostaining may be useful in distinguishing the carcinomatous component of the tumor.2,5 The pathology in this case did not require further studies with p53 immunostaining, as other markers were positive.

SummaryIn summary, spiradenocarcinoma is a

rare, aggressive tumor often evolving from a pre-existing benign lesion. The prognosis may be poor, as discovery of the

tumor occurs late. The trunk and extremi-ties are the most commonly involved sites; however, other sites have also been reported. Follow-up requires excision of the lesion and possible sentinel lymph node biopsy.

Amara Sayed, D.O., FACOFP,* Layne D. Nisenbaum, D.O., FAOCD***First-year Dermatology Resident, Columbia Hospital, West Palm Beach, FL**Program Director, Columbia Hospital, West Palm Beach, FL Island Dermatology, Laser and Anti-Aging Institute, Palm Beach, FL

SPIRADENOCARCINOMA: A CASE REPORT

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 We present a case of a 59-year-old female with a changing nodule on the upper extremity.

Fig.1: Low-power H&E

Fig. 2: High-power H&E

Fig. 3: H&E, high power, showing duct-like structures

References1. 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 immunohistochemical 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.

7. Fitzpatrick’s Dermatology in General Medicine (6th Edi-tion). Freedberg, Irwin M., Arthur Z. Eisen, Klaus Wolff , K. Frank Austen, Lowell A. Goldsmith, Stephen I Katz, 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. American Journal of Dermatopathology. 2000 Apr;22(2):97-103.

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. 2003 Jun;25(6):505-10.

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. 2004 Jun;8(3):162-6.

11. Russ BW, Meffert J, Bernert R. Spiradenocarcinoma of the scalp. Cutis. 2002 Jun;69(6):455-8.

20 SPIRADENOCARCINOMA: A CASE REPORT

Fig.4: Immunohistochemistry showing positive staining with cytokeratin 7

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

SICA, MILLER 23

Introduction:Keratitis-ichthyosis-deafness (KID)

syndrome is a rare disorder with auto-somal dominant and recessive inheritance reported. The syndrome is characterized by a triad of progressive, bilateral vascular-ized keratitis, congenital ichthyosis, and nonprogressive sensorineural deafness.1 We present a 5-month-old male with features consistent with KID syndrome, followed by a review of the pathogenesis and management.

Various reports in the literature have revealed several cutaneous features to be common in patients afflicted with this syndrome:1,2

fine dry scale and formation of hyperk-eratotic follicular spines

-clic, erythematous, keratotic plaques on the extensor surfaces and face

the palms and soles

“coarse-grained leather” appearance

and fungal infections, especially with C. albicans

eyelashes

oral mucosa Approximately 96% of affected patients

will present with ocular symptoms secondary to vascularizing keratitis.2 This may manifest at birth, during infancy, or in early childhood as photophobia, irritation, tearing, and impaired visual acuity.11,13 It may progress to chronic blepharitis, kerato-conjunctivitis sicca, and frank blindness.12 Hearing loss in KID Syndrome is typically severe and bilateral; however, it is not progressive. Moderate forms of hearing impairment are also observed.

Case Report:A 5-month-old African American male

presented for the issue of dry skin that manifested shortly after birth. He was accompanied by his mother and father, both of whom are deaf. His mother claimed to have a history of an inherited skin disorder.

Physical examination revealed multiple, sharply demarcated, er y thematous, hyperkeratotic plaques on the chin, nasal bridge, and chest (Figure 1). The palmar and plantar surfaces revealed a stippled pattern of hyperkeratosis (Figure 2). The fingernails and toenails appeared bilat-erally dystrophic (Figure 3). Two adja-cent purulent ulcers with honey-colored crust were present on the scalp (Figure 4). Alopecia was noted on the scalp, eyebrows, and eyelashes (Figure 1). Eye examina-tion revealed a clear discharge. The oral mucosa revealed adherent white plaques over the tongue. A wound culture was taken from a purulent lesion on the scalp.

The patient was started on a 10-day course of cephalexin for impetigo, and a one-week course of fluconazole for oral candidiasis. He was also given low-potency topical corticosteroids to use for one week on inflamed areas and emol-lients for his parents to apply liberally throughout the day to his entire body. Ophthalmology and otolaryngology consults were recommended. The patient was also referred to a tertiary care center for genetic analysis.

Upon follow-up three weeks later, the patient had responded well to the course of treatment and had no active dermato-logical issues. The initial wound culture of the impetiginized areas was positive with moderate growth of Staph aureus; however, this was sensitive to cephalexin. The ophthalmologic examination revealed early cataracts. Otolaryngology consult, further medical records, and genetic anal-ysis are pending.

Discussion:Keratitis-ichthyosis-deafness (KID)

Syndrome is a congenital disorder of the ectoderm that affects the epidermis, corneal epithelium, and the inner ear. It results from a germline missense mutation in the GJB2 gene that encodes connexin-26, a component of gap junctions in epithelial cells.5-10,14 Specifically, a D50N mutation, which substitutes aspartic acid with aspar-agine on codon 50, is common.7,8 The gap junction is a compact assembly of intercel-lular channels that direct and coordinate a variety of cellular signaling. Impairment of the signaling process results in disruption of cochlear and corneal differentiation, as well as epidermal cornification.10,11,14

Roger S. Sica, DO,* Richard A. Miller, DO, FAOCD***1st year resident, Suncoast Hospital, Department of Dermatology, Largo, FL**Program director, Suncoast Hospital, Department of Dermatology, Largo, FL

KID SYNDROME: A CASE REPORT AND REVIEW

ABSTRACT

Keratitis-ichthyosis-deafness (KID) syndrome is a rare disorder characterized by a triad of progressive, bilateral vascularized keratitis, congenital ichthyosis, and nonprogressive sensorineural deafness. We describe a 5-month-old boy who presented with ichthyosis and several salient physical findings of KID syndrome. The clinical features, inheritance, histology, laboratory data, and management options will be discussed.

Figure 1: Erythematous, keratotic plaques on nasal bridge and lower cutaneous lip

Figure 2: Stippled plantar keratoderma

A newly reported association with KID Syndrome is the “follicular occlusion triad”.3,4 This classically includes acne conglobata, dissecting cellulitis of the scalp and hidradenitis suppurativa. The reason for this association has yet to be elucidated.

There are nonspecific laboratory abnor-malities associated with the syndrome, including increased plasma IgE and IgG levels, as well as diminished chemotactic and lymphocytic response to C. albicans. Thus, an immunological impairment may also be implicated in the pathogenesis.

His to log y i s o f ten nonspec i f i c . Hyperkeratosis of the stratum corneum as well as papillomatosis and acanthosis of the epidermis is common. Vacuolization of the granular cell layer and follicular plugging are also observed.

Treatment of KID Syndrome remains supportive with topical emollients and keratolytics. Topical retinoids may also be beneficial. Because of the increased suscep-tibility to secondary infections, liberal use of oral antibiotics and antifungals is warranted. Close observation and biopsy of atypical keratotic papules are neces-sary because of the increased incidence of squamous-cell carcinoma. Despite some reports of successful treatment with oral retinoids10, they must be used with caution as they may intensify corneal neovascular-ization. Surgical debridement and excision have been reported in those with recalci-trant follicular occlusion triad.4

Prompt referral to an ophthalmologist and otolaryngologist is crucial to ensure any ocular and auditory pathology are properly evaluated. Useful treatments to achieve relief of ocular symptoms include topical steroids, artificial tears, and topical calcineurin inhibitors.13 Cochlear implants may be an option for improved hearing. Genetic testing of first-degree relatives who are symptomatic and genetic counseling are recommended.

Despite the possibility of severe sensory handicap, the life span of patients with KID Syndrome is normal. In the future, with advancements in molecular genetics, more treatment options may become avail-able. Until then, KID Syndrome must be recognized early to prevent an increased severity of sensory defects and an increased incidence of cutaneous malignancy.

References:1. Skinner B.A., Greist M.C., Norins A. The keratitis, ich-

thyosis, and deafness (KID) syndrome. Arch Dermatol (1981) 117: pp285-289.

2. Caceres-Rios H. Keratitis, ichthyosis, and deafness (KID syndrome): review of the literature and proposal of a new terminology. Pediatr Dermatol (1996) 13(2): pp105-113.

3. Montgomery Capt Jay R., et al. A novel connexin 26 gene mutation associated with features of the keratitis-ichthyosis-deafness syndrome and the follicular occlusion triad. J Am Acad Dermatol (2004) 51(3): pp377-82.

4. Maintz L. Keratitis-ichthyosis-deafness syndrome in association with follicular occlusion triad. Eur J Dermatol (2005) 15(5): 347-52.

5. Richard G. Missense mutations in GJB2 encoding con-nexin-26 cause the ectodermal dysplasia keratitis-ich-thyosis-deafness syndrome. Am J Hum Genet (2002) 70(5): 1341-8.

6. Jan A.Y. Genetic heterogeneity of KID syndrome: identi-fication of a Cx30 gene (GJB6) mutation in a patient with KID syndrome and congenital atrichia. J Invest Dermatol (2004) 122(5): 1108-13.

7. Janecke A.R. GJB2 mutations in keratitis-ichthyosis-deafness syndrome including its fatal form. Am J Med Genet (2005) 133(2): 128-31.

8. Yotsumoto S. Novel mutations in GJB2 encoding con-nexin-26 in Japanese patients with keratitis-ichthyo-sis-deafness syndrome. Br J Dermatol (2003) 148(4): 649-53.

9. Van Steensl M.A. A novel connexin 26 mutation in a patient diagnosed with keratitis-ichthyosis-deafness syn-drome. J Invest Dermatol (2002) 118(4): 724-7.

10. Bondeson M.L. Connexin 26 (GJB2) mutations in two Swedish patients with atypical Vohwinkel (mutilating keratoderma plus deafness) and KID syndrome both extensively treated with acitretin. Acta Derm Venereol (2006) 86(6): 503-8.

11. Sonoda S, et al. Two patients with severe corneal dis-ease in KID syndrome. Am J Ophthal (2004) 137(1): 181-3.

12. Messmer E.M. Ocular manifestations of keratitis-ichthyo-sis-deafness (KID) syndrome. Ophthalmology. (2005) 112(2): e1-6.

13. Tabet R. KID syndrome: pathogenesis of ocular lesions. J Fr Ophtalmol (2005) 28(5): 521-6.

14. Griffith A.J. Cochleosaccular dysplasia associated with a connexin 26 mutation in keratitis-ichthyosis-deafness syndrome. Laryngoscope (2006) 116(8): 1404-8.

24 KID SYNDROME: A CASE REPORT AND REVIEW

Figure 3: Nail dystrophy

Figure 4: Secondarily impetiginized ulcers

AFFILIATED DERMATOLOGYSM

Seeking BC/BE Dermatologists and Dermatologic Surgeons

26 CAROTENODERMA ASSOCIATED WITH RED PALM OIL CONSUMPTION

Carotenoderma is a yellow to orange discoloration of the skin usually caused by ingestion of excessive amounts of carotene-containing foods. Of the carotenoids, the carotenes, particularly beta-carotene, are most important in the development of carotenemia. The areas most often affected include the palms, soles, and nasolabial folds of the face. When faced with a patient with carotenoderma, it is important for the dermatologist to evaluate for etiologies, such as excessive dietary intake of caro-tenes, as well as metabolic disturbances and malignancy. We present a Liberian male who had carotenoderma due to red palm oil consumption, and we discuss an approach to a patient exhibiting yellowing of the skin.

Our patient is a 31-year-old Liberian male who presented with a two-month history of yellow to orange discoloration of the palms and soles. He denied any intake of carrots, excessive intake of any one type of vegetable, and any multivi-tamin supplementation. He reported cooking with red palm oil on a daily basis. Despite altering his diet by avoiding foods high in beta-carotene, including red palm oil, the discoloration persisted. Review of systems revealed complaints of occasional headache, night sweats, intermittent fever, fatigue, pruritus and slight weight loss of nine pounds. His medical and surgical histories were unremarkable. There was no family history of similar discoloration, diabetes mellitus or thyroid disease. He was on no medications. Physical exami-nation revealed a well appearing male with yellow-orange discoloration of the palms, soles and nose. His sclerae and oral mucosa were spared. Laboratory data revealed an elevated serum carotene level of 378 (upper limit of normal is 150μg/dL), which decreased to 191 upon exclusion of red palm oil from his diet. However, sub-sequent evaluation of his serum carotene level revealed an increase to 286. Thyroid function tests, comprehensive metabolic panel, complete blood count, erythrocyte sedimentation rate and vitamin A levels were all within normal limits. A hepatitis panel and lyme antibody testing were nega-tive. A fasting lipid profile was normal. CT scan of the head, abdomen, pelvis and plain films of the chest were all unremark-able. A biopsy of the right palm revealed

features suggestive of a keratoderma. A diagnosis of carotenoderma due to red palm oil consumption was made. Because of the lipophilic nature of beta-carotene, our patient continued to have clinical and laboratory evidence of carotenemia despite discontinued use of red palm oil.

Carotenoderma is asymptomatic and can occur in any age group, although it develops more readily in children. Accumulation in the skin lags behind the serum by two weeks. Excess carotene is excreted in sweat and sebaceous material, and is then reabsorbed by the stratum cor-neum. Deposition occurs predominantly on the palms and soles, where the stratum corneum is thickest, and the melolabial folds and forehead, where sebaceous glands abound. Notably, the sclerae are spared

The most common cause of caroteno-derma is excessive dietary intake of carote-noids. Foods rich in beta-carotene include carrots, oranges, green leafy vegetables and red palm oil. It is important to rule out other causes, such as a genetic defect in conversion of carotenes to retinol and a facilitated uptake of carotenes through the intestinal wall. Most importantly, one should consider and rule out metabolic causes that lead to carotenoderma, as well as malignancy.

Rare cases have been attributed to a genetic defect in the enzyme responsible for cleaving carotenoids into vitamin A. Once absorbed, beta-carotene is converted to vitamin A in the intestinal mucosa. The carotene-cleavage enzyme beta-carotene 15,15’-dioxygenase has been identified in the intestinal mucosa and may be the defec-tive or deficient enzyme in patients with no history of over-ingestion and no evidence of an underlying metabolic disease.

Metabolic disturbances associated with carotenemia include hypothyroidism, dia-betes mellitus, anorexia, liver disease, neph-rotic syndrome, and hyperlipoproteinemia. The conversion of beta-carotene into two molecules of vitamin A is accelerated by thyroxine. The yellow tint of the skin in hypothyroidism is due to beta-carotenemia secondary to decreased thyroxine levels. In diabetes mellitus, impaired conversion of carotene to vitamin A occurs, but only about 10% of patients will develop carote-noderma. Also, there is a linear relation-ship between serum lipoprotein levels and

carotene levels. Therefore, any disorder involving elevated lipids, including dia-betes mellitus and nephrotic syndrome, may manifest as carotenemia. In anorexia nervosa, carotenemia is attributed to fad dieting with excessive intake of foods rich in beta-carotene. In this case, serum carotene levels will be markedly increased and serum vitamin A levels will be slightly increased. Symptoms of hypervitaminosis A do not occur, though -- carotenemia has not been proven to result in hypervi-taminosis A. This is due to the fact that conversion is regulated by feedback inhibi-tion, and excessive beta-carotene is elimi-nated from the body without conversion to vitamin A. Therefore, hypervitaminosis A in a carotenemic patient is due to a simul-taneous overdose of the vitamin, not to the carotenemia.

Another important etiology to rule out is malignancy. One report in the literature by Olmedilla and colleagues describes a 29-year-old female with a brain tumor who received several months of carotenoid-free enteral nutrition, with no other source of beta-carotene supplementation. Analyses after several months on this diet showed that her beta-carotene concentrations had doubled. Authors postulate that, although diet is an important factor, other factors related to development of certain diseases may be relevant determinants of changes in the carotenoid profile.

Carotenoderma is endemic in West Africa, the region of our patient’s origin, where red palm oil is used for cooking. Red palm oil is the richest natural source of beta-carotene. Beta-carotene is a lipophilic vitamin and can remain in the tissue for months after adopting a carotenoid-free diet. One case involving a patient from Liberia who cooked with red palm oil revealed persistent yellow discoloration of the palms and soles of five months dura-tion despite discontinued use of the oil and normalization of the serum carotene level. This may explain our patient’s persistent carotenoderma and elevated serum beta-carotene levels.

Other causes of yellow discoloration of the skin include hyperbilirubinemia, lyco-penemia, riboflavinemia and quinacrine treatment for malaria. A careful history and physical exam coupled with appropri-ate serum laboratory studies will help to

Valerie A. Nozad, DO,* Mary K. McGonagle, DO,** Stephen M. Purcell DO, FAOCD****Dermatology Resident, 3rd Year, Philadelphia College of Osteopathic Medicine/Frankford Hospital**Attending in Private Practice at Philadelphia Institute of Dermatology***Program Director at PCOM/Frankford Hospital

CAROTENODERMA ASSOCIATED WITH RED PALM OIL CONSUMPTION

exclude these causes. A paraneoplastic phenomenon should also be kept in mind in patients whose history and laboratory data do not point to the underlying cause of the carotenemia.

References:1. Stack KM, Churchwell MA, Skinner RB. Xantho-

derma: Case Report and Differential diagnosis. Cutis 1988;41:100-2.

2. Olmedilla B, Granado F, Blanco I. Hyper-B-Carotenemia Unrelated to Diet: A Case of Brain Tumor. Internat J Vit Nutr Res 1995;65:21-3.

3. Christopher R et al. Carotenoderma in Metabolic Caro-tenemia. Indian Pediatrics 1997;34:1032-4.

4. Almond S, Logan RLF. Carotenaemia. Br Med J 1942;2:239.

5. Cohen L. Observations on carotenemia. Ann Intern Med 1958;48:219.

6. Person JR. Red palms and orange palms. Arch Dermatol 1981;117:757.

7. Monk BE. Metabolic carotenaemia. Br J Dermatol 1982;106:485.

8. Arya V et al . Carotenemia. Pediatr Dermatol 2001;41:441.

9. Svensson A, Vahlquist A. Metabolic carotenemia and car-otenoderma in a child. Acta Derm Venereol 1995;75:70.

10. Sharvill DE. Familial hypercarotenemia and hypovita-minosis A. Proc Roy Soc Med 1970;63:605.

11. Hughes JD, Wooten RL. The orange people. JAMA 1966;197:730.

12. Rock CL, Swendseid ME. Plasma carotenoid levels in anorexia nervosa and in obese patients. Methods in Enzymology 1993;214:116.

NOZAD, MCGONAGLE, PURCELL 27

28 NEW TECHNOLOGIES FOR EARLY DETECTION OF MELANOMA: UPDATE & PROGRESS - 2007

IntroductionIt is estimated that there will be nearly

100,000 new cases of malignant melanoma (including melanoma in situ) and 8,110 melanoma-related deaths, at an average age of 47, in the United States during 2007.1 More than half of the yearly 15,000 global melanoma deaths occur in the United States. Almost half of the new cases of melanoma projected this year (2007) will occur in 10 states, according to the American Cancer Society. The 10 states with the greatest annual incidence of mela-noma (per capita) include the following, in descending order: California, Florida, Texas, Pennsylvania, New York, Ohio, New Jersey, Michigan, Illinois, and Massachusetts.2

Notably absent from this dubious list is the state of Hawaii, which boasts a hot, tropical climate year-round. One explanation for the paradoxically low rates of melanoma in Hawaii is the large percentage of Asian-Americans in the state, estimated to be as high as 58% of the population; darker skin types, perhaps Fitzpatrick type III-IV, seen in Asian-Americans, confer added protec-tion from harmful ultraviolet irradiation. Greater awareness of the need for sun protection also helps lower the risk.

Despite advances in the development of chemotherapy and immunotherapy, the prognosis for patients with advanced mela-noma remains poor. Lifetime risk factors for development of melanoma include light skin color, family and/or personal history of skin cancer, presence of atypical nevi and ephelides, and history of severe, blistering sunburns early in life. Efforts to control melanoma mortality continue to be focused on the prevention and early detection of “thin” melanomas, loosely defined as those with a Breslow depth of <1 cm. Five-year survival rates for thin melanomas are 95-100%, but prognosis worsens as Breslow depth increases (five-year survival as low as 80% associated with

Breslow depth 1-2 mm, 60% with Breslow depth 2.1-4 mm, and 50% with Breslow depth >4 mm).5

Current Methods of Melanoma Detection & Prevention

The increased use of epiluminescence microscopy (dermoscopy) among derma-tologists in recent years brings hope that more atypical nevi and early melanomas may be detected before they progress to life-threatening disease. Since our previous update on new technologies for early detection of melanoma, published in the Journal of the American Academy of Dermatology in 2003, awareness of dermoscopy has led to more widespread adoption in clinical practice.3

The adoption of newer computer-based technologies, such as the scanning device MelaFind® (Electro-Optical Sciences, Inc, Irvington, NY), currently under Phase III trials and slated for FDA approval as early as late 2007, and Melanoscan®, a whole-body photographic scanner, is expected to broaden the technological repertoire avail-able to practitioners in dermatology.

During the past decade, atypical moles (dysplastic nevi) have been identified as the strongest indicators of melanoma risk.4 Dysplastic nevi often manifest asymmetry, border irregularity, and color variation. Thus, the presence of large numbers of these nevi can complicate attempts at mela-noma surveillance because it is often diffi-cult to differentiate dysplastic nevi from melanomas. Many dermatologists recom-mend prophylactic excision of all atyp-ical melanocytic lesions, but the criteria for dysplastic nevi remain blurred.5 For patients with hundreds of nevi, or multiple recurrent nevi, prophylactic excision of all atypical nevi remains impractical. An alternative approach to prophylactic exci-sion is to closely observe these patients using whole-body photography of nevi, coupled with regular frequent full-body

skin examinations and judicious use of dermoscopy when appropriate.

Visual examination of the skin for suspicious or atypical-appearing melano-cytic lesions can be supplemented with technological aids for the detection and diagnosis of early melanoma. Clinical diagnosis of melanoma depends primarily on the subjective view of the trained clini-cian and is limited by random lapses in visual judgment. We know that the clinical diagnosis of melanoma is subject to inac-curacies and unintentional error. Some employ the practice of taking multiple biopsies so as not to miss an early mela-noma. Retrospective studies indicate that the majority of lesions biopsied to rule out atypical melanocytic proliferation are, in fact, histologically proven to be benign.

New Technologies for Early Detection of Melanoma

New technologies to screen for atypical melanocytic lesions without the need for relatively invasive procedures that can result in patient anxiety, scarring, and in some cases infection, are both needed and recommended by many clinicians. Some specialized centers already employ detailed mole mapping and the use of digitized scanning devices like MelaFind® as an adjunct to visual inspection. The goal of these and other new technologies is to improve on what the human eye can detect. The implementation of these technologies remains dependent, however, on the will-ingness of both physician and patient to adopt new trends in skin cancer detection.

Dermoscopy, for example, has been shown to increase the diagnostic accuracy for melanoma; physician training is needed, however, and providers must be willing to attend workshops, lectures, and online training sessions in order to be adept in the use of this new diagnostic modality. Fewer than one in four dermatologists utilize dermoscopy; still, the widespread accep-

Kevin T. Belasco, DO, MS,* Richard Miller, DO, FAOCD**

NEW TECHNOLOGIES FOR EARLY DETECTION OF MELANOMA: UPDATE & PROGRESS - 2007

ABSTRACT

The lifetime risk of developing melanoma has risen dramatically over the past 50 years. Despite advances in the development of chemotherapy and immunotherapy, the prognosis for patients with advanced melanoma remains poor. Thus, the field of dermatology has recently explored novel and potentially life-saving approaches to early detection of early melanoma. The identification and diagnosis of early melanoma will be important in reducing morbidity and mortality, as well as the enormous financial cost to the health care system. In this report, we review the critical factors in early detection of melanoma and explore those technologies that have been adopted by dermatologists in recent years. We also summarize our own findings from a meta-analysis to determine factors that affect adoption of new technologies for melanoma in dermatology. We conclude with a review of novel applications of technology in melanoma diagnosis, including whole-body photography, scanning digital handheld devices, dermoscopy, and teledermatology.

tance of this and other visual aids in evalu-ation of melanocytic lesions represents a key step in the progress toward large-scale adoption of new technologies in dermato-logic practice.

While the cause of all melanomas is not known, it is estimated that 10% of mela-nomas are associated with familial or inher-ited syndromes.10 An additional tool in the early detection of heritable forms of mela-noma is a newly available blood test for detection of mutations in the p16 tumor-suppressor gene on chromosome 9 called Melaris® (Myriad Genetic Laboratories, Salt Lake City, UT). Most hereditary melanomas are believed to be caused by mutations in the p16 gene.15 Alterations in this gene significantly increase one’s risk of melanoma and pancreatic cancer. The p16 gene product regulates cell proliferation by inhibiting the cyclin-dependent kinase 4 (CDK4) protein; thus, mutations in p16 that disrupt function lead to unregulated cell growth. Carriers of the p16 mutation have an estimated 76% likelihood of devel-oping melanoma before the age of 80.15

A screening test for detection of the p16 mutation is not warranted in every patient with a personal or family history of melanoma. Each case scenario must be analyzed according to the individual needs of the patient. Nevertheless, the Melaris® test should be considered in patients with a strong history of pancreatic cancer or melanoma in multiple family members. Moreover, 10%-15% of individuals with greater than one melanoma are believed to have the p16 mutation, suggesting that those with a personal history of multiple primary melanomas may benefit from this test.15 The presence of p16 mutations in both pancreatic cancer and heritable melanoma suggests that the astute derma-tologist should question all melanoma patients about a family or personal history of pancreatic carcinoma.

The presence of a p16 mutation following Melaris® testing indicates an increased genetic susceptibility to melanoma that is best addressed with close observation, regular skin examinations, and consider-ation of baseline whole-body photography (mole mapping). Given the long-term risk of developing melanoma in patients with verifiable p16 mutations, these individuals could conceivably be candidates one day for experimental melanoma vaccines. Experimental vaccines against melanoma are currently being tested in patients with a history of metastatic disease who are at high-risk for melanoma recurrence.

Barriers to the Adoption of New Technologies in Melanoma Diagnosis

To promote new technologies and clinical tools in dermatology, one must first identify and understand those factors critical to the adoption of new diagnostic

habits. Inherent constraints in time and cost are practical considerations that must be addressed, as time pressure and rising costs in healthcare are frequently cited by providers as impediments to the adoption of new technologies in practice. Factors affecting the adoption of new technologies have been compiled based on our review of physician and patient focus groups, as well as a meta-analysis of the medical litera-ture (see Table 1). These factors have not changed since our original investigations and subsequent report in 2003.

Lack of reimbursement has been identi-fied as a major barrier to cancer screening. The adoption and use of new technologies in a clinical setting is directly related to the acceptance of a standard Current Procedural Terminology (CPT) code permitted by the American Medical Association’s Committee on Coding.6 Whole-body photography for monitoring of high-risk patients with dysplastic nevi or familial melanoma has been designated a provisional category III CPT code (0044T).6

Dermatologic photography is used for the surveillance of patients at high risk for skin cancer. Mole mapping allows for long-term surveillance and provides valu-able documentation. To assess the barriers to use mole mapping and dermoscopy for patients with pigmented lesions, Nehal et al. mailed a questionnaire to derma-tology residents across the country (n = 83, response rate 79%).7 The main reasons why physicians recommend and use photography or dermoscopy include that it helps improve early detection of melanoma, improves record keeping and documentation, results in fewer biop-sies, and reduces cost and anxiety. The main reasons given by physicians for not using dermoscopy or photography were equipment logistics, time, training limita-tions, and cost.7 Some physicians also expressed a fear of increased liability when performing photography.

Recent Innovations & Future Trends in Diagnostics for Melanoma

Technologic advances are playing an increasing role in cancer screening and early detection. MelaFind® is a small, handheld device with a camera attached to it. The device captures images of suspected moles and compares them with a data-base of skin lesions. The handheld camera takes photos in 10 different wavelengths of light. The pictures are compared against the existing database, and the patient is given feedback in less than 30 minutes. The device costs approximately $1,800.00 and boasts a reported melanoma detection rate of 98%.8 A Phase III investigational trial is underway, launched in January 2007, to assess and quantify sensitivity and specificity of MelaFind® in early detection among 1,550 patients. This Phase III non-

randomized, open-label study represents just one of many new trials underway that employs novel technologies for early detec-tion of pigmented lesions.

The manufacturer of MelaFind®, Electro-Optical Sciences, Inc, Irvington, NY, has also developed a novel multi-spectral imaging technology for the evalu-ation and differentiation of pigmented skin lesions of cosmetic importance. The company announced in March 2007 that they were partnering with L’Oreal to develop new digital scanning technolo-gies to evaluate cosmetically significant pigmented skin lesions.8

ConclusionScanning digital handheld devices,

whole-body photography, and dermoscopy represent just a few of the new technolo-gies on the horizon for early detection of pigmented skin lesions. In addition to novel techniques in diagnosis, telemedicine has emerged as a valuable tool in derma-tology. Teledermatology, whereby clinical images are transmitted to a specialty center for review and analysis, represents yet another technological tool used in cases when distance limits a patient’s access to a dermatologist. Telemedicine in derma-tology has especially gained momentum in rural settings where a pigmented-skin clinic or even a dermatologist may be 50 miles away, or even farther.9

Future studies will need to focus on strategies to overcome the barriers to adop-tion of new technologies in dermatologic practice summarized above. Focus groups, physician and patient questionnaires, and public awareness will be key to the adoption of these novel technologies. Telemedicine, dermoscopy, whole-body photography, and novel scanning devices for early detection of melanoma are valuable tools available to the dermatologist. These innovations are poised to have an enormous impact on morbidity and mortality from melanoma, and to significantly impact cost savings for the health care system.

AcknowledgementsThe authors acknowledge Susan A.

Oliveria, ScD, Allan C. Halpern, MD, and the Dermatology Service at the Memorial Sloan-Kettering Cancer Center in New York City. The first author is currently an osteo-pathic dermatology resident and conducted research in dermatology at the Memorial Sloan-Kettering Cancer Center. The first author also wishes to thank Richard A. Miller, DO, FAOCD, for his mentorship and guidance.

References1. American Cancer Society: Cancer Facts and Figures

2007. Atlanta, Ga: American Cancer Society, 20072. http://www.skincancer.org, accessed April 20073. Weinstock MA. Cutaneous melanoma: public health

BELASCO, MILLER 29

approach to early detection. Dermatol Ther. 2006 Jan-Feb;19(1):26-31

4. Elder DE, Goldman LI, Goldman SC, Greene MH, Clark WHJ. Dysplastic nevus syndrome: a phenotypic asso-ciation of sporadic cutaneous melanoma. Cancer 1980; 46:1787-94

5. Cohen MH, Cohen BJ, Shotkin JD, Morrison PT. Surgi-cal prophylaxis of malignant melanoma. Ann Surg 1991; 213:308-14

6. Oliveria SA, Sachs D, Belasco KT, Halpern AC. Adop-tion of new technologies for early detection of melanoma in dermatologic practice. J Am Acad Dermatol. 2003 Nov;49(5):955-9

7. Nehal K, Oliveria SA, Marghoob AA, Christo PJ, Dusza SW, et al. Use of photography and dermoscopy in der-matologic clinics: a survey of dermatology residency programs in the United States. Melanoma Res 2002; 12:161-7

8. http://www.eosciences.com/, accessed April 20079. Weinstock MA, Nguyen FQ, Risica P. Patient and refer-

ring provider satisfaction with teledermatology. J Am Acad Dermatol 2002;47:68-72

10. Halpern AC, Lieb JA. Early melanoma diagnosis: a suc-cess story that leaves room for improvement. Curr Opin Oncol. 2007 Mar;19(2):109-15

11. Tripp JM, Kopf AW, Marghoob AA, Bart RS. Manage-ment of dysplastic nevi: a survey of fellows of the Ameri-can Academy of Dermatology. J Am Acad Dermatol 2002;46:674-82

12. Mair F, Whitten P. Systematic review of studies of patient satisfaction with telemedicine. BMJ 2000;320:1517-20

13. Rigel DS, Carucci JA. Malignant melanoma: prevention, early detection, and treatment in the 21st century. CA Cancer J Clin 2000;50:215-36

14 .Slue WEJ. Total body photography for melanoma sur-veillance. NY State J Med 1992;92:494-5

15 .http://www.myriadtests.com/melanoma.htm, accessed April 2007

30 NEW TECHNOLOGIES FOR EARLY DETECTION OF MELANOMA: UPDATE & PROGRESS - 2007

TABLE 1Factors affecting the adoption of new technologies for melanoma diagnosis in dermatologic practice (adapted from Oliveria et al.6)

Patient factorsAcceptance-related and satisfaction-related factorsCost to patientLength of visitPatient privacy/discomfortConfidence/comfort with technologyAttitudes toward/perceived use of technologyPhysician-patient communication

Physician factorsPhysician characteristicsLocation/size of practiceAge of physicianLack of training/insufficient computer skillsKnowledge/attitudeAcademic affiliationSpecialtyLiability related to patient confidentialityCharacteristics of the technologyReliabilityTime efficiencyEase of usePerceived useAwareness/accessibility of technologyCost/cost-effectivenessHealth care system factorsFinancial costs/reimbursementCost-effectivenessTime efficiency

CLINDAMYCIN & TRETINOINCOME TOGETHER TO CREATE…

© 2007 Medicis Pharmaceutical Corporation ZNA 06-005R 09/30/08 JOACD

See reverse side for brief summary of Full Prescribing Information.

BRIEF SUMMARY (see package insert for Full Prescribing Information)

ZIANA™(clindamycin phosphate 1.2% and tretinoin 0.025%) Gel

Rx only For topical use only

INDICATIONS AND USAGEZIANA Gel is indicated for the topical treatment of acne vulgaris in patients 12 years or older.

CONTRAINDICATIONSZIANA Gel is contraindicated in patients with regional enteritis, ulcerative colitis, or history of antibiotic-associ-ated colitis.

WARNINGS AND PRECAUTIONSColitisSystemic absorption of clindamycin has been demonstrated following topical use of this product. Diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) have been reported with the use of topical clindamycin. When significant diarrhea occurs, ZIANA Gel should be discontinued.Severe colitis has occurred following oral or parenteral administration of clindamycin with an onset of up to several weeks following cessation of therapy. Antiperistaltic agents such as opiates and diphenoxylate with atropine may prolong and/or worsen severe colitis. Severe colitis may result in death.Studies indicate a toxin(s) produced by clostridia is one primary cause of antibiotic-associated colitis. The colitis is usually characterized by severe persistent diarrhea and severe abdominal cramps and may be associated with the passage of blood and mucus. Stool cultures for Clostridium difficile and stool assay for C. difficile toxin may be helpful diagnostically. Ultraviolet Light and Environmental Exposure Exposure to sunlight, including sunlamps, should be avoid-ed during the use of ZIANA Gel, and patients with sunburn should be advised not to use the product until fully recov-ered because of heightened susceptibility to sunlight as a result of the use of tretinoin. Patients who may be required to have considerable sun exposure due to occupation and those with inherent sensitivity to the sun should exercise particular caution. Daily use of sunscreen products and protective apparel (e.g., a hat) are recommended. Weather extremes, such as wind or cold, also may be irritating to patients under treatment with ZIANA Gel.

ADVERSE REACTIONSClinical Studies Experience Because clinical trials are conducted under prescribed con-ditions, adverse reaction rates observed in the clinical trial may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse reactions that appear to be related to drug use for approximating rates.The safety data presented in Table 1 (below) reflects ex-posure to ZIANA Gel in 1,853 patients with acne vulgaris. Patients were 12 years and older and were treated once daily for 12 weeks. Adverse reactions that were reported in 1% of patients treated with ZIANA Gel were compared to adverse reactions in patients treated with clindamycin phosphate 1.2% in vehicle gel, tretinoin 0.025% in vehicle gel, and the vehicle gel alone:

Cutaneous safety and tolerance evaluations were conducted at each study visit in all of the clinical trials by assessment of erythema, scaling, itching, burning, and stinging:

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

DRUG INTERACTIONSConcomitant Topical MedicationConcomitant topical medication, medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect, and products with high concentra-tions of alcohol, astringents, spices or lime should be used with caution. When used with ZIANA Gel, there may be increased skin irritation.ErythromycinZIANA Gel should not be used in combination with erythromycin-containing products due to its clindamycin component. In vitro studies have shown antagonism between these two antimicrobials. The clinical significance of this in vitro antagonism is not known.Neuromuscular Blocking AgentsClindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. Therefore, ZIANA Gel should be used with caution in patients receiving such agents.

USE IN SPECIFIC POPULATIONSPregnancyPregnancy Category C. There are no well-controlled trials in pregnant women treated with ZIANA Gel. ZIANA Gel should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. ZIANA Gel was tested for maternal and developmental toxicity in New Zealand White Rabbits with topical doses of 60, 180 and 600 mg/kg/day. ZIANA Gel at 600 mg/kg/day

(approximately 12 times the recom-mended clinical dose assuming 100% absorption and based on body surface area comparison) was considered to be the no-observed-adverse-effect level (NOAEL) for maternal and developmental toxicity following dermal administration of ZIANA Gel for two weeks prior to artificial insemination and continuing until gestation day 18, inclusive. For purposes of comparisons of the animal exposure to human exposure, the recommended clini-cal dose is defined as 1 g of ZIANA Gel applied daily to a 60 kg person.Clindamycin Teratology (Segment II) studies using clindamycin were performed orally in rats (up to 600 mg/kg/day) and mice (up

to 100 mg/kg/day) (583 and 49 times amount of clinda-mycin in the recommended clinical dose based on a body surface area comparison, respectively) or with subcutane-ous doses of clindamycin up to 180 mg/kg/day (175 and 88 times the amount of clindamycin in the recommended clinical dose based on a body surface area comparison, respectively) revealed no evidence of teratogenicity. TretinoinIn oral Segment III studies in rats with tretinoin, decreased survival of neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (~ 78 times the recom-mended clinical dose assuming 100% absorption and based on body surface area comparison).With widespread use of any drug, a small number of birth defect reports associated temporally with the administration of the drug would be expected by chance alone. Thirty cases of temporally associated congenital malformations have been reported during two decades of clinical use of another formulation of topical tretinoin. Although no definite pattern of teratogenicity and no causal association have been established from these cases, 5 of the reports describe the rare birth defect category, holoprosencephaly (defects associated with incomplete midline development of the forebrain). The significance of these spontaneous reports in terms of risk to the fetus is not known.Dermal tretinoin has been shown to be fetotoxic in rabbits when administered in doses 40 times the recommended human clinical dose based on a body surface area compar-ison. Oral tretinoin has been shown to be fetotoxic in rats when administered in doses 78 times the recommended clinical dose based on a body surface area comparison. Nursing MothersIt is not known whether clindamycin is excreted in human milk following use of ZIANA Gel. However, orally and parenterally administered clindamycin has been reported to appear in breast milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. It is not known whether tretinoin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ZIANA Gel is administered to a nursing woman.Pediatric UseSafety and effectiveness of ZIANA Gel in pediatric patients under the age of 12 have not been established.Clinical trials of ZIANA Gel included patients 12–17 years of age.Geriatric Use Clinical studies of ZIANA Gel did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Manufactured for: Medicis, The Dermatology Company®

Scottsdale, AZ 85258

Revised: 11/2006

300-13A

Table 1: Adverse Reactions Reported in at Least 1% of Patients Treated with ZIANA Gel: 12-Week Studies

ZIANA GelN=1853

N (%)

ClindamycinN=1428

N (%)

TretinoinN=846N (%)

VehicleN=423N (%)

PATIENTS WITH AT LEAST ONE AR 497 (27) 342 (24) 225 (27) 91 (22)

Nasopharyngitis 65 (4) 64 (5) 16 (2) 5 (1)

Pharyngolaryngeal pain 29 (2) 18 (1) 5 (1) 7 (2)

Dry skin 23 (1) 7 (1) 3 (<1) 0 (0)

Cough 19 (1) 21 (2) 9 (1) 2 (1)

Sinusitis 19 (1) 19 (1) 15 (2) 4 (1)

Note: Formulations used in all treatment arms were in the ZIANA vehicle gel.

Table 2: ZIANA Gel-Treated Patients with Local Skin Reactions

Local Reaction BaselineN=1835

N (%)

End of TreatmentN=1614

N (%)

Erythema 636 (35) 416 (26)

Scaling 237 (13) 280 (17)

Itching 189 (10) 70 (4)

Burning 38 (2) 56 (4)

Stinging 33 (2) 27 (2)

030507

NEUENSCHWANDER, MAHON 33

History and Clinical Presentation

A 45-year-old Caucasian female presented with a three-year history of painful aphthous ulcers. The aphthae appeared after an episode of tonsillitis, which was treated with antibiotics. The number and size of the aphthae varied, with usually at least two to three being present. She infrequently experienced disease-free periods lasting only a few days before new lesions appeared. The aphthae healed without scarring. She had been treated with oral prednisone, topical clobetasol gel, a steroid inhaler, colchicine and topical anesthetics with only minor improvement. The patient denied ever having genital or ocular lesions or other systemic symptoms. The patient denied use of tobacco products. No other family members have had similar lesions. She had also been evaluated by her family physi-cian, an oral surgeon, a rheumatologist and ophthalmologist with negative findings.

On physical examination, the patient was a healthy appearing middle aged female. Examination of the oral cavity revealed multiple 2-5 mm and larger 10 mm aphthae located on the lateral aspect of the tongue, soft palate, buccal mucosa and palatoglossal arch. Lesions demon-strated a discrete but irregular border with an erythematous halo (Figures 1 and 2). Lymphadenopathy was absent, and no other skin lesions were noted.

Laboratory tests consisting of a complete blood count, metabolic profile, iron, ferritin, zinc, folate, vitamin B12, HLA-B27, ANA, antiendomysial antibodies and total CD4 count were all within the normal range. Viral culture from the base of an ulcer was negative. G6PD level was also normal.

A tongue biopsy, performed prior her presentation, demonstrated a central erosion and an associated infiltrate composed predominantly of neutrophils, with lymphocytes and extravasated eryth-rocytes. The adjacent squamous mucosa

showed spongiosis with collections of neutrophils within the upper spinous layer (Figures 3 and 4).

The patient was started on pentoxifylline 400 mg three times a day. Use of a mouth-wash containing either triclosan or chlo-rhexidine twice daily was recommended. Topical clobetasol gel and anesthetics were continued, as they offered temporary relief. She continued to form aphthae on pentoxi-fylline, so dapsone 50 mg daily and colchi-cine 0.6 mg twice daily was instituted. The patient experienced mild improvement with treatment, but continues to form aphthae.

DiscussionRecurrent aphthous stomatitis (RAS) is

a common oral malady affecting approxi-mately 20% of the general population and characterized by recurring painful aphthae.4 Aphthae are painful ulcers located on nonkeratinized mucosa. Clinically, the aphthae are discrete, round-to-oval ulcers with a yellow-gray base and erythematous halo.1,3,6 They are categorized based on morphology as either minor, major or herpetiform. The most common are minor aphthae, comprising 80% of cases. Ulcers are less than 10 mm in diameter and heal without scarring within 10 days of onset. Major aphthae, also known as Sutton’s disease or periadenitis mucosa necrotica recurrens, is seen in 10% of cases. The aphthae are larger then 10 mm, heal slowly and often cause scarring. Herpetiform aphthae, the remaining 10% of cases, are numerous, small, 1-3 mm ulcerations that heal within 30 days and may result in scar-ring. These aphthae are not associated with the herpes simplex virus (HSV).1-8

The onset of RAS is often during young adulthood, peaks in the third and fourth decades and is more common in women.1,3 RAS is further sub-classified based on clinical severity. Simple aphthosis is defined as multiple episodes a year with distinct disease-free periods. Complex aphthosis is characterized by the following

criteria: (1) constant presence of three or more aphthae or (2) recurrent oral and genital ulcers; and (3) the exclusion of Behçet’s disease.1,6

RAS may be primary (idiopathic) or secondary to systemic disease. The differ-ential for oral aphthae is extensive and includes HSV, Behçet’s disease, erythema multiforme, cyclic neutropenia, inflam-matory bowel disease, gluten-sensitive enteropathy, lupus erythematosus, HIV, Sweet’s syndrome, periodic fever, apht-hous stomatitis, pharyngitis and adenitis syndrome (PFAPA), pyostomatitis vegetans and Reiter’s syndrome. Outbreaks may also be triggered by trauma, stress, nutri-tional deficiencies, allergens, medications and infections.1-7 Table 1 summarizes the distinguishing clinical features and perti-nent laboratory testing when evaluating a

Bradley G. Neuenschwander, DO,* Michael J. Mahon, DO, FAOCD***1st year Dermatology Resident, POH Medical Center/Michigan State University, Pontiac, Michigan**Program Director, POH Medical Center/Michigan State University, Pontiac, Michigan

IDIOPATHIC COMPLEX APHTHOUS STOMATITIS: A CASE REPORT AND REVIEW OF THE LITERATURE

ABSTRACT

Aphthous stomatitis is a relatively common oral disease affecting up to 20% of the population. The etiology is unknown, but appears to be multifactorial. Recurrent aphthae are seen in numerous systemic diseases and may also be induced by trauma, nutritional deficiency, stress and allergens. Medications used to control the disease include topical and oral agents, often used in combination. We present a case of a 45-year-old female with a three-year history of idiopathic complex aphthous stomatitis.

Figure 1

Figure 2

34 IDIOPATHIC COMPLEX APHTHOUS STOMATITIS: A CASE REPORT AND REVIEW OF THE LITERATURE

patient with oral aphthae. In a case series by Letsinger et al., inflammatory bowel disease was the most common underlying systemic disorder.1 A small percentage of patients with idiopathic aphthosis eventu-ally meets the criteria for Behçet’s disease and therefore warrant routine monitoring. Aphthae may be the initial feature and appear almost a decade prior to the diag-nosis of Behçet’s disease.9

The management of recurrent aphthous stomatitis is multifaceted. Underlying systemic disease should be identified and treated. Removing potential triggers such as oral hygiene products containing sodium lauryl sulfate, minimizing trauma, avoiding food and drink with a low pH, improving

oral hygiene and identifying offending medications and possible allergens is also called for.3,6,7 Symptomatic treatment with topical anesthetics (lidocaine, benzocaine, diphenhydramine elixir) and medicines that provide a protective barrier (Orabase) may help to reduce pain and promote healing.3,6 Scully notes that the use of mouthwashes containing chlorhexidine or triclosan will reduce the number of aphthae and increase the length of disease-free periods.3 In addi-tion to those listed above, other topical agents commonly used as first-line therapy include tacrolimus ointment and topical corticosteroids.1,3,6 A study performed by Letsinger et al. found that only 5% of patients using topical therapy achieved an improvement of 50% or more. This would suggest that topical treatments alone may only provide mild symptomatic relief and offer little in long-term improvement and disease modification.1 Initially, pentoxifyl-line, 400 mg three times daily, was reported to be an effective treatment for RAS and believed to potentially produce extended remission of the disease.5 However, a recent study by Thornhill et al. found the benefit of pentoxifylline to be minimal and that it failed to induce long-term remission as previously reported. They recommend use of pentoxifylline as adjunctive therapy or in resistant disease, and not as first-line therapy.8 Other systemic medicines used in treating RAS include colchicine, dapsone, cyclosporine and thalidomide.1,3,6 Colchicine, 0.6 mg three times daily, has been shown to significantly reduce or even prevent RAS.1,4 Dapsone, 25-100 mg daily, may also be effective, but as monotherapy it produces only minimal improvement. When used in combination with colchi-cine, a 50% improvement has been seen in 57% of patients.1 Thalidomide, 50-150 mg daily, has been shown to improve patient symptoms by 59%.1 Vujevich and Zirwas report a case of using adalimumab 40 mg

subcutaneous injections every other week. They report that after two treatments, a 90% improvement was noted, and after four months of treatment the aphthae had completely resolved.2

In the diagnosis and management of RAS, a detailed history and physical exami-nation is essential to identify underlying systemic disease and narrow the differential diagnosis for appropriate laboratory testing to be performed. Treatment is difficult and tends to be more effective when a combi-nation of topical and systemic medicines is used. Systemic agents used to treat RAS may have significant side effects; therefore, a candid discussion with the patient on therapeutic options is advisable.

References:1. Letsinger M, McCarty M, Jorizzo J. Complex aphthosis:

A large case series with evaluation algorithm and thera-peutic ladder from topical to thalidomide. J Am Acad Dermatol 2005;52:500-508

2. Vujevich J, Zirwas M. Treatment of severe, recalci-trant, major aphthous stomatitis with adalimumab. Cutis 2005;76:129-132

3. Scully C. Aphthous Ulceration. N Engl J Med 2006;355:165-172

4. Katz J, Langevitz P, et al. Prevention of recurrent apht-hous stomatitis with colchicine: An open trial. J Am Acad Dermatol 1994;31:459-461

5. Wahba-Yahav A. Pentoxifylline in intractable recurrent aphthous stomatitis: An open trial. J Am Acad Dermatol 1995;33:680-682

6. Bruce A, Rogers R. Acute oral ulcers. Dermatol Clin 2003;21:1-15

7. Zunt S. Recurrent aphthous stomatitis. Dermatol Clin 2003;21:33-39

8. Thornhill M, Baccaglini L, et al. A randomized, double-blind, placebo-controlled trial of pentoxifylline for the treatment of recurrent aphthous stomatitis. Arch Derma-tol 2007;143:463-470

9. McCarty M, Garton R, Jorizzo J. Complex aphthosis and Behçet’s disease. Dermatol Clin 2003;21:41-48

Figure 3

Figure 4

TRICKETT, WISCO, HODSON 35

Case ReportA 63-year-old African American male

presented with a twenty year history of intermittent pruritis and a cutaneous erup-tion that began 1 year ago. The lesions first appeared on the back and slowly spread to the buttocks, and bilateral upper and lower extremities. The patient was initially seen by his primary care provider two months prior who treated him with triam-cinolone 0.1% cream, hydroxazine, and ammonium lactate with only mild relief of his symptoms. His past medical history included diabetes mellitus type 2, diabetic nephropathy, hepatitis C with cirrhosis, hypertension, hyperlipidemia, peripheral vascular disease, gastroesophageal reflux disease, and gout.

Physical exam revealed multiple 2-4mm hyperpigmented nodules with central keratinous crusts involving the before mentioned areas (Figures 1 and 2). The lesions on the lower extremities coalesced into large plaques; some had pink flat tops, and some followed a linear pattern suggesting the Koebner Phenomenon. A punch biopsy was performed (Figure 3A and 3B) which shows a central cuplike kera-totic plug within an epidermal invagination overlying a focus of epithelial perforation. Inflammation and debris was found within the invagination along with basophilic collagen fibers. There was an adjacent mild superficial perivascular mixed infiltrate.

Based of his medical history and biopsy findings, this patient was diagnosed with acquired perforating dermatosis. We continued his treatment with triamci-nolone and hydroxazine with the addi-tion of flurandrenolide embedded tape (to prevent excoriation and rubbing) and Cetaphil® cream. In addition, he was started on narrow-band UVB light therapy which obtained control of his pruritis and

almost complete clearance of the lesions. The patient however had to stop after 16 treatments due to developing a phototoxic reaction. He was then maintained on Cetaphil® cream and has only had brief intermittent flares on the buttocks over the past two years that are controlled with clobetasol ointment.

DiscussionAcquired perforating dermatosis (APD)

is one of the perforating disorders and is histologically characterized by transepi-dermal elimination of collagen and elastic fibers. APD usually occurs in adult patients with diabetes and/or chronic renal failure. There does not appear to be any predilec-tion for sex or race. Most patients have end stage renal disease secondary to diabetes with many, but not all, having undergone hemodialysis.1-3 It is quite common, occur-ring in about 10% of dialysis patients, and is the most common perforating disorder.4 APD has also been less commonly asso-ciated with liver disease, malignancy, neurodermatitis, hyperparathyroidism, hypothyroidism, and HIV.3 There have also been reports of APD in diabetic patients with concomitant scabies infections.5

The lesions of APD are usually multiple, dome-shaped, 1-10mm hyperpigmented, hyperkeratotic papules or nodules, with a central hyperkeratotic plug. They are primarily distributed over the extremities, most commonly the legs, and usually on the extensor surfaces that can easily be reached. They can also be found on the buttocks, trunk, and face.1,3,6 Pruritus is a prominent feature in most cases, and koeb-nerization is very common.3,7,8

Histologically, the lesions of APD have acanthosis with central craters filled with a plug that extends from the epidermis to the reticular dermis. Early lesions

Cory Trickett, DO,* Oliver Wisco, DO,** Daryl Hodson, MD, FAAD***

ACQUIRED PERFORATING DERMATOSIS: A CASE REPORT AND BRIEF REVIEW

ABSTRACT

Acquired perforating dermatosis (APD) is characterized clinically by multiple 1- 10 mm pruritic papules with a central hyperkeratotic plug primarily located on the extremities and histologically by transepidermal elimination of collagen and elastic fibers. APD usually occurs in adult patients with diabetes and/or chronic renal failure. We report a case of a 63-year-old male with a past medical history significant for diabetes with diabetic nephropathy and hepatitis C with cirrhosis who presented with lesions morphologically and histologically consistent with APD.

The opinions expressed in this article are those of the authors and do not represent the viewpoint of the United States Air Force or United States Army at large.

Figure 1 Multiple hyperkeratotic papules with central crusts on the back.

Figure 2 Closer view on the lower back of the hyperkeratotic papules with central crusts, along with evidence of koebnerization.

36 ACQUIRED PERFORATING DERMATOSIS: A CASE REPORT AND BRIEF REVIEW

may not have developed the connection through the epidermis. The plug contains parakeratosis, basophilic granular debris, and bundles of degenerated collagen and elastin in vertical strands. Also, a dense inflammatory infiltrate of neutrophils, lymphocytes, histiocytes, macrophages, and mast cells may be found. As lesions mature, the plug becomes wider, moves towards the surface and is eliminated as the epidermis regenerates. Also, the collagen fibers become more apparent while the elastin fibers disappear.2,3,6,8

The pathogenesis of APD is not well understood and many theories have been postulated. These theories include diabetic microangiopathy, microtrauma due to chronic rubbing, an acquired abnormality of the collagen and elastin fibers, dysreg-ulation of vitamin A or D metabolism, and elevated serum and/or tissue levels of fibronectin.2,9 Diabetic microangiopathy accompanied by trauma (from scratching and rubbing) induced necrosis of the dermis appears to be the leading theory, however, this does not explain the cases reported in non-diabetic patients.3,7 It is plausible that microtrauma occurs in the absence of diabetes, and is simply exacer-bated by the microangiopathy frequently

found in diabetics. In regards to the role of pruritis, one case study demonstrated a difference in the amount of pruritus expe-rienced between those with chronic renal failure on haemodialysis who developed APD and those that did not.10 In addition, the koebnerization often demonstrated in APD patients supports this theory.8

In another case study, although all of the patients described had diabetes, it wasn’t until an infestation with scabies and the associated scratching that APD developed.5 The theory of an acquired abnormality of collagen and elastin has yet to be demon-strated, and at least morphologically there have been no changes found. If this theory is true, then the change would have to be at the chemical level which has not yet been demonstrated. Furthermore, increased levels of fibronectin, although not under-stood why, may be the culprit.6,8 Given the above, the pathogenesis of APD may be multi-factorial.

The differential diagnosis of APD includes prurigo nodularis, folliculits, prurigo simplex, arthropod bites, perfora-tion of exogenous foreign material, other perforating disorders, multiple keratoacan-thomas, and dermatofibromas. Of these, prurigo nodularis, from the medical history to morphology, most closely mimics APD, necessitating a biopsy to confirm the diag-nosis. Furthermore, both prurigo nodu-laris and folliculitis can coexist with APD, thus biopsy of just one lesion may not be sufficient.4,11

There have been multiple treatments anecdotally reported to help with APD. These include topical steroids, topical keratolytics, oral isotretinoin, UVB photo-therapy, h1-antihistamines, allopurinol, doxycycline, and cryotherapy.1,5,10,12 There have also been reports of patients experi-encing remission after renal transplant.10 In addition, a correlation between the control of pruritis to prevent scratching and the improvement of lesions has been reported.3

The case reported here represents a classic example of APD. It is a common disorder in patients with diabetes and/or chronic renal failure, especially in those undergoing hemodialysis. In addition, this patient’s history of cirrhosis from hepa-titis C likely contributed to the condition. The medical history and morphology are important in the diagnosis which can be confirmed by biopsy. Although the patho-genesis is not well understood, there are many treatments that have anecdotally been shown to be beneficial.

References:1. Rapini RP, Hebert AA, Drucker CR. Acquired Perforat-

ing Dermatosis: Evidence for Combined Transepidermal Elimination of Both Collagen and Elastic Fibers. Arch Dermatol 1989; 125(8): 1074-8.

2. Haftek M, Euvrard S, Kanitakis J, Delawari E, Schmitt D. Acquired perforating dermatosis of diabetes mellitus and renal failure: Further ultrastructural clues to its pathogen-esis. J Cutan Pathol 1993; 20(4): 350-5.

3. Faver IR, Daoud MS, Su WPD. Acquired reactive perfo-rating collagenosis. Report of six cases and review of the literature. J Am Acad Dermatol 1994; 30(4): 575-80.

4. Rapini RP. Perforating Diseases. In: eds. Bolognia JL, Jorizzo JL, Rapini RP. Dermatology. Mosby: Philadel-phia. 2003. 1497-1502.

5. Hinrichs W, Breuckmann F, Altmeyer P, Kreuter A. Acquired perforating dermatosis: A report on 4 cases associated with scabies. J Am Acad Dermatol 2004; 51(4): 665-7.

6. Farrell AM. Acquired perforating dermatosis in renal and diabetic patients. Lancet 1997; 349(9056): 895-6.

7. Kawakami R, Saito R. Acquired reactive perforating col-lagenosis associated with diabetes mellitus: eight cases that meet Faver’s criteria. Br J Dermatol 1999; 140: 521-4.

8. Poliak SC, Lebwohl MG, Parris A, Prioleau PG, Reactive perforating collagenosis associated with diabetes mel-litus. N Engl J Med 1982; 306(2): 81-4.

9. Morgan et al. Fibronectin and the Extracellular Matrix in the Perforating Disorders of the Skin. Am J Dermato-pathol 1998; 20(2): 147-54.

10. Maurice PDL, Neild GH. Acquired perforating dermatosis and diabetic nephropathy-a case report and review of the literature. Clin Exp Dermatol 1997; 22(6): 294-4.

11. Koo JYM, Han A. Prurigo Nodularis. In: eds. Bolognia JL, Jorizzol JL, Rapini RP. Dermatology. Mosby: Philadel-phia. 2003. 116-7.

12. Ohe S et al. Treatment of acquired perforating dermatosis with narrowband ultraviolet B. J Am Acad Dermatol 2004; 50(6): 892-4.

Figure 3a

Figure 3bPunch biopsy of a hyperkeratotic papule with central crust on the back, demonstrating a central cuplike keratotic plug within an epidermal invagination overlying a focus of epithelial perforation. There is an adjacent, mild, superficial perivascular mixed infiltrate (A, 4X magnification). Inflammation and debris is found within the invagination, along with basophillic collagen fibers (B, 20X magnification). (Hematoxylin-eosin stain)

SCHWEDELSON, SKOPIT 37

Case ReportA 12-year-old male presented with a

five-year history of skin tightening on his left lower back. The area initially increased in size, but had been stable for the last two years. He had been treated with unknown creams in the past by another dermatolo-gist, with no improvement. He was other-wise healthy and denied any past medical history. He denied any coldness or tingling in the fingertips, arthralgias, muscle weak-ness, muscle pain, dysphagia, or dyspnea.

Physical examination of the patient’s left flank revealed a mildly hyperpigmented, firm, indurated patch. The affected area measured approximately 5 cm by 4 cm. The area had no surrounding erythema and was nontender. There was disfigurement of the left flank from the sclerotic skin (Figures 1, 2, and 3). There was no dilatation of the vessels around the nail folds.

A punch biopsy revealed a normal epidermis. There were densely packed homogenous and thickened collagen bundles with decreased spaces between them and atrophic eccrine glands (Figures 4 and 5).

The patient was diagnosed with plaque morphea, also known as localized sclero-derma. Treatment options are currently being considered; they include PUVA versus methotrexate.

DiscussionMorphea (localized scleroderma) is an

inflammatory disease primarily of the dermis and subcutaneous fat. It ultimately leads to a scar-like sclerosis. Morphea is usually a harmless entity; however, in about 10% of patients, the scar formation may lead to disfigurement and growth retardation.1

The first description of a patient with a generalized hardness of the skin was described by an Italian physician, Carlo Curzio, in 1753.1 The term scleroderma is derived from the Greek words sklero, which means hard or indurated, and derma, which means skin.

In the pediatric age group, localized forms of scleroderma are much more common than systemic forms. The Mayo Clinic classification of localized sclero-derma includes plaque morphea, gener-

alized morphea, bullous morphea, linear scleroderma, and deep morphea.2 Few adequate studies have addressed the ques-tion of the incidence or prevalence of this disorder, which is believed to occur in up to 1 per 100,000 of the population.3

Morphea usually starts with superficial erythema or inflammation of the skin, which spreads. The plaque lesions some-times have a purple ring appearance with central clearing. After some time, the skin hardens and then may turn an ivory color. Loss of hair and anhydrosis are common, as are changes in pigmentation. Children with localized forms of scleroderma have normal nail folds, which is important in differenti-ating from systemic scleroderma. Dilatation of the nail fold vessels are typical abnormali-ties seen in systemic scleroderma.

There is usually no progression of the plaque type of morphea. Other local-ized types may involve muscle or bone. Progression to systemic sclerosis is very rare.

Morphea is diagnosed primarily by the clinical picture and aided by biopsy, but there are some investigations that may be useful. Antinuclear antibodies are present in 20% to 75% of cases. Rheumatoid factor is seen in 20% to 40% of patients. Occasionally, antibodies to extractable nuclear antigens (ENA) are seen, such as anti-Ro/SSA, but not the antibodies more typical of systemic scleroderma, such as antitopoisomerase.4 The erythrocyte sedi-mentation rate is rarely elevated unless very diffuse disease is seen. C-reactive protein may be mildly elevated in some patients. In two studies of localized scleroderma, eosinophilia was shown in nearly one-third of the subjects, perhaps suggesting some overlap in disease mech-anisms with eosinophilic fasciitis.5,6 In addition to the markers of inflammation, procollagen type 1 carboxy-terminal propeptide is elevated in about 30% of patients; the serum levels correlate to the extent of the skin involvement.1

The histology of morphea depends on the stage and depth of the disease. A sample from the inflammatory border would show vessel walls with endothelial edema. Capillaries and small arterioles are surrounded by an infiltrate that contains primarily CD4+ T-cells and sometimes eosinophils, plasma cells, and mast cells.

At later stages, the inflammatory infil-trate ultimately disappears except in some areas of subcutaneous fat. The epidermis is normal, but rete ridges in the papil-lary dermis may fade, leaving a flattened dermo-epidermal junction. Capillaries and small vessels are significantly reduced in number, and homogenous collagen bundles with decreased space between the bundles replace most structures. Eccrine glands appear atrophic, and sweat ducts transverse the thickened dermis. The underlying subcutis is homogenized and hyalinized.1

The use of MRI and ultrasound shows promise in supporting the clinical

Allison Schwedelson, D.O.,* Stanley Skopit, D.O., F.A.O.C.D.***1st-year resident, Nova Southeastern University/Broward General Medical Center**Program Director, Nova Southeastern University/Broward General Medical Center

MORPHEA: CASE REPORT AND REVIEW OF THE LITERATURE

Figure 1

Figure 2

Figure 3

38 MORPHEA: CASE REPORT AND REVIEW OF THE LITERATURE

management and greater understanding of disease characteristics. MRI can demon-strate the true depth of soft-tissue lesions and the degree to which different tissues are involved. High-frequency ultrasound may also be helpful. Both of these tech-niques can demonstrate inflammation in lesions thought to be undergoing sponta-neous atrophy.4

Most reports suggest that morphea is a disease that can be particularly progressive for the first two years but may continue to spread or deepen in involvement for up to five or six years. Thereafter it seems to be nonprogressive.

Therapy for morphea is challenging. There have been many case reports or case series, but few controlled trials have been published. Plaque-type morphea is generally of cosmetic concern only, and therefore treatments with toxicity risks are not justified. These lesions may remit spontaneously, leaving only pigmentary changes. These types should be treated with mainly topical therapies such as moisturizing agents, corticosteroids, or calcipotriene. On the other hand, when there is risk of disability or disfigurement, systemic therapy should be considered. Extracorporeal photochemotherapy with UVA and psoralen has been reported to be helpful in some studies.7,8,9 Methotrexate has been used successfully in some chil-dren, but those studies were not controlled trials.2 In a randomized controlled trial, use of intralesional cytokine interferon gamma proved no better than placebo for estab-lished lesions; however, it may prevent the appearance of new lesions.10 Penicillamine, sulphasalazine, oral steroids (alone), and

etretinate have all been reported as being variably effective in some cases in different series.11,12,13,14

In summary, morphea is a somewhat rare diagnosis, but one that many dermatolo-gists will see in their lifetime. Treatment is challenging and should be catered to the patient’s needs, always weighing the risks with the benefits. Patients, especially children, with potentially disfiguring or disabling lesions need to be treated promptly. It is critical that controlled clin-ical trials are developed in order to treat patients effectively.

References:1. Bolognia J, Jorizzo J, Rapini R. Dermatology 2003.

p1503-1515.2. Zulian, F. Scleroderma in Children. Pediatric Clinics of

North America 2005;52;2.3. Peterson LS, Nelson AM, Su WP, et al. The epidemiology

of morphea (localized scleroderma) in Olmsted County 1960-1993. J Rheumatology 1997;24:73-80.

4. Murray, K, Laxer, R. Scleroderma in Children and Ado-lescents. Rheumatic Diseases Clinics of North America. 2002;28:3.

5. Bodemer C, Belon M, Hamel-Teillac D, et al. Sclero-derma in children: a retrospective study of 70 cases. Ann Dermatology Venereol 1999;126:691-4.

6. Falanga V, Medsger Jr. TA. Frequency, levels, and significance of blood eosinophilia in systemic sclerosis, localized scleroderma, and eosinophilic fasciitis. J Am Acad Dermatol 1987;17:648-56.

7. Morison WL. Psoralen UVA therapy for linear and gener-alized morphea. J Am Acad Dermatol 1997;37:657-9.

8. Grundmann-Kollman M, Ochsendorf F, Zollner TM, et al. PUVA-cream phototherapy for the treatment of localized scleroderma. J Am Acad Dermatol 2000;43:675-8.

9. Studer E, Kaufmann R, Podda M. PUVA-cream photo-chemotherapy for the treatment of localized scleroderma. J Am Acad Dermatol 2000;43:675-8.

10. Hunzelmann N, Anders S, Fierlbeck G, et al. Double-blind placebo-controlled study of intralesional interferon gamma for the treatment of localized scleroderma. J Am Acad Dermatol 1997;36:433-5.

11. Falanga V, Medsger Jr. TA. D-penicillamine in the treatment of localized scleroderma. Arch Dermatol 1990;126:609-12.

12. Joly P, Bamberger N, Crickx B, et al. Treatment of severe forms of localized scleroderms with oral corticos-teroids: follow-up study on 17 patients. Arch Dermatol 1994;130:663-4.

13. Neuhofer J, Fritsch P. Treatment of localized scleroderma and lichen sclerosis with etretinate. Acta Derm Venereol 1984;64:171-4.

14. Stava Z, Kobikova M. Salazopyrin in the treatment of scleroderma. Br J Dermatol 1977;96:541-4.

Figure 4

Figure 5

FLOWERS, KEEHAN, WAY 39

Case PresentationA 39-year-old Hispanic male presented

with a six-month history of an asymp-tomatic lesion that developed on his central forehead. It gradually progressed to involve the nose. The outbreak began after a motor vehicle accident; however, there was no associated trauma to the area. Medical evaluation was sought because of the progression of the lesion onto the nose. The patient denied pruritis, bleeding, crusting, or pain in the area of the lesion. He denied any other dermatologic complaints. His past medical history was negative for any medical problems, and he had no personal or family history of skin cancer. His family history was significant only for hypertension. The patient took no medications, denied any allergies to medi-cations, denied tobacco use and admitted to only occasional ethanol use.

Physical examination revealed a well-nourished Hispanic male in no acute distress. Comprehensive cutaneous exami-nation of the face revealed a linear, plaque-like eruption extending down the forehead in a vertical fashion from the glabella to the left lateral nose. The lesion appeared viola-ceous in color and polygonal in shape with a broad, flat top (Figure 1, 2 and 3). There was no evidence of excoriation, secondary infection, drainage, scale, crust, atrophy, lichenification, or telangiectasia. The patient had no mucosal or nail changes, and the remainder of his skin exam was normal.

Clinically, the appearance of the lesion was consistent with lichen planus (LP). The differential diagnosis for a linear, violaceous, polygonal plaque on the face includes polymorphic light eruption, granuloma annulare, sarcoidosis, erythema dyschromicum perstans, fixed drug erup-tion, drug-induced photosensitive lichenoid eruption, pigmented basal cell carcinoma, and melasma.

A 3mm punch biopsy was performed on the glabella in the center of the lesion and sent for H&E and microscopic review. Histopathologic examination showed hyperkeratosis, follicular plugging, epidermal atrophy, thickening of the base-ment membrane and liquefaction degen-eration of the basal layer (Figure 4). There was also a superficial and deep perivascular and periadenexal inflammatory infiltrate composed of lymphocytes and histiocytes with melanophages in the dermis (Figure 5). Pathologically, this was consistent with discoid lupus erythematosus (DLE).

As the lesion was not clinically consis-tent with DLE, the permanent-section slides were reviewed within the context of the clinical medical photographs taken at the patient’s first visit. After clinical corre-lation, the dermatopathologic addendum to the initial report stated that this lesion likely represents a manifestation of actinic

lichen planus. The addendum added that there may be overlap between LP and lupus erythematosus on occasion, which was the likely explanation for the histo-logical findings.

After the biopsy site healed and the sutures were removed, treatment was begun with topical desonide 0.05% foam applied twice daily to the affected area of

Jessica Flowers, D.O.,* Patrick Keehan, D.O.,** Bill Way, D.O., F.A.O.C.D.****Intern, Sun Coast Hospital, Largo, Florida

LICHEN PLANUS ACTINICUS: A CASE PRESENTATION AND REVIEW OF THE LITERATURE

ABSTRACT

A 39-year-old Hispanic male presented with a six-month history of a growing lesion on his central forehead and nose. The lesion was asymptomatic and appeared as a linear, violaceous, polygonal plaque extending down the forehead in a vertical fashion from the glabella to the left lateral nose. A punch biopsy revealed findings consistent with lichen planus actinicus.

Lichen planus actinicus (LPA) is thought to be a photosensitive or photo-induced variant of classic lichen planus (LP) that has a predilection for sun-exposed areas of skin. LPA commonly occurs at a younger age than classic LP and lacks pruritus and koebnerization. Nails, scalp and buccal mucosa are often spared in LPA. The clinical presentation of LPA varies, with four different types described in the literature: annular, dyschromic, pigmented and classic plaque-like. Treatment of LPA generally involves UV avoidance, sunscreens and topical or intralesional steroids.

Figure 2

Figure 3

Figure 1

the forehead and nose. The patient was instructed to avoid sun exposure and to wear sunscreens daily. The patient is currently continuing with the regimen and has shown considerable improvement.

DiscussionLichen planus actinicus (LPA) is also

known as lichen planus (LP) subtropicus, LP tropicus, LP atrophicus annularis and lichenoid melanodermitis. Some refer-ences consider summertime actinic lichenoid eruption to be synonymous with LPA, but this condition is now regarded by many texts as a separate entity based on a different histologic pattern that is not consistent with LPA.1 The terms “tropicus” and “subtropicus” were derived from early reports of the lesions occurring in tropical, warm climates such as the Middle East, Ethiopia and Kenya. The first reported case was in 1949 from Drostrovsky and Sagher2,3,4 in Israel, although cases have now come from the United States, India, Italy, Egypt, North Africa, Afghanistan and Turkey.4,5,6 In one article, the author stated that the incidence of LPA does not differ between Israel, Europe and North America.4 LPA is thought to be a photosensitive variant of LP, with most reported cases occurring in older children and young adults of darker skin colors, especially of Middle Eastern descent.4,7,8 Lesions have an earlier age of onset than classic LP, with the average age of 25.7 There is no predilection for either sex.

Unlike classic LP, the lesions of LPA tend to be asymptomatic, without pruritus or koebnerization of lesions.4 The onset of the eruption typically occurs during spring or summer, on sun-exposed surfaces of the skin, and have a longer course of seasonal occurrences.9,10,11 Nails, scalp and buccal mucosa are generally spared.11 Lesions may completely resolve without treatment in the fall and winter months, leaving post-inflammatory hyperpigmented patches.7 Most cases have a reported recurrence upon subsequent spring and summer months or with increased UV-exposure.12

Four types of LPA have been described: annular, dyschromic, pigmented and classic plaque-like.13 The annular type has a similar appearance to granu-loma annulare and tends to consist of erythematous hyperpigmented plaques arranged in an annular configuration. Sometimes it appears as a raised border with normal or hyperpigmented skin in the center.4,13,14 These lesions may begin as a pigmented patch that develops an elevated border with time.10 The annular type is the most common presenting form of LPA.12 In the dyschromic or lichenoid type, there tends to be small, whitish, angular papules that may coalesce into plaques.12,13 The pigmented type usually presents as melasma-like hyperpigmented macules and patches ranging from 5 mm to 50 mm.4,12,13 This is the least common variant.3 The classic plaque-like type clinically ranges from violaceous papules to brown plaques with central depression and erythematous, raised borders.13,14 All forms occur almost exclusively on sun-exposed areas, especially the face, neck, forearms and dorsum of hands.5

Etiology:Although the etiology and pathogen-

esis of the eruption is unknown, sunlight appears to be a precipitating factor, along with some type of genetic or racial predis-position.4 It is postulated that ultraviolet radiation of basal keratinocytes may lead to expression of altered self-antigens that recruit cytotoxic T-cells, leading to the characteristic histological findings.13 In a report by van der Schroeff in 1983, LP-like lesions were induced in one patient who underwent repeated doses of UV-B radia-tion. UV-A irradiation produced no cuta-neous response.

Histopathology:Histopathologic findings of LPA are vari-

able and may resemble LP, discoid lupus erythematosus (DLE), solar or radiation dermatitis, or even eczema.10,11,15 Some lesions appear microscopically as classic LP, with hyperkeratosis of the stratum corneum, wedge-shaped hypergranulosis, necrotic keratinocytes with the character-istic mid-dermal band-like lymphocytic infiltrate in the papillary dermis, and

pigment incontinence.3,11,13 Civatte bodies are usually present.5 Subepidermal clefts (Max-Joseph spaces) may be seen.15,16 Many specimens have shown pseudoepithe-liomatous hyperplasia and spongiosis.7 The epidermal changes may exhibit epidermal atrophy,4 saw-toothed hyperplasia,5,16 or parakeratosis and liquefaction degenera-tion of the basal cell layer.14 The thinned epidermis may show keratotic plugging with periappendageal inflammation and mucin deposition in the reticular dermis, resembling DLE.4,11 Thus, the differentia-tion from DLE must be made clinically.

In LPA, there is generally negative direct immunofluorescence and an absence of a thickened basement membrane, as seen with DLE.16,17 Dermal changes may also include increased vascularity with capillary dilation in the papillary layer.7 The lupus erythematosus-lichen planus (LE-LP) overlap syndrome may appear histologi-cally similar to LPA.5 Clinically, LE-LP overlap syndrome presents with ulcerated, atrophic, violaceous plaques with promi-nent telangiectasias on the palms and soles, which is vastly different from the presen-tation of LPA.5 Still other forms mimic melasma, with superficial perivascular inflammatory infiltrate, melanophages with hyperpigmentation of suprabasal and basal layers, and vacuolar degeneration of the basal keratinocytes.3,17 The lichenoid infiltrate that is present in LPA, along with the wedge-shaped hypergranulosis, focal parakeratosis, subepidermal clefts and colloid bodies, make the distinction between LPA and melasma.3,16

Treatment:Treatment strategies have included

several modalities. Historically, treatments have included Grenz rays, bismuth, arsenic compounds, and a variety of topical or oral steroids.2,5,14 Many of these modalities have fallen out of use, as newer and safer options are now available. Considering the apparent precipitation by UV-exposure, the mainstay of treatment is the use of broad-spectrum sunscreens and sun avoidance. Topical steroids have proven beneficial in many cases, as well as intralesional steroids, anti-malarials, hydroquinone and oral retinoids.10 One case studied the use of acetretin 0.5 mg/kg per day for four months and 0.1% betamethasone dipropionate cream once a day for two weeks. This lead to complete resolution of lesions after two months of therapy.14 Other studies have been performed using topical tacrolimus combined with oral hydroxychloroquine 400 mg daily, with improvement after one month of therapy.5

Conclusion:Linear, violaceous, polygonal plaques on

the face can resemble a variety of cutaneous diseases. Even with histologic examination,

40 LICHEN PLANUS ACTINICUS: A CASE PRESENTATION AND REVIEW OF THE LITERATURE

Figure 4

Figure 5

FLOWERS, KEEHAN, WAY 41

clinical correlation is often necessary for a correct diagnosis. LPA has several histo-pathologic presentations, making the diag-nosis challenging. LPA is an uncommon variant of LP, with a predilection for sun-exposed areas of the skin and most cases occurring in spring and summer months. Although no conclusive studies have been done to determine the exact etiology of LPA, UV radiation is thought to be an elic-iting cause, with possible genetic or envi-ronmental factors. Generally, the condition improves with the use of sunscreens and with sun avoidance. Several topical and oral medications have been used to treat LPA, with variable results.

References and Sources:1. Bolognia, ed. Lichen Planus and Lichenoid Dermatoses.

Dermatology 2003: Elsevier; First Edition. pp.175-196.2. Alabi, et al. Lichen Planus in tropical Africa. Trop Geogr

Med 1981;33(2):143-7.3. al-Fouzan, et al. Melasma-like (pigmented) actinic lichen

planus. Int J Dermatol 1992;31(6):413-5.4. Katzenellenbogen, et al. Lichen Planus Actinicus

(lichen planus in subtropical countries). Dermatologica 1962;124:10-20.

5. Meads, et al . L ichen Planus Act inicus. Cut is 2003;72(5):377-81.

6. Zanca, et al. Lichen Planus Actinicus. Int J Dermatol 1978;17(6):506-8.

7. Sharquie, et al. Lichenoid dermatosis. A clinical and his-topathological study. Saudi Med J 2002;23(11):1335-8.

8. Canizares, ed. Lichen Planus. Clinical Tropical Dermatol-ogy 1975: Blackwell Scientific Publishing. pp.374-375.

9. Singh, et al. Lichen Planus in India: an appraisal of 441 cases. Int J Dermatol 1976;15:752-6.

10. MacFarlane, et al. A case of Actinic Lichen Planus. Clin Exp Dermatol 1989;14(1):65-8.

11. Salman, et al. Actinic Lichen Planus. A clinicopathologic study of 16 patients. J Am Acad Dermatol 1989;20(2 Pt 1):226-31.

12. Peretz, et al. Annular Plaque on the Face. Arch Dermatol 1999;135:1543-8.

13. Kim, et al. Lichen Planus Actinicus. Derm Online J 2007;13(1):13.

14. Jansen, et al. Lichen Planus actinicus treated with acit-retin and topical corticosteroids. J Eur Acad Dermatol Venereol 2002;16(2):174-5.

15. Elder, et al. Lichen Planus. Lever’s Histopathology of the Skin 2004: J.B. Lippincott Co.; Ninth Edition. pp168-174.

16. Salman, et al. Actinic Lichen Planus mimicking melasma. A clinical and histopathologic study of three cases. J Am Acad Dermatol 1988;18(2 Pt 1):275-8.

17. Aloi, et al. Actinic Lichen Planus simulating melasma. Dermatology (Basel, Switzerland) 1997;195(1):69-70.

42 EXTRAFACIAL GRANULOMA FACIALE

IntroductionGranuloma faciale is an uncommon

entity that presents with red-to-violaceous plaques on the face. Lesions are smooth, have dilated follicular ostia, and are usually enveloped with telangiectasias.1 Etiology is unknown, but a small-vessel vasculitis is often present. The diagnosis is confirmed with a relatively specific histopathological pattern. This pattern consists of a small-vessel vasculitis with a dense inflamma-tory infiltrate and a grenz zone. The grenz zone is a narrow band of normal tissue at the dermal-epidermal junction and around pilosebaceous units.2 This disease often affects middle-aged men, usually on sun-exposed areas of the face. Extrafacial lesions of this disease are rare, but have been reported. Fortunately, systemic involvement is virtually nonexistent, and no associated illnesses have been delineated.

Case ReportA 52-year-old male farm manager

presented with several weeks’ history of red lesions on his nose and left preau-ricular region (Figures 1, 2). They were pruritic, occasionally painful, and had been increasing in size and number. Two weeks prior to presentation to the office, he had noticed similar lesions on the dorsum of his left hand (Figure 3). The patient had no previous dermatological history except for mild occasional eczema, which was controlled with emollients.

Biopsies were taken to rule out malig-nancy of both the facial and hand lesions. Microscopic description revealed small-vessel vasculitis with the presence of neutrophils and eosinophils. A grenz zone was noted. Prominent telangiectasias were also noted (Figures 4, 5). The diagnosis of granuloma faciale was made.

The patient was hesitant to use any systemic or intralesional therapy, so we

elected for a topical regimen of hydrocor-tisone probutate cream in the morning and tacrolimus ointment in the evening. Frequent application of sunscreen was also encouraged. After one month of therapy, the left preauricular region had resolved, the nasal lesions had improved 50%, and the hand lesions had improved 70% (Figures 6, 7).

DiscussionThere have been reported cases of extra-

facial granuloma faciale, but the incidence remains low.3-14 Systemic involvement has been nearly nonexistent, with just one case involving the nasal mucosa.10 A recent review of 66 cases only revealed one patient with coexistent facial and extra-facial lesions.15 An additional study of 11 patients only revealed two patients with extrafacial lesions.16 An overall review of the cases does mimic the classically defined lesions outlined in leading dermatologic textbooks.

No etiology has been accepted for this entity. Direct immunofluorescence studies have shown presence of immunoglobulin in the vessels and at the dermal-epidermal junction, suggesting its cause.17, 18

The differential diagnosis is diverse at initial clinical presentation. Often, clini-cians do not diagnose these lesions at first, mistaking it for much more common entities such as acneiform eruptions, basal cell carcinoma, cutaneous sarcoid, and lymphoma cutis.15 The presence of extra-facial lesions at time of initial presentation makes diagnosis even more of a challenge; however, histopathological analysis makes the diagnosis clear for dermatopathologists. Granuloma faciale has certain microscopic features that help differentiate it from other clinical diagnoses. A small-vessel vascu-litis is usually present, with an infiltrate predominantly consisting of neutrophils and eosinophils. GF is noted for its relative

John P. Minni, DO,* Dana L. Haake, MS3,** Jeffrey Martin, DO,*** Mark C. George, PA-C,*** Evangelos G. Poulos, MD,**** Layne D. Nisenbaum, DO******3rd-year dermatology resident, Columbia Hospital, West Palm Beach, FL**3rd-year medical student, PCOM Georgia***Island Coast Dermatology, Fort Myers, FL****Global Pathology, Miami, FL*****Program director, Columbia Hospital, Island Dermatology and Laser Institute, Palm Beach, FL

EXTRAFACIAL GRANULOMA FACIALE

ABSTRACT

Granuloma faciale (GF), a rare, fibrosing, small-vessel vasculitis of unknown etiology, is usually confined to the face. Extrafacial presentations are increasingly rare. We present a case of extrafacial granuloma faciale treated conservatively with topical therapy, achieving moderate success.

Figure 1

Figure 2

Figure 3

abundance of eosinophils, although a few reported cases do not have this feature.15

The sparing of follicular structures sepa-rates GF from acneiform eruptions. The appearance of a grenz zone at the dermal-epidermal junction and around pilose-baceous units helps differentiate it from erythema elevatum diutinum, which shares a very similar histopathological pattern.2

Leukocytoclastic vasculitis should not be an overwhelming feature, as this would point to that diagnosis.

GF treatment, like its etiology, has been elusive. Anecdotal evidence for various treatment modalities has varied without definitive clinical trials. Treatment often begins with topical and intralesional corti-costeroids. Immunomodulators such as tacrolimus have exhibited some success.19-21 Multiple cases have been reported in which LASER therapy has been used success-fully.19,22 PUVA therapy has also been reported in one case.23 Systemic therapy has been tried on a few occasions, with success with high-dose dapsone and anti-malar-ials.10,24 Since our patient was reluctant to use systemic or even intralesional therapy, and there have been a few relative successes with topical tacrolimus, we decided on a simple therapeutic regimen consisting of a midpotency corticosteroid in the morning and topical tacrolimus nightly. In four weeks of therapy, he had some success, which follows reports of previous cases utilizing tacrolimus. The extrafacial lesions were reduced most notably. In the interim, no new lesions have appeared.

Granuloma faciale remains a clinically difficult diagnosis. However, with clinical and histological data, diagnosis becomes lucid. Extrafacial lesions can and do occur and should be considered when a patient has this entity. Dermatologists and dermatopathologists should be aware that extrafacial lesions can, in fact, co-exist with the more classic, facially located lesions.

References:1. Freedberg IM, et al. Fitzpatrick’s Dermatology in Gen-

eral Medicine. 6th edition. McGraw-Hill. 2003. Vol. 1. pp967-70.

2. Elder DE, et al. Lever’s Histopathology of the Skin. 9th Edition. Lippincott. 2005. p231.

3. Castano E, Segurado A, Iglesias L, Lopez-Rios F, Rodriquez-Peralto. JJ Granuloma faciale entirely in an extrafacial location. Br J Dermatol. 1997 Jun;136(6):978-9. Review.

4. Castellano-Howard L, Fairbee SI, Hogan DJ, Fenske NA, Messina JL. Extrafacial granuloma faciale: report of a case and response to treatment. Cutis. 2001 May; 67(5):413-5.

5. Cecchi R, Paoli S, Giomi A. Granuloma faciale with extra-facial lesions. Eur J Dermatol. 2002 Sep-Oct;12(5):438.

6. De D, Kanwar A, Radotra B, Gupta S. Extrafacial granu-loma faciale: report of a case. J Eur Acad Dermatol Venereol. 2007 Oct;21(9):1284-6.

7. Inanir I, Alvur Y. Granuloma faciale with extra-facial lesions. Br J. Dermatology Review. 2001 Aug;145(2):360-2.

8. Kavanagh GM, McLaren KM, Hunter J. Extensive extra-facial granuloma faciale of the scalp. Br J Dermatol. 1996 Mar;134(3):595-6.

9. Konohana A J Dermatol Extrafacial granuloma faciale 1994 Sep;21(9):680-2.

10. Rossiello L, Palla M, Aiello FS, Baroni A, Satriano RA. Granuloma faciale with extrafacial lesions. Skinmed. 2007 May-Jun;6(3):150-1.

11. Roustan G, Sanchez Yus E, Salas C, Simon A. Gran-uloma faciale with extrafacial lesions. Dermatology.

1999;198(1):79-82. Review.12. Rusin LJ, Dubin HV, Taylor WB. Disseminated granuloma

faciale. Arch Dermatol. 1976 Nov;112(11):1575-713. Sears JK Gitter DG Stone MS Extrafacial granuloma

faciale. Arch Dermatol.1991 May;127(5):742-3. 14. Verma R, Das AL, Vaishampayan SS, Vaidya S. Keloidal

granuloma faciale with extrafacial lesions. Indian J Der-matol Venereol Leprol. 2005 Sep-Oct;71(5):345-7.

15. Ortonne N, Wechsler J, Bagot M, Grosshans E, Cribier B. Granuloma faciale: a clinicopathologic study of 66 patients. J Am Acad Dermatol. 2005 Dec;53(6):1002-9.

16. Marcoval J, Moreno A, Peyr J. Granuloma faciale: a clini-copathological study of 11 cases. J Am Acad Dermatol. 2004 Aug;51(2):269-73.

17. Nieboer C, et al. Immunofluorescence studies in granu-loma eosinophilic faciale. J Cutan Pathol. 1978;5:68-75

18. Zirwas MJ, Abell E, et al. Immunofluorescence find-ings in granuloma faciale: report of two cases. J Cutan Pathol. 2003;30:314-17

19. Ludwig E, Allam J-P, Bieber T, et al. New treatment modalities for granuloma faciale. Br J Dermatol. 2003;149:634-7.

20. Marcoval J, Moreno A, et al. Granuloma faciale: Treat-ment with topical tacrolimus. J Am Acad Dermatol. 2006:55;S1110-1111

21. Mitchell D. Successful treatment of granuloma faciale with tacrolimus. Dermatol Online J. 2004;10:23

22. Ammirati CT, Hruza GJ. Treatment of granuloma faciale with the 585nm pulsed dye laser. Arch Dermatol. 1999;135:903-5.

23. Hudson LD. Granuloma faciale: treatment with topical psoralens and UVA. J Am Acad Dermatol. 1983;8:559

24. Van de Kerkof PCM. On the efficacy of dapsone in granuloma faciale. Acta Derm Venereol. 1994;74:61-2

Figure 4

Figure 5

Figure 6

Figure 7

MINNI, HAAKE, MARTIN, GEORGE, POULOS, NISENBAUM 43

44 PEDIATRIC GENITAL WARTS-CASE STUDY AND REVIEW

Report of a Case:An 18-month-old Hispanic female

presented with her mother to the office with over 50 flesh colored papules along her genital and anal region. The largest papule was a 4-mm flesh-colored lesion on the anus. There was also a 3-mm flesh-colored lesion midline, superior to the labia majora. There were multiple, tiny (1 mm) flesh-colored papules spread throughout the vaginal area as well as inside the vaginal opening and along the anal area. The mother stated that a small single “wart” first appeared on the anus more than six months prior. The warts then spread up into the vaginal area as well as inside the vaginal opening and up to the superior edge of the labia majora.

The mother stated that she, her husband, and her other child did not have any of these “warty” growths in their respective genital regions. The mother also stated that her daughter was in extreme discom-fort due to the pruritic warts all over the vaginal and anal areas. When questioned, the mother said that the child was never out of her sight and that she does not know how the child could have contracted these warts. It was determined that a biopsy was the best course of action to determine the etiology of these many papules and the risk the warts posed to the young child.

Diagnosis: Condyloma

Discussion: Verrucae are warts that are commonly

seen in children and young adults. They are caused by the human papillomavirus (HPV). Verrucae are easily transmitted from one person to another via physical contact. Microabrasions on the epithelial surface allow the virons from the infected individual to enter the noninfected person. A pregnant woman can pass the virus by vaginal birth. This transmission increases the risk that the infant will develop recur-rent respiratory papillomatosis, a disease in which benign, squamous papillomas grow within the respiratory tract. These papil-lomas are very aggressive and can cause sudden respiratory obstruction.

The transmission is most common by direct contact, but it also can occur indi-rectly through contaminated surfaces, such

as in a swimming pool or gymnasium. The basal keratinocytes are the target for the HPV infection. Autoinoculation of the virus from one site of the body to another is frequently seen. The verrucae are clas-sified based on anatomical location and clinical morphology.

Condyloma acuminatum (venereal wart) occurs on the genitals and rectum of males and females. The warts appear with a soft, smooth surface and are tan in color. The cauliflower masses can reach up to a centimeter in diameter and are peduncu-lated. There are over 25 HPV subtypes that infect the anogenital region. The subtypes 6 and 11 usually cause condy-lomata acuminata, and they are consid-ered low-risk for causing intraepithelial neoplasms. HPV subtypes 16, 18, 31, 33 and 45 are high-risk subtypes and are more commonly associated with intraepi-thelial neoplasms (cervical cancers). HPV 1 and 4 cause plantar warts, and HPV 2, 3, and 10 cause warts on the hands and fingers. A biopsy is performed to deter-mine the subtype of the condyloma and thus the risk of developing dysplasia.

HPV infections involving the lower genital tract are some of the most common sexually transmitted diseases observed in adolescents and young adults. Genital warts seen in prepubertal children are of special concern. A thorough history and physical exam of a prepubertal child is important to determine the risk that the child has contracted the warts through sexual contact. Though the transmission of HPV can occur during vaginal delivery or other physical contact, sexual abuse should be considered.

Treatment is usually accomplished with cryosurgery with liquid nitrogen. This is applied weekly or biweekly; it is inex-pensive and should not result in scarring. Podophyllin 10% to 25% can also be used. Podophyllin is a plant alkaloid used to treat genital warts by inhibiting DNA replication and thus stopping cell growth. It takes several applications to observe the disap-pearance of the warts.

Periactin (cyproheptadine) was prescribed to our patient as an antihistamine to control the itching. Hydrocortisone cream was also prescribed to control the inflammation. A biopsy was preformed to identify the genital wart etiology.

Differential Diagnosis: Condyloma acuminatum (venereal wart), Verruca

vulgaris (common wart), Molluscum contagiosum, benign neoplasms and squamous intraepithelial lesions, as well as other associated diseases such as gonorrhea, AIDS, chlamydia, syphilis and other STDs.

Resources:1. Abbas Abul K., Nelson Fausto, and Vinay Kumar. Robbins

& Cotran Pathologic Basis of Disease. 7th ed. Philadel-phia: The Curtis Center, 2005. 1265-1269.

2. Johnson, Richard A., Dick Suurmond, and Klaus Wolff. Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatol-ogy. 5th ed. New York: McGraw-Hill, 2005. 886-892.

3. Horn, Thomas D., Anthony J. Mancini, Jose M. Mas-caro, Stuart J. Salasche, Jean-Hilaire Saurat, and Georg Stingl. Dermatology. Vol. 1. New York: Mosby, 2003. 1217-1231.

Robert A. Norman, DO, MPH, Steven Nodine, OMS IIILake Erie College of Osteopathic Medicine, Bradenton, FL

PEDIATRIC GENITAL WARTS—CASE STUDY AND REVIEW

Figure 1

Keep out of reach of children.

Brief Summary of Full Prescribing InformationINDICATIONS AND USAGEORACEA is indicated for the treatment of only infl ammatory lesions (papules and pustules) of rosacea inadult patients.The dosage of ORACEA differs from that of doxycycline used to treat infections. To reduce the development of resistant bacteria as well as to maintain the effectiveness of other antibacterial drugs, ORACEA should be used only as indicated. CLINICAL PHARMACOLOGYPharmacokineticsORACEA capsules are not bioequivalent to other doxycycline products.

CONTRAINDICATIONSThis drug is contraindicated in persons who have shown hypersensitivity to doxycycline or any of the other tetracyclines.

WARNINGSTeratogenic effects: 1) Doxycycline, like other tetracycline-class antibiotics, can cause fetal harm when administered to a pregnant woman. If any tetracycline is used during pregnancy or if the patient becomes pregnant while taking these drugs, the patient should be informed of the potential hazard to the fetus and treatment stopped immediately. ORACEA should not be used during pregnancy (see PRECAUTIONS: Pregnancy).2) The use of drugs of the tetracycline class during tooth development (last half of pregnancy, infancy, and childhood up to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). This adverse reaction is more common during long-term use of the drug but has been 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 be effective or are contraindicated.3) All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fi bula growth rate has been observed in premature human infants given oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued. Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can cause retardation of skeletal development on the developing fetus. Evidence of embryotoxicity has been noted in animals treated early in pregnancy (see PRECAUTIONS: Pregnancy section). 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 in patients who present with diarrhea subsequent to the administration of antibacterial agents.Treatment with antibacterial agents alters the normal fl ora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium diffi cile is a primary cause of “antibiotic-associated colitis”. If a diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe cases, consideration should be given to management with fl uids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium diffi cile colitis. Metabolic effects: The anti-anabolic action of the tetracyclines may cause an increase in BUN. While this is not a problem in those with normal renal function, in patients with signifi cantly impaired function, higher 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 drug and possible liver toxicity. Under such conditions, lower than usual total doses are indicated, and if therapy is prolonged, serum level determinations of the drug may be advisable. Photosensitivity: Photosensitivity manifested by an exaggerated sunburn reaction has been observed in 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 artifi cial sunlight (tanning beds or UVA/B treatment) while using ORACEA. If patients need to be outdoors while using ORACEA, they should wear loose-fi tting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician.

PRECAUTIONSGeneral: Safety of ORACEA beyond 9 months has not been established. As with other antibiotic preparations, use of ORACEA may result in overgrowth of non-susceptible micro-organisms, including fungi. If superinfection occurs, ORACEA should be discontinued and appropriate therapy instituted. Although not observed in clinical trials with ORACEA, the use of tetracyclines may increase the incidence of vaginal candidiasis. ORACEA should be used with caution in patients with a history of or predisposition to candidiasis overgrowth. Bacterial resistance to tetracyclines may develop in patients using ORACEA. Because of the potential for drug-resistant bacteria to develop during the use of ORACEA, it should be used only as indicated. Autoimmune Syndromes: Tetracyclines have been associated with the development of autoimmune 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 of all tetracycline-class drugs should be discontinued immediately. 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 tissue, oral cavity (teeth, mucosa, alveolar bone), sclerae and heart valves. Skin and oral pigmentation has been reported to occur independently of time or amount of drug administration, whereas other pigmentation has been reported to occur upon prolonged administration. Skin pigmentation includes diffuse pigmentation as well as over sites of scars or injury. Pseudotumor cerebri: Bulging fontanels in infants and benign intracranial hypertension in adults have been reported in individuals receiving tetracyclines. These conditions disappeared when the drug was discontinued.Laboratory Tests: Periodic laboratory evaluations of organ systems, including hematopoietic, renal and hepatic 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, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. 2. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline-class drugs in conjunction with penicillin. 3. The concurrent use of tetracycline and methoxyfl urane has been reported to result in fatal renal toxicity. 4. Absorption of tetracyclines is impaired by bismuth subsalicylate, proton pump inhibitors, antacids containing aluminum, calcium or magnesium and iron-containing preparations. 5. Doxycycline may interfere with the effectiveness of low dose oral contraceptives. To 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 with the concomitant use of isotretinoin and tetracyclines. Since both oral retinoids, including isotretinoin and acitretin, and the tetracyclines, primarily minocycline, can cause increased intracranial pressure, the concurrent use of an oral retinoid and a tetracycline should be avoided.

MICROBIOLOGYThe 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 fl ora 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 dosages of 20, 75, and 200 mg/kg/day for two years. An increased incidence of uterine polyps was observed in female rats that received 200 mg/kg/day, a dosage that resulted in a systemic exposure to doxycycline approximately 12.2 times that observed in female humans who use ORACEA (exposure comparison based upon area under the curve (AUC) values). No impact upon tumor incidence was observed in male rats at 200 mg/kg/day, or in either gender at the other dosages studied. Evidence of oncogenic activity was obtained in studies with related compounds, i.e., oxytetracycline (adrenal and pituitary tumors) and minocycline (thyroid tumors). Doxycycline demonstrated no potential to cause genetic toxicity in an in vitro point mutation study with 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 suggest that doxycycline is a weak clastogen.Oral administration of doxycycline to male and female Sprague-Dawley rats adversely affected fertility and reproductive performance, as evidenced by increased time for mating to occur, reduced sperm motility, velocity, and concentration, abnormal sperm morphology, and increased pre-and post-implantation losses. Doxycycline induced reproductive toxicity at all dosages that were examined in this study, as even the lowest dosage tested (50 mg/kg/day) induced a statistically signifi cant reduction in sperm velocity. Note that 50 mg/kg/day is approximately 3.6 times the amount of doxycycline contained in the recommended daily dose of ORACEA for a 60-kg human when compared on the basis of AUC estimates. Although doxycycline impairs the fertility of rats when administered at suffi cient dosage, the effect of ORACEA on human fertility is unknown.

Pregnancy: Teratogenic Effects: Pregnancy Category D. (see WARNINGS section). Results from animal studies indicate that doxycycline crosses the placenta and is found in fetal tissues.

Nonteratogenic effects: (see WARNINGS section). Labor and Delivery: The effect of tetracyclines on labor and delivery is unknown.

Nursing Mothers: Tetracyclines are excreted in human milk. Because of the potential for serious adverse reactions in infants from doxycycline, ORACEA should not be used in mothers who breastfeed. (see WARNINGS section).

Pediatric Use: ORACEA should not be used in infants and children less than 8 years of age (see WARNINGS section). ORACEA has not been studied in children of any age with regard to safety or effi cacy, therefore use in children is not recommended.

ADVERSE REACTIONSAdverse Reactions in Clinical Trials of ORACEA: In controlled clinical trials of adult patients with mild to moderate rosacea, 537 patients received ORACEA or placebo over a 16-week period. The most frequent adverse reactions occurring in these studies are listed in the table below.

Incidence (%) of Selected Adverse Reactions in Clinical Trials of ORACEA (n=269) vs. Placebo (n=268)

ORACEA PlaceboNasopharyngitis 13 (4.8) 9 (3.4)Pharyngolaryngeal Pain 3 (1.1) 2 (0.7)Sinusitis 7 (2.6) 2 (0.7)Nasal Congestion 4 (1.5) 2 (0.7)Fungal Infection 5 (1.9) 1 (0.4)Infl uenza 5 (1.9) 3 (1.1)Diarrhea 12 (4.5) 7 (2.6)Abdominal Pain Upper 5 (1.9) 1 (0.4)Abdominal Distention 3 (1.1) 1 (0.4)Abdominal Pain 3 (1.1) 1 (0.4)Stomach Discomfort 3 (1.1) 2 (0.7)

Note: Percentages based on total number of study participants in each treatment group.

Adverse Reactions for Tetracyclines: The following adverse reactions have been observed in patients receiving tetracyclines at higher, antimicrobial doses: Gastrointestinal: anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, and infl ammatory lesions (with vaginal candidiasis) in the anogenital region. Hepatotoxicity has been reported rarely. Rare instances of esophagitis and esophageal ulcerations have been reported in patients receiving the capsule forms of the drugs in the tetracycline class. Most of the patients experiencing esophagitis and/or esophageal ulceration took their medication immediately before lying down. (see DOSAGE AND ADMINISTRATION section).Skin: maculopapular and erythematous rashes. Exfoliative dermatitis has been reported but is uncommon. Photosensitivity is discussed above. (see WARNINGS section).

Renal toxicity: Rise in BUN has been reported and is apparently dose-related.(see WARNINGS section). Hypersensitivity reactions: urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness, pericarditis, and exacerbation of systemic lupus erythematosus. Blood: Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have been reported.

OVERDOSAGEIn case of overdosage, discontinue medication, treat symptomatically, and institute supportive measures. Dialysis does not alter serum half-life and thus would not be of benefi t in treating cases of overdose.

DOSAGE AND ADMINISTRATIONTHE DOSAGE OF ORACEA DIFFERS FROM THAT OF DOXYCYCLINE USED TO TREAT INFECTIONS. EXCEEDING THE RECOMMENDED DOSAGE MAY RESULT IN AN INCREASED INCIDENCE OF SIDE EFFECTS INCLUDING THE DEVELOPMENT OF RESISTANT MICROORGANISMS.One ORACEA Capsule (40 mg) should be taken once daily in the morning on an empty stomach, preferably at least one hour prior to or two hours after meals. Effi cacy beyond 16 weeks and safety beyond 9 months have not been established. Administration of adequate amounts of fl uid along with the capsules is recommended to wash down the capsule to reduce the risk of esophageal irritation and ulceration. (see ADVERSE REACTIONS section).

HOW SUPPLIEDORACEA (beige opaque capsule printed with CGPI 40) containing doxycycline, USP in an amount equivalent to 40 mg of anhydrous doxycycline. Bottle of 30 (NDC 64682-009-01).

Storage: All products are to be stored at controlled room temperatures of 15°C-30°C (59°F-86°F) and dispensed in tight, light-resistant containers (USP). Keep out of reach of children. Patent Information: U.S. Patents 5,789,395; 5,919,775; 7,232,572; 7,211,267 and patents pending. ORACEA is a registered trademark of CollaGenex Pharmaceuticals, Inc., Newtown, PA, 18940

Manufactured by:CardinalHealthWinchester, KY 40391

Marketed by:CollaGenex Pharmaceuticals, Inc.Newtown, PA, 18940

7961-01 BPI 06/07

KREITZER, KORMAN, TAMBURRO 47

Case PresentationThe patient is an 11-year-old black

female born with marked cutaneous scale. As a maturing infant, it was noted that she had sparse hair, periorbital wrin-kling, and hyperpigmentation. Her teeth were reduced in number and abnormally peg-shaped. Her past medical history is significant for mild developmental delay and atopic dermatitis. She takes no medi-cations. Her mother states she must always be in cool rooms at home and at school due to her history of high febrile episodes as a child. Numerous family members report similar physical appearances and history of febrile episodes as children.

Physical examination revealed a well appearing black female in no acute distress, very pleasant in nature. Frontal bossing, sparse scalp hair, and peg-shaped teeth were also present. Periorbital wrinkling and hyperpigmentation were present, along with hyperlinear palms. Hoarseness, saddle nose deformity and full everted lips were also noted (Figures 1, 2, 3). Her mother was present during the exam and had similar physical features.

Starch-iodine sweat function test showed an absence of functioning sweat glands in comparison to control (Figure 4). To show the absence of eccrine sweat glands to confirm the diagnosis, a punch biopsy of the palm or scalp was offered; however, the patient refused.

Treatment options for the patient were discussed, including controlling ambient temperatures to prevent high fevers and the use of external methods for cooling, e.g. air conditioning or cooling vests. Dental restoration was encouraged and should be of primary importance, as the teeth can be made to have a normal appearance.

Discussion:Hypohidrotic ectodermal dysplasia is a

rare genetic disorder characterized by fine, sparse hair, peg-shaped teeth, and dimin-ished or absent eccrine sweat gland func-

tion. Affected individuals have a typical facial appearance as well, with frontal bossing, saddle nose, and full everted lips.1 The inability to sweat may put infants at risk for life-threatening hyperthermia.2

The most common form of hypohidrotic ectodermal dysplasia is X-linked, but both autosomal dominant and autosomal reces-sive inheritance have now been demon-strated.3 Our patient appears to follow the autosomal dominant mode of inheritance per family tree (Figure 5).

The disorder is caused by defects in the ectodysplasin signal transduction pathway. Epithelial cells in developing hair follicles, teeth, and eccrine sweat glands use this pathway during the developmental process. Defects in this pathway result in aplasia, hypoplasia, or dysplasia of these structures.4 Three genes are involved: ectodysplasin (EDA1), EDA-receptor (EDAR) and EDAR-associated death domain (EDARADD). The pathway is active at an important time in development, and the change in gene expression has an affect on cellular proliferation and survival.5 Another geno-type has recently been reported in fami-lies affected by hypohidrotic ectodermal dysplasia and immunodeficiency. This X-linked defect is localized to the NEMO gene, and complete loss of function of this gene causes a related disorder in female patients called incontinentia pigmenti.6 Clinical molecular testing is available for the ectodysplasin and NEMO genes; however, clinical diagnosis can usually be made on history and physical exam. Female carriers of the X-linked form are common and may present with no detectable features or may have all features of the disorder. Variability is based on random X-inactivation.7 Treatment options are controlling temper-ature to prevent high fevers and the use of external methods of cooling, including air conditioners and cooling vests. Our patient had episodes of high fevers as a child, but controlling temperatures both at home and at school have prevented any further episodes. The patient’s mother had similar episodes as a child, with no signifi-

cant medical complications. The patient we have presented is in the process of dental restoration and will have dental implants as a teenager. Her atopic dermatitis is well controlled with topical emollients and mid-potency topical steroids as needed. The National Foundation for Ectodermal Dysplasias is an important resource avail-able to these patients. This organization publishes educational materials for both patients and physicians, along with a bimonthly newsletter.

Todd Kreitzer, D.O., RPh,* Neil Korman, M.D., PhD,** Joan Tamburro, D.O., FAOCD****2nd-year dermatology resident, University Hospitals, Cleveland, OH**Attending Physician, University Hospitals, Cleveland, OH***Program Director, University Hospitals/Richmond Heights, Cleveland, OH

HYPOHIDROTIC ECTODERMAL DYSPLASIA: A CASE PRESENTATION

ABSTRACT

Hypohidrotic ectodermal dysplasia is an uncommon, inherited disorder of ectodermal structures. Distinguishing features are thin, sparse hair, missing or peg-shaped teeth, and an inability to sweat properly. The most common form is X-linked recessive, but autosomal dominant and autosomal recessive cases have been described. We present a case of a young black female diagnosed with hypohidrotic ectodermal dysplasia.

Figure 1

Figure 2

In summary, hypohidrotic ectodermal dysplasia is an uncommon genetic disorder with characteristic features of sparse hair, peg-shaped teeth, and hypohidrosis. Life-threatening complications of the disease include the brain-damaging effects of hyperthermia. Skin biopsies with absence of eccrine glands and starch-iodine palm-sweat tests can aid in the diagnosis. Treatment options are aimed at control-ling body temperature. Different modes of inheritance are present, including X-linked recessive, autosomal dominant, and auto-somal recessive. Although our patient likely has an autosomal dominant form, X-linked recessive inheritance is most common.

References:1. Rouse C; Siegfried E; Breer W; Nahass G. Hair and

Sweat Glands in Families with Hypohidrotic Ectodermal Dysplasia. Arch Dermatol. Jul 2004; 140: 850-855.

2. Cambiaghi S; Restano L; Paakkonen K; Caputo R; Kere J. Clinical Findings in Mosaic Carriers of Hypohidrotic Ectodermal Dysplasia. Arch Dermatol. Feb 2000; 136: 217-224.

3. Vincent M; Cossee M; Vabres P; Stewart F; Bonneau D; Calvas P. Pitfalls in Clinical Diagnosis of Female Carri-ers of X-linked Hypohidrotic Ectodermal Dysplasia. Arch Dermatol. Sep 2002; 138:1256-1258.

4. Bolognia J; Jorizzo J; Rapini R. Dermatology. Mosby; 2003. p. 905-907.

5. Shimomura Y; Nobuyuki S; Akinori M; Hashimoto T; Ito M; Kuwano R. A Rare Case of Hypohidrotic Ectodermal Dysplasia Caused by Compound Heterozygous Mutations in the EDAR gene. Journal of Investigative Dermatology. Sep 2004 123, 649-655.

6. Zonana J et al. A Novel X-linked Disorder of Immunode-ficiency and Hypohidrotic Ectodermal Dysplasia Is Allelic to Incontentia Pigmenti and Due to Mutations in IKK-gamma (NEMO). Am J Hum Genet. Dec 2000; 67(6): 1555-1562.

7. Clarke A; Burn J. Sweat testing to identify female carriers of X-linked hypohidrotic ectodermal dysplasia. Journal of Medical Genetics, 1991, Vol 28, 330-333.

48 HYPOHIDROTIC ECTODERMAL DYSPLASIA: A CASE PRESENTATION

Figure 3

Figure 4

Figure 5

GOODMAN, ELIAS, SKOPIT 49

IntroductionPsoriasis vulgaris is a T cell–mediated

inflammatory skin disease affecting an esti-mated 2.1% of the US population.1 A subset of psoriasis patients exhibit inverse psoriasis, or flexural psoriasis, which clas-sically occurs in the axillary vaults, groin, under the breasts, and in other skin folds around the genitals and buttocks.2 Topical corticosteroids remain the treatment of choice for the many variants of psoriasis. It is commonly known that the local adverse events associated with topical corticos-teroid use; including cutaneous atrophy, telangiectasia, and striae formation, are more pronounced when intertriginous areas are treated because these areas are more sensitive to corticosteroid penetra-tion.5 Thus, the location of psoriasis in intertriginous areas, poses a unique chal-lenge for treatment.3,4

Psoriasis is a disorder of epidermal hyper-proliferation, decreased epidermal turnover and associated impaired barrier function of the epidermis.6 The pathophysiological findings of psoriasis guide our ability to treat this disease with safe and efficacious modalities known as the non-steroidal topical barrier repair creams.

N-palmitoylethanolamide Cream (PEA or Mimyx®) is a member of a novel class of topical therapy for acute and chronic dermatitis. PEA is a steroid-free, topical calcineurin inhibitor-free topical therapy with proven efficacy and safety in patients of all ages. PEA cream restores the disrupted skin barrier and reduces exposure to environmental triggers. In addition, it replenishes deficient lipids including PEA, which modulate skin immune response, and relieves symptoms of eczema.7, 8 PEA has demonstrated anti-inflammatory prop-erties providing skin-soothing effects.9-11 The ability to restore the skin barrier is essential in controlling psoriatic erup-tions. PEA allows for control by replen-ishing the skin with natural lipids such

as hydrogenated lecithin, olea europaea, palm glycerides, and squalene. PEA also preserves the ability to mimic the lamellar structure of the skin barrier, and maintains a moist wound and skin environment to promote healing.12-13 Transepidermal water loss (TEWL) is another key component to impaired barrier function. PEA is shown to decrease TEWL which is critical for skin barrier repair.14-15 In one study, PEA signif-icantly reduced TEWL in damaged skin compared to the natural healing process.1

Case StudiesThree separate patients presented to

the Department of Dermatology as new patients complaining of an itchy rash in their underarms, groin, and in between their buttocks. All three patients had denied ever being evaluated by another physician for this rash, and deny any topical treatments since the onset of the rash. Shave biopsies were performed on the affected intertriginous areas, and results did confirm the clinical suspicion of inverse psoriasis. The same treatment was initiated in all three patients, which included twice daily application of Desonide topical cream 0.05% to the involved areas for two weeks. In addition, all patients applied Mimyx® cream to these areas twice daily. Patients were given strict instructions how to use medications and educated to continue Mimyx® cream twice daily after discon-tinuing the Desonide topical cream.

ConclusionThe goal of our treatment regimen is

to suppress inverse psoriasis flares while preventing subsequent psoriatic flares after acute control is achieved. Our study assesses the ability of Mimyx® cream to be safe and effective in accomplishing this objective. The study to date has shown all three patients with a complete resolution of their inverse psoriasis with the aforemen-tioned treatment regimen. The patients

Marcus B. Goodman, DO*, Merrick D. Elias, DO, FAOCD**, Stanley Skopit, DO, FAOCD***

CASE SERIES: N-PALMITOYLETHANOLAMIDE CREAM (PEA OR MIMYX®) USED AS AN ADJUNCT TO PREVENT INVERSE PSORIASIS FLARE FREQUENCY

ABSTRACT

Inverse psoriasis is a chronic subset of psoriasis that poses a difficult treatment regimen. Typical treatment modalities have hindered the ability of physicians to safely manage this condition in the past. Newer formulations and compounds that have recently been introduced, have allowed us to approach our understanding of treating this condition in a safe and effective manner.

Figure 1. Inguinal Fold

Figure 2. Intergluteal Fold

Figure 3. Axillary Vault

continue to apply Mimyx® cream twice daily. This application cycle has allowed our patients to be flare-free without further topical corticosteroids therapy other than the initial treatment. Flare was defined as the reappearance of pruritus and/or visible psoriasis areas as initially evaluated.

Patients had minimal complaints related to the Mimyx® applications. No serious adverse events were recorded, other than mild transient stinging was reported by one patient at the onset of treatment. Mimyx® Cream is contraindicated in patients with known hypersensitivity to any of the components of the formula-tion. Mimyx® Cream does not contain a sunscreen and should not be used prior to extended exposure to the sun if being utilized for non-intertriginous psoriasis.16 Mimyx® purports to be a very safe alterna-tive to topical corticosteroids due to the fact that it has no age or duration restric-tions. Medical practitioners need to have the ability to utilize medications for psori-asis in intertriginous areas that are safe and effective as well as provide an improvement in the quality of life. As discovered in our small case series, the key goal of providing an adjunctive therapeutic modality in the prevention of inverse psoriasis flare frequency was achieved. Randomized, blinded studies with a larger sample size are needed to further corroborate our data.

References:1. Krueger G, Koo J, Lebwohl M, Menter A, Stern RS, Rol-

stad T. The impact of psoriasis on quality of life: results of a 1998 National Psoriasis Foundation patient-member-ship survey. Arch Dermatol. 2001;137:280–284

2. Lebwohl M, Freeman AK, Chapman MS, Feldman SR, Hartle JE, Henning A, for the Tacrolimus Ointment Study Group Journal of the American Academy of Dermatology- 2004 11 (Vol. 51, Issue 5)

3. Lebwohl MG, Heymann WR, Berth-Jones J, Coulson I editor. Treatment of skin disease: comprehensive thera-peutic strategies. St Louis: Mosby; 2002;.

4. Van de Kerkoff P. Papulosquamous and eczematous dermatoses: psoriasis. In: Bologna JL, Jorizzo JL, Rap-ini RP editor. Dermatology. St Louis: Mosby; 2003;p. 125–149.

5. Stoughton RB, Cornell RC. Corticosteroids. In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF, eds. Dermatology in general medicine. New York: McGraw-Hill 1993:2846-2850

6. Krueger GG, Bergstresser PR, Lowe NJ, Voorhees JJ, Weinstein GD. Psoriasis. J Am Acad Dermatol. 1984;11:937–947

7. Eberlein-Koening et al. Abstract submitted for presenta-tion at: 64th Annual Meeting of the American Academy of Dermatology; March 2006; San Francisco, Ca

8. Kemeny, Abstract submitted for presentation at 64th Annual Meeting of the American Academy of Dermatol-ogy; March 2006; San Francisico, Ca

9. Jorizzo, Poster presented at: 63rd Annual Meetin of the American Academy of Dermatology; February 18-22, 2005; New Orleans, La. Poster P729

10. Facci et al, Proc Natl Acad Sci USA, 1995;92: 3376-338011. Matias et al. Eur J Biochem, 2002; 269: 3771-2778.12. Liorca et al. Rev Intern Dermatol Dermocosm.

2003;6:425-430.13. Grove and Zerweck. Submitted for presentation at: 64th

Annual Meeting of the American Academy of Dermatol-ogy; March 2006; San Francisico,Ca.

14. Werner and L indberg. Acta Derm Venereo l , 1985;65;102-105.

15. Grove and Zerweck. Submitted for presentation at; 64th Annual Meeting if the American Academy of Dermatol-ogy; March 2006;San Francisco, Ca.

16. MimyX Cream [package insert]. Coral Gables, FL: Stiefel Laboratories, Inc.; 2005.

50 CASE SERIES: N-PALMITOYLETHANOLAMIDE CREAM (PEA OR MIMYX®) USED AS AN ADJUNCT TO PREVENT INVERSE PSORIASIS FLARE FREQUENCY

TRUESDALE, GREENFIELD, BASS, BUSH, WETHERINGTON 51

IntroductionNephrogenic fibrosing dermopathy

(NFD) causes diffuse thickening and hard-ening of the skin, mostly in the extremi-ties. NFD occurs in dialysis patients with chronic renal disease. The skin lesions can progress rapidly, sometimes leading to joint contractures and immobility. NFD can evolve into a systemic disease called neph-rogenic systemic fibrosis (NSF), leading to fibrosis and calcification of multiple organs and muscles.1 Cases of NFD have been linked to exposure to gadolinium-containing contrast agents during magnetic resonance imaging (MRI) studies. Thus, clinicians should be aware of the poten-tial risk for developing NFD with the use of gadolinium contrast in patients with chronic renal disease and should avoid its use whenever possible. Only a small percentage of NFD patients had no identi-fied exposure to gadolinium contrast, but these patients still had undergone dialysis for chronic renal disease.2

Gadolinium contrast is primarily renally excreted. It is estimated that 65% to 78% of gadolinium contrast can be renally cleared after one session of hemodialysis and 98% cleared after three sessions. Peritoneal dialysis, on the other hand, may be less effective in the clear-ance of gadolinium contrast compared to hemodialysis. For example, in a St. Louis study in 2001, it took 22 days for patients undergoing continuous peritoneal dialysis to excrete only 69% of the gadolinium contrast. Such slow clearance of the gado-linium contrast media leads to prolonged exposure to the heavy metal gadolinium among peritoneal dialysis patients. In most studies, patients undergoing peri-toneal dialysis with gadolinium-contrast exposure seem to be at a higher risk for developing NFD, but there is still a risk

present for those undergoing hemodial-ysis, and that risk should not be ignored.2,3

If at all possible, the use of gadolinium contrast media should be avoided in patients with chronic renal failure, partic-ularly in patients undergoing peritoneal dialysis. Other radiological modalities such as ultrasound and CT may be suit-able substitutes. If gadolinium contrast is necessary, and if patients have an estab-lished access for hemodialysis, immediate hemodialysis should be given after contrast administration to facilitate renal clear-ance of the contrast. Clinicians who treat patients with chronic renal disease should be aware of the risk for NFD and consider the diagnosis in patients with diffuse thick-ened, scaly skin on the extremities.2,3

Case PresentationA 62-year-old Caucasian male on hemo-

dialysis for chronic renal failure secondary to type 2 diabetes mellitus presented with progressive skin lesions. They were consis-tent with thickening and hardening of the skin and appeared on his lower and upper extremities as well as his upper body, with minimal truncal involvement. Flexure contractures were noted in his fingers and toes (Figure 1). Sclerotic, hyperpigmented plaques were apparent, with orange-colored skin (Figures 2 and 3). The patient complained of pain with occasional mild pruritus and a burning sensation. The sclerotic plaques on the patient’s feet were so thick that walking became extremely limited and quite painful. Extensive weak-ness and numbness had developed in both of his legs. The patient had limited range of motion in the joints in his extremities, also making ambulation quite difficult. He could not fully extend his knees, nor could he walk more than 100 feet per day. The rest of the time he remained confined to his wheelchair.

Kelly Anne Truesdale,* Melinda F. Greenfield, DO,** Chris Bass, PA,*** Kevin Bush, PA,**** R. Wesley Wetherington, MD******3rd-year medical student, Philadelphia College of Osteopathic Medicine, Georgia Campus**Dermatology private practice, Albany, Georgia; clinical instructor in dermatology, Philadelphia College of Osteopathic Medicine, Georgia Campus***Dermatology physician assistant, Albany, Georgia****Dermatology physician assistant, Albany, Georgia*****Dermatopathology private practice, Marietta, Georgia

A CASE PRESENTATION OF NEPHROGENIC FIBROSING DERMOPATHY

ABSTRACT

Nephrogenic fibrosing dermopathy (NFD) is a scleromyxedema-like disorder with significant thickening and hardening of the skin. This disorder affects individuals with renal disease who have undergone dialysis, and it appears to be linked with gadolinium exposure during MRI imaging. The disease produces skin and connective-tissue fibrosis, leading to nephrogenic systemic fibrosis and eventually death. NFD causes pruritus, burning pain, and flexure contractures that can lead to impairments in joint mobility. No cure or effective treatment currently exists for NFD. The intent of this case study is to provide education about this disease and its association with gadolinium contrast, and stress that its prevention is of paramount importance in order to avoid increasing the number of cases of this disease around the world.

Figure 1 Flexure contractures of the fingers and toes with orange hyperpigmented plaques.

Figure 2 Patient’s right lower extremity with orange colored skin and numerous sclerotic hyperpigmented plaques

The patient had a history of essential hypertension, congestive heart failure (CHF), and chronic obstructive pulmo-nary disease (COPD). He had been under-going hemodialysis since June 2005 and had been on the renal transplant list since March 2007. This scleroderma-like condi-tion began around March 2007 with no pain and only occasional itching. He’d had both an MRI and MRA scan with gado-linium contrast media a few months before acquiring this skin condition. Because his skin continued to thicken and harden, his arteriovenous fistula for his dialysis treat-ments had been moved several times. The skin had become so hard and thick that it made inserting the dialysis needles impos-sible, because the needles bend very easily and could not pierce his skin. This inevi-tably left scarring (Figure 4).

Physical examination revealed sclero-dactyly and tightening of the skin, with multiple sclerotic plaques. Skin lesions were hyperpigmented with an orange-colored surface and were localized to his arms, thighs, legs, and upper body.

HistopathologyNFD has some unique histopathological

features, but it also resembles scleromyxe-dema. For example, collagen bundles are thickened with clefts surrounding them (Figure 5). Mucin deposition is apparent, as well as an excess of fibroblasts and elastic fibers. The thick elastic fibers usually orient themselves in a parallel fashion to the collagen bundles. Inflammation is usually not present.4

Within 20 weeks of onset of clinical manifestations, NFD lesions show large, epithelioid/stellate spindle cells infiltrating through the dermis. Spindles cells arrange themselves among the thick collagen bundles. Most of the spindle cells are CD34 pro-collagen positive cells. Multinucleated CD68 factor XIIIa positive cells are gener-ally present (Figure 6).4

More than 20 weeks after onset of symptoms, NFD lesions usually have less prominent clefts, less mucin, and a reduced number of CD34 pro-collagen positive cells. Calcification may also be present.4

A skin biopsy from the right thigh of our patient was consistent with the classic histo-logical findings in NFD (Figures 7 and 8). The biopsy showed the presence of dermal thickening in addition to dense collagen with prominent clefts.

Treatment OptionsCurrently, no cure or effective treatment

exists for NFD, but the patients’ cutaneous symptoms may be medically managed in an effort to improve quality of life. Treatment options for NFD are limited but include renal transplantation, oral and topical steroids, plasmapheresis, photo-

52 A CASE PRESENTATION OF NEPHROGENIC FIBROSING DERMOPATHY

Figure 4 The current location of our patient’s AV fistula for hemodialysis. The thickness of the skin here has made needle insertion quite difficult, leaving extensive scarring behind.

Figure 5 (A) H & E stain; (B) Trichrome stain showing marked dermal thickening with accumulation of thick collagen bundles separated by large clefts in the deep dermis.5

Figure 6 The presence of CD34 positive spindle fibroblasts and cells staining with both CD68 (red) and factor XIIIa (green) labeled antibodies. These cells are most likely dendritic cells co-expressing both CD68 and factor XIIIa epitopes. CD68+ or factor XIIIa+ cells are a constant finding in early disease.

Figure 7 Section of skin from the patient’s right thigh showing thickened dermis filled with dense clefted collagen bundles and focal mucin deposition. Large dense fibrous bands traverse the subcutaneous tissue. Fibroblast proliferation is noted even at low-magnification.

Figure 8 High-magnification biopsy image of fibroblastic proliferationof dermal and subcutaneous tissue

Figure 3 Sclerotic hyperpigmented plaques on the hands and fingers with notable orange colored skin

pheresis, ultraviolet therapy, high-dose intravenous immunoglobulin therapy, and physical therapy.4

The anemia of many chronic renal disease patients is commonly treated with erythropoietin to promote red blood cell production. For patients with NFD, reducing the administered erythropoietin doses may be helpful.6

Oral steroids such as prednisone have been helpful to some patients with NFD, but they are not often used as treatment due to their side effects. Topical Dovonex has been shown to improve symptoms in patients with early-stage NFD, but very little improvement has been demonstrated in late-stage NFD. Thalidomide use has improved some patients’ NFD symptoms while they’re taking the drug, but the long-term effects of the drug may outweigh its benefits. Plaquenil has also been used to treat NFD, but careful monitoring is neces-sary to minimize any potential side effects. Some patients have reported improvements in symptoms with Minocycline and similar antibiotics. Pentoxifylline has had some reports of success at improving symptoms of NFD by decreasing the blood viscosity and, therefore, improving circulation. It may also have some anti-oxidant effects.4

Plasmapheresis has been shown to improve NFD symptoms in patients who have had dual liver and kidney transplants.4

Physical therapy, especially swimming, may improve patients’ range of motion and joint mobility and may also slow the progression of joint immobility.4

ConclusionNephrogenic fibrosing dermopathy,

which can become nephrogenic systemic fibrosis, is a debilitating disease that produces skin and connective-tissue fibrosis with eventual systemic effects, ending ultimately in death. It appears to affect individuals with chronic renal disease who have undergone dialysis. NFD causes pruritus, burning pain, and flexure contractures, leading to impaired range of motion and mobility.

Although not completely proven, many cases of NFD and NSF have been linked to gadolinium-contrast MRI in dialysis patients. The FDA has, therefore, advised clinicians to limit gadolinium-contrast use in patients with chronic renal disease, even though not all dialysis patients with chronic renal disease who have a gadolinium-contrast MRI develop NFD. Certainly, further investigation is needed to determine if gadolinium exposure is the common trigger for the onset of all cases of NFD. There is currently no cure or effec-tive treatment for NFD, so education about this disease and its prevention is of the utmost importance. Since this disease is relatively new to the medical world, many hospitals continue to use gadolinium in all

patients, including those with renal disease. This may have the effect of increasing the number of cases of NFD in the United States and around the world.

References:1. Cowper SE, Bucala R. (2003). Nephrogenic fibrosing der-

mopathy: Suspect identified, motive unclear. American Journal of Dermapathology, 25(4), 358.

2. Centers for Disease Control and Prevention (CDC). Nephrogenic fibrosing dermopathy associated with expo-sure to gadolinium-containing contrast agents — St. Louis, Missouri, 2002-2006. MMWR Morbidity Mortality

Weekly Report 2007 Feb 23; 56:137-41.3. Grobner T. (2006). Gadolinium—a specific trigger for the

development of Nephrogenic Fibrosing Dermopathy and Nephrogenic Systemic Fibrosis? Nephrology Dialysis Transplantation, 21, 1104-1106.

4. Cowper SE. Nephrogenic Fibrosing Dermopathy [NFD/NSF Website]. 2001-2007. Available at http://www.icnfdr.org. Accessed 10/06/2007.

5. Mendoza FA, Artlett CM, Sandorfi N, Latinis K, Piera-Velazquez S, Jimenez SA. (2006). Description of 12 cases of nephrogenic fibrosing dermopathy and review of the literature. Seminars in Arthritis and Rheumatism. 35 (4): 238-49.

6. LeBoit PE. (2003). What Nephrogenic Fibrosing Dermop-athy might be. Archives of Dermatology, 139(7), 903-906.

TRUESDALE, GREENFIELD, BASS, BUSH, WETHERINGTON 53

54 MYCOBACTERIUM CHELONAE INFECTION FOLLOWING A FULL THICKNESS SKIN GRAFT

IntroductionWith a large repertoire of cutaneous

surgical interventions including cosmetic surgery and skin rejuvenation proce-dures, postoperative wound infections are becoming an increasingly important consideration in dermatology. Although dermatological procedures are not routinely performed under strictly sterile conditions, they seldom result in infectious complica-tions. Wound infections following excisions and micrographically controlled proce-dures arise in less than 3% of cases, which is comparable to the expected rate for clean surgical procedures.1 Most pathogens that complicate surgical procedures include Staphylococcus aureus, Staphylococcus epidermidis, and Pseudomonas aeruginosa; however atypical bacterial infections can occasionally occur.

The pathogenesis, clinical presentation, diagnosis and finally treatment of atypical mycobacteria infections will be discussed in this article with special focus on the organism Mycobacterium chelonae.

In this report, we present a patient who developed an atypical mycobacterial infection following staged reconstruction surgery of a squamous cell carcinoma. We also describe the clinical efficacy of clarithromycin in treating this infection.

Case ReportA healthy 67 year-old Caucasian male

had Mohs excision of a squamous cell carcinoma of his right dorsal hand followed by a full thickness skin graft. Six weeks after surgery, he presented to the clinic with complaints of new-onset burning, erythema and violaceous noduless at the periphery of the skin graft. He had no systemic symptoms. The patient’s medical history was significant only for hepatitis C and hypercholesterolemia.

On examination, four compressible nodules were noted at the perimeter of

the skin graft scar. The nodules were 0.4 to 0.8 cm in diameter and located where the silk sutures were placed (Figure 1). No fluctuance, drainage or tenderness was noted. The nodules were punctured by #11 blade and superficial exploration with splinter forceps was performed, revealing no foreign bodies. This presentation was felt to be consistent with a suture granuloma reaction. A bacterial culture was obtained, revealing no growth and a two-week course of cephalexin 500 mg po tid was initiated to cover for a possible low-grade cellulitis. Intralesional triamci-nolone injections were performed on the nodules with minimal improvement.

Persistent erythema and nodules at the wound site were seen 1 month later. The concern at that time was still a possible foreign body versus an infectious process, therefore tissue biopsies were obtained for bacterial and fungal culture and histopa-thology. Cultures were positive for acid-fast bacilli (AFB) and the patient was started on minocycline 100 mg po bid for biopsy proven infectious granuloma (Figures 2 and 3). It was postulated that the patient had developed Mycobacterium marinum although patient denied exposure to fish tanks or marine water. On follow-up exam after 2 weeks of minocycline, there was no significant improvement so the area was re-biopsied for histology and culture. Again histopathology revealed non-caseating granulomatous inflammation but this time negative fungal and acid fast bacilli stains.

The patient had been on minocycline for 6 weeks with no response. Patient was switched to trimethoprim/sulfamethoxazole and biopsies were repeated for histology and culture, again revealing granuloma formation with positive AFB on culture. The cultures were sent to the Good Samaritan Regional Medical Center Laboratory (Pottsville, PA) for identification.

DNA probes came back negative for M. avium complex and M. tuberculosis, but came back positive for M. chelonae.

Lela Lankerani, D.O.,* J. Greg Brady, D.O.,** Stephen Purcell, D.O.****Second-year Dermatology Resident, Department of Dermatology, Frankford Hospitals/ PCOM, Philadelphia, PA**Attending, Department of Dermatology, Frankford Hospitals/PCOM, Philadelphia, PA***Program director, Dermatology Residency, Department of Dermatology, Frankford Hospitals/PCOM, Philadelphia, PA

MYCOBACTERIUM CHELONAE INFECTION FOLLOWING A FULL THICKNESS SKIN GRAFT: A CASE REPORT AND REVIEW OF LITERATURE

ABSTRACT

Mycobacterium chelonae (M. chelonae) is a rare but recognized cause of localized cutaneous infections following trauma and medical procedures. Because of their diverse manifestations and resistance to various therapies, infections with mycobacteria are often misdiagnosed, leading to delay in and sometimes failure of therapy. We describe an immunocompetent patient who developed a localized infection due to M. chelonae following surgery for squamous cell carcinoma of the right dorsal hand. The clinical efficacy of clarithromycin and the features of M. chelonae infection are discussed.

Figure 1 The violaceous nodules seen here were 0.4 to 0.8 cm in diameter and located at the silk suture sites at the perimeter of the graft

Figure 2 H&E stain (20X), punch biopsy specimen from the right dorsal hand showing non-caseating granuloma formation

Figure 3 Ziehl-Neelson stain (40X) demonstrating acid-fast bacilli

The patient was placed on clarithromycin 500 mg po bid for 6 months by the infec-tious disease department at Lehigh Valley Hospital (Allentown, PA). After 6 months of therapy, there had been complete flat-tening of the nodules and repeat bacte-rial culture was negative. The patient was without evidence of recrudescence at follow-up 3 months later.

Our patient was immunocompetent and developed disease localized to his surgical wound. A definitive source for this patient’s infection was not identified although his domestic water supply may have been a possible source. No other patients under-going surgery in our surgery unit have ever developed M. chelonae infection leading us to believe that contamination of the wound did not occur from our surgical instru-ments or water supply.

DiscussionMycobacteria are nonmotile, slender,

weakly gram positive acid fast bacilli. The genus Mycobacterium, can be further divided into obligate or facultative human pathogens. The facultative pathogens, which are the nontuberculous mycobac-teria, are further classified as slow or fast growers based on Runyons Classification system. Runyon classifies the nontuber-culous organisms based on pigmentation produced under light and dark conditions and their rate of growth (Table 1). The rapidly growing mycobacteria (RGM), Runyon IV organisms, do not produce pigment and most commonly grow to visible colony size on Lowenstein-Jensen media within 7 days at 25 to 40 degrees Celsius. M. chelonae can be differenti-ated from Mycobacterium fortuitum and Mycobacterium abscessus by specific growth media requirements such as iron, nitrate and polymixin B. In the past several years, molecular methods including Polymerase Chain Reaction (PCR) anal-

ysis and 16s ribosomal DNA sequencing have been developed for identification of mycobacteria.3,4

In immunocompetent patients, primary cutaneous infections are usually local-ized and seen following minor surgical procedures, accidental insult to the skin, or exposure to contaminated liquids or equipment. RGM infections can be seen following dermatologic surgery including excisions, MOHS micrographic surgery, laser resurfacing, and soft tissue augmen-tation; following plastic surgery proce-dures including liposuction, liposculpture, face lifts, blepharoplasty, and augmen-tation mammoplasty; and other insults including trauma, tattooing, contraceptive implants, acupuncture, and pedicures.5 In immunocompromised patients, infection tends to be disseminated and can cause pulmonary disease, osteomyelitis, endo-carditis and lymphadenitis.1

M. Chelonae is a rapid grower that was first isolated from a sea turtle in 1903 and originally speciated in 1923. M. Chelonae is an environmental saprophyte, seen in soil, dust and animals. Infection is acquired from the environment through inoculation and not transmitted person-to-person. It is also found in domestic water supplies and surgical materials, although the source is often not identified. It is resis-tant to many disinfectants including 10% povidone-iodine, 2% formaldehyde, 2% alkaline gluteraldehyde and 0.3 and 0.7 μg/ml chlorine.5,6

The cutaneous presentation is often delayed with clinical manifestations gener-ally evident within 4-6 weeks. Incubation periods range from 1 week to 2 years. The most common presentation is multiple erythematous subcutaneous nodules occur-ring on the distal limbs however cutaneous manifestations can vary from nodules, papulopustules, abscesses, local inflam-mation, cellulitus, to sinuses and ulcers with extensive subcutaneous necrosis and

purulent or serosanguineous drainage. It follows a chronic indolent course and often heals with scarring.7

On biopsy, histopathology may demon-strate suppurative and granulomatous inflammation. Necrosis is commonly present but caseation is minimal. The lesions display micro-abscesses with foreign-body giant cells. Acid-fast bacilli are infrequently seen but when seen tend to appear as extracellular clumps within microabscesses. AFB are usually best visu-alized in areas of suppuration and are often absent in sections without acute inflam-mation. As AFB stains are often negative on pathology, the gold standard for diag-nosis is tissue culture. The histopathologic pattern of atypical mycobacterial infections may simulate foreign body reactions, deep mycoses, or neutrophilic dermatoses.3,5,6

Although incision and drainage, debridement, and surgical removal of infected nodules may be beneficial, the mainstay of therapy is oral antibiotics. Nontuberculous mycobacteria are resis-tant to all antituberculosis drugs and a multi-drug approach with antibacterials must be taken to avoid the development of resistance. The optimal duration of therapy is unknown and duration of treat-ment is guided by clinical response. It has been suggested that therapy for minimal localized disease should be 2-4 months and extensive disease should be treated for at least 6 months. A good margin of safety is to continue antibiotics for 4 to 6 weeks after complete wound healing.5

M. Chelonae has had the most drug resistance in the past making it difficult to treat. Only 10-20% of infections resolve without treatment, and this resolution may take many months. Some success with doxycycline, minocycline, erythromycin, ciprofloxacin, amikacin, sulfonamides, imipenem and linezolid has been described but high rates of resistance and relapse have also been described.6

Clarithromycin, a macrolide, which became available in 1993, and has become the mainstay of oral therapy for these species. It is usually given at the dose of 500 mg orally twice a day and is often used because of low drug resis-tance. Clarithromycin has low minimal inhibitory concentrations (MIC) versus M. chelonae, good oral absorption, excel-lent tissue concentrations, a long half-life (4.7 hours), and low toxicity. It works by binding to the 50s ribosomal subunit of the organism, inhibiting its protein synthesis. Clarithromycin has been well tolerated by patients infected with M. chelonae. The most common side effects have been gastrointestinal upset including nausea and diarrhea, as well as metallic taste.6 A few cases of acquired clarithromycin resistance with monotherapy have been described.6,8,9 To avoid the emergence of resistance, at least one additional antimicrobial agent is

LANKERANI, BRADY, PURCELL 55

recommended as well. This second agent should be selected on the basis of suscepti-bility testing.

The patient should be reevaluated every 2-3 weeks to determine the adequacy of therapy and follow up cultures may be indicated to confirm resolution of infec-tion. Removal of foreign bodies is essential and extensive disease, abscess formation or difficulties with drug therapy necessitate surgical intervention.

In summary, we present a case of M. chelonae infection occurring in a surgical scar resembling a suture granuloma. With the persistence of erythematous nodules, we became suspicious for a chronic infectious process caused by a less common entity.

The diagnosis of RGM cutaneous infec-tions may be difficult and relies on the combination of a strong clinical index of suspicion, detailed history, and histopatho-logic findings. Patients who present after procedures with nodules, chronic indura-tion, erythema, ulceration, and/or abscess formation that do not respond to the usual treatments warrant biopsy and culture for atypical mycobacteria.

References1. Garmen M, and Orengo I. Unusual infectious complica-

tions of dermatologic procedures. Dermatol Clin 2003; 21:321-335.

2. Kullavanijaya, P. Atypical mycobacterial cutaneous infec-tion. Clin Dermatol 1999; 17:153-158.

3. Jogi R, and Tyring R. Therapy of nontuberculous myco-bacterial infections. Dermatol Ther 2004; 17:491-498.

4. Uslan D, Kowalski T et al. Skin and soft tissue infections due to rapidly growing mycobacteria. Arch Derm 2006; 142:1287-1292.

5. Hutcheson A, and Lang P. Atypical mycobacterial infec-tions following cutaneous surgery. Dermatol Surg 2007; 33:109-113.

6. Saluja A, Peters N, Lowe L and Johnson T. A surgical wound infection due to Mycobacterium chelonae suc-cessfully treated with clarithromycin. Dermatol Surg 1997; 23: 539-543.

7. Bolognia J, Jorizzo J, and Rapini R. Mycobacterial Infec-tions. Dermatology London Mosby; 2003. p. 1161-1162

8. Tebas P, Sultan F et al. Rapid development of resistance to clarithromycin following monotherapy for disseminated Mycobacterium chelonae infection in a heart transplant patient. Clin Infect Dis 1995; 20:443-444.

9. Nori S, Greene M et al. Infectious occupational expo-sures in dermatology-A review of risks and prevention measures: I. For all dermatologists. JAAD 2005; 53: 1010-1019.

56 MYCOBACTERIUM CHELONAE INFECTION FOLLOWING A FULL THICKNESS SKIN GRAFT

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58 CUTANEOUS MANIFESTATION OF METASTATIC PROSTATE CANCER

IntroductionProstate cancer is the second most

common cancer found in American men, next to non-melanoma skin cancer. It is the second leading cause of death among American men, with lung cancer being first. It is estimated that one in six men will be diagnosed with prostate cancer at some point in their lifetime. The overwhelming majority of prostate cancers develop from the gland cells, making almost all pros-tate cancers of the adenocarcinoma type. Approximately nine of 10 prostate cancers are classified as local or regional disease, which means the cancer is confined to the prostate gland or has local extension to surrounding tissues. Therefore, metastatic prostate cancer is an exceedingly rare disease, and we will discuss a case of pros-tate cancer with cutaneous extension.1

Case Study

HistoryAn 83-year-old, frail Caucasian male

presented to the clinic with a chief complaint of pain, swelling and bruising of his middle to lower abdomen for approxi-mately seven weeks. He stated the condi-tion had been getting worse as far as the bruising was concerned, but his abdominal pain had remained constant. During this seven-week period, he began to develop two raised, cribriform, skin-colored to slightly ecchymotic plaques on his lower abdomen with overall edematous appear-ance. These plaques were asymptomatic and had grown slightly in size over the last month. This patient had an exten-sive pertinent past medical history, which included high blood pressure, benign prostatic hyperplasia, laryngeal cancer with laryngectomy, and multiple non-melanoma skin cancers. More recently, he was also diagnosed with prostate cancer.

He was currently following up with hematology/oncology for his newly diag-nosed prostate cancer, but he had not

received any therapy for prostate cancer or his abdominal complaints prior to his visit to our office.

Complete review of symptoms was posi-tive for malaise, minor arthralgias and myalgias, abdominal pain, recent unex-plained weight loss and dysuria.

Differential DiagnosisThe differential diagnosis included

lymphedema secondary to obstruction from metastatic prostate cancer, inferior vena cava (IVC) syndrome, trauma-induced ecchymosis, squamous-cell carcinoma and metastatic prostate cancer to skin.

Assessment The patient was originally diagnosed

with IVC syndrome with massivelymphedema of his abdomen, and he was

sent to radiology for appropriate imaging studies, which included abdominal X-rays and CAT scan of his abdomen and pelvis. These initial studies were negative for any obstructive process, and the patient was notified and instructed to return to the office for further work-up.

Upon return, the patient’s clinical condi-tion remained stable, and at this time it was decided to perform two 5mm punch biopsies on the abdominal plaques with the suspicion of cutaneous extension of prostate cancer. During the interim, the patient was instructed to follow up with his oncologist with the presumptive diag-noses. The pathology report was deter-mined to be metastatic adenocarcinoma secondary to prostate cancer extension. The prostate origin of the adenocarcinoma was confirmed by immunohistochemical staining for prostate-specific antigen.2

DiscussionThe prostate is a walnut-sized gland

located in front of the rectum and under-neath the urinary bladder. Its function is to produce seminal fluid, which helps protect and nourish sperm cells. The cells that make up the prostate gland are secretory

cells, basal cells, scattered neuroendocrine cells, urothelium, and ejaculatory duct/seminal vesicle cells. Over 99% of prostate cancer is of the adenocarcinoma variety.3

EpidemiologyThere are over 300,000 cases per year

of prostate cancer in the United States (second to skin cancer in occurrence rates). It accounts for approximately 41,000 deaths per year (second to lung cancer). Twenty percent of American men are diagnosed with prostate cancer during their lifetimes, and 3% will die of their disease. Clinical disease and high-grade prostatic intraepi-thelial neoplasia (PIN) is more common in blacks than in whites, with higher stage at presentation, although stage-adjusted survival is similar in both groups.4 Clinical disease is rare in Asians.

Prostate cancer is not associated with sexually transmitted disease, smoking, occupational exposure, or diet. Prostate-cancer patients overall face a 27% prob-ability of developing metastatic disease within seven years of initial diagnosis.5 Generally, the usual sites for extension include lymph nodes, bone, lungs, liver and brain. It should be noted that these are the most common sites for solid tumor exten-sion, but it can affect any part of the body.

TreatmentAlthough early detection of prostate

cancer provides very good outcomes, as with most cancers, late disease with distant metastases usually carries a poor prognosis. Of the various treatment options available, most are palliative for such late disease. Because of our patient’s advanced age, multiple medical problems and his own desires, it was decided that the only course of action was to make him as comfortable as possible.

ConclusionAs a physician, not just a dermatologist,

it is unfortunate to diagnose any patient

Joseph S. Machuzak, DO,* Megan G. Machuzak, DO**, Stephen E. Kessler, DO****2nd-year Resident, WUHS - Phoenix Area Dermatology, Phoenix, AZ**Attending Physician, Midwestern University/Phoenix, Department of Dermatology***Program Director, WUHS - Phoenix Area Dermatology, Phoenix, AZ

CUTANEOUS MANIFESTATION OF METASTATIC PROSTATE CANCER

ABSTRACT

Prostate cancer is an extremely common cancer affecting many American men. In 2001, approximately 198,100 new cases of prostate cancer were diagnosed in the United States, and 31,500 men died from the disease. Although exceedingly rare, metastatic prostate cancer with cutaneous extension can occur, and we present a case where one individual was afflicted with such a disease.

with metastatic cancer, as the outcomes are usually very grave. I do believe that we can help individuals to understand the nature of their condition, as well as show compas-sion and help them live the rest of their lives as comfortably as possible.

References:1. Wu J, Huang D, Pang K, Tyring S. International Journal

of Dermatology, Volume 45, Number 8, August 2006. pp. 946-948(3).

2. Bahram S, April D. Umbilical metastasis from prostate carcinoma (Sister Mary Joseph’s nodule): A case report and review of literature. Journal of Cutaneous Pathology. 2007;34(7): 581–583.

3. Epstein JI. The Lower Urinary Tract and Male Genital System, Pathologic Basis of Disease, Volume 7. London: Elsevier-Saunders; 2004.

4. Haas GP, Sakr WA. Epidemiology of prostate cancer. CA Cancer J Clin. 1997 Sep-Oct;47(5):273-87.

5. Whittemore AS, Wu AH. Am J Epidemiol. 1995 Apr 15;141(8):732-40.

MACHUZAK , MACHUZAK, KESSLER 59

60 BIOSCREEN: AN INNOVATIVE APPROACH TO A COMMON DISEASE

IntroductionAcne is ubiquitous and nondiscrimina-

tory, affecting nearly all ages and races. Furthermore, it is by no means a harm-less condition. It has the potential to leave permanent scars on the skin of those affected and is associated with increased psychological morbidity. The exact preva-lence of acne is difficult to discern because statistical accuracy is compromised by a lack of criteria uniformity in describing the disease.1 Recent studies have estimated that 45 million people in the United States from the age of 12 to 44 have acne. Almost 90% of this number is composed of individuals aged 12 to 24.2 Studies which have employed the Leeds Acne Grading scale estimate that greater than 90% of males and 80% of females will be affected by acne by 21 years of age.1 The majority of adult acne is persis-tent from earlier years, but may present as late-onset acne.3 Also, up to 85% of women over the age of 25 report premenstrual increases in their acne severity.2 Interestingly, it has been shown that less than one third of those with acne will actually pursue profes-sional medical treatment.1

The key to the successful treatment of acne is a keen understanding of the patho-genesis that leads to clinically apparent lesions. Acne is a multifactorial disease of the pilosebaceous unit. This unit includes a hair follicle, hair shaft and sebaceous gland. Acne can be categorized as non-inflammatory lesions including opened/closed comedones or inflammatory lesions which include pustules, papules and cysts. There are four factors that have been identi-fied as essential to the development of acne lesions in the pilosebaceous unit. These include follicular epidermal hyperprolifera-tion, excess sebum production, presence and activity of Propionibacterium acnes and inflammation.4 Follicular epithelial hyper-

proliferation and alteration of keratinocyte desquamation is considered the first step in the pathogenesis of acne. This results in an accumulation of keratinocytes and an eventual follicular plugging. The stimulus of this hyperproliferation has not been clearly established, but interleukins, changes in linoleic acid concentrations and androgens have all been implicated in this process.5

The onset of acne typically occurs during adrenarche at an average of eight years of age. During this time the body experiences a substantial increase in the production of androgenic hormones. Androgens in the circulation are taken up locally into the cells of the pilosebaceous unit where they are metabolized. This metabolism stimulates sebum production locally and also results in increases in the number of sebaceous lobules and the size of the follicle. This process creates the environment for a micro-comedo.4 Sebum has both comedogenic and irritant qualities.6 Higher sebum secretion rates are associated with higher levels of P. acnes densities and a more severe clinical picture of acne.7 The clinically evident lesions of acne develop when the piloseba-ceous unit filled with sebum and keratin becomes inhabited by P. acnes. P. acnes is a gram positive, anaerobic commensal skin organism that is found in high numbers in sebaceous regions and is the most prevalent organism found in acne lesions.4 P. acnes creates by-products that are proinflamma-tory and act as chemotactic factors. These by-products include lipases, proteases, and hyaluronic acid. They work by surrounding the pilosebaceous unit, diffusing through the follicular wall and producing enzymes that are destructive to the natural follicle barrier.6 Various studies have shown that the severity of acne is related to the interactions between bacteria and the body’s immune response. It creates this immune response by recruiting CD4 lymphocytes and neutrophils. These

neutrophils subsequently penetrate and weaken the wall of the follicle. The altered barrier eventually ruptures and allows more lipids, keratinocytes and bacteria to be released into the dermis.4 All of this results in an inflammatory foreign body reaction which clinically presents itself as acne.

Using the current understanding of acne pathogenesis, many different treatment modalities have been employed. The most common of which include antibiotics, retinoids and hormonal therapy. Topical antibiotics are both antimicrobial and weakly comedolytic. Systemic antibiotics decrease the inflammation and microor-ganisms that cause acne. While systemic antibiotics have proved to be important to acne treatment, long term antibiotic use has been documented to cause resistance in both the common microorganisms that contribute to acne and additional poten-tially harmful species. Specifically, concern over resistant species of Streptococcus pyogenes and Staphylococcus aureus makes using these antibiotics less ideal.5

The treatment of acne has evolved in the last twenty-five years with the introduc-tion of both topical and systemic retinoids. Although systemic retinoids target all four of the factors described above, they are well known for their long list of side effects including teratogenicity.5 In addition, various hormonal modalities including oral contraceptives have been employed in the treatment of acne.4 They work by decreasing circulating free testosterone.5 Spironolactone, which has anti-androgen effects, has also been effective in the treat-ment of acne. Spironolactone binds the androgen receptor which causes a reduc-tion in androgen production.6 Both oral contraceptives and spironolactone may have stigmas that could prevent some patients from employing them in acne treatment.

Ryan M. Carlson, D.O.,* Michelle Bruner, D.O.,** Steven K. Grekin, D.O., FAOCD**** Chief Dermatology Resident, Oakwood Southshore Medical Center, Trenton, Michigan** Traditional Rotating Internship, Oakwood Southshore Medical Center, Trenton, Michigan*** Department of Dermatology, Program Director, Oakwood Southshore Medical Center, Trenton, Michigan

BIOSCREEN: AN INNOVATIVE APPROACH TO A COMMON DISEASE

ABSTRACT

Background: Acne is extremely common and popular therapeutic modalities often produce unsatisfactory results, encouraging new approaches to treatment.

Objectives: To evaluate the clinical efficacy of a novel product for the treatment of inflammatory acne vulgaris.Methods: A study was performed with Bioscreen on 10 patients over the course of three months. Patients were evaluated

weekly for the first month then biweekly for the remaining two months. Subjects were treated by both topical and oral routes, with adjustments in the dosing regimen based on clinical results.

Results: There were 10 patients in the study, all of which completed the study and demonstrated at least a mild-moderate reduction in inflammatory acne lesions. There were no side effects reported, and all patients continue to use Bioscreen to date.

Conclusions: Bioscreen is safe, well-tolerated, and effective for treatment of inflammatory acne. Further studies with more patients will be necessary to substantiate the current findings.

The impetus for this clinical study arose from the problems with current popular treatments, creating a desire for new and potentially better tolerated treat-ment modalities. We introduce the agent Bioscreen to the world of acne treatment regimens. Bioscreen is an all natural anti-microbial and anti-inflammatory treat-ment that applies an innovative theory to acne eradication.

MethodsClinical trials were performed with

Bioscreen on 10 patients over the course of three months. All patients showed at least mild-moderate improvement, with no observed side effects or concerns

from the study group. Each patient was treated by both topical and oral routes, with adjustments in the dosing regimen based on clinical results. We now describe two case reports, emphasizing the safety, efficacy, and tolerability of this new and exciting product.

CASE 1:A 21-year old Caucasian female

presented with a 4-5 year history of acne. She had been an established patient of ours for over 2 years. Numerous acne regimens had been implemented, including topical benzoyl peroxide/clindamycin products, oral antibiotics, anti-bacterial cleansers, and chemical peels. She had noticed flares around her menstrual period, and was

even counseled on potential Aldactone use. Similar to many acne patients, she has had periods of clearing, only followed up with bouts of flaring. She was placed on Bioscreen, with one pill by mouth daily and application of the topical product three times a day. The patient was given informed consent regarding this product, including education on the mechanism of action and expectations. A baseline picture was taken at this time (see Figure 1). Physical exami-nation at baseline revealed many erythema-tous papules and pustules, with some cyst formation on her forehead and periorally. Scattered open and closed comedones were also present on exam. The patient was seen for follow-up weekly for the first month then biweekly for the next 2 months, with pictures taken at each visit (see Figures 2, 3). Even as early as one week (Figure 2) there was a dramatic decrease in both the number and size of inflammatory lesions. She continued to have improvement and clearing over time, mostly in regard to acne that was inflammatory in nature. At the end of the study (see Figure 3), she had minimal inflammatory lesions and only areas of post-inflammatory hyperpigmen-tation. Throughout the study, comedonal activity was decreased, although slight. She was very satisfied with the results and did not relate any side effects or complaints with use of the product. This patient continues to use Bioscreen both topically and orally as maintenance therapy to date.

CASE 2:A 17 year-old Caucasian male presented

with a one year history of acne. He had only tried OTC antibacterial washes and topical products without much benefit. The study parameters were discussed in detail with the patient, informed consent was provided, and he was started on Bioscreen. He was instructed to apply the topical solution three times daily and take the oral pill once a day. A baseline photo-graph was taken (see Figure 4). Physical examination showed multiple erythema-tous papules, pustules, and cysts with many open and closed comedones involving the cheeks, forehead, nose, chin and jawline. He was seen weekly for the first month and biweekly thereafter, and pictures were taken at each visit (see Figures 5, 6). There was marked improvement in the inflam-matory component of his acne, even after the first week (see Figure 5). Comedonal lesions were diminished in number, but not significantly. He continued to have marked reduction in inflammatory lesion count throughout the remainder of the study, particularly evident at the 2 month period (see Figure 6). There were no adverse effects reported. He too continues to use the product and is pleased with the success he is making.

Figure 1: At baseline, scattered across the face are erythematous papules and pustules with cysts periorally. Open and closed comedones are also noted clinically.

CARLSON, BRUNER, GREKIN 61

Figure 2: As early as one week there was a marked reduction in cystic activity and improvement in the papu-lopustular component.

Figure 3: At 3 months, there is continued improvement with near clearing of erythematous papules, pustules, and cysts.

Figure 4: At baseline, there are numerous erythematous papules and pustules with scattered comedones.

Figure 5: One week into treatment there is a remarkable reduction in overall erythematous lesion count.

Figure 6: Continued improvement at the 3-month period.

DiscussionThe science behind Bioscreen requires

a different vocabulary from that which is commonly used when referring to antibi-otics and microorganisms. Typical antimi-crobial theory uses a language of proteins, enzymes, and DNA. However, Bioscreen operates at an electronic level and employs a language of protons, electrons, and water mediums. It works through a mechanism of bio-electric activities. Different microorganisms can be defined by their electronic and magnetic param-eters. These parameters include protons, electrons, magnetic fields, coefficient of electrical resistance and the move-ment of microorganisms in association with all of these variables. The success of Bioscreen is a result of its ability to interfere with these specific parameters, thus disrupting the electronic charge of the water environment of microorgan-isms. In part the Bioscreen strategy is based on the assumption that there is an intrinsic neutral property to water at the molecular level in the absence of microor-ganisms. Microorganisms alter this envi-ronment in a species and patient-specific manner, which increases the positive or negative charge of the water medium. In vivo studies have demonstrated that the antigenic ability of P. acnes is in part determined by its microenvironment.8 Bioscreen works through a mechanism of adjusting the water in the microenviron-ment to the opposite of that in which the organism flourishes, leaving the organism vulnerable.

Operating at a parallel level is the science employed in studying antimicro-bials in the food industry. Technologies for inactivating microorganisms which colo-nize food consumed by the public use a process called pulsed electric fields (PEF).9 In this technology, which is currently being used to eradicate harmful organ-isms from consumer food products, the exact mechanism of antimicrobial inac-tivation is only minimally understood.10 The efficacy of PEF lies in the belief that when microorganisms are placed under substantial stresses, the energy the organism expends to overcome the hostile environment can lead to metabolic exhaustion and ultimately death. PEF consists of passing a short, high-voltage pulsed electric field through a liquid food which is held between two electrodes. PEF is hypothesized to cause irreversible elec-troporation of the cell membrane, causing intracellular components to leak from the cell. The outcome of the damage to the vital components of the cell is cell lysis and death.10 Although the antimicrobial mechanism differs from Bioscreen, the same theory of environmental manipula-tion is employed.

ConclusionBioscreen is an appealing product

on many levels. An understanding of the pathogenesis of acne, and the road blocks to effective treatment makes the use of Bioscreen a welcome innovation. The product is 100% natural, composed completely of non-toxic herbs and minerals, and has been determined “Generally Regarded as Safe” by the FDA. The ingre-dients in decreasing order of concentra-tion include water, citrus paradise, eugenia, carophyllata, organum heracleoticum and carumcarvi, with the exact percentages being proprietary information. Bioscreen has no known side effects. Its mechanism of destruction has exhibited the ability to spare innate bacteria that normally live in the human body, such as Lactobacilli. The product is 100% biodegradable and comes in a powder or liquid, and can be applied in various vehicles depending on the desired therapy. This versatility is ideal for derma-tological applications. Our current clinical trials have shown positive outcomes, with a significant reduction in inflammatory acne. We believe that using this product in conjunction with a comedolytic agent will provide the best results for those patients with mixed inflammatory and comedo-genic acne. Results to this date have been extremely promising and further study data will no doubt enhance the desirability of this treatment modality.

References:1. Smithard A, Glazebrook C, Williams H. Acne Prevalence,

Knowledge About Acne and Psychological Morbidity in Mid-Adolescence: A Community-Based Study. Br J Der-matol. 2001;145:274-279.

2. White G. Recent Findings in the Epidemiologic Evidence, Classification, and Subtypes of Acne Vulgaris. J Am Acad Dermatol. 1998;39:S34-S37.

3. Goulden V, Stables G, Cunliffe W. Prevalence of Facial Acne in Adults. J Am Acad Dermatol. 1999;41:577-580.

4. Zaenglein A, Thiboutot D. Expert Committee Rec-ommendations for Acne Management. Pediatrics 2006;118:1188-1199.

5. Harper J. An Update on the Pathogenesis and Man-agement of Acne Vulgaris. J Am Acad Dermatol. 2004;51:36-38.

6. Habif, Thomas. Clinical Dermatology Fourth Edition. Philadelphia: Mosby, 2004.

7. Mourelatos K, Eady E, Cunliffe W, et al. Temporal Changes in Sebum Excretion and Propionibacterial Colo-nization in Preadolescent Children With and Without Acne. Br J Dermatol. 2006:1-10.

8. Jappe U, Ingham E, Henwood J, et al. Propionibacterium Acnes and Inflammation in Acne; P. acnes has T-Cell Mitogenic Activity. Br J Dermatol. 2002;146:202-209.

9. Calderon-Miranda M, Barbosa-Canovas G, Swanson B. Inactivation of Listeria innocua in Liquid Whole Ege by Pulsed Electric Fields in Nisin. Int J Food Microbiol. 1999;51:7-17.

10. Ross A, Griffiths M, Mittal G, et al. Combining Nonthermal Technologies to Control Foodborne Microorganisms. Int J Food Microbiol. 2003;89:125-138.

Dr. Steven K. Grekin is a clinical investigator for HBA Products (Novi, MI)

62 BIOSCREEN: AN INNOVATIVE APPROACH TO A COMMON DISEASE

PETERSON, ANDERSON 63

BackgroundIn 1971, Wells described four patients

who presented with clinically similar cutaneous lesions. Biopsy of these lesions revealed a shared histopathology of dermal eosinophilia, phagocytic histiocytes, and the presence of “flame figures.” This original report initiated the term: Well’s syndrome.1 Later, in 1979, Wells and Smith introduced the term “eosinophilic cellulitis” based on similar findings of an additional 8 patients.2 Presently, Wells’ syndrome and eosinophilic cellulites are used interchangeably.

Over the last 25 years, several case reports have surfaced, which have validated Wells’ original description. Despite these reports, the pathogenesis of Wells syndrome is elusive. Our current concept of Wells’ syndrome is founded upon clinical and pathological correlation with a growing understanding of the biology of eosinophils.

According to some authors, Wells’ syndrome can be divided into primary and secondary categories. Primary Wells’ syndrome is defined as a “polymorphous, chronic, recurrent disease with eosinophil infiltration and granulomatous inflam-mation together with blood and bone marrow eosinophilia.3 Secondary Wells’ syndrome shares similar histopathologic features to primary Wells’ syndrome. It has been linked to numerous etiologies and is considered a reactionary pattern character-ized by massive eosinophil infiltration.3 In this article, Wells’ syndrome will designate both primary and secondary designations, unless otherwise defined.

Clinically, Wells’ syndrome paint a varied picture. An early inflammatory phase can present as localized erythema and edema of the skin. Later, a granulomatous phase will show well demarcated erythematous nodules and plaques with significant indu-ration. Fever, malaise, arthritis, pruritis, vesicles or erosions can be present, but are not distinguishing features. Typically, lesions last 2-8 weeks, can be recurrent and resolve without scarring. White blood cell

count is usually normal, but up to 50% of patients can have peripheral eosinophilia. Wells syndrome should only be diagnosed in the absence of systemic symptoms.

Histologically, Wells’ syndrome can be divided into 3 stages. In the acute stage, marked dermal edema is noted with the striking widespread infiltration of the upper and deep dermis with eosinophils. Later, as eosinophils degranulate, major basic protein and nuclear fragments are deposited on collagen bundles leading to the development of flame figures. Flame figures are then surrounded by histiocytes. Finally, longstanding lesions exhibit phago-cytic histiocytes and giant cells around the flame figures.1,2,4

Case ReportA 68 year old Caucasian female with

rheumatoid arthritis was seen with a 3 week history of expanding erythematous nodules and plaques. Numerous 5-10 mm non painful nodules were noted in both axilla, while multiple 4-6 mm indurated erythematous plaques were located on both of thighs medially, and posteriorally. The lesions had no scale, did not blanch, and were essentially asymptomatic. She had no prior history of similar outbreaks, reported no fever, malaise, and had not tried any specific treatments. She had been on infliximab and methotrexate for greater than 1 year for treatment of rheu-matoid arthritis.

A skin biopsy specimen was revealed a dense reticular cellular infiltrate composed large histiocytes and numerous eosino-phils with degenerated collagen bundles. The eosinophils and histiocytes focally surround degenerated collagen, forming flame figures. Diagnosis was consistent with Wells’ syndrome.

Laboratory evaluation revealed hemo-globin of 15, hematocrit of 41.9, white blood cell count of 9.10, 79% nuetrophils, 1.1% eosinophils, all within normal limits. Bone marrow biopsy showed no immu-nohphenotypic abnormality.

Chad R. Peterson D.O.,* Don A. Anderson D.O. F.A.O.C.D., F.A.S.M.S. **

WELLS’ SYNDROME:EOSINOPHILIC CELLULITIS SECONDARY TO INFLIXIMAB INFUSION THERAPY

ABSTRACT

Wells’ syndrome, also known as eosinophilic cellulitis, encompasses an inflammatory dermatoses with histologic findings of edema, eosinophilic infiltrate, eosinophilic degranulation leading to degenerated collagen and flame figures, and varied accompanying histiocytic infiltrate. The clinical and histological encounter prompts a thorough review of infectious associations, systemic causes, and drug reactions which have been reported to cause eosinophilic cellulitis. We present a case of Wells’ syndrome associated with infliximab therapy and review the literature for other known associations.

Fig 1 Indurated, elevated erythematous plaque of 3 weeks duration on the left posterior medial thigh. Additional plaques and nodules are noted near the largest plaque on the left thigh and on the opposite right thigh.

Fig 2 Close up view of indurated, elevated erythematous plaques consistent with Wells’ syndrome

Fig 3 Indurated, elevated erythematous plaques and nodules of 3 weeks duration on the right and left inner thighs.

64 WELLS’ SYNDROME: EOSINOPHILIC CELLULITIS SECONDARY TO INFLIXIMAB INFUSION THERAPY

Fig 4 A moderately dense cellular infiltrate centered in the deep reticular dermis

Fig 5 A moderately dense cellular infiltrate centered in the deep reticular dermis comprised of a mixture of large cells and several eosinophils.

Fig 6 A moderately dense cellular infiltrate centered in the deep reticular dermis comprised of a mixture of large cells and several eosinophils. The eosinophils and larger cells focally surround brightly eosinophilic and basophilic degenerated collagen bundles (so called flame figures)

Fig 7 A moderately dense cellular infiltrate centered in the deep reticular dermis comprised of a mixture of large cells and several eosinophils. The eosinophils and larger cells focally surround brightly eosinophilic and basophilic degenerated collagen bundles (so called flame figures)

Fig 8 Histiocytic infiltrate with numerous admixed eosinophils and degenerated collagen bundles. The histologic findings are most suggestive of Well’s syndrome like hypersensitivity reaction.

Fig 9 Early lesions of Well’s syndrome are typically ssociated with intense tissue eosinophilia. Older lesions often have an associated histiocytic component, as is seen with this case.

Fig 10 Eosinophils and histiocytes surrounding collagen bundles.

Fig 11 Admixture of eosinophils and histiocytes.

Fig 12 Admixture of eosinophils and histiocytes.

Therapeutically, local intralesional injections with traimcinolone 8 mg/ml (Kenalog) were administered which were of no benefit. Topical corticosteroid treat-mtents were not initiated and the patient refused oral prednisone therapy.

8 weeks after her initial presentation, subtle new papules and nodules continued to appear in her axilla and thighs bilater-ally. Suspecting a drug reaction, consul-tation was obtained with the patient’s rheumatologist. The decision was made to discontinue infliximab used for rheu-matoid arthritis and switch the patient to abatacept (Orencia).

8 weeks later, having stopped inflximab infusion therapy, there was a marked improvement clinically. The smaller nodules had regressed, and the larger plaques exhibited less induration, erythema and had decreases in size and volume. No new lesions were noted.

A follow up 3 months later demonstrated complete resolutions of all lesions. No recurrence has occurred to date.

DiscussionRecently, Wells’ syndrome has been

linked to adalimumab (Humira) and etanercept (Enbrel).19,20 Therefore, with the above noted case presentation, Wells syndrome is a possibility with all three of the TNF alpha inhibitor used in derma-tology, namely: adalimumab, etanercept, and now infliximab.

As previously mentioned, secondary Wells’ syndrome represents a reactionary pattern with significant eosinophil infil-tration and degranulation. In addition to drug reactions7, 19, 20 other reported causative agents include: insect bites,5,6 ur ticar ia,8 bacter ia or parasites,9,10 Churg-Strauss syndrome11 idiopathic hypereosinophilc syndrome,12 and solid malignancies.13 Documented viral etiolo-gies include HSV 2,14 parvovirus B19,15 VZV,16 and molluscum contagiosum treated with cryotherapy.17 Wells’ syndrome has also occurred after tetanus-diphtheria immunization.18

Important discoveries with regards to immunology have provided a founda-tion uncovering the etiology of Wells syndrome. Evidence now shows a corre-lation between clinical activity, eosino-philic counts and serum IL-5 levels with respects to eosinophilic cellulitis. French et al report that “because IL-5 is chemot-actic for eosinophils, can increase the adhesion and survival of mature eosino-phils, can stimulate eosinophil function, and can increase eosinophil production, it might be implicated in the pathogensis of eosinophil mediated skin diseases and might be a potential target for therapeutic intervention.”21

Furthermore, in the above noted article, a “monoclonal population of T cells in the

peripheral blood” was shown for the first time to be the cause of the elevated Il-5 levels in a patient with eosinophilic cellu-litis. Elevated levels of IL-5 normalized with interferon alpha.21 Such evidence has led some to suggest comprehensive hema-tologic testing including bone marrow biopsy for a thorough evaluation of Wells syndrome.

Treatment options are as varied as proposed etiologies for Wells syndrome. Systemic steroids are suggested as the most effective regimen, coupled with tapering dosages and Class I topical steroids under occlusion until resolution. Other options include dapsone, antihistamines, minocycline, doxycycline and low dose cyclosporine. Recommendations for treat-ment options are based primarily on case reports without overwhelming evidence. Furthermore, it should be noted that cases of Wells syndrome have resolved upon treatment of the underlying condition such as viral infection, parasitic infection or withdrawl of an offending drug.

SummaryThe reported cases of Wells’ syndrome

share a similar histology and clinical presentation, but vary with respects to etiology. As to date, the pathogenesis is still elusive, therefore clinical history is para-mount to uncovering the inciting event. Viral, bacterial, and arthropod stimuli must be evaluated, with additional attention given to systemic causes. This case report highlights another important precipitating cause of Wells’ syndrome: medications. Infliximab can now be added to etanercept and adalimumab as TNF alpha inhibitor medications which have been linked to Wells’ syndrome.

Bibliography:1. Wells GC. Recurrent granulomatous dermatitis with

eosinophilia. Trans St John’s Hosp Dermatol Soc 1971;57:46-56

2. Wells GC, Smith NP. Eosinophilic cellulites. Br J Derma-tol 1979;100:101-9.

3. Braun-Falco O, Plewig G, Wolff H, Winkelmann R. Inflammations with hypereosinophilia. In: Braun-Falco O, Plewig G, Wolff H, Winkelmann RK, editors. Derma-tology. Berlin: Springer-Verlag; 1991. P.953-4

4. Wood C, Miller C, Jacobs A, Hart R, Nickoloff BJ. Eosinophhilic Infiltration with Flame figures: a distinc-tive tissue reaction seen in Wells’ syndrome and other disease. Am J of Dermatopath. 1986;8:186-93

5. Schorr WF, Tauscheck AL, Dickson KB, Melski MD. Eosinophilic cellulites (Wells’ syndrome): histologic and clinical features in arthropod bite reactions. J Am Acad Dermatol 1984;11:1043-9.

6. Anderson CR, Jankins D, Tron V, Prendiville JS. Wells’ syndrome in childhood: case report and review of the literature. J Am Acad Dermatol 1995;33:857-64.

7. Kaufmann D, Pichler W, Beer JH. Severe episode of high fever with rash, lymphadenopathy, neutropenia and eosinophilia after minocycline therapy for acne. Arch Intern Med 1994;154:1983-4

8. Dijkstra J, Bergfeld WF, Steck WD, Tuthill RJ. Eosino-philic cellulites associated with urticaria: A report of two cases. J Am Acad Dermatol. 1986;14:32-38.

9. Tsuda S, Tanaka K, Miasato M, Nakama T, Sasai Y. Eosinophilic cellulites (Wells’ syndrome) associated with ascariasis. Acta Derm Venereol 1994;74:294

10. Van den Hooganband HM. Eosinophilic cellulites as a result of onchocerciasis. Clin Exp Dermatol. 1983:8:405-408.

11. Seung CL, Sham SS, Jee BL, Young HW. Wells’ syn-drome associated with Churg-Strauss syndrome. J Am Acad Dermatol. 2000;43:556-557.

12. Bogenrieder T, et al. Wells’ syndrome associated with idiopathic hypereosinophilic syndrome. Br J Dermatol. 1997;137:978-82.

13. Farrar CW, Guerin DM, Wilson NJE. Eosinophilic cel-lulites associated with squemous cell carcinoma of the bronchus. Br J Dermatol. 2001;145:678-679.

14. Ludwig, RJ et al. Herpes simples virus type 2 associated eosinophilic cellulites (Wells’ syndrome); J am Acad Der-matol. 2003;48:S60-1.

15. Toulon A. et al. Wells’ syndrome after primoinfection by parvovirus B19 in a child. J Am Acad Dermatol. 2007;S50-1.

16. Reichel M, Isseroff RR, Vogt PJ, Gandour-Edwards R. Wells’ syndrome in children: varicella infection as a pre-cipitating event. Br J Dermatol 1991;124:187-90.

17. Stavropoulos PG, Kostakis PG, Panagiotopoulos AK, Papakonstantinou AM, Petridis AP, Georgala S. Mollus-cum contagiosum and cryosurgery: triggering factors for Wells’ syndrome? Acta Derm Venereol 2003;83:380-81

18. Calvert J, Shors AR, Hornung R. Poorsattar S, Sidbury R. relapse of Wells’ syndrome in a child after tetanus-diphtheria immunization. J Am Acad Dermatol. 2006;May 232-3.

19. Winfield H, Lain E, Horn T, Hoskyn J. Eosinophilic cel-lulitis like reaction to subcutaneous Etanercept injection. Arhc Dermatol. 2006;142:218-220.

20. Boura P, Sarantopoulos A, Lefaki I, Skendros P, Papa-dopoulos P. Eosinophilic cellulites (Wells’ syndrome) as a cutaneous reactin to the administration of adalimumab. Annals of Rheum diseases 2006;65:839-840.

21. French L, Shapiro M, Junkins-Hopkins JM, Wolfe J, Rook A. eosinophilic fasciitis and eosinophilic cellulitis in a patient with abnormal circulating clonal T cells: Increased production of interleukin 5 and inhibition by interferon alfa. J Am Acad Dermatol. 2003 Dec:1170-4

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