FOUNDING SPONSORS: ALLERGAN SKIN CARE • CONNETICS CORPORATION • GLOBAL PATHOLOGY LABORATORY • MEDICIS • NOVARTIS PHARMACEUTICALS • 3M PHARMACEUTICALS Journal of the AMERICAN OSTEOPATHIC COLLEGE OF DERMATOLOGY Journal of the 2004-2005 Officers President: Ronald C. Miller, DO President-Elect: Richard A. Miller, DO American First Vice-President: Bill V. Way, DO Second Vice-President: Jay S. Gottlieb, DO Third Vice-President: Donald K. Tillman, DO Osteopathic Secretary-Treasurer: Jere J. Mammino, DO Immediate Past President: Stanley E. Skopit, DO College Trustees: Daniel S. Hurd, DO Jeffrey N. Martin, DO David W. Dorton, DO of Dermatology Marc I. Epstein, DO Executive Director: Rebecca Mansfield, MA
Editors Jay S. Gottlieb, D.O., F.O.C.O.O. Stanley E. Skopit, D.O., F.A.O.C.D.
Associate Editor James Q. Del Rosso, D.O., F.A.O.C.D.
Editorial Review Board Ronald Miller, D.O. Eugene Conte, D.O. Evangelos Poulos, M.D. Stephen Purcell, D.O. AOCD • 1501 E. Illinois • Kirksville, MO 63501 Darrel Rigel, M.D. 800-449-2623 • FAX: 660-627-2623 www.aocd.org Robert Schwarze, D.O. Andrew Hanly, M.D. COPYRIGHT AND PERMISSION: written permission must be Michael Scott, D.O. obtained from the Journal of the American Osteopathic College of Dermatology for copying or reprinting text of more than half page, Cindy Hoffman, D.O. tables or figures. Permissions are normally granted contingent upon Charles Hughes, D.O. similar permission from the author(s), inclusion of acknowledgement Bill Way, D.O. of the original source, and a payment of $15 per page, table or figure of reproduced material. Permission fees are waived for authors Daniel Hurd, D.O. wishing to reproduce their own articles. Request for permission Mark Lebwohl, M.D. should be directed to JAOCD c/o AOCD PO Box 7525 Kirksville, MO 63501 Edward Yob, D.O. Copyright 2003 by the Journal of the American Osteopathic Jere Mammino, D.O. College of Dermatology Schield M. Wikas, D.O. Printed by: Stoyles Graphics Services, Mason City, IA 50401 Journal of the American Osteopathic College of Dermatology Journal of the VOLUME 4 , NUMBER 1 AUGUST 2005 American Osteopathic College of Dermatology
CONTENTS
Letter from The JAOCD Editors...... 4 Letter from Director of Development for the AOCD...... 8 Dystrophic Epidemolysis Bullosa: Case Report and Literature Review ...... 9 Iqbal A. Bukhari, MD Familial Cylindromatosis: A Case Report...... 12 Scott A. Smith, D.O., Anita C. Gilliam, M.D., Ph.D., Paradi Mirmirani, M.D. Adamantinoid Trichoblastoma/Cutaneous Lymphadenoma: A case report and review of literature ...... 17 Angela Marie Leo, BS, Mary Jo Robinson, DO Hyperhidrosis: A Review of Pathogenesis and Management...... 20 Shari Y. Sperling, Charles A. Gropper, M.D., Helene E. Price, M.D., Cindy Hoffman, D.O. A Review of Occupational Skin Disorders for the Practicing Clinician...... 24 Erik Austin, D.O., M.P.H., Bill V. Way, D.O., FAOCD Pemphigus Foliaceus in association with Lisinopril ...... 28 Jocelyn E. Harris, D.O., Stephen M. Purcell, D.O. Drug Induced Eccrine Gland Necrosis in a Patient with Altered Mental Status: A Case Presentation and Review...... 30 Laura Ziton, D.O., Tracy Favreau, D.O., Brian Portnoy, D.O. Pemphigus Foliaceus: A Case Report with Review of Literature...... 35 Michael Hohnadel D.O., Bill V. Way, D.O. Trichostasis Spinulosa: A Commonly Overlooked Entity ...... 39 Patrick Keehan, MSIV, Bill V. Way, D.O. Hypertrophic Lichen Planus and Lupus Erythematosus Overlap Syndrome: A Case Report and Review...... 41 Michelle Endicott, D.O. Lichen Planopilaris: A Case Presentation and Review of the Literature...... 45 Edward M. Galiczynski, Jr., Scott J.M. Lim Herpes Simplex and HIV Infection: A Case Report and Review of the Literature...... 47 Frank T. Armstrong, D.O., Marya Cassandra, D.O., Richard Miller, D.O., FAOCD X-Linked Ichthyosis...... 49 Tara H. Lawlor, D.O., Donald J. Adler, D.O. Merkel Cell Carcinoma: A Case Report...... 52 Norma Montiel, D.O., Evangeline Perez, D.O., Zoila Flashner, M.D. Unilateral Laterothoracic Exanthem-A Case Report...... 55 Gandhari Warner, D.O., Jonathan Stuart Crane, D.O., Ronald P. Benjamin, M.D., Patricia Hood, PA-C, Carla DiBenedetto, PA-C. Hormonal Controls of Hair: What is the Role of Menopause?...... 59 Michelle Endicott, D.O., Paradi Mirmirani, M.D. Cellulitis Due to Aeromonas and Flavobacterium: A Case Review...... 61 W. Elliot Love, Paul M. Newell, MD Metastatic Testicular Choriocarcinoma Mimicking Pyogenic Granulomas: Case Report and Literature Review...... 63 Mary Veremis-Ley, Kimberly Hollandsworth, MD Surgical Pearls ...... 65 Jay S. Gottlieb, D.O., F.O.C.O.O. Dystrophic Calcinosis Cutis...... 70 Bill Way, D.O., FAOD, Zainab Rashid Physicians Assistants in Dermatology: Understanding the Effects of the Sun on the Skin ...... 72 Amy D. Gottlieb, Melissa Marchisotto, MPA, PA-C, Jay S. Gottlieb, D.O., F.O.C.O.O. L ETTER F ROM T HE JAOCD EDITORS
JAY S. GOTTLIEB, D.O. STANLEY E. SKOPIT, D.O. JAMES Q. DELROSSO, D.O. Fourth Issue of the JAOCD is the best yet!
Well things do just keep getting better! This is our fourth issue of the JAOCD. Each issue has gotten better and more informative. As a member of the AOCD, you should take great pride in our publication.
We have more residents in our programs then ever. The Education Evaluation Committee (EEC) has made it mandatory for each resident to submit their annual paper for publication to a medical journal. The residents have had the requirement to write one paper each year of their residency that is suitable for publication. It will require a very small effort on the resident’s behalf to take the next step and submit their manuscript for consideration for publication.
As the editors of the JAOCD, we hope that the residents will consider the JAOCD when the time comes for them to submit their annual papers. They will see that it is a relatively easy process and it is our hope that they will be encouraged to submit other papers throughout their three years of residency.
We continue to strive for improvement and growth in every aspect of our journal. We continue to strive for the next milestone and be able to publish the JAOCD four times a year. Again, when this happens, we will be able to have our journal listed in the Library of Congress as well as have it listed in Index Medicus.
We will continue to solicit your contribution in the way of presenting an interesting case or even a pearl on office management. We require consistency. Consider becoming a consistent contributor, always looking out for what would be interesting
to the readers of our journal. JAOCD Founding Sponsor
We extend our sincere appreciation for continued support to our Founding Sponsors. Our deepest thank you goes to Allergan Skin Care, Connetics Corporation, Global Pathology Laboratory Services, Novartis Pharmaceuticals Corporation, Medicis-The Dermatology Company and 3M Pharmaceuticals who have made the financial commitment to the JAOCD.
Jay S. Gottlieb, D.O., F.O.C.O.O. (Editor) Stanley E. Skopit, D.O., F.A.O.C.D. (Editor) James Q. Del Rosso, D.O., F.A.O.C.D. (Associate Editor)
4 At the first sign of...
In patients with recurrent genital herpes or herpes zoster
5 ® Geriatric Use Famvir Of 816 patients with herpes zoster in clinical studies who were treated with Famvir, 248 (30.4%) were *65 years of (famciclovir) age and 103 (13%) were *75 years of age. No overall differences were observed in the incidence or types of Tablets adverse events between younger and older patients. ADVERSE REACTIONS Rx only Immunocompetent Patients BRIEF SUMMARY: Please see package insert for full prescribing information. The safety of Famvir® (famciclovir) has been evaluated in clinical studies involving 816 Famvir-treated patients with INDICATIONS AND USAGE herpes zoster (Famvir, 250 mg t.i.d. to 750 mg t.i.d.); 528 Famvir-treated patients with recurrent genital herpes Herpes Zoster: Famvir® (famciclovir) is indicated for the treatment of acute herpes zoster (shingles). (Famvir, 125 mg b.i.d. to 500 mg t.i.d.); and 1,197 patients with recurrent genital herpes treated with Famvir as suppressive therapy (125 mg q.d. to 250 mg t.i.d.) of which 570 patients received Famvir (open-labeled and/or Herpes Simplex Infections: Famvir is indicated for: double-blind) for at least 10 months. Table 5 lists selected adverse events. •treatment or suppression of recurrent genital herpes in immunocompetent patients. •treatment of recurrent mucocutaneous herpes simplex infections in HIV-infected patients. Table 5 CONTRAINDICATIONS Selected Adverse Events Reported by *2% of Patients in Placebo-Controlled Famvir® (famciclovir) Trials* Famvir® (famciclovir) is contraindicated in patients with known hypersensitivity to the product, its components, Incidence and Denavir® (penciclovir cream). Recurrent Genital Herpes- PRECAUTIONS Herpes Zoster Genital Herpes Suppression General Event Famvir® Placebo Famvir® Placebo Famvir® Placebo The efficacy of Famvir® (famciclovir) has not been established for initial episode genital herpes infection, (n=273) (n=146) (n=640) (n=225) (n=458) (n=63) ophthalmic zoster, disseminated zoster or in immunocompromised patients with herpes zoster. %%%%%% Dosage adjustment is recommended when administering Famvir to patients with creatinine clearance values Nervous System <60 mL/min. (See DOSAGE AND ADMINISTRATION in the full prescribing information). In patients with underlying Headache 22.7 17.8 23.6 16.4 39.3 42.9 renal disease who have received inappropriately high doses of Famvir for their level of renal function, acute renal Paresthesia 2.6 0.0 1.3 0.0 0.9 0.0 failure has been reported. Migraine 0.7 0.7 1.3 0.4 3.1 0.0 Information for Patients Gastrointestinal Patients should be informed that Famvir is not a cure for genital herpes. There are no data evaluating whether Nausea 12.5 11.6 10.0 8.0 7.2 9.5 Famvir will prevent transmission of infection to others. As genital herpes is a sexually transmitted disease, patients Diarrhea 7.7 4.8 4.5 7.6 9.0 9.5 should avoid contact with lesions or intercourse when lesions and/or symptoms are present to avoid infecting Vomiting 4.8 3.4 1.3 0.9 3.1 1.6 partners. Genital herpes can also be transmitted in the absence of symptoms through asymptomatic viral shed- Flatulence 1.5 0.7 1.9 2.2 4.8 1.6 ding. If medical management of recurrent episodes is indicated, patients should be advised to initiate therapy at Abdominal Pain 1.1 3.4 3.9 5.8 7.9 7.9 the first sign or symptom. Body as a Whole Drug Interactions Fatigue 4.4 3.4 6.3 4.4 4.8 3.2 Concurrent use with probenecid or other drugs significantly eliminated by active renal tubular secretion may result Skin and Appendages in increased plasma concentrations of penciclovir. Pruritus 3.7 2.7 0.9 0.0 2.2 0.0 Rash 0.4 0.7 0.6 0.4 3.3 1.6 The conversion of 6-deoxy penciclovir to penciclovir is catalyzed by aldehyde oxidase. Interactions with other Reproductive Female drugs metabolized by this enzyme could potentially occur. Dysmenorrhea 0.0 0.7 2.2 1.3 7.6 6.3 Carcinogenesis, Mutagenesis, Impairment of Fertility *Patients may have entered into more than one clinical trial. Famciclovir was administered orally unless otherwise stated. The following adverse events have been reported during post-approval use of Famvir: urticaria, hallucinations and Carcinogenesis: Two-year dietary carcinogenicity studies with famciclovir were conducted in rats and mice. An confusion (including delirium, disorientation, confusional state, occurring predominantly in the elderly). Because increase in the incidence of mammary adenocarcinoma (a common tumor in animals of this strain) was seen in these adverse events are reported voluntarily from a population of unknown size, estimates of frequency cannot be female rats receiving the high dose of 600 mg/kg/day (1.5 to 9.0x the human systemic exposure at the recommended made. Table 6 lists selected laboratory abnormalities in genital herpes suppression trials. daily oral doses of 500 mg t.i.d., 250 mg b.i.d., or 125 mg b.i.d. based on area under the plasma concentration Table 6 curve comparisons [24 hr AUC] for penciclovir). No increases in tumor incidence were reported in male rats Selected Laboratory Abnormalities in Genital Herpes Suppression Studies* treated at doses up to 240 mg/kg/day (0.9 to 5.4x the human AUC), or in male and female mice at doses up to 600 mg/kg/day (0.4 to 2.4x the human AUC). Parameter Famvir® Placebo (n=660)† (n=210)† Mutagenesis: Famciclovir and penciclovir (the active metabolite of famciclovir) were tested for genotoxic potential %% in a battery of in vitro and in vivo assays. Famciclovir and penciclovir were negative in in vitro tests for gene mutations in bacteria (S. typhimurium and E. coli) and unscheduled DNA synthesis in mammalian HeLa 83 cells Anemia (<0.8 x NRL) 0.1 0.0 (at doses up to 10,000 and 5,000 mcg/plate, respectively). Famciclovir was also negative in the L5178Y mouse Leukopenia (<0.75 x NRL) 1.3 0.9 lymphoma assay (5000 mcg/mL), the in vivo mouse micronucleus test (4800 mg/kg), and rat dominant lethal Neutropenia (<0.8 x NRL) 3.2 1.5 study (5000 mg/kg). Famciclovir-induced increases in polyploidy in human lymphocytes in vitro in the absence of AST (SGOT) (>2 x NRH) 2.3 1.2 chromosomal damage (1200 mcg/mL). Penciclovir was positive in the L5178Y mouse lymphoma assay for gene ALT (SGPT) (>2 x NRH) 3.2 1.5 mutation/chromosomal aberrations, with and without metabolic activation (1000 mcg/mL). In human lympho- Total Bilirubin (>1.5 x NRH) 1.9 1.2 cytes, penciclovir caused chromosomal aberrations in the absence of metabolic activation (250 mcg/mL). Serum Creatinine (>1.5 x NRH) 0.2 0.3 Amylase (>1.5 x NRH) 1.5 1.9 Penciclovir caused an increased incidence of micronuclei in mouse bone marrow in vivo when administered intra- Lipase (>1.5 x NRH) 4.9 4.7 venously at doses highly toxic to bone marrow (500 mg/kg), but not when administered orally. *Percentage of patients with laboratory abnormalities that were increased or decreased from baseline and were Impairment of Fertility: Testicular toxicity was observed in rats, mice, and dogs following repeated administration outside of specified ranges. of famciclovir or penciclovir. Testicular changes included atrophy of the seminiferous tubules, reduction in sperm † n values represent the minimum number of patients assessed for each laboratory parameter. count, and/or increased incidence of sperm with abnormal morphology or reduced motility. The degree of toxicity NRH = Normal Range High. to male reproduction was related to dose and duration of exposure. In male rats, decreased fertility was observed NRL = Normal Range Low. after 10 weeks of dosing at 500 mg/kg/day (1.9 to 11.4x the human AUC). The no observable effect level for sperm and testicular toxicity in rats following chronic administration (26 weeks) was 50 mg/kg/day (0.2 to 1.2x the human HIV-Infected Patients systemic exposure based on AUC comparisons). Testicular toxicity was observed following chronic administration In HIV-infected patients, the most frequently reported adverse events for famciclovir (500 mg twice daily; n=150) to mice (104 weeks) and dogs (26 weeks) at doses of 600 mg/kg/day (0.4 to 2.4x the human AUC) and 150 mg/kg/day and acyclovir (400 mg, 5x/day; n=143), respectively, were headache (16.7% vs. 15.4%), nausea (10.7% vs. (1.7 to 10.2x the human AUC), respectively. 12.6%), diarrhea (6.7% vs. 10.5%), vomiting (4.7% vs. 3.5%), fatigue (4.0% vs. 2.1%), and abdominal pain (3.3% vs. 5.6%). Famciclovir had no effect on general reproductive performance or fertility in female rats at doses up to 1000 mg/kg/day (3.6 to 21.6x the human AUC). Two placebo-controlled studies in a total of 130 otherwise healthy men with a normal sperm profile over an 8-week Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) baseline period and recurrent genital herpes receiving oral Famvir (250 mg b.i.d.) (n=66) or placebo (n=64) therapy for [see USP Controlled Room Temperature]. 18 weeks showed no evidence of significant effects on sperm count, motility or morphology during treatment or during an 8-week follow-up. Pregnancy Teratogenic Effects–Pregnancy Category B: Famciclovir was tested for effects on embryo-fetal development in rats and rabbits at oral doses up to 1000 mg/kg/day (approximately 3.6 to 21.6x and 1.8 to 10.8x the human systemic exposure to penciclovir based on AUC comparisons for the rat and rabbit, respectively) and intravenous doses of 360 mg/kg/day in rats (2 to 12x the human dose based on body surface area [BSA] comparisons) or 120 mg/kg/day in rabbits (1.5 to 9.0x the human dose [BSA]). No adverse effects were observed on embryo-fetal development. Similarly, no adverse effects were observed following intravenous administration of penciclovir to rats (80 mg/kg/day, 0.4 to 2.6x the human dose [BSA]) or rabbits (60 mg/kg/day, 0.7 to 4.2x the human dose [BSA]). There are, however, no adequate and well-controlled studies in pregnant women. Because animal repro- T2004-06 duction studies are not always predictive of human response, famciclovir should be used during pregnancy only if REV: MARCH 2004 89011404 the benefit to the patient clearly exceeds the potential risk to the fetus. Pregnancy Exposure Registry: To monitor maternal-fetal outcomes of pregnant women exposed to Famvir, Novartis Manufactured by: Pharmaceuticals Corporation maintains a Famvir Pregnancy Registry. Physicians are encouraged to register their Novartis Farmacéutica S.A. patients by calling (888) 669-6682. 08210 Barberà del Vallès Barcelona, Spain Nursing Mothers Following oral administration of famciclovir to lactating rats, penciclovir was excreted in breast milk at concentra- tions higher than those seen in the plasma. It is not known whether it is excreted in human milk. There are no data Distributed by: on the safety of Famvir in infants. Novartis Pharmaceuticals Corp. Usage in Children East Hanover, NJ 07936 Safety and efficacy in children under the age of 18 years have not been established. ©Novartis In Recurrent Genital Herpes FAMVIR ® stops pain and burning in a median of 2 days or less with episodic therapy*†1 • Median time (days) to cessation vs placebo (pain: 2.0 vs 2.4, P<.006; burning: 1.7 vs 2.1, P<.001) FAMVIR keeps patients outbreak-free for nearly a year with suppressive therapy 2,3 • Median time to first recurrence was 336 days with FAMVIR vs 47 days with placebo (P<.001)2 • The safety and efficacy of FAMVIR for suppressive therapy have not been established beyond 1 year In Herpes Zoster Only FAMVIR is proven to shorten the median duration of PHN by 100 days vs placebo‡§4,5 • For patients ≥50 years
FAMVIR (famciclovir) Tablets are indicated for the treatment or suppression of recurrent genital herpes in immunocompetent patients; the treatment of recurrent muco- cutaneous herpes simplex infections in HIV-infected patients; and the treatment of acute herpes zoster (shingles). In clinical trials, the most commonly reported adverse events vs placebo were headache (zoster: 22.7% vs 17.8%; episodic: 23.6% vs 16.4%; suppression: 39.3% vs 42.9%); nausea (zoster: 12.5% vs 11.6%; episodic: 10.0% vs 8.0%; suppression: 7.2% vs 9.5%); and diarrhea (zoster: 7.7% vs 4.8%; episodic: 4.5% vs 7.6%; suppression: 9.0% vs 9.5%). The efficacy of FAMVIR has not been established for initial-episode genital herpes infection, ophthalmic zoster, disseminated zoster, or in immunocompromised patients with herpes zoster. There is no cure for genital herpes. There is no evidence that FAMVIR can stop the spread of herpes to others. FAMVIR, Pregnancy Category B, is contraindicated in patients with known hypersensitivity to the product, its components, or DENAVIR® (penciclovir cream). See brief Prescribing Information on previous page. *In patients with moderate to severe genital herpes. †In clinical studies designed for medication to be administered within 6 hours of symptom or lesion onset. ‡No significant difference in overall incidence of PHN for famciclovir vs placebo. In patients <50 years, no statistically significant difference seen in duration of PHN. §Therapy should be initiated as soon as herpes zoster is diagnosed. The efficacy of treatment started more than 72 hours after rash onset has not been established. References: 1. Data on file, Novartis Pharmaceuticals Corp. 2. Diaz-Mitoma F, Sibbald RG, Shafran SD, et al, for the Collaborative Famciclovir Genital Herpes Research Group. Oral famciclovir for the sup- pression of recurrent genital herpes: a randomized controlled trial. JAMA. 1998;280:887-892. 3. Tyring SK, Diaz-Mitoma F, Shafran SD, et al. Oral famiciclovir for the suppression of recurrent genital herpes: the combined data from two randomized controlled trials. J Cutan Med Surg. 2003;7:449-454. 4. Tyring S, Barbarash RA, Nahlik JE, et al, and the Collaborative Famciclovir Herpes Zoster Study Group. Fam- ciclovir for the treatment of acute herpes zoster: effects on acute disease and postherpetic neuralgia: a randomized, double-blind, placebo-controlled trial. Ann Intern Med.1995;123:89-96. 5. Dworkin RH, Boon RJ, Griffin DRG, Phung D. Postherpetic neuralgia: impact of famciclovir, age, rash severity, and acute pain in herpes zoster patients. J Infect Dis. 1998;178(suppl 1):S76-S80.
FAMVIR is a registered trademark of Novartis. www.FAMVIR.com ©2005 Novartis Printed in U.S.A. 6/05 FVR-AD-0162-A FAST THAT LASTS DIRECTOR OF DEVELOPMENT FOR THE AOCD
SHIRLEY GOTTLIEB
The AOCD has seen a tremendous growth over the past few years, with the number of resident’s almost doubling and an increased membership in the organization. Because of this unprece- dented growth, the Executive Committee has decided to bring on a Director of Development, in order to expand the relationships it has with its current corporate partners, as well as to cultivate and develop relationships with new partners.
The Foundation for Osteopathic Dermatology (FOD) was also formed in order to raise awareness and provide the public with necessary health information, and to support research through grants and awards.
The AOCD strives for the creative delivery of highly sophisticated education and training programs. Contributions that are made, allow the AOCD to grow these opportunities, as well as to operate the organization. This is an ambitious goal, and will require the combined efforts of every member, and every component of the organization.
Consistent commitment will allow the AOCD to be well positioned to serve its members and to continue to enhance patient care.
I am enjoying the opportunity of serving this well respected organization, and fulfilling its commitment to its members, who represent all facets in the field of dermatology, and at all stages of their professional career.
I will be in contact with all members throughout this year, and I look forward to serving your organization and working with you to advance the AOCD.
Please feel free to contact me.
Respectfully, Shirley Gottlieb Director of Development 954-963-5862 (office) 954-232-2025 (cell) 954-985-3934 (fax) [email protected]
8 Dystrophic Epidemolysis Bullosa: Case Report and Literature Review
Iqbal A. Bukhari, MD, King Fahad Hospital of the University
ABSTRACT
Epidermolysis bullosa (EB) is a group of inherited blistering disorders that can be life threatening to the affected newborns and infants. The generalized dystrophic type of EB is responsible for the most severe debilitating disease. In this report I am presenting a case of dystrophic type of EB which had poor prognosis and update the literature about dystrophic epidermolysis bullosa. Key words: epidermolysis bullosa, transmission electron microscopy, genetic disorder.
revealed cleavage at the dermoepidermal Introduction: junction with normal epidermal and dermal EB is a mechanobullous disease that constituents. Immunoflorescence for IgM, predominantly affects skin and mucous IgA, IgG, C3 and fibrinogen was negative membranes. The key clinical feature is while for antigen type IV collagen, laminin increased fragility of the skin, which mani- and bullous pemphigoid were not done due fests as blisters and erosions secondary to unavailability of the reagents. minor trauma. This is due to genetic aber- Transmission electron microscopy rations at the level of the cutaneous base- revealed basal cells were present with con- ment membrane zone (BMZ). Diagnosis of tinuous basal lamina and a cleavage plane the condition is by detailed history, clinical localized below the lamina densa that lines features, transmission electron microscopy the blister roof (figure 3). Comment on the (TEM), immunofluorescence antigen map- anchoring fibrils could not be specified due ping and immunohistochemical staining to specimen quality. A diagnosis of reces- with EB specific monoclonal antibodies.1 sive dystrophic EB of Hallopeau-Siemens type was entertaine. A strict management Case Report: plan was undertaken. During the first week of treatment, the A full-term baby boy was born to a 22- neonate general condition was stable with year old primigravida through normal spon- no further seizures. No new blisters formed taneous vaginal delivery. At the time of the and the old blisters appeared to be healing delivery, the baby was jaundiced (total with scarring. During the second week the bilirubin 3.7 mg/dl; normal 0.1-1.0) meco- infant had difficulty with oral feeding and he Figure 1 nium stained and weighing 3.17 kilograms looked ill, although his vital signs were sta- DEB with erosions and healing with apgar score 7 at the seventh minute. ble. Blood cultures and the skin surface scared areas on the left foot. In addition he was having large bullous culture demonstrated pseudomonas aerug- lesions on the back and feet dorsa. Some inosa. The skin, mouth lesions, ears, and of the lesions were ruptured with denuded nose were also culture positive for ulcerated areas. Apart from that his vital pseudomonas aeruginosa. signs, systemic examination, oral mucosa, Changes to the antibiotic protocol were nails and hair were within normal limit. based on the antibiotic sensitivity results. Family history was negative for any genetic Unfortunately, the patient skin condition disorder. Basic laboratory evaluation was worsening and nasogastric tube feed- including complete blood count, serum ing was institued. By the end of the second electrolytes, liver and renal function tests, week, the patient had cyanosis with oral stool and urine analysis were normal. and nasal bleeding. The vital signs deterio- During the first 24 hours the neonate rated and a prolonged prothrombin and developed seizure for which he was started partial thromboplastin time with marked on phenobarbital, ampicillin and leucopenia were evident. Cardiopulmonary cephalosporin because of suspected sep- arrest ensued and the patient failed resus- sis. On the second day, the neonatologist citation efforts. consulted us for his skin lesions. Full cuta- neous evaluation revealed ulcerated areas on the back, upper and lower limbs and Discussion: oral mucosa (figure 1,2). No intact blisters EB is a mechanobullous disease that Figure 2 were seen. So our preliminary diagnosis predominantly affects the skin and mucous Multiple erosions on the left hand. was inherited form of EB. Two skin punch membranes. The prevalence rate of epi- biopsies were taken from the edge of intact dermolysis bullosa (EB) is estimated to be feature in EB is increased fragility of the newly formed blisters on the left foot and 19 per million in the United States. The skin, which manifests as blisters and ero- arm for light microscopy, immunoflores- prevalence rate of dystrophic epidermoly- sions secondary to minor trauma. How- cence and transmission electron sis (DEB) is estimated at 2.4 cases per mil- ever, there is considerable phenotypic microscopy. Histological evaluation lion population.2 The diagnostic clinical
BUKHARI 9 Table 1: Classification of inherited Epidermolysis Bullosa (EB) .
Major types Mode of inheritance Major subtypes Level of cleavage
EB simples Autosomal dominant EBS-Weber-Cockyne EBS-Kobner Intraepidermal EBS-Dowling-Meara EBS-Muscular dystrophy
Junctional EB Austosomal recessive JEB-Herlitz Figure 3 JEB-Non-Herlitz Intralamina densa Transmission electron microscopy JEB-Pyloric atresia showing a cleavage plane localized below the lamina densa (LD) that lines the blister roof. LL, lamina Dystrophic EB Autosomal dominant Dominant DEB Sublamina densa lucida; BK, basal keratinocyte. Autosomal recessive Recesive DEB-Hallopeau- variability, and the presence of extracuta- Siemens neous manifestations adds to the complex- ity of this disorder.1 Recessive DEB-non- Halloeau-Siemens In 1999, classification of inherited EB was revised based on commonly recog- nized forms and the associated genes blistering at sites of trauma that heals after cutaneous neoplasms, eczema, atopic and involved.3 Table 1 lists the currently recog- several months without scarring.8 In allergic dermatitis. nized types and subtypes of inherited EB. Recessive Dystrophic Epidermolysis Bul- There are additional clinical phenotypes of Extra-cutaneous involvement may lusa of Hallopeau-Siemens Subtype DEB still recognized as subtypes in the include the abnormality of the teeth, gas- (RDEB-HS), patients have exceedingly revised classification system which include trointestinal tract, upper respiratory tract, fragile skin that blisters at birth. It is dominant DEB-pretibial, DEB-transient bul- genitourinary tract, eyes and cardiovascu- extremely pruritic and painful and mucosal 12 lous dermolysis of the newborn, dominant lar system. Gastrointestinal manifesta- blisters usually occur. DEB-pruriginosa, recessive DEB-inversa, tions include dysphagia, esophageal recessive DEB-centripetalis and DEB, Extensive scarring may lead to contrac- stricture, pyloric stenosis, anal stricture, 13 autosomal dominant/autosomal recessive tures or fusions of digital web spaces chronic constipation and fecal impaction. heterozygote.3 (pseudosyndactyly). The oral cavity and Dental involvement may include gingival esophagus may become severely involved blisters or erosions, enamel hypoplasia, Physiologically, the basement mem- with subsequent development of microsto- dental caries, malocclusion and premature brane zone (BMZ) is important for stable mia, obliteration of oral vestibule, and loss of teeth.14 Tracheolaryngeal symptoms association of the epidermis to the underly- ankyloglossia. Enamel hypoplasia and may include chronic hoarseness, inspira- ing dermis and it consists of hemidesmo- cementum disorders may also occur. A tory stridor and laryngeal stenosis or somes, anchoring filaments, and anchoring devastating complication unique to patients obstruction.15 fibrils that form an interconnecting network with RDEB, is the increased propensity for extending from the intracellular milieu of Genitourinary involvement may include squamous cell carcinoma of the skin.1 basal keratinocytes across the dermoepi- urethral meatal stenosis, urinary retention, dermal basement membrane to the under- In Recessive Dystrophic Epidermolysis glomerulonephritis, nephrotic syndrome lying dermis. Any aberrations in this of Non–Hallopeau–Siemens Subtype secondary to renal amyloidosis and men- 16,17 network can lead to increased fragility of (RDEB-nHS) patients lack the cutaneous strual abnormalities. Ocular findings the skin at the level of the BMZ. Genetically and extracutaneous features characteristic range from corneal erosion, corneal scar- a large number of mutations linked to type of the Hallopeau–Siemens subtype. In ring, symblepharon, blepharitis, ectropion, 18 VII collagen gene (COL7AI) located at inverse RDEB, blisters are present at birth lacrimal duct obstruction and blindness. 3p21.1 in both recessive (RDEB) and domi- and later cutaneous lesions are localized Otitis externa, external auditory canal nant forms of DEB (DDEB).4,5,6 Clinically almost exclusively in skin folds. Milia, stenosis, chronic otitis media and hearing most patients with DEB have a relatively atrophic scarring, scarring alopecia and loss have also been reported.19 Anemia and mild dominantly inherited disease and only nail dystrophy can be seen. In RDEB-cen- growth retardation attributed to iron defi- a minority suffer from severe recessive tripetalis, lesions occur during infancy and ciency and chronic disease are frequently subtypes. have a progressive centripetal spread with seen. Common causes of death in DEB no intra-oral or other extra-cutaneous In Dominant Dystrophic Epidermolysis patients include squamous cell carcinoma, involvement.9,10 Epidermolysis bullosa pru- Bullosa (DDEB) the clinical spectrum sepsis, pneumonia, respiratory failure, fail- riginosa can be both autosomal dominant ranges from a milder phenotype, mani- ure to thrive, renal failure, heart disease and recessive manifesting highly pruritic, 1 fested by localized blistering at sites of and stroke. violaceous, pretibial cutaneous nodules maximal trauma to generalized blisters that Our patient presented with RDEB-HS and plaques that may be confused with subsequently heal with scarring. The age type which was complicated with sepsis to hypertrophic lichen planus and nodular of onset is early childhood. The nails of which he succumbed. An early detailed prurigo. both upper and lower extremities tend to history including mapping of the family be abnormal with no extracutaneous mani- The onset of skin lesions is variable and pedigree is mandatory. An absence of 11 festations.7 An uncommon variant of dys- can occur as late as 10 years of age. other known affected family members does trophic EB called transient bullous Besides blistering in DEB, other skin disor- not establish the mode of transmission to dermolysis of the newborn presents with ders that may occur simultaneously include be autosomal recessive. Spontaneous
10 EPIDEMOLYSIS BULLOSA mutation or the incomplete penetrance of antibiotics to lesions and nonstick dress- underlying epidermolysis bullosa pruriginosa. J Invest Dermatol 1999:112:904-7. an autosomal dominant trait could play a ings to denuded areas, and draining the 12. Holbrook KA. Exracutaneons epithelial involvement in role.20 blisters.1 Methyl-cellulose containing artifi- inherited epidermolysis bullosa. Arch Dermatol 1988:124:726-31. Non-molecular laboratory tests that may cial tears are useful to prevent ocular abra- 13 Travis SP, McGrath JA, Tumbull AJ et al. Oral and gastroin- be helpful in establishing a diagnosis of EB sions.18 Stool softeners for management of testinal manifestations of epidermolysis bullosa. Lancet chronic constipation.25 Oral prophylaxis with 1992;340:1505-6. include transmission electron microscopy 14. Wright JT, Fine JD, Johnson LB et al. Hereditary epider- (TEM), immunofluorescence antigen map- sucralfate prevents blister formation and molysis hullosa; oral manifestations and dental manage- provides comfort for mouth lesions.26 Non- ment. Pediatr Dent 1993;15:242-8. ping and immunohistochemical staining 15. Gonzalez C, Roth R. Laryngotracheal involvement in epi- with EB specific monoclonal antibodies. healing areas of the skin can be treated dermolysis bullosa. Int J Pediatr Otolaryngol 1989;17:305- TEM remains the gold standard for it per- with split-thickness skin grafts and careful 11. 16. Kretkowski RC. Urinary tract involvement in epidermolysis mits not only identification of the ultrastruc- use of hand splints help prevent develop- bullosa. Pediatrics 1973;51:938-41. tural level of skin cleavage, but also the ment of mitten defomities.27 17. Gunduz K, Vatausever S, Turel A et al. Recessive dys- trophic epidermolysis bullosa complicated with nephrotic appearance of the specific structures such A nutritionist should be consulted about syndrome due to secondary amyloidosis. lnt J Dermatol as keratin, tonofilaments, hemidesmo- the nutritional needs of an infant with DEB. 2000;39;151-3. 18. Brodie SE. Ophthalmological aspects of epidermolysis bul- somes, sub-basal dense plates and The caloric and nutritional requirements losa. In: Lin AN, Carter DM. editors. Epidermolysis Bul- 21 anchoring fibrils. In DEB, TEM features can be twice that of children without blister- losa: Basic and Clinical Aspects. New York: include abnormal fibrils and blister forma- ing disease.1 With possible future isolation Springer-Verlag, 1992. p. 18590. 19. Thawley SE, Black MJ, Dudek SE et al. External auditory tion beneath the lamina densa of the der- of the corresponding normal alleles, gene canal stricture secondary to epidermolysis bullosa. Arch rnoepidermal junction. TEM demonstrated therapy can become a potential cure for Otolaryngol 1977;103:55-7. 22 28 20. Fine Jo-D, Bauer EA, Briggaman RA et al. Revised clinical this feature in the case of our patient. these conditions. and laboratory criteria for subtypes of inherited epidermol- The major disadvantages of TEM are ysis bullosa: a consensus report by the subcommittee on 1 Diagnosis and Classification of the National Epidermolysis technical difficulties and cost. Immunofluo- Conclusion: Bullosa Registry. J Am Acad Dermatol 1991;24:119-35. rescence antigen mapping involves a mod- 21. Tidman Mj, Eady RAJ. Evaluation of anchoring fibrils and This is a case presentation and discus- other components of the dermal-epidermal junction in dys- ified indirect immunofluorescence method trophic epidermolysis by a quantitative ultrastructural tech- using patient's skin and antibodies against sion of a severe case of RDEB of Hallo- niques. J Invest Dermatol 1985;84:374-7. three known basement membrane anti- peau Siemens type with no known affected 22. Glorio RR, Solari A, Woscoff A. Diagnosis by electron microscopy of recessive dystrophic epidermolysis bullosa. gens (bullous pemphigoid antigen-3, family member. Our patient’s condition was Medicina (Buenos Aires) 2000;60:354-6. laminin-1, type IV collagen). All three anti- complicated by sepsis and eventual death. 23. Fine JD, Horiguchi Y. lmmunoelectron microscopy and immunufluosescence antigen mapping: diagnostic appli- bodies bind exclusively to the induced blis- DEB is an aggressive disease process with cations. Clin Dermatol 1991;9:179-85. ter's roof.23 Prenatal diagnosis is important severe potential complications. This case 24. McGrath JA, Handyside AH. Preimplantation genetic diag- should help alert physicians to develop a nosis of severe inherited skin diseases. Exp Dermatol not only to identify fetal anomalies, but also 1995:7:65-72. to provide choices to parents at risk of hav- strict and proper management plan. A 25. Ergun G, Schaefer RA. Gastrointestinal aspects of epider- ing a child with EB which is done by obtain- multidisciplinary approach through cooper- molysis bullosa. 1n: Lin AN, Carter DM, editors. Epider- molysis Bullosa: Basic and Clinical Aspects. New York: ing samples of fetal skin at 17 to 21 weeks ation of pediatricians, dermatologists and Springer-Verlag, 1992. p. 169-184. of gestation for light and electron micro- nutritionists can help these patients 26. Marini I, Vecchiet F. Sucralfate: a help during oral manage- ment in patients with epidermolysis bullosa. J Periodontol scopic examination and immunohisto- through their disease process. 2001:72:691-5. chemical evaluation. 27. Glicenstein J, Mariani D, Haddad R. The hand in recessive dystrophic epidermolysis bullosa, Hand Clin 2000;16.637- Features that suggest diagnosis of DEB References 45. include: dermoepidermal junction separa- 28. Chen M, Kasahara N, Keene DR et al. Restoration of type 1.Das BB, Sahoo S. Dystrophic Epidermolysis bullosa. J Peri- VII collagen expression and function in dystrophic epider- tion below the lamina densa where lamina natol. 2004; 24 (1): 41-7. molysis bullosa. Nat Genet 2002:32:670-5. densa forms the blister roof, absent or 2. Fine JD, Johnson LB, Suchindran C, Moshell A, Gedde- Dahl Jr T. The epidemiology of inherited epidermolysis poorly developed anchoring fibrils, and bullosa. Findings in US, Canadian, and European study reduced or absent expression of type VII populatiens. In: Fine JD, Baner EA, McGuire J, Moshell A, 1 editors. Epidermolysis Bullosa: Clinical, Epidemiologic, collagen. DNA based test for first- and Laboratotory Advances and Findings of the National trimester prenatal diagnosis using DNA Epidermolysis Bullosa Registry. Baltimore, MD: The Johns Hopkins University Press; 1999. p. 101-3. from chorionic villi and amniotic fluid as 3. Fine JD, Eady RAJ, Bauer EA et al. Revised classification early as 10 weeks of gestation is new system for inherited epidermolysis bullosa: report of the method of making the diagnosis of EB. In Second International Consensus Meeting on diagnosis and classification of epidermolysis bullosa. J Am Acad embryos resulting from in vitro fertilization, Dermatol 2000;42:1051-66. preimplantation diagnosis can be per- 4. Uitto J, Christiano AM. Molecular basis for the dystrophic forms of epidermolysis bullosa: mutations in the type VII formed at the eighth cell stage before the collagen gene. Arch Dermatol Res 1994;287:16-22. embryo is implanted in the uterus.24 If the 5. Parente MG, Chung LC, Rynanen J et al. Human type VII collagen-cDNA cloning and chromosomal mapping of the diagnosis reveals a normal or carrier geno- gene. Proc Natl Acad Sci USA 1991:88:6931-5. type, the original blastocyst can be 6.Uitto J, Pulkkinen I, Christiano AM. The molecular basis of implanted into the uterus while the the dystrophic forms of the epidermolysis bullosa. In: Fine JD, Bauer FA, McGuire J, Moshell A, editors. Epidermoly- embryos that have an affected genotype sis Bullosa: Clinical, Epidemiologic, and Laboratory are discarded. 1 Advances and Findings of the National Epidermolysis Bul- losa Registry. Baltimore, MD: The Johns Hopkins Univer- Therapy for EBD should be directed sity Press; 1999. p. 326-50. toward prevention of skin trauma and 7. Lichienwald DJ, Hanna W, Sauder DN et al. Pretibial epider- molysis bullosa: report of a case. J Am Acad Dermatol avoiding new blister formation, prevention 1999;22:346-50. of secondary bacterial infection, aggressive 8. Hashimoto K, Burk JD, Bale GF et al. Transient bullous der- molysis of the newborn. J Am Acad Dermatol treatment of infection when it occurs, mea- 1989;21:708-13. sures to improve wound healing, mainte- 9. Pearson RW, Faller AS. Dermolytic (dystrophic) epidermoly- nance of good nutrition, treatment of all sis bullosa inversa. Arch Dematol 1988;124:544-7. 10. Fine JD, Osment IS, Gay S. dystrophic epidermolysis bul- correctable complications and, finally, reha- losa: a new variant characterized by progressive symmet- bilitation. rical centripetal involvement with scarring. Arch Dermatol 1985;121:1014-7. Prevention of infection is achieved by 11. Mellerio JE, Ashton GM, Mohammedi R et at. Allelic het- changing dressings daily, applying topical erogeneity of dominant and recessive COL7A1 mutations
BUKHARI 11 Familial Cylindromatosis: A Case Report
Scott A. Smith, D.O.* , Anita C. Gilliam, M.D., Ph.D., Paradi Mirmirani, M.D. * 2nd year resident, Department of Dermatology, University Hospitals Health System of Cleveland, Case Western Reserve University, Cleveland, Ohio; Department of Dermatology, Wade Park Veterans Administration, Cleveland, Ohio.
ABSTRACT
Cylindromas are benign adnexal tumors whose histogenesis is still controversial. The scalp is most frequently involved, but other areas of the body may be affected. The lesions are smooth, domed, and erythematous to blue nodules, often with promi- nent telangiectasias, which can be solitary or multiple. Solitary tumors are sporadic, while the multiple tumors are inherited in an autosomal dominant pattern. We present a case report and a review of the current understanding of familial cylindromatosis.
Case Report & Review of Literature Histopathology Cylindromatosis has two presentations, the solitary, sporadic variant and the multi- History of Present Illness ple, inherited variant. The multiple variant, which is referred to as familial cylindro- A 78-year-old white man was seen for matosis (OMIM #132700), is a rare autoso- numerous, asymptomatic lesions on his mal dominant disorder with variable scalp. The patient states that the first lesion expression. There is a predisposition to arose approximately thirteen years ago. multiple adnexal neoplasms. Familial cylin- He has continued to develop more lesions, dromatosis is also known as ‘turban tumor which have slowly increased in size. The syndrome,’ because of the confluence of lesions are asymptomatic and have never multiple cylindromas on the scalp, resulting bled or ulcerated. He has not sought med- in partial or complete hair loss. Figure 1 ical attention for these lesions and has Tumors begin to appear in the second to never tried any treatment for them (Figures third decade, with a predilection for hairy 1,2). areas. The tumors gradually increase in The patient’s past medical history is sig- number and grow in size.1 In 1994, van nificant for colon cancer, which was diag- Balkom and Hennekam reviewed the cur- nosed fifteen years ago, and treated with a rent publications and their personal cases hemicolectomy, chemotherapy and radia- and found the range of onset was from 1.5 tion at that time. The patient also has a years to 69 years, with the mean of 23.2 past medical history of coronary artery dis- years. They also found that in a series of ease, hyperlipidemia, and hypertension. 74 cases of multiple cylindromas, 96% of The patient did not have a history or family those had scalp involvement, and 70% history of skin cancer. were in the nasolabial area, and back and The patient has ten siblings. One of his chest at 43% and 42%, respectively.1 two sisters had similar lesion which were There is no sex or ethnic predisposition. larger, more numerous, and first appeared in her mid 30’s. The patient did not think CYLD gene Figure 2 that his parents or any of his other 9 sib- Familial cylindromatosis (FC) is inherited lings had any had anything similar. He is with an estimated 100% penetrance by the father of four daughters and grandfa- adulthood, but with variable expression.2, 3 proved that MFT and FC were allelic disor- ther of two grandsons, ages 20 and 12 and There can be a wide variety in the degree ders caused by different mutations of the two granddaughters, ages 26 and 15. of expression even in the same family. The same gene and that CLYD 1 gene muta- None of these individuals has any compa- gene responsible is CYLD 1 gene, which tions are associated with several different rable findings. The family tree is shown was localized in 1995 to chromosome band phenotypes.10 The gene locus of 16q12- (Figure 3). 16q12-q13 and identified in 2000.4,5,6,7 The q13 has also been implicated in the sporadic form was demonstrated to also be Brooke-Spiegler syndrome, which is the Histopathology a result of a defect at 16q, as well 4,8. occurrence of multiple trichoepitheliomas Poblete Guitterez et al. found that a sin- and cylindromas.12 Biopsy demonstrated islands of basaloid gle frame-shift mutation in the CYLD 1 was The function of the gene was thought to dermal cells with a ‘jigsaw puzzle’pattern associated with the co-occurrence of cylin- be that of a tumor suppressor, however the surrounded by a hyaline band. Within the dromas and trichoepitheliomas in a family exact mechanism of action had not been islands, there were two cell types noted, suffering from familial cylindromatosis.9 elucidated until recently. The CYLD protein the peripheral cells had small dark staining Zhang et al. discovered by mutation analy- operates in the TNF-a pathway by blocking nuclei and were arranged in a palisading sis that frameshift mutation in the CYLD 1 the activation of NF-kB, which is an fashion and the more central cells had gene was also responsible for multiple inhibitor of apoptosis. Therefore, a defect in larger, pale staining nuclei. These findings familial trichoepitheliomas (FMT:OMIM the CYLD gene product allows for unre- are diagnostic of benign cylindromas (Fig- 601606), which has been previously linked stricted cell proliferation.13,14,15,16 ures 4,5). to chromosome 9p21.10,11 Zhang et al, also
12 FAMILIAL CYLINDROMATOSIS: A CASE REPORT Figure 3
Figure 3 Family TreeThe proband is represented by , the affected sister is , unaffected female , and unaffected male . Malignancy Patients affected with multiple cylindro- mas have no predisposition to basal cell carcinomas or squamous cell carcinoma, which originate from the epidermis.4 There is a small risk of cylindroma undergoing malignant transformation, which is quite rare. There are only 33 cases of malignant transformation in the literature.26,27 Individu- als with multiple cylindromas appear to be at greater risk than those with solitary tumors.28,29,30 Gerretsen et al. reports that malignant tumors were distinguished from Figure 4 benign lesion by their rapid growth, long- standing ulceration, or bleeding.28 The However, the association of trichoepithe- histopathologic criteria of malignancy liomas and cylindromas favors an origin included tumor cell pleomorphism, frequent from a pluripotential cells with potentiality of mitotic figures, with the loss of jigsaw pat- primary epithelial germ cells, which would tern, peripheral palisading, hyaline explain the formation of both hair structures sheaths, and dual cell population.28,31 In a and apocrine structures.22,23,24 This idea, review, by Gerretsen et al, 16 of 24 cases supported by Leonard et al, who found loss of malignant cylindromas, had extensive of heterozygosity at chromosome 16q in local infiltrative growth or distant metas- numerous other adnexal tumors, besides tases.28 Figure 4 cylindromas, suggesting origin from a pluripotential cell.25 In addition, there have Origin of tumor cells been no reported cases of cylindromas Treatment The cell-of-origin of cylindromas is still involving the palms or soles, where apoc- Patients may want the tumors removed controversial. The coexistence of cylindro- rine glands are absent. At this time, there is because they may occasionally be painful, mas and eccrine spiradenomas 17,18 and currently no conclusive evidence for the but more frequently because they can be previous studies add credence to the argu- cell of origin in cylindromas. disfiguring. In a patient with numerous ment for an eccrine origin of cylindro- tumors, surgical excision can be limited to mas.1,17,18,19,20,21 the tumors that are the most bothersome.
SMITH, GILLIAM, MIRMIRANI 13 Martins and Bartolo reported treating two References: 15. Trompouki E, Hatzivassiliou E, Tsichritzis T, Farmer H, patients’ scalp cylindromas using high 1. van Balkom, I DC, Hennekam RC M. Dermal eccrine cylin- Ashworth A, Mosialos G. CYLD is a deubiquitinating energy (40-50W), continuous wave CO2 dromatosis. J. Med. Genet. 1994;31: 321-324. enzyme that negatively regulates NF-kB activation by TNFR family members. Nature. 2003 Aug 14;424(6950): laser (Med-Hitec). They reported no recur- 2. Gerretsen AL, Beemer FA, Deenstra W, Hennekam FAM, 793-6. rence of treated lesions, however one of van Vloten W. Familial cutaneous cylindromas: Investiga- the patients had areas of atrophy and tions in five generations of a family. J Am Acad Derm 16. Lakhani SR. Putting the brakes on cylindromatosis? N Engl 1995; 33(2):199-206. J Med. 2004 Jan 8;350(2):187-8. alopecia following treatment.17 Weyers et al reported the use of electrosurgery, with 3. Welch JP, Wells RS, Kerr CB. Ancell-Speigler cylindromas 17. Martins C and Bartolo E. Brooke-Spiegler syndrome: (turban tumours) and Brooke-Fordyce trichoepitheliomas: Treatment of cylindromas with CO2 laser. Dermatol Surg only a few recurrences. The patient was evidence for a single entity. J Med Genet 1968;5:29-35. 2000;26:877-882. satisfied with the cosmetic result.32 4. Biggs, P. J.; Wooster, R.; Ford, D.; Chapman, P.; Mangion, 18. Goette DL, McConnell MA, Fowler VR. Cylindroma and A new possible mechanism for the pro- J.; Quirk, Y.; Easton, D. F.; Burn, J.; Stratton, M. R. Famil- eccrine spiradenomas coexistent in the same lesion. phylaxis of cylindromas has recently been ial cylindromatosis (turban tumour syndrome) gene Archives of Dermatology 1982; 118:273-274. localised to chromosome 16q12-q13: evidence for its role proposed utilizing the affect of aspirin on as a tumour suppressor gene. Nature Genet 1995; 11: 19. Cotton DWK, Braye SG. Dermal cylindromas originate the TNF-a pathway. In familial cylindro- 441-443. from the eccrine sweat gland. Br J Dermatol 1984;111:53- 61. matosis, the inability of mutated CYLD to 5. Verhoef S, Schrander-Stumpel CTRM, Vuzevski V D, Tem- inhibit the activation of NF-kB results in pelaars A, Jansen LAJ, Malfeyt GAM, Ceelen TL, Lind- 20. Crain RC, Helwig EB. Dermal cylindroma (dermal eccrine hout D, Halley DJJ, van den Ouweland, AMW. cylindroma). Am J Clin Pathol 1961;35:504-14. unrestricted cell proliferation. Aspirin func- Familial cylindromatosis mimicking tuberous sclerosis complex tions in the TNF-a pathway as an inhibitor and confirmation of the cylindromatosis locus, CYLD1, in 21. Munger Bl, Graham JH, Helwig EB. Ultrastructure an histo- for the release of NF-kB. Therefore, aspirin a large family. J. Med. Genet. 1998;35:841-45. chemical characteristics of dermal eccrine cylindroma (tur- ban tumor). J Invest Dermatol 1962; 39:577-95. may work in the place of the defective 6. Takahashi M, Rapley E, Biggs P J, Lakhani SR, Cooke D, CYLD protein in preventing proliferation of Hansen J, Blair E, Hofmann B, Siebert R, Turner G, Evans 22. Delfino M, D’Anna F, Ianniello S, Donofrio V. Multiple 13,14,15,16 DG, Schrander-Stumpel, C, and 17 others : Linkage and hereditary trichoepithelioma and cylindroma (Brooke- new cylindromas. LOH studies in 19 cylindromatosis families show no evi- Spiegler syndrome). Dermatologica 1991;183(2): 150-3. dence of genetic heterogeneity and refine the CYLD locus on chromosome 16q12-q13. Hum. Genet. 106: 58-65, 23. Rasmussen JE. A syndrome of trichoepitheliomas, milia, Conclusions 2000. and cylindromas. Archives of Dermatology 1975;11:610- 614. Cylindromatosis has two presentations, 7. Bignell, G. R.; Warren, W.; Seal, S.; Takahashi, M.; Rapley, E.; Barfoot, R.; Green, H.; Brown, C.; Biggs, P. J.; 24. Elder D, Elenitsas R, Jaworsky C, Johnson B: Tumors of the sporadic form and the multiple variant Lakhani, S. R.; Jones, C.; Hansen, J.; and 29 others : the epidermal appendages; In: Lever's Histopathology of form. The multiple variant is a rare autoso- Identification of the familial cylindromatosis tumour-sup- the Skin. ed 8. Philadelphia: Lippincott-Ravens, 1997: mal dominant disorder with a proposed pressor gene. Nature Genet 2000; 25: 160-165. 748. 100% penetrance, but variable expression. 8. Thomson SA, Rasmussen SA, Zhang J, Wallace MR. A new 25. Leonard N, Chaggar R, Jones, Takahashi M, Nikitopoulou The variable expression was seen in our hereditary cylindromatosis family associated with CYLD 1 A, Lakhani SR. Loss of heterozygosity at cylindromatosis on chromosome 16. Hum Genet 1999;105:171-173 gene locus CYLD, in sporadic adnexal tumours. J Clin patient’s family history in which we Pathol 2001;54:689-692. addressed four generations and only a sis- 9. Poblete Gutierrez P, Eggerman T, Holler D, Juger F, Beer- mann, Grubendorf-Conen E, Zerres K, Merk H, Frank J. 26. Requena L, Kiryu H, Ackerman AB. Cylindroma. In: Neo- ter and the proband are affected. This Phenotype diversity in familial cylindromatosis: a plasms with Apocrine Differentiation. Philadelphia: Lippin- patient had late onset of disease in his frameshift mutation in the tumor suppressor gene CYLD cott-Raven, 1998: 733-50. underlies different skin appendages. J Invest Derm 60’s. His sister developed cylindromas in 2002;119(2):527-531. 27. Durani BK, Kurzen H, Jaeckel A, Kuner N, Naeher H, his mid 30’s. Cylindromatosis has not been Hartschuh W. Malignant transformation of multiple cylin- reported to be associated with any sys- 10. Zhang X, Liang Y, He, P, Yang S, Wang S, Chen J, Yuan dromas. Br J Dermatol. 2001 Oct;145(4):653-6. W, Xu S, Cui Y, Huang W. Identification of the cylindro- temic manifestations, unlike tuberous scle- matosis tumor-suppressor gene responsible for multiple 28. Gerretsen AL, van der Putte Sc, Deenstra W, van Vloten rosis, Muir-Torre, Gardner’s and Cowden’s familial trichoepithelioma. J Invest Derm 2004;122(3):658- WA. Cutaneous cylindroma with malignant transformation. syndromes, which also present with multi- 664. Cancer.1993 Sep1;72(5):1618-23. ple adnexal tumors. Our patient’s initial 11. Harada H, Hashimoto K, Ko MSH. The gene responsible 29. Lin PY, Fatteh SM, Lloyd KM. Malignant transformation in for multiple trichoepithelioma maps to chromosome 9p21. solitary dermal cylindroma. Arch Pathol Lab Med tumors began approximately two years J Invest Derm1996;107:41-43. 1987;111:765-7. after diagnosis with colon cancer, this is likely coincidental in his age group. 12. Fenske, C.; Banerjee, P.; Holden, C.; Carter, N. Brooke- 30. Biernat W, Biernat S. Cutaneous adnexal carcinoma aris- Spiegler syndrome locus assigned to 16q12-q13. J Invest ing within a solitary cylindroma-spiradenoma. Am J Der- Although the conversion to malignancy is Derm 2000;114: 1057-1058. matopathol 1996; 18:77-82. rare, because of the aggressive nature of 13. Brummelkamp T, Nijman S, Dirac A, Bernards R. Loss of 31. Urbanski S, From L, Abramowicz A, Joaquin A, Luk S. the malignant cylindromas, any sympto- cylindromatosis tumour suppressor inhibits apoptosis by Metamorphosis of dermal cylindroma: possible relation to matic lesions should be biopsied. activation of the NF-kB. Nature. 2003 Aug malignant transformation. J Amer Acad Derm. 14;424(6950):797-801. 1985;12(2):188-195.
14. Kovalenko A, Chable-Bessia C, Cantarella G, Israel A, 32. Weyers W, Nilles M, Eckert F, Schill W. Spiradenomas in Wallach D, Courtois G. the tumour suppressor CYLD neg- Brooke-Spiegler syndrome. Am J Dermatopathol. atively regulates NF-kB signaling by deubiquitination. 1993;15(2):156-161. Nature. 2003 Aug 14;424(6950):801-5.
14 FAMILIAL CYLINDROMATOSIS: A CASE REPORT For anywhere there’s acne, there’s EVOCLIN.
Finally, an acne formulation that’s easy to apply over multiple body areas.1 EVOCLIN comes in a patient- preferred foam vehicle, with minimal residue.1,2 It’s effective in reducing inflammatory and noninflammatory lesions. Plus it’s safe and well tolerated.3 Looking for a treatment that works anywhere there’s acne? EVOCLIN is here. EVOCLIN is a once-a-day topical clindamycin foam for the treatment of acne vulgaris. The most common adverse events were headache (3%) and application-site reactions including burning (6%), itching (1%), and dryness (1%). EVOCLIN is contraindicated in individuals with a history of hypersensitivity to preparations containing clindamycin or lincomycin, or a history of regional enteritis, ulcerative colitis, or antibiotic-associated colitis. Diarrhea, bloody diarrhea, and pseudomembranous colitis have been reported with systemic and rarely with topical clindamycin. Discontinuation is recommended if diarrhea develops. Please see following page for full prescribing information. For further details, visit www.evoclin.com. Genotoxicity tests performed included a rat micronucleus test and an Ames Salmonella reversion test. Both tests were negative. Reproduction studies in rats using oral doses of clindamycin hydrochloride and clindamycin palmitate hydrochloride have revealed no evidence of impaired fertility. (clindamycin phosphate) Foam, 1% Pregnancy: Teratogenic effects - Pregnancy Category B Reproduction studies have been performed in rats and mice using subcutaneous and Rx Only oral doses of clindamycin phosphate, clindamycin hydrochloride and clindamycin palmitate hydrochloride. These studies revealed no evidence of fetal harm. The highest FOR TOPICAL USE ONLY. NOT FOR OPHTHALMIC, ORAL, OR INTRAVAGINAL USE. dose used in the rat and mouse teratogenicity studies was equivalent to a clindamycin DESCRIPTION phosphate dose of 432 mg/kg. For a rat, this dose is 84 fold higher, and for a mouse 42 fold Evoclin (clindamycin phosphate) Foam, 1%, a topical antibiotic in a foam vehicle, contains higher, than the anticipated human dose of clindamycin phosphate from Evoclin based on clindamycin phosphate, USP, at a concentration equivalent to 10 mg clindamycin per a mg/m2 comparison. There are, however, no adequate and well-controlled studies in gram in a vehicle consisting of cetyl alcohol, dehydrated alcohol (ethanol 58%), pregnant women. Because animal reproduction studies are not always predictive of polysorbate 60, potassium hydroxide, propylene glycol, purified water, and stearyl human response, this drug should be used during pregnancy only if clearly needed. alcohol, pressurized with a hydrocarbon (propane/butane) propellant. Nursing Mothers: It is not known whether clindamycin is excreted in human milk Chemically, clindamycin phosphate is a water-soluble ester of the semi-synthetic following use of Evoclin. However, orally and parenterally administered clindamycin has antibiotic produced by a 7 (S)-chloro-substitution of the 7 (R)-hydroxyl group of the parent been reported to appear in breast milk. Because of the potential for serious adverse antibiotic, lincomycin, and has the structural formula represented below: reactions in nursing infants, a decision should be made whether to discontinue nursing Figure 1: Structural Formula or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness of Evoclin in children under the age of 12 have
CH3 not been studied. H3C N Geriatric Use: The clinical study with Evoclin did not include sufficient numbers of H H Cl patients aged 65 and over to determine if they respond differently than younger patients. H ADVERSE REACTIONS N CH H 3 ≥ H The incidence of adverse events occurring in 1% of the patients in clinical studies comparing Evoclin and its vehicle is presented below: O Selected Adverse Events Occurring in ≥1% of Subjects HO O Adverse Event Number (%) of Subjects OH Evoclin Foam Vehicle Foam N = 439 N = 154
SCH3 Headache 12 (3%) 1 (1%) Application site burning 27 (6%) 14 (9%) OPO3H2 Application site pruritus 5 (1%) 5 (3%) Application site dryness 4 (1%) 5 (3%) The chemical name for clindamycin phosphate is methyl 7-chloro-6,7,8-trideoxy-6-(1- methyl-trans-4-propyl-L-2-pyrrolidinecarboxamido)-1-thio-L-threo-␣-D-galacto- Application site reaction, 3 (1%) 4 (3%) octopyranoside 2-(dihydrogen phosphate). not otherwise specified CLINICAL PHARMACOLOGY Pharmacokinetics: In an open label, parallel group study in 24 patients with acne In a contact sensitization study, none of the 203 subjects developed evidence of allergic vulgaris, 12 patients (3 male and 9 female) applied 4 grams of Evoclin Foam once-daily for contact sensitization to Evoclin. five days, and 12 patients (7 male and 5 female) applied 4 grams of Clindagel® Orally and parenterally administered clindamycin has been associated with severe (clindamycin phosphate) Topical Gel, 1%, once daily for five days. On Day 5, the mean Cmax colitis, which may end fatally. and AUC(0-12) were 23% and 9% lower, respectively, for Evoclin Foam than for Cases of diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) Clindagel®. have been reported as adverse reactions in patients treated with oral and parenteral Following multiple applications of Evoclin Foam less than 0.024% of the total dose was formulations of clindamycin and rarely with topical clindamycin (see WARNINGS). excreted unchanged in the urine over 12 hours on Day 5. Abdominal pain and gastrointestinal disturbances, as well as gram-negative folliculitis, References: 1. Feldman SR, Sangha N, Setaluri V. Topical Microbiology: The clindamycin component has been shown to have in vitro activity have also been reported in association with the use of topical formulations of corticosteroid in foam vehicle offers comparable coverage against Propionibacterium acnes, an organism which is associated with acne vulgaris; clindamycin. compared with traditional vehicles. J Am Acad Dermatol. however, the clinical significance of this activity against P. acnes was not examined in OVERDOSAGE clinical trials with this product. Cross-resistance between clindamycin and erythromycin Topically applied Evoclin may be absorbed in sufficient amounts to produce systemic 2000;42:1017-1020. 2. Data on file [001], Connetics has been demonstrated. Corporation. 3. EVOCLIN™ prescribing information. effects (see WARNINGS). CLINICAL STUDIES DOSAGE AND ADMINISTRATION In one multicenter, randomized, double-blind, vehicle-controlled clinical trial patients Apply Evoclin once daily to affected areas after the skin is washed with mild soap and Evoclin, the “wisp” logo, and the foam dollop are trademarks, with mild to moderate acne vulgaris used Evoclin (clindamycin phosphate) Foam, 1% or allowed to fully dry. Use enough to cover the entire affected area. and VersaFoam and Connetics are registered trademarks of the vehicle foam once daily for twelve weeks. Treatment response, defined as the Connetics Corporation. proportion of patients clear or almost clear, based on the Investigator Static Global Assessment (ISGA), and the mean percent reductions in lesion counts at the end of treatment in this study are shown in the following table: To Use Evoclin: © 2005 Connetics Corporation 1. Do not dispense Evoclin directly onto your PRM-CLF-030 Evoclin Foam Vehicle Foam hands or face, because the foam will begin 2/05 Efficacy Parameters N=386 N=127 to melt on contact with warm skin. Printed in USA Treatment response (ISGA) 31% 18%* 2. Remove the clear cap. Align the black mark with the nozzle of the actuator. Percent reduction in lesion counts 3. Hold the can at an upright angle and then Inflammatory Lesions 49% 35%* press firmly to dispense. Dispense an amount directly into the cap or onto a cool Noninflammatory Lesions 38% 27%* surface. Dispense an amount of Evoclin that will cover the affected area(s). If the Total Lesions 43% 31%* can seems warm or the foam seems runny, *P< 0.05 run the can under cold water. 4. Pick up small amounts of Evoclin with your INDICATIONS AND USAGE fingertips and gently massage into the Evoclin is indicated for topical application in the treatment of acne vulgaris. In view of the affected areas until the foam disappears. potential for diarrhea, bloody diarrhea and pseudomembranous colitis, the physician should consider whether other agents are more appropriate. (See CONTRAINDICATIONS, WARNINGS, and ADVERSE REACTIONS.) CONTRAINDICATIONS Throw away any of the unused medicine that you dispensed out of the can. Evoclin is contraindicated in individuals with a history of hypersensitivity to preparations Avoid contact of Evoclin with eyes. If contact occurs, rinse eyes thoroughly with water. containing clindamycin or lincomycin, a history of regional enteritis or ulcerative colitis, or a history of antibiotic-associated colitis. WARNINGS HOW SUPPLIED Orally and parenterally administered clindamycin has been associated with severe Evoclin containing clindamycin phosphate equivalent to 10 mg clindamycin per gram, is colitis, which may result in patient death. Use of the topical formulation of available in the following sizes: 100 gram can - NDC 63032-061-00 and 50 gram can - NDC clindamycin results in absorption of the antibiotic from the skin surface. Diarrhea, 63032-061-50 bloody diarrhea, and colitis (including pseudomembranous colitis) have been reported with the use of topical and systemic clindamycin. STORAGE AND HANDLING Studies indicate a toxin(s) produced by Clostridia is one primary cause of Store at controlled room temperature 20°- 25°C (68°- 77°F). antibiotic-associated colitis. The colitis is usually characterized by severe FLAMMABLE. AVOID FIRE, FLAME OR SMOKING DURING AND IMMEDIATELY persistent diarrhea and severe abdominal cramps and may be associated with the FOLLOWING APPLICATION. passage of blood and mucus. Endoscopic examination may reveal Contents under pressure. Do not puncture or incinerate. Do not expose to heat or store pseudomembranous colitis. Stool culture for Clostridium difficile and stool assay at temperature above 120°F (49°C). for C. difficile toxin may be helpful diagnostically. Keep out of reach of children. When significant diarrhea occurs, the drug should be discontinued. Large bowel endoscopy should be considered to establish a definitive diagnosis in cases of Manufactured for Printed in USA severe diarrhea. Antiperistaltic agents, such as opiates and diphenoxylate with Connetics Corporation October 2004 atropine, may prolong and/or worsen the condition. Palo Alto, CA 94304 USA Diarrhea, colitis, and pseudomembranous colitis have been observed to begin up to several weeks following cessation of oral and parenteral therapy with For additional information: clindamycin. 1-888-500-DERM or visit Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. www.evoclin.com In moderate to severe cases, consideration should be given to management with fluids AW No: AW-0317-r3 and electrolytes, protein supplementation and treatment with an antibacterial drug clinically effective against C. difficile colitis. U.S. Patent Pending Avoid contact of Evoclin with eyes. If contact occurs, rinse eyes thoroughly with water. PRECAUTIONS General: Evoclin should be prescribed with caution in atopic individuals. Drug Interactions: Clindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. Therefore, it should be used with caution in patients receiving such agents. Evoclin is a trademark, and VersaFoam, the V logo, the interlocking C logo, and Connetics are registered trademarks of Connetics Corporation. Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenicity of a 1% clindamycin phosphate gel similar to Evoclin was evaluated © 2004 Connetics Corporation by daily application to mice for two years. The daily doses used in this study were approximately 3 and 15 times higher than the human dose of clindamycin phosphate from 5 milliliters of Evoclin, assuming complete absorption and based on a body surface area comparison. No significant increase in tumors was noted in the treated animals. A 1% clindamycin phosphate gel similar to Evoclin caused a statistically significant shortening of the median time to tumor onset in a study in hairless mice in which tumors were induced by exposure to simulated sunlight. Adamantinoid Trichoblastoma/Cutaneous Lymphadenoma: A Case Report and Review of Literature
Angela Marie Leo, BS*, Mary Jo Robinson, DO** *University of Medicine and Dentistry of New Jersey-School of Osteopathic Medicine, Stratford, NJ **Department of Pathology, Division of Dermatopathology, University of Medicine and Dentistry of New Jersey-School of Osteopathic Medicine, Stratford, NJ
ABSTRACT
Cutaneous lymphadenoma is an uncommon benign tumor of the skin whose histogenesis has been debated in the literature. We report 3 additional cases of this tumor, all of which were located on the face. The histology of the lesions we report is consis- tent with past descriptions in which follicular and epithelial attachments as well as follicular germs are present. Immunohisto- chemical staining was performed on Case 1. The tumor cells were positive for high molecular weight keratin, CD 45, CD 30, S-100, and sparsely positive for CD 34. The tumor cells stained negative for EMA, PAS, and CD 20. The immunohistochemical staining pattern of these cases, the presence of epidermal and follicular attachments and the presence of follicular germs gives support to a follicular form of differentiation. Regardless of the histogenesis, cutaneous lymphadenoma is a benign entity that has been successfully treated by excision and has no published reports of recurrence.
Introduction In 1987 Santa Cruz and Barr described 8 cases of what they called a lymphoep- ithelial tumor of the skin.1 In 1991 they renamed this benign tumor of the skin a cutaneous lymphadenoma.2 This tumor took on yet another designation in 1993 when it was classified as a nodular variant of trichoblastoma.3 To date, at least 46 cases of this entity have been reported in the literature. A review of literature shows the age at diagnosis to range from 144 to Figure 2 755 (mean: 44) and that the ratio of males Figure 1 Well defined lobules of a cutaneous to females is 1.4:1. The typical clinical Cutaneous lymphadenoma encased lymphadenoma encased with fibrous description is of an asymptomatic flesh col- by fibrous tissue at periphery and tissue and made up of several popula- ored papule or nodule. Most of the lesions composed of lobules of basaloid cells tions of cells and surrounded by a were located on the head, with three without distinct attachment to the epi- peripheral palisading layer of basaloid located on the lower extremity. Common dermis. (20x) cells. (400x) clinical impressions include a basal cell carcinoma and calcified cyst. All published reports of cutaneous lymphadenoma were cured by excision and no recurrences have been reported. The histogenesis of this tumor has been debated in the literature. Santa Cruz and Barr initially speculated this tumor was dif- ferentiated from an immature piloseba- ceous gland,2 which has been supported by several authors.1-12 Other suggested ori- gins include basal cell carcinoma13 and sweat duct tumors.14-17 We agree with the authors whose histologic studies support follicular differentiation, a form of tri- Figure 3 Figure 4 choblastoma. We report 3 additional cases Focal squamoid differentiation resem- Tumor lobule showing well defined of this tumor. bling squamous eddies with in the indentation containing immature cells tumor lobules. (200x) resembling a follicular germ. (200x) Case Report Histology We report a case (Case1) of adamanti- choblastoma. Case 2 was on the forehead noid trichoblastoma on the forehead of a of a 67-year-old female. Clinically, this The histopathologic features of our 50-year-old female. The clinical impression lesion resembled a calcified cyst or basal cases are similar to previously documented was that of a fibrous tumor. A review of our cell carcinoma. Case 3 was on the fore- reports of adamantinoid trichoblastoma. files, from 1995 until the present, yielded head of a 31-year-old male. The clinical Case 1 is a symmetrical, well-circum- two additional cases of adamantinoid tri- impression was that of a keloid. scribed lesion encased by fibrous tissue
LEO, ROBINSON 17 that does not, however, form a definitive capsule (Figure 1). Irregularly shaped lob- ules of cells were present in the dermis and showed minimal attachment to the epider- mis. The lobules were composed of a peripheral layer of palisading basaloid cells that surrounded a mixed population of inner cells (Figure 2). The inner cell popu- lation included large, clear Reed-Sternberg like cells, small, mature lymphocytes and epithelioid cells. Some nests also exhibited areas of squamoid keratization resembling squamous eddies (Figure 3). A follicular germ was also present in this lesion (Fig- ure 4). Fibroblastic stroma surrounded the Figure 5 nests and contained a variable number of Tumor lobules with more extensive lymphocytes. Cases 2 and 3 show a range squamoid differentiation and less lym- of histopathologic findings, including some phocytic infiltrate. At 12 o’clock there of those described in Case 1. Case 2 Figure 7 is infundibular attachment of the CD 45 staining of the lymphocyctic exhibited infundibular attachment (Figure tumor lobules. (100x) 5). The amount of lymphocytic infiltrate in infiltrate in the tumor lobules and the lobules and stroma ranged from mini- stroma. (200x) mal in Cases 2 and 3 to significant in Case 1. Immunohistochemistry Immunohistochemical staining was per- formed on Case 1. The number of stains performed was limited due to the small size of the biopsy. The tissue was stained for high molecular weight keratin, CD 20, CD 45, CD 30, S-100, epithelial membrane antigen (EMA) and PAS. Case 3 was origi- nally stained for L26, UCHL and CD 34. In addition, Case 3 was stained for CD 20 Figure 6 and CD 45. CD 30 staining the large, clear Reed- CD 30 stained the large, clear Reed- Sternberg like cells within the tumor Sternberg like cells within the lobules (Fig- lobule. (400x) ure 6). Most of the lymphocytes in the tumor lobules and in the peripheral stroma choblastoma, and basal cell carcinoma Figure 8 6 stained positive for CD 45 in Cases 1 and supports this classification. Follicular dif- S-100 staining of the dendritic cells 3 (Figure 7). CD 20 was essentially nega- ferentiation, in our cases, is supported by within the tumor lobules. (400x) tive in Case 1 and rarely positive in Case 3. the high molecular weight keratin staining EMA was consistently negative in the of the basaloid cells of the tumor, as well tumor lobules. However, normal eccrine as, the epidermal and follicular attach- ducts at the periphery of tumor stained ments. In Case 2, there was a focus of epi- positive. Many dendritic cells were S-100 dermal and follicular attachment, as well as positive in the lobules of the tumor (Figure a follicular germ in Case 1. The presence 5,6,11,15 8). High molecular weight keratin stained of epidermal and/or follicular attach- 2,6,11,12, 15 6,9,10,12 positive in the peripheral basaloid cells of ment and follicular germs have the tumor lobules and scattered positive been described by other authors and sug- cells were also seen in the central portion gest a follicular origin. of the lobule (Figure 9). CD 34 was We were able to perform EMA and PAS, sparsely and focally positive at the periph- both of which were consistently negative ery of the tumor in the fibroblastic stroma and both of which showed positive internal and negative in the tumor lobules. The control of the normal eccrine ducts at the PAS stain was negative. periphery. Negative staining with EMA fails to support an eccrine differentation as sug- Figure 9 gested by other authors who found positive High molecular weight keratin staining Discussion EMA staining.14-17 It is not known whether of the peripheral basaloid cells and Adamantinoid trichoblastoma is a rare positivity in these prior reports represents scattered staining of cells within the benign tumor of the skin whose exact his- true eccrine differentiation or the entrap- tumor lobule. (100x) togenesis remains uncertain. However, ment of pre-existing structures.2 The failure most authors seem to support a follicular of the stain in our material suggests that phocytes. This lymphocytic infiltrate stained differentiation, a form of trichoblastoma. A this tumor is not of an eccrine different ion. negative with CD 20 and positive with CD past study comparing the immunohisto- The fibroblastic stroma surrounding the 45. This is a finding consistent with other chemistry of cutaneous lymphadenoma, tri- nests contained a variable number of lym- authors and indicates that the infiltrate is made up predominately of T lymphocytes
18 ADAMANTINOID TRICHOBLASTOMA/CUTANEOUS LYMPHADENOMA: A CASE REPORT AND REVIEW OF LITERATURE and a lesser number of B lymphocytes. have speculated that these cells may rep- lymphoepithelial tumor of the skin (“cutaneous lymphade- noma”). Dermatology Online. 1999;5(1):5. Variation in the number of lymphocytes resent histiocytes or activated lympho- 8. Rodriquez-Diaz E, Roman C, Yuste M, Moran AG, Ara- might be explained as a function of the age cytes.8 mendi T. Cutaneous lymphadenoma: an adnexal neo- plasm with intralobular activated lymphoid cells. American of the lesion, with older lesions exhibiting a Regardless of its histogenesis, adaman- Journal of Dermatopathology. 1998;20(1):74-78. greater amount of infiltrate. However, tinoid trichoblastoma is a benign entity that 9. Betti R, Alessi E. Nodular trichoblastoma with adamanti- future studies would be needed to support noid features. American Journal of Dermatopathology. has been successfully treated by excision. 1996;18(2):192-195. this. To date there have been no reports of a 10. Diaz-Cascajo C, Borgi S, Rey-Lopez A, Carretero-Hernan- dez G. Cutaneous lymphadenoma. A peculiar variant of Some authors have studied CD 34 and reoccurrence in any of the cases which nodular trichoblastoma. American Journal of Der- found it to be positive in the fibroblastic have been published. matopathology. 1996;18(2):186-191. stroma surrounding the tumor lobule. This 11. Masouye I. Cutaneous lymphadenoma: report of 2 cases. Dermatology. 1992;185(1):62-65. pattern of staining is found in trichoblas- References: 12. Wechsler J, Fromont G, Andre JM, Zafrani ES. Cuta- tomas and trichoepitheliomas.6 In one of neous lymphadenoma with focal mucinosis. Journal of 1. Santa Cruz DJ, Barr RJ. Lymphoepithelial Tumor of the Cutaneous Pathology. 1992;19(2):142-1444. our cases, there was only sparse and focal Skin. Journal of Cutaneous Pathology. 1987; 14:369. 13. Aloi F, Tomasini C, Pippione M. Cutaneous lymphade- positivity at the periphery of the tumor lob- 2. Santa Cruz DJ, Barr RJ, Headington JT. Cutaneous lym- noma. A basal cell carcinoma with unusual inflammatory phadenoma. American Journal of Surgical Pathology. reaction pattern? American Journal of Dermatopathology. ules. There has been one published report 1991; 15(2):101-110. 1993; 15(4):353-357. of a cutaneous lymphadenoma with 3. Ackerman AB, editor. Neoplasms with Follicular Differentia- 14. Tsang WY, Chan JK. So-called cutaneous lymphade- desmoplastic stroma.18 However, this tion: Lea and Febiger; 1993. noma: a lymphotropic solid syringoma? Histopathology. 4. Inaloz HS, Chowdhury MM, Knight AG. Cutaneous lym- 1991; 19(4):382-385. seems to be a rare finding. phadenoma. Journal of the European Academy of Der- 15. Requena L, Sanchez Yus E. Cutaneous lymphadenoma The staining of the large cells with CD30 matology and Venereology. 2001; 15(5):481-483. with ductal differentiation. Journal of Cutaneous Pathol- 5. Botella R, MacKie. Cutaneous lymphadenoma: a case ogy. 1992; 19(5):429-433. suggests these may be of lymphocytic dif- report and review of literature. British Journal of Derma- 16. Pardal-de-Oliveira F, Sanches A. Cutaneous lymphade- ferentiation, as seen in Hodgkin’s lym- tology. 1993; 128(3):339-341. noma. Histopathology. 1994; 25(4):384-387. 6. McNiff JM, Eisen RN, Glusac EJ. Immunohistochemical 17. Dahill SW, Seywright M. Synchronous occurrence of cuta- phoma. However, there is some variation comparison of cutaneous lymphadenoma trichoblastoma, neous lymphadenoma and syringoid eccrine carcinoma in among studies as to the number of CD 30 and basal cell carcinoma: a support for classification of a single patient. Histopathology. 1998;33(1);89-90. lymphadenoma as a variant of trichoblastoma. Journal of 18. Schroch RG. Cutaneous lymphadenoma with desmoplas- positive cells typically found in this lesion, Cutaneous Pathology. 1999;26(3)119-124. tic trichoepitheliomatoid features. Journal of Cutaneous as well as its histogenesis. Other authors 7. Pujol RM, Matias-Guiu X, Taberner R, Alomar A. Benign Pathology. 1997;24:123.
LEO, ROBINSON 19 Hyperhidrosis: A Review of Pathogenesis and Management
Shari Sperling*, Charles A. Gropper, M.D.**, Helene E. Price, M.D.***, Cindy Hoffman, D.O., F.A.O.C.D.**** *4th year medical student, New York College of Osteopathic Medicine ** Assistant Clinical Professor of Dermatology, Mount Sinai Medical Center, New York, NY, Chief of Dermatology, St. Barnabas Hospital and Bronx Veterans Affairs Medical Center *** Clinical Instructor of Neurology, Mount Sinai Medical Center New York, NY **** Dermatology Program Director, Lutheran Medical Center, Brooklyn, NY
ABSTRACT
Hyperhidrosis is the excessive production of sweat in amounts greater than needed physiologically for thermoregulation. A literature review was performed concerning the pathophysiology, diagnosis and treatment of hyperhidrosis.
mal rates of eccrine secretion from palmar Figure 1 Introduction surfaces. Some patients may perspire 50 Minor Starch Iodine Test Hyperhidrosis is a chronic disorder that mg of sweat per minute in the axillae and can affect any part of the body, particularly others may produce 30 mg of sweat in the the hands, axillae and plantar surfaces of palms.4 Secondary skin infections and the feet. (1) Although under reported, idio- bromhidrosis, odor due to perspiration, pathic hyperhidrosis has been estimated to may occur due to the excessive moisture affect 0.6-1% of the population according and maceration of the skin from the accu- to a study of young Israelis. (2) A more mulation of sweat.7 recent survey of the United States popula- tion has shown a prevalence of 2.8% of Anatomy individuals affected with hyperhidrosis, with only 38% of affected individuals discussing There are three types of sweat glands -- hyperhidrosis with their health care profes- eccrine, apocrine, and apoeccrine -- pre- sional. (3) The disorder typically presents sent on every part of the skin except the itself in childhood and adolescence and lips and glans penis. Eccrine glands, also persists throughout life. Excessive sweat- known as merocrine glands, are located ing may be associated with social embar- deep in the reticular dermis surrounded by rassment and interferes in both personal a rich capillary plexus. Each gland consists and professional aspects of life. Sweating of a single coiled secretory duct leading attacks may be precipitated by emotional into an excretory duct which spirals stressors such as social situations or public upwards into the epidermis and opens onto speaking, high ambient temperature and the skin surface.8 Eccrine glands secrete a ingestion of stimulants such as coffee. (4) dilute solution of urea, lactic acid and Many treatment options have been offered sodium chloride.9 Eccrine glands regulate to treat hyperhidrosis, including topical temperature by cooling the body through antiperspirants, oral medications, psy- the evaporation of water from the skin.10 chotherapy, iontophoresis, BOTOX injec- They also function as a natural method to Starch iodine test, with the darkened tions, and surgery. remove toxins from the body. Eccrine area showing location of excessive glands are found in the greatest density in sweating before and after treatment Background Information the axillae, palms, soles and forehead.10 with BTX-A. Photo courtesy of Markus Apocrine glands play no role in ther- Naumann, MD Sweating is an integral function of the moregulation and do not contribute to © 2004 International Hyperhidrosis human body that maintains temperature, hyperhidrosis. These glands are different Society. skin hydration and fluid and electrolyte bal- than eccrine glands in that they are larger ance. There are approximately 2 - 3 million and open into hair follicles.9 They become glands and sustain copious amounts of sweat glands on the skin, including around most active at the onset of puberty and are fluid.(9) 3,000 sweat glands per square inch on the seen in largest quantities in the axillae, per- palms of hands. Adults produce an aver- ineum, and areolae. They are the phyloge- Primary and Secondary age of 100 ml of sweat daily without exces- netic remnant of the mammalian sweat Hyperhidrosis sive heat or exercise. With strenuous work gland and produce pheromones. Apocrine There are two major types of hyperhidro- or exercise, a person can produce 10 L per glands produce sex hormones, and thus, sis -- primary and generalized. Primary, or 24 hours. On average, there is an esti- are responsible for an individual’s sexual idiopathic, hyperhidrosis is the most com- mated 500 ml of water excreted in sweat scent. Sweat generated from apocrine mon form of this disorder. It typically is 5 per day. glands is initially odorless and develops an bilateral and symmetric, involving the axil- The most common form of hyperhidrosis odor only after interaction with skin bacte- lae, palms, soles or face in individuals occurs in the palms and soles (60%), but ria. under the age of 25. 11 the condition also manifests in the axillae Apocrine glands are located in the axil- Generalized hyperhidrosis may be the 6 (30-40%) and face (10%). Patients with lae and appear during puberty. These consequence of an underlying metabolic hyperhidrosis exceed 12 to 30 time’s nor- glands are much larger than the eccrine disorder, febrile illness or malignancy and
20 HYPERHIDROSIS Table I. Causes of Hyperhidrosis Table II. Lab Studies Primary Thyroid function tests Hyperthyroidism Idiopathic Thyrotoxicosis Secondary Physiological Blood glucose levels Diabetes mellitus Emotional Hypoglycemia Environment Exercise Menopause Urinary catecholamines Pheochromocytoma Metabolic disorders Diabetes mellitus Uric acid levels Gout Hypoglycemia Gout Purified protein derivative (PPD) Tuberculosis Pheochromocytoma Hyperthyroidism Thyrotoxicosis Chest radiography Tuberculosis Febrile Illnesses Neoplasm Medications Antiemetics, propanolol, pilocarpine, tricyclic antidepressants cholinergic neurons which secrete acetyl- evidence that primary palmar hyperhidrosis Chronic alcoholism choline at the sympathetic nerve endings, is a hereditary disorder with variable pene- Neoplasia while apocrine glands are regulated by trance and no sex - linked transmission.17 Hodgkin disease sympathetic adrenergic nerve fibers. Central nervous system lesions Innervation of eccrine sweat glands begins Diagnostic Testing Tuberculosis in the hypothalamus, via the thermosensi- The amount of sweating can be mea- tive preoptic sweat center, and travels sured using several different techniques. through the brainstem and medulla.7 The usually presents in adults who suffer from The Minor starch - iodine test assesses the nerve fibers synapse at the intermediolat- sweating both during the day and at night. amount of sweat by placing a paper satu- eral cell nuclei of the spinal cord in the Other causes of excessive sweating rated with iodine, or placing a layer of respective endocrine glands.13 Hyperhidro- include medications, metabolic disorders, iodine - starch mixture, on the affected sis occurs as a result of a dysfunction of menopause, spinal cord injuries, gustatory area of skin. The skin is wiped with a the central sympathetic nervous system sweating, chronic alcoholism, subacute brown - orange iodine solution and then and affects the hypothalamic nuclei, pre- bacterial endocarditis, hyperthyroidism, lightly dusted with baking cornstarch pow- frontal areas and their cholinergic connec- hypoglycemia, Hodgkin’s disease, tubercu- der. As sweat emerges from the eccrine tions.14 The reflex circuit hyperexcitablity is losis and neurologic or neoplastic dis- glands, the iodide molecule and the starch believed to cause the neurogenic over eases. 8,10 (Table I) in the powder produce a colorimetric reac- activity involved in eccrine secretion.14 tion, causing the powder to turn deep pur- The workup for hyperhidrosis consists of Sweating on the palms, soles and axillae ple. This technique enables the physician several lab studies to exclude underlying is caused by emotional stress, while sweat- to map the exact location of active sweat- disorders. This consists of thyroid function ing on the face, chest and back is due gen- ing and later use that original mapping as tests to exclude hyperthyroidism or thyro- erally to heat stimuli. Emotional sweating is comparison for efficacy of treatment.4 (Fig- toxicosis, urinary catecholamines to regulated by the cerebral cortex, while ther- ure I) exclude pheochromocytoma, blood glu- mal sweating is believed to be controlled cose levels to exclude diabetes mellitus or Gravimetric testing is used as a research by the hypothalamus.10 Therefore, emo- hypoglycemia, uric acid levels to exclude tool to document response to treatment. tional sweating does not occur while sleep- gout, and a purified protein derivative Sweating is measured by placing filter ing, while thermal sweating occurs (PPD) to exclude tuberculosis. A chest x- paper in contact with the palm for a fixed throughout the day.15 Emotional sweating 4 ray may also rule out tuberculosis as well amount of time and then weighing it. on the palms and soles can be either con- as neoplastic diseases.12 Lab tests are tinuous or phasic. Continuous sweating unnecessary if the presentation is charac- occurs more frequently during the summer Treatment teristic of primary hyperhidrosis.11 (Table II) and is not precipitated definitively by emo- There are several treatments available to Pathophysiology of sweating tional factors. However, phasic sweating temporarily relieve symptoms of hyper- occurs with minor emotional or mental hidrosis, including prescription - strength Eccrine glands are primarily responsible activity and no difference has been noted antiperspirants, aldehydes, oral anticholin- for thermoregulation. Sweat production is between summer and winter months. ergics, psychotherapy, ionotophoresis, bot- normally controlled by the hypothalamus, Histologically, there is no increase in the ulinum toxin type A (Botox) injections and which incorporates sensory information number or size of eccrine glands in surgical procedures. from the body to increase and decrease patients with hyperhidrosis. It is believed body temperature. Conductive heat loss is that hyperhidrosis is caused by neurogenic Aluminum Chloride achieved through the diversion of blood over activity of normal number and normal flow to superficial vessels, while evapora- Over the counter antiperspirants are - sized sweat glands.7 Part of the neuro- tive heat loss occurs with eccrine sweat beneficial for individuals with mild symp- genic aspect of sweating may be heritable secretion.8 toms. These products usually contain alu- since 30% to 50% of patients have a family minum and work by partially obstructing The sympathetic nervous system medi- 16 history of excessive sweating. Based on the opening of the sweat glands. Prescrip- ates eccrine and apocrine sweat gland a prospective study published in the Jour- tion strength antiperspirants, such as 20% function. Eccrine glands are innervated by nal of Vascular Surgery, there has been aluminum chloride in alcohol (Drysol) or
SPERLING, GROPPER, PRICE, HOFFMAN 21 with it. Benzodiazepines are helpful in forms of the A serotype are Botox and Dys- Table III. Treatment Algorithms reducing the emotional stimulus to exces- port. A new B serotype, called Myobloc in sive perspiration by decreasing anxiety.8 the United States and Neurobloc in Axillary hyperhidrosis These agents should be used only for brief Europe, was recently approved by the 1. Over the counter antiperspirants amounts of time in order to prevent prob- Food and Drug Administration for cervical 2. Topical therapy with aluminum chloride lems with dependency.8 Beta - blockers dystonia.4 The A serotypes have been 3. Intradermal injections of botulinum have also been used to reduce emotional studied more and have had more clinical toxin stimuli which leads to excessive sweating. experience in the treatment of hyperhidro- 4. Surgery sis.4 Palmar hyperhidrosis Ionotophoresis In large quantities, Botulinum toxin is 1. Topical therapy with aluminum chloride Iontophoresis is the least expensive responsible for a type of food poisoning 2. Ionotophoresis treatment available for long - term results known as botulism. When administered in 3. Intradermal injections of botulinum toxin for localized areas of hyperhidrosis. The small amounts, BOTOX inhibits the release 4. Endoscopic thoracic sympathectomy mechanism is not fully understood, but it of acetylcholine, preventing the transmis- Plantar hyperhidrosis has been thought to cause a temporary sion of nerve impulses to the sweat glands, 1. Topical therapy with aluminum chloride blockage of the sweat duct at the level of resulting in decreased sweating.27 2. Tap water ionotophoresis the stratum corneum. An ionized sub- Botox is used on the palms, soles and 3. Intradermal injections of botulinum toxin stance is introduced, by a direct current, axillae with a total body surface area of the through intact skin by placement of the treated area being less than one percent.4 6.25% aluminum tetrachloride (Xerac), are patient’s hands in a bath of warm water or Topical or nerve block anesthesia may be usually the first line agents.10 These topical electrolyte solution with anticholinergic used prior to injections, with the Minor 8 treatments are applied 2-3 times a week, in agents. A direct low - intensity current (15- starch - iodine technique used to identify the evening. It is believed that these agents 18 mA), supplied by a D/C generator the area being treated. The angle of the mechanically obstruct the distal sweat immersed in water, is directed across the needle should be less than 45 degrees to 22 gland ducts by facilitating the formation of a palms or soles. The treatment stuns the prevent backflow, with the distance precipitate18 or by causing atrophy of the sweat glands and decreases the secretion between injection sites ranging from 0.5 to secretory cells.19 Burning and irritation are of sweat for approximately 6 hours to a 2 centimeters.9 Intracutaneous injections 23 common side effects, especially when week. Patients undergo three to four are recommended rather than subepider- treating the axillae. Long - term use of treatments per week, each lasting twenty mal injections, since the latter are too close 11 antiperspirants sometimes results in the to thirty minutes. Contraindications to to nerve endings.15 degeneration of the eccrine unit and reso- treatment include pregnancy, cardiac pace- Repeated injections are required to (8) lution of localized hyperhidrosis.19 makers and metal orthopedic implants. maintain dryness and are effective from Complications include temporary erythema one to six months on average. Reported Aldehydes of the treated skin with a transient rash and cases have shown the duration of anhidro- Topical aldehyde agents, such as peeling and cracking of skin but such side sis in the axillae from 4-6 months, 3-12 formaldehyde and glutaraldehyde, are effects have no long - term adverse effects. months to palmar treatment, with an aver- effective for the palms and soles, but are However, long - term maintenance treat- age of 6 months on the palms.4 It has been ments are required to keep patients symp- suggested that the palms do not have a short - lasting. They reduce perspiration by 24 occluding the sweat duct through denatur- tom free. longer duration of anhidrosis due to prob- ing keratin at the top of eccrine pores.20, 21 Botulinum toxin therapy lems with backflow, smaller diffusion dis- Obstruction of the sweat gland is localized tance in thick palmar skin, and the higher to the superficial stratum corneum. Fre- Neuromuscular blocking agents act at number of cholinergic nerve endings in pal- quent application is necessary since epi- the neuromuscular junction of skeletal mar skin.4 dermal regeneration within a few days muscle and autonomic ganglia, inhibiting Aside from pain during injections, the reopens the lumen.7 Side effects include the transmission of nerve impulses. Botu- most common side effect of Botox is bruis- irritation and yellow - brown discoloration of linum toxin type A (Botox) has been ing and mild soreness in the treated areas. the skin.7 approved by the Food and Drug Adminis- Certain patients also exhibit weakness and tration (FDA) in the treatment of hyper- instability of the lumbrical muscles of the Anticholinergics hidrosis based on results from two phase - hand. The weakness typically subsides 25 Oral anticholinergic agents competitively three clinical studies. Botox has also and is spontaneously reversible. Botox is inhibit the binding of acetylcholine released proven successful in the treatment of cervi- contraindicated if there is an infection at preglandularly to its cholinergic receptor, cal dystonia, facial wrinkles, spasticity and the proposed site of injection or a known thus blocking neuroglandular signaling. migraines. A clinical study involving 322 hypersensitivity reaction to any of the However, these agents lack specificity and patients with excessive axillary sweating ingredients in the formulation. In addition, therefore block normal physiologic cholin- was performed. Fifty - seven out of 104 patients with myasthenia gravis or Eaton - ergic signaling, causing unappealing side (55%) patients treated with BOTOX Lambert syndrome should use Botox with effects. The adverse effects of anticholiner- achieved an effective response, while only caution since they may be at an increased gic medications consist of dry eyes and six out of 108 (6%) patients treated without rate of developing speech impairment or mouth, blurry vision and bowel and bladder Botox showed improvement. Eighty - four respiratory compromise.26 out of 104 (81%) Botox treated patients function disturbances.8 Botox treatments have proven to be achieved greater than a 50% reduction in effective. There have been no reports of Psychotherapy sweating, compared to only 44 out of 108 compensatory sweating in individuals (41%) treated without Botox.26 Another treated in the palms or axillae.4 Psychotherapy has limited effects in the study showed the median duration of majority of patients. Psychological prob- response to BOTOX was 201 days or 6.7 Surgery lems are generally a result of hyperhidro- months.26 sis, not the primary cause.22 Therefore, The major surgical methods for treat- psychiatric care cannot cure this disorder, There are several serotypes of the botu- ment of hyperhidrosis are sympathectomy, but may help the patient accept and cope linum toxin. Two commercially available excision of affected glands and subcuta-
22 HYPERHIDROSIS neous liposuction. Sympathectomy has the management and treatment of hyper- 308. (7) Cohen J, Solish, N. “Treatment of hyperhidrosis with bot- been performed since 1920 and involves hidrosis. They suggest criteria for estab- ulinum toxin”, Facial Plastic Surgery Clinics of North destruction of the ganglia responsible for lishing a diagnosis of primary hyperhidrosis America, November 2003; 11(4): 493-502. (8) Atkins J, Butler, P. “Hyperhidrosis: A Review of Current hyperhidrosis. Thoracic ganglia 1 (T1) con- -- excessive, visible sweating for at least Management”, Plastic and Reconstructive Surgery, 2002; trols facial hyperhidrosis, thoracic ganglia 2 six months without an apparent cause, with 110 (1):222-8 and 3 (T2 and T3) are responsible for pal- at least two of the following characteristics: (9) Odderson, Ib R. “Treatment of hyperhidrosis and drooling with botulinum exotoxin”, Physical Medicine and Rehabili- mar hyperhidrosis and thoracic ganglia 2, 3 bilateral and symmetric sweating, sweating tation Clinics, November 2003; 14(4): 837-854. and 4 (T2, T3 and T4) control axillary that impairs daily activities, frequency of at (10) Smith, Christopher. “Idiopathic hyperhidrosis”, UpToDate 12 2004. www.uptodate.com hyperhidrosis. Sympathectomy interrupts least one episode a week, age of onset (11) Hornberger J, Grimes K, Naumann M, Glaser DA, Lowe the nerve tracks and ganglia which trans- less than 25 years, positive family history, N, Naver H, Ahn S, Stolman L. “Recognition, diagnosis, and treatment of primary focal hyperhidrosis”, Journal of mit the signals to the sweat glands and and cessation of focal sweat during sleep. the American Academy of Dermatology, August 2004; treats palmar, facial and axillary hyper- Secondary causes of excessive sweating 51(2) hidrosis.22 Endoscopic Thoracic Sympa- must be ruled out to make a diagnosis of (12) Altman, Rachel. “Hyperhidrosis”, eMedicine, 2004. www.emedicine.com 11 thectomy is considered a safe procedure primary hyperhidrosis. (13) Sato K, Kang WH, Saga KT. “Biology of sweat glands and and is minimally invasive.22 The rate of their disorders I. Normal sweat gland function”, J Am Recent algorithms have been developed Acad Dermatol, 1989;20:537-563. definitive cure is almost 100% if performed in treating the different types of hyperhidro- (14) Manca D, Valls- Sole J, Callejas MA. “Excitability recov- by an experienced surgeon.22 sis. (Table III) First - line therapy for axillary ery curve of the sympathetic skin response in healthy vol- unteers and patients with palmar hyperhidrosis”, Clin There have been several complications hyperhidrosis is topical aluminum chloride Neurophysiol, 2000; 111:1767-1770. reported with endoscopic thoracic sympa- antiperspirants. Botulinum toxin is second (15) Thomas I, Brown J, Vafaie J, Schwartz R. “Palmoplantar Hyperhidrosis: A Therapeutic Challenge”, American Fam- thectomy: compensatory sweating in previ- line treatment, followed by local surgery ily Physician, 2004 ously unaffected areas (50-60%), gustatory and sympathectomy.31 In selected cases, (16) Sato K, Kang WT, Saga KT, Sato KT. “Biology of sweat glands and their disorders II. Disorders of sweat gland sweating (5-10%), recurrence of hyper- iontophoresis and systemic anticholinergic function”, J Am Acad Derm, 1989; 20:713-726. hidrosis, pneumothorax, intercostals neu- drugs may be attempted before surgery (17) Ro KM, Cantor RM, Lange KL, Ahn, SS. “Palmar hyper- ralgia and Horner syndrome (1%). The although there is a lack of convincing evi- hidrosis: evidence of genetic transmission”, Journal of 11 Vascular Surgery, 2001; 35(2):382-6. cure rate is estimated to be 95-98% of dence for their effectiveness. In addition, (18) Quatrale RP, Coble DW, Stone KL, et al. “The mechanism patients with palmar hyperhidrosis, 75-80% iontophoresis is not used in the axillary of antiperspirant action by aluminum salts II. Histologic observations of human eccrine sweat glands inhibited by with axillary hyperhidrosis and 25 % of region due to the location and difficulty of aluminum chorohydrate”, J Soc Cosmet Chem, 1981; patients with plantar hyperhidrosis.23 Iso- using an iontophoresis machine in the axil- 32:107-136. (19) Holzle E, Braun- Falco O. “Structural changes in axillary lated plantar hyperhidrosis requires a Lum- lae. eccrine glands following long- term treatment with alu- bar Sympathectomy, which is an open First line treatment for palmar and plan- minum chloride hexahydrate solution”, Br J Dermatology, abdominal procedure, while diffuse hyper- 1984; 110; 339. tar hyperhidrosis is topical aluminum chlo- (20) Sato K, Dobson RL. “Mechanism of the antiperspirant hidrosis of the trunk or generalized to the ride, followed by iontophoresis. If effect of topical glutaraldehyde”, Arch Dermatol, whole body cannot be treated surgically. iontophoresis does not prove to be benefi- 1969;100:564-569 (21) Gordon Bl, Maibach HI. “Eccrine anhidrosis due to glu- Other, less common surgical procedures cial, botulinum toxin, systemic medications, taraldehyde, formaldehyde, and iontophoresis”, J Invest are surgical excision of affected sweat surgery and sympathectomy should be Dermatol, 1969; 53:436-439. 31 (22) Tarfusser, Ivo. “Hyperhidrosis”, 1999, UpToDate. glands, subcutaneous liposuction and sub- attempted. Patients with plantar hyper- www.uptodate.com cutaneous curettage. Surgical excision is hidrosis should be educated regarding (23) Naunheim, Keith. “Hyperhidrosis”, The Society of Tho- racic Surgeons Patient Information, 2000. beneficial for axillary sweating since it local hygiene measures. These include (24) Connolly M, de Berker D. “Management of primary hyper- removes the affected sweat glands. Subcu- changing socks twice daily, using hidrosis: a summary of the different treatment modalities”, taneous liposuction is used to remove absorbent foot powder twice daily and American Journal of Clinical Dermatology, 2003; 4(10): 681-697. 11 eccrine sweat glands that cause axillary alternating pairs of shoes. (25) “FDA approves BOTOX for hyperhidrosis treatment”, Der- hyperhidrosis. This procedure is associ- matology Times, August 2004. (26) BOTOX prescribing information ated with smaller scars and diminished hair Conclusion (27) Wollina U, Karamfilov T. “Botulinum toxin A for palmar loss in the affected area. Curettage is per- hyperhidrosis”, J Eur Acad Dermatol Venereol, 2001; 15(6): 555-558. formed to destroy eccrine glandular tissue Hyperhidrosis is a common disorder (28) Bar LH, Kuypers BR. “Behavior therapy in dermatologic from beneath the skin surface.7 affecting up to 3% of the population. It can practice”, Br J Dermatol, 1973; 88:591. be a devastating condition to affected indi- (29) Duller P, Gentry WD. “Use of biofeedback in treating chronic hyperhidrosis: a preliminary report”, Br J Dermatol, Alternative Treatments viduals, but there are several treatments 1980; 103:143-146. available to manage it. The success of (30) Shenefelt PD. “Hypnosis in dermatology”, Arch Dermatol, 2000; 136:393-399. Several alternative treatments have treatment depends on the severity of the (31) Hilton, Lisette. “Stopping sweat… and soon. Botulinum been used with some success in treating problem and area of the body affected. toxin effective for pediatric hyperhidrosis”, Dermatology hyperhidrosis. These include biofeedback, However, newer treatment options offer Times, 2003. hypnosis and several relaxation tech- patients a better prognosis. niques.28, 29, 30 Several herbal remedies, such as St. Johns’ Wort and chamomile, have References been used; however, no well - documented (1) Moran KT, Brady MP. “Surgical management of primary clinical trials have supported these treat- hyperhidrosis”, Br J Surg, 1991; 78:279. ments. 7 (2) Adar R, Kurchin A, Zweig A, Mozes M. “Palmar hyper- hidrosis and its surgical treatment: a report of 100 cases”, Ann Surg, 1977; 186:34-41. (3) Strutton DR, Kowalski JW, Glaser DA, Stang PE. “U.S. Management prevalence of hyperhidrosis and impact on individuals with axillary hyperhidrosis: Results from a national survey”, Treatment for idiopathic hyperhidrosis is Journal of the American Academy of Dermatology, 2004; based on the severity and location of 51(2):241-248. (4) Glogau, Richard. “Treatment of hyperhidrosis with botu- symptoms, and treatment options today linum toxin”, Dermatology Clinics, 2004; 22: 177-185 have proven effective. Conservative mea- (5) Ham, A. A; Histology, J.B Lippincott Company, Philadel- phia/ Toronto, 1974. sures should generally be attempted (6) Nauman, M. “Treatment of focal hyperhidrosis with botu- before more invasive treatments. linum toxin A”, In: Brin MF, Jankovic J, Hallett M, eds. Scientific and therapeutic aspects of botulinum toxin. Hornberger et al propose a protocol for Philadelphia: Lippincott Williams & Wilkins 2002: 303-
SPERLING, GROPPER, PRICE, HOFFMAN 23 A Review of Occupational Skin Disorders for the Practicing Clinician
Erik Austin, D.O., M.P.H., Bill V. Way, D.O., FAOCD, Department of Dermatology - Texas Division, Northeast Regional Medical Center
ABSTRACT
Occupational skin disorder is defined as any abnormality of the skin that is a direct result of, or has been aggravated by, the patient's work environment. Among all occupational diseases, occupational skin disorders are known to be one of the most com- mon. In fact, occupational skin diseases constitute approximately 10% or more of reported occupational disorders. The thirteen most common occupational dermatoses are presented herein in an easy to assimilate fashion. Given the impact of skin disease on patients' lives, as well as the financial loss to workers and their employers, the practicing clinician should be fully equipped to evaluate, diagnose, treat, and prevent occupational skin disorders. The intent of this review is to enhance the practicing clini- cian's knowledge and recognition of occupational skin diseases, with special emphasis on performance of a comprehensive med- ical history with the occupational dermatology patient, so that the clinician can better serve his or her patients who have work-related skin diseases and disorders.
Introduction hobby exposures, (5) a review of allergies • Connective Tissue Diseases and medications, and (6) a review of the • Granulomas Among all occupational diseases, occu- use of any personal protective equipment • Disorders of Hair and Nails pational skin disorders are known to be and personal hygiene practices at work. • Infections and Infestations one of the most common. In fact, occupa- During the medical history, further evalu- • Conditions Caused by Physical and tional skin diseases constitute approxi- ation should include asking the patient the Mechanical Agents mately 10% of reported occupational following questions: (1) What do you think diseases.1 However, this figure is likely an is causing the problem? (2) Do any co- • Systemic Diseases Due to Percuta- underestimate of the actual prevalence of workers have the same problem? (3) How neous Absorption occupational skin disorders due to a signifi- is your condition on days off or on vaca- Irritant Contact Dermatitis cant underreporting, by either the worker or tion? (4) Have there been any recent physician, of skin disease in the occupa- changes in your work practices? Effective Irritant contact dermatitis accounts for 3 tional setting.2 diagnosis of many skin conditions requires 80% of all occupational skin diseases. The definition of an occupational skin a thorough investigation of occupational- Any substance in the workplace may act as disorder is as follows: any abnormality of related etiologies, whether the setting is pri- an irritant and damage skin at the site of the skin that is a direct result of, or has mary care, occupational medicine, or contact. Common irritants include: acids, been aggravated by, the work environment. dermatologic consult. alkalis, adhesives, glues, cement, aromatic In 1999, the highest incidence of occupa- chemicals, bacteria, fungi, chemical salts, tional skin disease reported to the Occupa- Investigation and Fact Finding foods, fiberglass, metals, oils and greases, tional Safety and Health Administration To obtain information related to the plants, sawdust, soaps, detergents, sol- was in the "agriculture, forestry, and fishing ingredients, physical properties, and vents, ethylene oxide and other gases, tar sector."3 adverse health effects of a chemical agent, and asphalt. Given the impact of skin disease on it is advised that the health care provider Symptoms of irritant contact dermatitis patients' lives, as well as the financial loss ask the worker, employer, or manufacturer range from dryness to erythema, swelling, to workers and their employers, the practic- for copies of the Material Safety Data vesicles, and later exudation. Burning or ing clinician should be fully equipped to Sheets for the agents to which the worker stinging may also occur. evaluate, diagnose, treat, and prevent is exposed. The federal Chemical Hazard Irritant contact dermatitis reactions may occupational skin disorders. The intent of Communication Standard (29 CFR be classified as acute, acute-delayed (8-24 this article is to enhance the practicing clini- 1910.1200) and “right to know” laws hours following exposure), subclinical, cian's knowledge and recognition of occu- require employers to provide employees chronic, or subjective (stinging and burning pational skin disorders, via review of the detailed information about hazardous with a lack of clinical signs). common occupational skin diseases, with chemicals used in the workplace.4 Finally, Many substances that produce an irritant special emphasis on performance of a if necessary, one can visit the work-site, or contact dermatitis upon patch testing may comprehensive medical history with the arrange for a paraprofessional, to observe not produce irritant contact dermatitis occupational dermatology patient. daily job activities. under actual conditions of exposure, which are less extreme.5 Thus, patch testing with Initial Evaluation of Occupa- Review of Common Occupa- irritants should be avoided. On the other tional Skin Disorders tional Dermatoses hand, patch testing with allergens is useful for excluding allergic contact dermatitis as Initial evaluation of an occupational skin The common occupational dermatoses a diagnosis. Usually, patient history and disorder consists of a routine medical his- consist of the following: unusual/asymmetric patterns upon exam tory, as well as a complete occupational • Irritant Contact Dermatitis distinguish irritant contact dermatitis from history including the following: (1) a • Allergic Contact Dermatitis other disorders. detailed description of the patient's current • Photosensitivity Disorders job activities, (2) a detailed description of The primary treatment of irritant contact • Acne and Folliculitis all part-time and past jobs, (3) a history of dermatitis involves eliminating exposure to the patient's exposure to any hazardous • Disorders of Pigmentation the irritant or implementation of a substitute agents, (4) a history of any home and • Vascular Disorders agent. In addition, it is important to protect • Skin Cancer the worker from exposure with gloves,
24 A REVIEW OF OCCUPATIONAL SKIN DISORDERS FOR THE PRACTICING CLINICIAN boots, facemask, apron, and/or coveralls. tant and allergic contact dermatitis. Treat- mentation may spread to distant body sites The patient should be advised to avoid ment should also include the recommenda- not in contact with the chemical. Also, toxic strong soaps and detergents that might tion for utilization of sunscreen and vitiligo may present with concomitant aller- cause further irritation but can be encour- protective clothing. If the sensitizer is gic contact dermatitis. aged to use emollients and moisturizers. If unknown, for further evaluation, the clini- The differential diagnosis of toxic vitiligo clinically indicated, topical steroids may be cian may consider photopatch testing. includes: (1) natural tanning, which is usu- used, and in severe cases, oral prednisone ally lighter in color, and (2) idiopathic tapered over 2 weeks may be prescribed. Acne and Folliculitis vitiligo, which occurs preferentially around There are a number of specific acne body orifices, knees, elbows, dorsal hands, Allergic Contact Dermatitis conditions that are related to the work envi- axillas, and groin. Allergic contact dermatitis is a Type-IV, ronment. Acne mechanica may occur due Treatment of pigmentation disorders delayed hypersensitivity, cell-mediated to tight-fitting gear or clothing. Oil acne may involves eliminating continued exposure to immune reaction. Once sensitization has occur secondary to oils and greases the offending agent in order to reduce the occurred, even small amounts of repeat (petroleum or plant oils, halogenated aro- likelihood of permanent hypopigmentation exposure to an allergen may cause der- matic hydrocarbons such as polychlori- or hyperpigmentation. Furthermore, hyper- matitis. Sensitization usually takes 7-10 nated biphenyls, dibenzofurans, and pigmentation usually resolves with time, days after first contact with the allergen.2 dioxin). Typically, work-related acne pre- however, localized hyperpigmentation may However, sensitization may take months or sents as papules and pustules on the be treated with 2% hydroquinone. Hypopig- years to develop. Upon repeat exposure to hands and forearms. mentation may be permanent; on the other an allergen, most reactions occur within Chloracne may result from topical expo- hand, it may sometimes resolve and may 24-48 hours. sure to or ingestion of halogenated aro- later re-pigment with topical or oral pso- Common allergens include the following: matic hydrocarbons. Chloracne typically ralen ultraviolet A therapy. (1) topical medications – neomycin, benzo- presents as closed comedones and 1 mm caine, thimerosal, (2) preservatives – to 1 cm cysts in the malar region of the Vascular Disorders formaldehyde, (3) plants/trees – rosin, (4) face. Unlike the large, overactive seba- Urticaria is an allergic reaction consisting antiseptics – chlorhexidine, (5) rubber – ceous glands of acne, the glands of chlo- of wheals or hives and, perhaps, itching carbamates, (6) sulfonamides – thioureas, racne are conspicuously destroyed.6 and redness appearing within 15-30 min- (7) leather – potassium dichromate, (8) Folliculitis may occur secondary to irri- utes following exposure, commonly via paper – dyes, (9) glues and bonding tant chemicals or an infection and typically inhalation of an antigen. Contact urticaria is agents – acrylic and epoxy resins, (10) presents as small erythematous follicular a reaction that may be classified as allergic cement – chromium, and (11) metals – pustules on the face, neck, forearms, or non-allergic. Flushing is a transient red- nickel, chromate. hands, abdomen, buttocks, or thighs. ness of the skin, primarily the face, which The symptoms of allergic contact der- A history of exposure to oil, grease, may occur with exposure to disulfiram matitis are clinically indistinguishable from asphalt, tar, et cetera is key to distinguish- (antabuse) used to accelerate curing in the irritant contact dermatitis. Definitive diagno- ing acne and folliculitis from other condi- rubber industry. Nonspecific causes of sis of allergic contact dermatitis is via patch tions. Treatment consists of improvement redness include: sun, heat, alcohol, organic testing, whereas treatment is the same as of personal hygiene in the occupational solvent vapors, and emotional stress. that for irritant contact dermatitis. setting, as well as topical or systemic More often than not, urticarial lesions sub- antibiotic management. Oil acne usually side within 24 hours when exposure is Photosensitivity Disorders resolves after exposure or contact with the eliminated. Also, 0.5% menthol in calamine In occupational dermatology, the two offending agent is eliminated. It is notewor- may be used for its soothing properties; in main photosensitivity disorders are: (1) thy that chloracne is commonly resistant to addition, systemic antihistamines may be phototoxic contact dermatitis and (2) pho- pharmacologic treatment, including sys- integrated into the treatment regimen. toallergic contact dermatitis. Phototoxic temic tretinoin. Skin Cancer contact dermatitis occurs when an irritant on skin is activated by ultraviolet light. Disorders of Pigmentation Ionizing radiation may induce the follow- Photoallergic contact dermatitis occurs Contact with various agents in the work- ing: radiodermatitis, pre-malignant actinic when a chemical on skin is converted to an place may produce increased and/or keratosis (AK), as well as squamous cell allergen by ultraviolet light. decreased pigmentation. Pigmentation carcinoma (SCC), basal cell carcinoma Photosensitivity disorders usually pre- may result from: inflammation, trauma, fric- (BCC), and malignant melanoma (MM). sent as acute sunburns or eczematous tion, exposure to dyes, coal tar, pitch, Skin cancer is common in outdoor workers reactions, in a photodistribution, at the site asphalt, creosote and furocoumarins, and may be seen in x-ray technicians and of exposure. Common photosensitizers chronic systemic intoxication from heavy dentists. include: furocoumarins (natural chemicals) metals (silver, mercury), and contact with Actinic keratoses are small, flat, red found in fruits and vegetables; polycyclic foreign material that may be embedded via macules with scales and may develop into aromatic hydrocarbons in tar and creosote; explosive forces. SCC. Arsenic keratoses may become perfumes; and medications. Arsenic intoxication commonly presents squamous cell carcinomas or basal cell Clinical symptoms of photosensitivity dis- with a diffuse hyperpigmentation pattern carcinomas. orders may involve erythema, edema, and with drop-like areas of hypopigmentation Keratotic papillomas (tar warts) are possibly vesicles and bullae with later exu- (“raindrops on a dusty road”). small, wart-like, papillomatous growths dation. Burning or stinging may also occur Toxic vitiligo is due to chemical depig- resulting from exposure to polycyclic aro- and post-inflammatory hyperpigmentation mentation at the site of contact with pheno- matic hydrocarbons in soot, carbon black, typically follows. lic or catecholic derivatives encountered coal tar, pitch, and certain oils. Keratotic The differential diagnosis includes por- with exposure to rubber and plastic addi- papillomas may become SCCs, BCCs, or phyria, polymorphous light eruption, lupus tives, photograph developing solutions, keratoacanthomas. erythematosus, and photosensitive drug lubricating oils, adhesive resins, and clean- The differential diagnosis of occupational eruption. Treatment is the same as for irri- ing solutions. With repeated contact, depig- skin cancer includes: viral warts, sebor-
AUSTIN, WAY 25 rheic keratoses, benign keratotic nevi, and Disorders of Hair and Nails Conditions Caused by Physical benign pigmented cutaneous lesions. and Mechanical Agents Actinic keratoses, arsenic keratoses, and Toxic alopecia may occur 1-2 weeks fol- keratotic papillomas may be treated con- lowing acute, toxic exposure to thallium- Physical and mechanical agents that servatively with cryotherapy or elec- containing rodenticides, boric acid, arsenic, may result in occupational skin conditions trodessication. Treatments for SCC, BCC, chloroprene, and high dose ionizing radia- include: heat, cold, ultraviolet light, elec- and MM are similar to those for skin cancer tion. Traction alopecia results from trauma, tricity, wind, radiation, vibration, friction, in the general population. e.g., catching hair in machinery. Hair and pressure, etc. Miliaria is a common con- nail discoloration occurs secondary to dition manifested by swelling and obstruc- Connective Tissue Diseases chemical stains, e.g., yellow staining from tion of the sweat gland ducts following Vasospastic disease includes vibration nitrophenolic and other organic nitrates. exposure to heat and humidity. Miliaria white finger syndrome – paroxysmal Nail shape and growth abnormalities presents as small, pruritic, red papules. vasospasm of hands secondary to vibra- are due to physical or chemical injury to Electrical burns may produce tissue dam- tory tool use. Cold exposure may con- the nail folds, e.g., absorption of pesti- age presenting with erythema to blistering and necrosis. Often the damage is much tribute to attacks. Vibration white finger cides into the nail fold. Treatment involves deeper than clinically apparent. Blisters or syndrome is synonymous with Raynaud’s removal from exposure. callosities occur due to friction. Treatment phenomenon. Infections and Infestations involves eliminating exposure. Miliaria Occupational scleroderma is a condi- may improve with drying lotions Infectious agents that cause occupa- tion that is indistinguishable from idio- (calamine). Chapping and dermatitis from tional skin disease may include: bacteria, pathic scleroderma, which may have the low humidity may be treated with moistur- fungi, viruses, rickettsia, protozoa, meta- following cutaneous features: Raynaud’s, izers and low-potency topical steroids. digital ulcers, cutaneous sclerosis, calci- zoa, helminths, and arthropods. nosis, telangiectases, and hyperpigmen- Common bacterial infections and asso- Systemic Diseases Due to tation or hypopigmentation. Occupational ciated occupations include: (1) staphylo- Percutaneous Absorption scleroderma may be induced by silica in coccus/streptococcus – agricultural Toxic systemic diseases may result mining, epoxy resin curing agents, and workers, butchers, meat packers, slaugh- from exposure via skin absorption. Skin terhouse workers, (2) cutaneous and chlorinated organic solvents (trichloroeth- absorption may be increased by the fol- atypical mycobacteria – farmers, vets, ylene, perchloroethylene). lowing: (1) entrapment of substance butchers, pathologists, fishermen and Acroosteolysis consists of lytic lesions against skin due to rubber gloves, cloth- aquarium keepers, (3) tularemia – of the distal and middle phalanges from ing, etc., (2) damage to the stratum exposure to uncured vinyl chloride hunters, vets, farmers, butchers, fur han- corneum, (3) damage to the skin from monomer, which is used in the manufac- dlers, (4) brucellosis – farmers, vets, cuts, lacerations, abrasions, etc., and (4) ture of plastics and during the cleaning of slaughterhouse workers, meat packers, contact of a toxic substance with specific reactor vessels. Of note: acroosteolysis livestock workers, (5) anthrax – sheep anatomic areas of the skin (e.g., genital, may be complicated by angiosarcoma of and wool handlers, butchers, farmers, eyelid, and facial areas). and (6) erysipeloid – meat and fish han- the liver. Chemicals that may cause systemic Treatment of occupational connective dlers. toxicity are as follows: (1) aniline dyes – tissue diseases is the same as for other Common viral infections and associ- methhemoglobinemia, liver disease, and connective tissue diseases. Basically, ated occupations include: (1) herpes sim- bladder cancer, (2) arsenic – peripheral avoidance of exposures or triggers known plex – health care workers, (2) viral warts neuritis, gastrointestinal and cardiac dis- to cause connective tissue diseases is – meat handlers, sportspersons, and (3) turbances, (3) benzene – acute myeloge- key. In addition, warm clothing and pro- orf – shepherds. nous leukemia, aplastic anemia, and tective gloves or pads may be used to Common fungal infections and associ- myelofibrosis, (4) cyanide salts – cellular decrease tool vibrations and to prevent ated occupations include: (1) candida – asphyxia and death, (5) mercurials – vibration white finger syndrome. health care workers, (2) dermatophytes – nephritis, gastroenteritis, central and farmers, milkers, cattle tenders, vets, (3) peripheral nervous system abnormalities, Granulomas coccidioidomycosis – migrant workers, (6) methyl-n-butyl ketone – peripheral Granulomas are hard, firm, violaceous farmers, construction workers, baseball neuropathy, (7) polyhalogenated aromatic or red-brown papules and nodules at the players, lab workers, (4) sporotrichosis – hydrocarbons – liver disease and por- site of contact and result from penetration gardeners, horticulturists, vets, miners, phyria. (8) organic solvents – central ner- of the skin. Foreign body granulomas are (5) blastomycosis – farmers, forestry and vous system abnormalities, (9) non-allergic inflammatory reactions construction workers, and (6) chromomy- neuromuscular insecticides – cardiovas- cular, gastrointestinal, and neuromuscular caused by silk, nylon, paraffin, wood cosis – agricultural workers in tropical cli- abnormalities, and (10) hydrofluoric acid splinters, plant spines, and talc. Allergic mates. – hypocalcemia, hyperkalemia, and hypo- granulomas are delayed hypersensitivity Common parasitic infections and asso- magnesemia. reactions caused by zirconium, beryllium, ciated occupations include: (1) cutaneous and tattoo pigments. Infectious granulo- leishmaniasis – tropical forest workers, Treatment of systemic diseases due to mas may be caused by various infectious (2) helminths – skin divers, lifeguards, percutaneous absorption focuses on reversing the systemic toxicity. agents and are associated with sporotri- dock workers, (3) scabies – nursing home chosis. In addition, human hair contact, and hospital workers, and (4) lyme dis- such as occurs with hairdressers, and ease – outdoor workers, loggers, ranch- Conclusions animal hair contact, such as by contact ers. The practicing clinician has an obliga- with cow hair, may lead to formation of a Treatment of occupational skin infec- tion to perform a thorough medical history granuloma. Treatment of granulomas tions and infestations is the same as that and physical exam with specific attention consists of removal of the foreign body for the general population. paid to the patient’s occupational and and, if necessary, intralesional steroids. environmental history. The practitioner
26 A REVIEW OF OCCUPATIONAL SKIN DISORDERS FOR THE PRACTICING CLINICIAN who has knowledge of the agents utilized and the conditions that are associated with the occupational environment will be at an extreme advantage in diagnosing occupationally-related skin disease. Finally, the clinician should create a com- prehensive treatment plan for each patient, but, at the same time, he or she should not forget to address issues of prevention in the workplace.
References 1. Emmett EA. Occupational contact dermatitis, #1: Inci- dence and return to work pressures. Am J Contact Derm 2002;13:30-34. 2. McCunney RJ, editor. A Practical Approach to Occupa- tional and Environmental Medicine, 3rd ed. Philadelphia: Lippincott Williams and Wilkins Publishing, 2003. 3. American Academy of Dermatology. Proceedings of the National Conference on Environmental Hazards to the Skin. Schaumburg, IL: American Academy of Dermatol- ogy 1994;61-79. 4. Himmelstein JS, Frumkin H. The right to know about toxic exposures. N Engl J Med 1985;312(11):687-90. 5. Orkin M, Maibach HI, Dahl MV. Dermatology, 1st ed. Connecticut: Appleton and Lange Publishing, 1991. 6. Plewig G, Kligman AM. Acne and rosacea, 2nd ed. New York: Springer-Verlag Publishing, 1993.
AUSTIN, WAY 27 Pemphigus Foliaceus in Association with Lisinopril
Jocelyn E. Harris, D.O.*, Stephen M. Purcell, D.O.** *Jocelyn E. Harris, D.O. is a resident in dermatology at Lehigh Valley Hospital, Allentown, Pennsylvania. **Stephen M. Purcell, D.O. is the chairman and program director of the Lehigh Valley Hospital Dermatology Residency Program, Allentown, Pennsylvania.
ABSTRACT
Pemphigus foliaceus is a cutaneous autoimmune blistering disease. Environmental factors, including numerous drugs, are thought to play a role in its pathogenesis. Drugs that induce pemphigus are generally divided into two groups according to their chemical structure: thiol (sulfhydryl [SH]-containing) and non-thiol drugs. Lisinopril is a non-thiol drug that contains an active amide group, which can trigger acantholysis and may potentially cause a more severe and protracted course of pemphigus. This is a case report of a patient who developed pemphigus foliaceus after taking lisinopril.
Case Report A diagnosis of pemphigus foliaceus (PF) A 52 year-old Hispanic male presented was made and drug induced PF was sus- with three week history of a “burning” and pected. The patient’s lisinopril was discon- pruritic rash on his head and chest. Clini- tinued after consulting with his primary care cal examination revealed multiple verru- physician. He was started on a treatment cous and crusted, erythematous papules course of systemic prednisone. In addition and plaques that were scattered over the to corticosteroids, several steroid-sparing face, chest, abdomen, back, buttocks and agents were prescribed, including azathio- extremities (Figure 1). There were several prine, dapsone, and mycophenolate eroded and hemorrhagic areas with rare mofetil. Due to the changing status of our flaccid vesicles and bullae. Nikolsky sign patient’s medical coverage, it was difficult was positive. The patient’s mucous mem- to maintain a consistent treatment regimen. branes were clear. Although the patient did experience episodes of improvement in his disease, Figure 1 The patient’s medical history included his condition remains active two years after Crusted and erythematous papules diabetes mellitus, hypertension, hypercho- his initial presentation. and plaques with erosions. lesterolemia and seasonal allergies. His medications upon presentation included lisinopril and atorvastatin. The lisinopril was Discussion started approximately 5 months prior to the Pemphigus foliaceus is generally a onset of his rash. benign variety of pemphigus. It appears A total of three punch biopsies were pre- most commonly in the elderly1, but can formed, two for hematoxylin and eosin affect people of any race, age or sex. Other staining (H&E) and one for immunofluores- than the cutaneous manifestations of PF, cence. The first H&E biopsy showed a sub- patients are usually in good health. corneal pustule with acantholysis in the Typically the disease presents with upper epithelial cell layers. In the dermis, small, fluid-filled blisters most commonly on there was a mixed inflammatory infiltrate the face and scalp. As the disease pro- composed of lymphocytes, neutrophils and gresses involvement of the torso and Figure 2 eosinophils (Figure 2). Based on the fact extremities is seen. Because the vesicles Suprabasal acantholysis and a mixed that the split appears to be within the upper and bullae form in the upper layers of the inflammatory infiltrate with layers of the epithelium, the diagnosis of epidermis, they rupture very easily; as a eosinophils. pemphigus foliaceus or pemphigus erythe- result, erosions and crusts may be the only matosus was favored. The second H&E clinical findings.2,3 On the face, scalp and Drugs that induce pemphigus are generally biopsy showed a subcorneal blister con- upper trunk the lesions are often scaly or divided into two groups according to their taining acantholytic cells and a mixed cell crusty on a red and inflamed base. chemical structure: thiol (sulfhydryl [SH]- infiltrate with eosinophils present around Patients sometimes experience a burning containing) and non-thiol drugs.7 venules of the superficial plexus. These sensation or localized pain. Unlike pemphi- Most of the drugs reported to provoke findings were also consistent with pemphi- gus vulgaris, pemphigus foliaceus is char- the onset or relapse of pemphigus are thiol gus foliaceus/erythematosus. Immunofluo- acterized by a chronic course, with little or drugs. These drugs possess powerful rescent stained sections demonstrated no involvement of the mucous acantholytic qualities in vitro.8 The role that intercellular staining of the epithelium with membranes.3,4 The superficial blisters in PF the sulfhydryl radical group plays in pro- IgG and C3. The IgM, IgA, and fibrinogen are induced by IgG autoantibodies directed ducing pemphigus in vivo has been exten- stains were negative. against the cell adhesion molecule, sively studied.7 It has also been The antinuclear antibody was negative, desmoglein 1 (160 kD)5, expressed mainly demonstrated that “masked” thiol drugs, ruling out the diagnosis of pemphigus ery- in the granular layer of the epidermis. which are drugs that may undergo meta- thematosus. Intercellular substance anti- It is well established that pemphigus foli- bolic changes to form thiol (sulfur-contain- body was positive (1:20 titer). The aceus may be drug induced. Some of the ing) groups, can induce pemphigus.4 basement membrane zone antibody, more commonly reported causative agents Thiol-induced pemphigus usually presents endomysial IgA antibody, and gliadin anti- include penicillamine and captopril.5,6,7 as the foliaceus variant and has a more body IgG and IgA were all negative.
28 PEMPHIGUS FOLIACEUS IN ASSOCIATION WITH LISINOPRIL favorable prognosis than the pemphigus the concentration of thiol drugs.8 Drugs with References: 5 vulgaris variant upon drug withdrawal. an active amide group are thought to result 1. Sami N. Blistering diseases in the elderly: diagnosis and Non-thiol drugs are thought to have an in a more severe and chronic manifestation treatment. Dermatol Clin 2004;22(1):73-86. 7 2. Perry H, Brunsting LA. Pemphigus foliaceus. Arch Dermatol active amide group in their molecular of disease. Therefore, lisinopril may poten- 91:10,1965. make-up that allows acantholysis to occur. tially cause a more severe and protracted 3. Diaz LA. Endemic pemphigus foliaceus (fogo selvagem), I. Clinical features and immunopathology. J Am Acad Der- These drugs may share a chemical struc- course of pemphigus. matol 1989;20(4):657-9. ture that is capable of triggering pemphi- It has been shown that when the 4. McKenna JK. Dermatologic drug reactions. Immunol Allergy gus.7 Clin North Am 2004;24(3):399-423. causative agent of pemphigus is a non- 5. Brenner S. Bialy-Golan A, Anhalt GJ. Recognition of pem- Captopril, an angiotensin converting thiol drug, there is only a 15% chance that phigus antigens in drug induced pemphigus vulgaris and pemphigus foliaceus. J Am Acad Dermatol 1997;36:919- enzyme (ACE) inhibitor, is a frequent spontaneous recovery will occur upon with- 23. 5 cause of pemphigus. Of the ACE inhibitors, drawal. There has been only one other 6. Ruocco V, Pisani M. Induced pemphigus. Arch Dermatol captopril is the only one that contains a reported case of pemphigus foliaceus in Res 1982;274:123-40. 7. Wolf R, Brenner S. An active amide group in the molecule of thiol group in its structural make-up. association with lisinopril in the literature. drugs that induce pemphigus: A casual or causal relation- Another ACE inhibitor, lisinopril Unlike our patient, this patient’s rash ship? Dermatol 1994;189:1-4. 8. de Angelis E, Lombardi ML, Grassi M, Ruocco V. Enalapril: (C21H35N3O7), does not contain a thiol improved greatly within 48 hours of discon- a powerful in vitro non-thiol acantholytic agent. Int J Der- group, but it does contain an amide group. tinuation of lisinopril, although follow-up in matol 1992;31(10):722-4. 9. Patterson CR, Davies MG. Pemphigus foliaceus: an Lisinopril is a derivative of the active this patient was limited to three weeks sec- adverse reaction to lisinopril. J Dermatolog Treat 9 9 metabolite of enalapril. Enalapril has been ondary to death from unrelated causes. 2004;15(1):60-2. reported to induce pemphigus in vivo 10,11 Two years after our patient’s initial presen- 10. Lo Schiavo A. Guerrera V. Cozzani E. Aurilia A. Ruocco E. Pinto F. In vivo enalapril-induced acantholysis. Dermatol and induce severe acantholysis of ker- tation, his condition remained active, 1999;198(4):391-3. atinocytes with suprabasal clefting in vitro. despite discontinuation of lisinopril. 11. Ruocco V, Satriano RA, Guerrera V. "Two-step" pemphigus induction by ACE-inhibitors. Int J Dermatol 1992;31(1):33- In fact, it has been shown in vitro that 6. enalapril can produce acantholysis in a shorter amount of time and at one-tenth
HARRIS, PURCELL 29 Drug Induced Eccrine Gland Necrosis in a Patient with Altered Mental Status: A Case Presentation and Review
Laura Ziton, D.O.I, Tracy Favreau, D.O.II, Brian Portnoy, D.O.III I D.O. Department of Family Medicine, Resident, Broward General Medical Center, Fort Lauderdale Florida. II D.O. Department of Dermatology, Resident, Nova Southeastern University, Fort Lauderdale Florida III D.O. Director of Clinical Dermatology, Nova Southeastern University, Fort Lauderdale Florida
ABSTRACT
Background: Drug induced bullae with eccrine gland necrosis is a rare clinicopathologic entity most often reported with a comatose state. It is associated with bullae formation on pressure surfaces within twenty four hours of drug overdose and self res- olution within fourteen days. Subject: We report a case with histopathologic features of bullae and sweat gland necrosis in a non-comatose patient with altered mental status. The report is unique as the patient developed bullae on therapeutic drug doses over the global body surface with course complicated by necrotizing fasciitis. Conclusion: Drug bullae and eccrine necrosis cases have been reported predominantly in drug overdose coma patients with lesions developing on pressure surfaces. This case provides evidence for development of this rare reaction in a patient with thera- peutic drug levels and over the global body surface. A comprehensive review of the clinical, pathophysiologic, pharmacologic and histopathologic findings associated with this condition are summarized.
admission the patient developed a tense Introduction bullous eruption on bilateral thighs, buttock Drug induced cutaneous bullae with and inguinal area (Figure 1), which eccrine gland necrosis is a rare but well extended to the abdomen, back, neck and described phenomenon. The first published arms over the following day (Figure 2). A case report was reported in 1812 by punch biopsy was performed at two sites, Napoleon’s surgeon, Larry. He reported which demonstrated histopathological evi- cutaneous blisters in soldiers with carbon dence of subepidermal bullae formation monoxide induce coma. But it was not until (Figure 3) and eccrine gland necrosis (Fig- 1963 that the characteristic histopathologi- ure 4). Dermatopathology revealed no evi- cal findings of eccrine necrosis were dis- dence of inflammatory infiltrates. Figure 1 covered in association with barbiturate Phenobarbital and lorazepam were discon- Tense bullae on right buttock and induced coma.2 Similar entities have been tinued with resolution of bullae within 7 thigh. reported sporadically over the years, occur- days. Unfortuneately, several ruptured sites ring most frequently in barbiturate over- developed secondary MRSA infection dose coma patients with lesions complicated by necrotizing fasciitis which developing over pressure surfaces. The required extensive surgical debridement following case involves a non-comatose and skin grafting. patient with altered mental status that develops drug induced bullae with eccrine Review of Literature necrosis over the global body surface with only therapeutic doses of phenobarbital Drug induced bullae with eccrine gland and lorazepam. necrosis has been most frequently associ- ated with drug induced coma, but it has also been reported with drug intoxication Case Study and coma due to various CNS diseases A 50 year-old female was admitted for (Table 1—adapted from ref. 8 & 10). This altered mental status after being found on tendency accounts for the popular terming Figure 2 the floor of her apartment due to an appar- of the entity as “coma blisters”. The lesions Bullous extension to abdomen and ent hydroxyzine overdose. Upon examina- can be associated with disorders of back with musky macules of rupture tion the patient was confused with slurred impaired consciousness3,4 such as in our sites on left thigh. case. Only recently has a case been speech. She stated that she had tripped decrease cutaneous oxygen consumption.6 on her way to the bathroom and com- reported in a non-comatose patient with no 5 Bullous eruption with therapeutic drug lev- plained of hip pain. The patient had been evidence of altered mental status. The els as illustrated in our case is very rare. diagnosed with a seizure disorder one above report and the one presented in this Note however that our patient was given month prior to this incident. Additionally, manuscript downplay the role of CNS two drugs well associated with bullae her admission toxicology screening was depression in bullous eruption. development and it is plausible that a syn- positive for benzodiazepines but levels of The majority of drug-induced bullae ergistic effect was observed. With the prescribed antiepileptic were undetectable. cases are reported in associated with bar- advent of new medications over the past She was placed on phenytoin and pheno- bituate overdose; however, several other few decades, the case reports of drug barbital for seizure prophylaxis and drugs have been implicated (Table 2 induced eccrine gland necrosis has ciprofloxacin for treatment of UTI. adapted from ref. 10). The drug-induced increased. Most recently chemotherapeu- Lorazepam was added the following day bullae may be attributed to a greater ten- tic agents idarubicin and cytosine arabi- for agitation and anxiety. On day three of dency for barbiturates than other drugs to noside7 have been implicated. Although
30 DRUG INDUCED ECCRINE GLAND NECROSIS IN A PATIENT WITH ALTERED MENTAL STATUS hypersensitivity reaction. The pathophysiology of drug-induced Table 1: CNS Disorders eccrine gland necrosis is not completely Associated With Bullae understood. It is known that ischemia from local pressure effects fragile eccrine gland Stroke first16 but this does not account for cases of Diabetic Ketoacidosis global body eruption. The suppression of respiratory and circulatory function in coma Ependymoma patients may lead to generalized hypoxia Glioblastoma and subsequent epidermal necrosis,3 but Head trauma this implication has not been supported by Hypoglycemic coma histological studies. Excretion of drug Syringomyelia metabolites via eccrine glands with direct Figure 3 toxicity induced necrosis has also been Viral encephalitis Epidermolysis associated with forma- implicated3 but is not supported by histolog- tion of subepidermal bullae. ical studies. Other immune mediated mechanisms have also been proposed Table 2: Drugs Associated With with various immunoglobulins identified by direct immunofluorescence of epithelial Eccrine Gland Necrosis cells and adnexal structures.8 However, this is a nonspecific finding, possibly a nor- Acetylcarbromal mal physiologic reaction to tissue injury. Amitriptyline Although none of the current theories Barbiturates account for all of the various case reports, Benzodiazepines an interplay of these mechanisms may link differing patient histories to this unique clin- Dihydrocodeine ical entity. Glibenclamide The differential diagnosis in cases of Glutethimide drug and coma induced bullae is neu- Heroin Figure 4 trophilic eccrine hidradenitis. This is a self- Imipramine Hematoxylin/eosin stained sections limiting, inflammatory condition most Ma huang commonly caused by chemotherapeutic with extensive necrosis of eccrine Methadone secretory units. agents in immunocompromised patients. It is histologically differentiated from drug- Methaqualone toxicity has been related to specific drug induced bullae by the presence of eccrine Morphine classes, similar histological findings have 17 associated neutrophilic infiltrate. Phenobarbital been cited in non-drug-induced coma.8, 9 The treatment of drug induced bullae This implies that pharmacologic induction Phenylpropanolamine with eccrine necrosis is supportive. Since alone is insufficient for bullous formation. Pseudoephedrine 27% of total body heat loss occurs via Additionally, it is important to note is that an sweat evaporation18 and eccrine function is Theophylline event of coma blisters does not preclude compromised in this condition, monitoring the further use of inducing drugs in for hyperthermia is essential. Interestingly, patients, as evidenced by several cases of and degree of CNS depression in relation there is no evidence of progression of bul- drug re-introduction after resolution of bul- to bullae development. From this we may lous lesions to toxic epidermal necrolysis. lae.10, 11 build a risk profile by which to identify However, the natural course of bullae The characteristic bullous lesions of this patients at greatest risk for eccrine necro- expansion and rupture leaves the subcuta- sis and develop prospective studies of condition are typically few in number, which neous tissues susceptible to secondary generally localized over peripheral IV greatest insight. 12 infection. This can progress to sepsis sites , pressure surfaces or bony promi- and/or necrotizing fasciitis as seen in our nences. These lesions generally appear patient. Such complications are rare but Acknowledgments within 24 hours of drug overdose and self- devastating. The authors gratefully acknowledge Dr. resolve in 7-14 days after drug cessation. Andrew Hanly, Dr. George Poulos and Dr. Due to the uncommon nature of bullae Sweat gland necrosis differentiates drug Myron Howell for their assistance with this with eccrine necrosis and the variations in induced coma lesions from bullae due to manuscript. case history and presentation, it is difficult other etiologies.13, 14 In one study, biopsies to confer direct causation to CNS depres- from 7 patients were analyzed and the sion or pharmacologic action. Rather it is References results indicate that the secretory portion of evident that these are predisposing or initi- 1 Larry DJ. Memoires de Chirurgie Militaire et Campagnes. the eccrine gland is the first and most sus- Paris: Smith and Buisson. Vol. 3:13. 1812. ating factors in a condition without clear ceptible to necrosis followed by other 2 Adebahr G. Hautveranderungen bel Schlafmittelvergiftung. pathophysiologic mechanisms. Since the Der Landarz. 1963; 30:1302-1307. adnexal structures and lastly the 3 You MY, Yun SK, Ihm W. Bullae and sweat gland necrosis course is self-limiting, underlying autoim- epidermis.8 Vascular changes correlated after an alcoholic deep slumber. Cutis 2002; 69:265-268 munity or infection is unlikely. Certainly 4 Mehregan D, Daoud M, Rogers R. Coma blisters in a patient proportionately with epidermal damage and prospective studies will be most informative with diabetic ketoacidosis. J Am Acad Dermatol. 1992 consisted of neutrophilic inflammatory infil- Aug.; 27:269-10 to determine the pathogenic mechanisms 5 Ferreli C, Sulica VI, Aste N, Atzori L, Pinna M, Biggio P. trate of arterioles. These findings contradict of this entity but such studies would be Drug induced sweat gland necrosis in a non- a former theory that pressure is the main comatose patient: a case presentation. J Euro Acad extremely difficult given the rarity of occur- cause of cutaneous changes in drug Derm Vener. 2003; 17:443-445. rence. More realistic may be a retrospec- 6 Naylor PFD, Evans NTS. The action of locally applied barbi- induced coma.15 All immunoglobulin studies turates on skin oxygen tension and rate of oxygen utiliza- tive study quantifying degree of hypoxia, performed show no evidence of a drug tion. Br J Dermatol. 1970; 82:600-605. cutaneous circulatory losses, drug dosages 7 Lane JE, Brown CA, Lesher JL. Pressure-induced bullae and
ZITON, FAVREAU, PORTNOY 31 sweat gland necrosis following chemotherapy induction. Amer J Medicine 2004 Sept.; 117:441-3. 8 Kato N, Ueno H, Mimura M. Histopathology of cutaneous changes in non-drug-induced coma. Am J Dermatopathol. 1996 Aug; 18(4):344-350. 9 Arndt KA, Mihm MC, Parrish JA. Bullae: a cutaneous sign of a variety of neurologic diseases. J Invest Dermatol. 1973; 60:312-320. 10 Setterfield JF, Robinson R, MacDonald D, Calonje E. Coma induced bullae and sweat gland necrosis following clobazam. Clin Exp Derm 2000; 25:215-8. 11 Dunn C, Held J, Spitz J, Silvers D, Grossman M, Kohn S. Coma blisters: report and review. Cutis 1990 Jun; 45(6):423-426. 12 Haroun M, Jakubovic H, Nethercott J. Localized subepider- mal bullae after intravenous phenobarbital. Cutis. 1987 Mar; 3993):233-4. 13 Leavell UW. Sweat gland necrosis in barbiturate poisoning. Arch Dermatol. 1969; 100: 218-221. 14 Mandy S, Ackerman AB: Characteristic traumatic skin lesions in drug induced coma. JAMA. 1970; 213:253-256. 15 Sanchez Y, Requena L, Simon P. Histopathology of cuta- neous changes in drug-induced coma. Am J Der- matopathol. 1993; 15:208-216. 16 Arndt KA. Bullae in comatose patients. Arch Dermatol. 1980; 116-119. 17 Allegue F, Soria C, Rocamora A et al. Neutrophilic eccrine hidradenitis in two neutropenic patients. J Am Acad Derm. 1990; 23:1110-1113. 18 Ganong W. Review of Medical Physiology. New York, New York McGraw Hill; 2001. p. 242-247
32 DRUG INDUCED ECCRINE GLAND NECROSIS IN A PATIENT WITH ALTERED MENTAL STATUS
REQUESTING MEMBERS FOR THE JAOCD Editorial Review Board
Dear AOCD Colleague,
We are all proud that our college has its own journal, the JAOCD. I am soliciting my fellow AOCD members to sit on the editorial review board of the JAOCD. I give my utmost thank you to the current members of the JAOCD editorial review board for all of their help in reviewing manuscripts to be considered for publication. If you would be interested in helping improve the JAOCD by reviewing 1-2 resident manuscripts every three to four months, please contact me. Your help would be greatly appreciated and you will be listed as a member of the editorial review board in each issue of the journal. Please consider becoming an integral part of the Journal of the American Osteopathic College of Dermatology. Sincerely,
Jay S. Gottlieb, D.O. Editor JAOCD [email protected] Phone-954-963-5875 Pemphigus Foliaceus: A Case Report with Review of Literature
Michael Hohnadel D.O. and Bill V. Way, D.O., KCOM, Duncanville TX
ABSTRACT
Pemphigus foliaceus is an immune mediated superficial blistering disorder where antibodies are directed at desmoglein type 1. This paper presents a classic case of pemphigus foliaceus and a review of literature concerning the pathophysiology, diagnosis and treatment of this disorder.
cell infiltrate in the dermis consistent with Pemphigus Foliaceus either a superficial blistering disorder or A 31-year-old Hispanic American male bullous impetigo. (Figure 5) Direct immuno- reported to our clinic with a one-month his- fluorescence (DIF) studies of peri-lesional tory of a rash which first presented on the skin revealed IgG and complement deposi- face and then quickly spread to the upper tion in the epidermis. Indirect immunofluo- chest, back, scalp and thighs. The lesions rescence (IIF) was positive with a 1:80 titer began as erythematous papules that over for intracellular substance antibodies (Ab) several days developed into red, weeping and negative for the basement membrane erosions that would not heal. The patient zone antibodies. Studies for ANA, HIV and described the lesions as stinging and burn- RPR were negative. Aerobic bacterial cul- ing without pruritus. He did not feel system- tures were positive for moderate growth of ically ill. Staphylococcus Aureus. A CBC and a Examination revealed a well appearing CMP were within normal limits. male with numerous erythematous, weep- Based on the clinical presentation, der- ing erosions, distributed on the malar matopathology and microbial culture cheeks, the central chest and back. There results, the patient was diagnosed with was lesser involvement of the scalp and pemphigus foliaceus with a secondary bac- thighs (Figures 1 and 2). Many lesions terial infection. Treatment was initiated with exhibited a ring of scale and some lesions oral prednisone at a dose of 60 mg qd. were crusted (Figures 3 and 4). Nikolsky’s Topical triamcinolone acetonide 0.1% sign could be elicited at the periphery of cream (TAC) and clobetasol propionate the erosions. No oral or ocular lesions were foam 0.05% were started for the skin and seen. scalp lesions, respectively. In addition, Except for the cutaneous lesions, the cephalexin 500 mg tid for 7 days was uti- Figure 1 patient’s medical history and review of sys- lized to address the staphylococcal infec- tems were unremarkable. He had never tion. The lesions improved over the next had a similar cutaneous eruption in the several weeks, at which point methotrexate past. He reported being in good health with (MTX) was started as a steroid-sparing no chronic medical conditions and had no agent. history of hospitalizations or surgery. Clinical Course There was no family history of similar dis- eases. He related a negative personal or The patient was gradually tapered off of family history of cancer. He denied taking oral steroids and the MTX was increased any medications, either prescribed or over based on clinical presentation. After the counter. The patient is employed as a approximately 2 months of therapy he had truck driver of non-hazardous cargo. Travel completely discontinued prednisone and history included several trips yearly to Mex- was taking 12.5 mg of MTX per week. Over ico to see family. He denied any travel to the next 6 weeks the dose of MTX was central or South America. increased to 15 mg qw to attain adequate The differential diagnosis after examina- control. The frequency of new lesions had tion included: pemphigus foliaceus, bullous reduced to approximately 2-4 per week. impetigo, pemphigus erythematosus, suba- TAC and clobetasol foam continued to be cute cutaneous lupus erythematosus and applied topically to any new lesions. pemphigus vulgaris. Two 4-mm punch biopsies were Discussion obtained from the left upper arm for H&E and immunofluorescence studies. H & E Epidemiology pathology specimens revealed superficial Pemphigus foliaceus is a rare superficial acantholysis with suppuration between the Figure 2 stratum corneum and the superficial granu- blistering disorder whose frequency varies lar layer as well as a mixed inflammatory by the population studied. In Western
HOHNADEL, WAY 35 sky’s sign and Asboe - Hansen sign.4 Fogo Selvagem near rivers that have large Over time, the lesions may coalesce to black fly populations. As mentioned earlier, form large denuded areas. Patients often this type of pemphigus foliaceus has a high complain of stinging or burning but will prevalence in endemic regions of the Latin have surprisingly few other complaints. In America with up to 3.4% of the population fact, those afflicted are otherwise in good being affected. Our patient had no history health. An important physical feature that of residence or travel to these endemic distinguishes pemphigus foliaceus from regions.1,7,9,10 pemphigus vulgaris is the absence oral Another important variant to consider is lesions.5 drug induced pemphigus. Frequently reported inciting agents are penicillamine, Histopathology captopril and nifedipine, although many Well-formed lesions of pemphigus foli- other drugs having been implicated. The Figure 3 aceus are characterized by superficial bul- clinical and histopathological appearance is lae with the cleft occurring in the granular identical to classic pemphigus foliaceus. It cell layer or just beneath the stratum is theorized that the pharmaceuticals form corneum. Fibrin and occasional neutrophils a hapten with desmoglein resulting in anti- may be present. A superficial dermal infil- genicity and production of anti-desmoglein trate composed of neutrophils and antibodies. Most patients go into remission eosinophils is usually present. 6,7 when the drugs are discontinued. Our Immunofluorescence studies revealed patient not any medications at the time of IgG and complement deposition within the onset of his blistering disorder.7,11 intracellular space of the epidermis with a Pemphigus erythematosus is believed to predilection for the superficial epidermis in be a localized type of pemphigus with both clinically normal and affected skin. lupus erythematosus like features including However, the staining pattern with direct malar distribution of lesions, positive ANAs immunofluorescence (DIF) is often nonspe- and basement membrane antibody deposi- cific with a more generalized pattern of tion.(7) Our patient’s seborrheic distribu- Figure 4 immunoglobulin deposition being seen.6,7 tion, negative ANA and lack of basement membrane antibodies distribution excluded Pathogenesis this subtype. The blistering of pemphigus foliaceus is Paraneoplasic pemphigus is associated induced by deposition of IgG antibodies with a striking stomatitis as well as an directed at desmoglein-1. This molecule, association with non-Hodgkins lymphoma along with desmoglein-3, is critical to (42%), chronic lymphocytic leukemia (29%) proper cell-cell adhesion through desmoso- and other malignancies. There was no evi- mal structures. In the epidermis dence of malignancy in the patient’s evalu- desmoglein-1 is expressed more promi- ation.7, 12, 13,14 nently in the superficial regions near the IgA pemphigus presents with pustules, granular layer and its dissolution explains which coalesce into annular patterns with the superficial blister formation of pemphi- central crust. As opposed to IgG antibod- gus foliaceus. This is in contrast to pemphi- ies, IgA is the predominate antibody Figure 5 gus vulgaris where the IgG antibodies may directed against surface components of be directed at only desmoglein-3 or to both keratinocytes.15 Lastly, pemphigus herpeti- Europe and North America the annual inci- desmoglein-1 and desmoglein-3. Antibod- formis presents with urticarial plaques and dence is approximately 0.5 to 1 per million ies directed at only desmoglein-3 disrupt eosinophilic spongiosis.14,15 per year. However, in some endemic primarily oral mucosa, as this is the pre- regions of Brazil the prevalence is esti- dominant adhesion molecule present in Lab studies mated to be as high as 3.4 % of the popu- this mucosal tissue. This results in the well- A punch biopsy for H&E combined with lation.1 Males and females are equally known oral erosions that herald pemphigus DIF is a generally adequate to diagnose affected.2 The average age of onset for non vulgaris. Antibodies directed against both pemphigus foliaceus. The H&E stain pro- endemic pemphigus foliaceus is 40-50 desmoglein types 1 and 3 results in full vides information on the level of the blister years of age while the endemic variety pri- thickness epidermal dissolution as well as formation and cell types present while DIF marily affects young adults. Rare reports of the mucosal lesions seen in pemphigus elucidates the type and location of the neonatal involvement in pemphigus foli- 8,9 vulgaris. immune globulin deposition. aceus affected mothers have been reported and are usually thought to be sec- Pemphigus Subtypes When there is widespread deposition of immunoglobulins within the full thickness of ondary to maternal placental transfer of Subtypes of pemphigus are generally antibodies.3 the epidermis, it may not be possible to recognized. Due to the patient’s hispanic ascertain definitively if pemphigus vulgaris Presentation ethnicity, Fogo Selvagem, a subtype or pemphigus foliaceus is the underlying endemic to Central and South America is disease. In such cases indirect immunoflu- The classic presenting signs of pemphi- important to consider. This variant is orescence (IIF) is often helpful. IIF utilizing gus foliaceus typically include flaccid thought to have an infectious etiology, per- different substrates such as monkey or superficial blisters which quickly denud into haps viral, spread by the black fly, Simulin guinea pig esophagus will show a different shallow weeping erosions and are distrib- pruinosum. The presumed infection then pattern of immune globulin deposition for uted with a greater density in the sebor- induces an auto immunity to desmoglein pemphigus foliaceus verses pemphigus rheic areas of the face, chest and back. type 1 which in turn induces blistering. vulgaris. Generally, IIF is not a reliable sin- The lesions may exhibit both positive Nikol- This is supported by the high prevalence of gle test for pemphigus foliaceus due to the
36 PEMPHIGUS FOLIACEUS: A CASE REPORT WITH REVIEW OF LITERATURE rare occurrence of pemphigus like antibod- IgA antibodies is seen along the basement pressive modalities to prevent a rebound in ies in some normal patients.16 membrane as opposed to the IgG found in antibody titer after the therapy is discontin- Enzyme linked immunoabsorbant assay the epidermis in pemphigus foliaceus. Sub- ued.27 Complications include electrolyte (ELISA) is also available to test the sera of corneal pustular dermatosis begins as imbalances, pulmonary edema, hypoten- suspected pemphigus foliaceus cases. polycyclic lesions with superficial pustules. sion and need to maintain venous access.14 ELISA can detect not only the presence of Although histologically similar to the IgA Other agents reported to be have been anti-desmoglein antibody but can specifi- subtype of pemphigus foliaceus, the lack of used with limited success include: tetracy- cally identify their target as either anti- antibody deposition in SCPD helps to dis- cline, nicotinamide, dapzone, plaquenil and desmoglein-1 or antidesmoglein-3 tinguish these two entities.6 gold.7,10,28 antibodies. Armed with this knowledge Treatment of pemphigus pemphigus foliaceus may be distinguished Conclusion: from pemphigus vulgaris. In addition, quan- foliaceus titative testing of circulating antibodies can Prednisone is the mainstay of pharma- Pemphigus foliaceus is a relatively rare measure disease activity.17,18,19 cological therapy for pemphigus foliaceus. disease with diverse etiologies. While not Dosages of 1.0 mg/kg/day are started and frequently life threatening, it is disfiguring, Differential Diagnosis the number of new lesions forming is used may be painful and may require significant Several other entities may have a clinical to measure the effectiveness of the treat- immunomodulatory therapy for adequate presentation similar to pemphigus foli- ment. A response is expected within 1-2 control. Our case demonstrates many of aceus. Pemphigus vulgaris may present week. Topical corticosteroids may be the features of classic pemphigus foliaceus with weeping ulcers distributed in sebor- applied to new lesions as they appear as and exemplifies a realistic level of control rheic areas. However, oral lesions, which an adjunct to limit inflammation and blister- that can be achieved through the use of often herald the onset of pemphigus vul- ing. In some cases topical steroids alone steroids and methotrexate. We believe garis, are not seen in pemphigus may be effective.19 methotrexate is a good choice for the gen- foliaceus.2 In addition, H & E staining of Corticosteroid sparing agents must fre- eral dermatologist due to familiarity of use biopsy specimens of pemphigus vulgaris quently be utilized for adequate long-term with other dermatologic conditions, ease of will reveal a deep blister with ‘tomb stoning’ control of severe pemphigus foliaceus. Our administration and known side effects pro- of basal keratinocytes adherent to the patient experienced good results with file. basement membrane secondary to unaf- methotrexate. As with all cases of fected hemidesmosomal attachments. As methotrexate use, CBC, CMP, liver function References discussed earlier, DIF and IIF studies will testing and periodic liver biopsy are 1.) Warren SJ. The prevalence of antibodies against also reveal blister formation occurring required. Concomitant folic acid supple- desmoglein 1 in endemic pemphigus foliaceus in Brazil. N lower in the epidermis in pemphigus vul- mentation is recommended.22 Engl J. of Med 2000; 343(1): 23-30. 6,7 2.) Sami N, Yeh SW, Ahmed AR. Blistering diseases in the garis. In more difficult cases of pemphigus foli- elderly: diagnosis and treatment. Dermatology Clinics Bullous impetigo may present with ery- 2004; 22(1): 73-86 aceus, other immunosuppressive medica- 3.) Hirsch et al. Neonatal pemphigus foliaceus. JAAD 2003; thematous blistering and weeping ero- tions may be utilized. Azathiprine and 49-2: 187-9. sions. Histopathogically, pemphigus mycophenolate are popular agents used 4.) Grando SA et al. History and clinical significance of mechanical signs in blistering dermatoses: A reappraisal. foliaceus and bullous impetigo both show a alone or in conjunction with steroids. A pri- JAAD 2003; 48-1: 86-92. superficial blister in the epidermis. This is mary advantage to these agents is the 5.) Blauvelt A. Allergic and immunologic diseases of the skin. explained by the finding that exfoliative J. Allergy Clin Immunol 2003; 111: 560-70. potential for clinical remissions of pemphi- 6.) Weedon D. Skin Pathology 2nd ed. Churchill Livingstone, toxin-A, produced by Staphylococcus gus foliaceus for limited periods.19, 23 Hepa- 2002. Aureus, cleaves desmoglein-1 resulting in 7.) Bolognia J. Dermatology. Mosby 2003. totoxicity is a limiting side effect. 8.) Amagi M. Desmoglein as a Target in Autoimmunity and blister formation similar to pemphigus foli- Cyclophosphamide was found to be effec- Infection. JAAD 2003; 48-2: 244-52 aceus.20,8 However, in bullous impetigo no tive as mono therapy for pemphigus foli- 9.) Anhalt G, Diaz, L. Pemphigus vulgaris-A model for cuta- neous autoimmunity. JAAD 2004; 51: S20-1. immunoglobulin deposition will be seen aceus with complete remission obtained in 10.) Zhu YI. Dapsone and sulfones in dermatology: overview during DIF or IFF studies. It should be 17 of 20 study patients. Interestingly, when and update. JAAD 2001; 45(3): 420-34. noted that cultures from pemphigus foli- 11.) Brenner S. Drug induced pemphigus. Clin Dermatol. 1998; relapses did occur the disease was less 16: 393-7. aceus lesions are often positive for Staphy- severe than during previous occurrences 12.) Anhalt et al. Paraneoplastic pemphigus. An autoimmune lococcal or Streptococcal bacteria, but this demonstrating a disease modifying ability. mucocutaneous disease associated with neoplasia. N 6,7 Engl J Med 1990; 323: 1729-35. is not typically a significant finding. Severe side effects such as sterility, hemor- 13.) Anhalt G. Making sense of antigens and antibodies in Subcutaneous lupus erythematosus rhagic cystitis, leukopenia and increased pemphigus. JAAD 1999; 40: 763-6. 14.) Robinson N. Hashimoto T. Amagai M. Chan L. The new (SCLE) may present as red scaling lesions incidence of neoplasia relegate this med- pemphigus variants. JAAD 1999; 40(5) 649-71. but seldom has prominent blister formation. ication to a secondary role.24 15.) Isogai R. A case of herpetiform pemphigus with anti- desmoglein 3 IgG autoantibodies. J Dermatology 2004; SCLE lesions are typically photo distributed In a recent study of 11 patients, intra- 31(5): 407-10. as opposed to the seborrheic distribution of venous immunoglobulin (IVIG) was suc- 16.) Sabolinski ML et al Substrate specificity of anti-epithelial pemphigus foliaceus. H&E will reveal antibodies of pemphigus vulgaris and pemphigus foli- cessful at inducing complete remission in aceus sera in immunofluorescence test on monkey and hydropic degeneration of basal ker- resistant cases of pemphigus foliaceus. All guinea pig sections. J Invest Dermatol 1987;88: 545-9. atinocytes and dermis will have an infiltrate 17.) Ishii K. Characterization of autoantibodies in pemphigus patients were undergoing therapy with using antigen specific ELISA with baculovirus-expressed of lymphohistocytic cells. On DIF, a granu- other immunomodulatory agents without recombinant desmogleins. J Immunol 1997; 159(4): 2010-7 lar deposition of multiple types of adequate results. After addition of IVIG, a 18.) Komai A. The clinical transition between pemphigus foli- aceus and pemphigus vulgaris correlates well with the immunoglobulins is typically seen at the complete and sustained remission was changes in autoantibody profile assessed by ELISA. Br J basement membrane as well as surround- obtained for up to 18 months after IVIG Dermatol 2001; 144(6):1177-82. ing hair follicles. Occasionally a granular 19.) Korman N. New immunomodulating drugs in autoimmune was discontinued. No adverse side effects blistering diseases. Derm clinincs 2001; 19(4): 637-48. deposition of immunoglobulin may be were noted.25 A second smaller study of six 20.) Amagai M. et al. Toxin in bullous impetigo and staphylo- noted in the epidermis of SCLE.6,7,21 26 coccal scalded skin syndrome targets desmoglein-1. patients yielded similar results. Nature Medicine 2000;6:1275-7. Other disease processes to consider Plamapheresis is a useful therapy in 21.) Odom R. Diseases of the Skin 9th ed. Saunders, 2000. would include linear IgA dermatosis and 22.) Wolverton S. Comprehensive Dermatologic Drug Therapy. order to quickly lower antibody titers for Saunders 2001. subcorneal pustular dermatosis (SCPD). In patients with severe, recalcitrant disease. It 23.) Aberer W. Azathioprine in the treatment of pemphigus vul- linear IgA dermatosis, a linear deposition of is frequently utilized with other immunosup- garis. A long term follow up. JAAD 1987; 16: 527-33.
HOHNADEL, WAY 37 24.) Cummins D, Minouni D, Anhalt G, Nousari C. Oral cyclophosphamide for the treatment of pemphigus vul- garis and foliaceus. JAAD 2003: 49: 276-80. 25.) Ahmed R., A, Naveed S. IV Immunoglobulin therapy for patients with pemphigus foliaceus unresponsive to con- ventional therapy. JAAD 2002; 46: 42-9. 26.) Bystryn JC. Treatment of pemphigus with IV Immunoglob- ulin. JAAD 2002; 47(3): 358-63. 27.) Turner MS. The use of plasmapheresis and immunosup- pression in the treatment of pemphigus vulgaris. JAAD 2000; 43(6): 1058-64. 28.) Korman N. New and emerging therapies in the treatment of blistering diseases. Dermatology Clinics 2000; 18(1): 127-37, ix-x.
38 PEMPHIGUS FOLIACEUS: A CASE REPORT WITH REVIEW OF LITERATURE Trichostasis Spinulosa: A Commonly Overlooked Entity
Patrick J. Keehan, D.O.*, Bill V. Way, D.O.**, Mark R. Matthews, M.D.*** Dermatology Institute of North Texas, Dermatology Residency Program for the Texas Division of the Kirksville College of Osteopathic Medicine Dermatology Department, Northeast Regional Medical Center * Resident - Plaza Medical Center, Fort Worth, Texas ** Dermatology Residency Program Director – Northeast Regional Medical Center/Kirksville College of Osteopathic Medicine, Department of Dermatology, Texas Division. Duncanville, Texas *** Fellow – University of Texas Southwestern Medical Center, Department of Dermatology, Division of Dermatopathology. Dallas, Texas
Trichostasis spinulosa (TS) is a condition have been implemented either as a sole References in which telogen hairs are retained pre- therapy or after the application of a wax 1. Champion, R.H., Burton, J.L., Burns, D.A., and S.M. Breath- dominantly in sebaceous follicles.1 depilatory.1,2 However, depilation can be nach. Textbook of Dermatology. Volume 4. 6th ed. Oxford: Blackwell Science Ltd., 1998. Although it is a relatively common skin dis- time consuming if large areas require treat- 2. Odom, Richard B., William D. James, and Timothy G. order, it is often overlooked. We report a ment.4 In the past, application of 0.05% Berger. Andrews’ Diseases of the Skin: Clinical Dermatol- ogy. 9th ed. Philadelphia: W. B. Saunders Company, case of TS in an elderly gentleman and tretinoin solution applied daily for two to 2000. discuss various treatment options. three months had been suggested as the 3. Manuskiatti, W., Tantikun, N. Treatment of Trichostasis most effective form of treatment.2 Today, Spinulosa in Skin Phototypes III, IV, and V with an 800-nm Case Report 0.04% and 0.10% tretinoin gel microspe- here (Retin-A Micro®) can be used in its The patient was a sixty nine year-old place. Hydroactive Adhesive Pads (Biore®) Caucasian man who was seen for actinic have been used with success as well.6 A keratosis. Upon further examination, there recent study examined the use of an 800- were several black, pinpoint follicular nm pulsed diode laser in treating TS in thir- lesions on his nose with soft hairs project- teen subjects with skin phototypes III, IV, ing from the surface. These lesions were and V. This study found complete clear- similar in appearance to open comedones ance of the dark plugs for 8 to 12 weeks (Fig 1-2). The contents of several of the fol- after two treatments with the additional licles were expelled with an acne extractor, benefit of smoother skin.3 fixed to a slide using Acrymount™ mount- ing medium, and examined microscopi- cally. The diagnosis of trichostasis Figure 3 spinulosa was made at this time. 25-30 Vellus Hairs Discussion Trichostasis spinulosa is a common dis- order of hair follicles that gives the appear- ance of open comedones. When examined closely, however, bundles of soft hair that project 2 to 3 mm above the skin surface can be seen. When examined microscopi- cally, the hairs are round at the proximal end and shredded distally (Fig 3-5).2 The most common locations are on the nose, forehead, shoulders, and back espe- cially in the intrascapular region.1,2,3 Although it has been reported in ages Figure 1 Figure 4 ranging from 17 to over 60 years, it is clas- Trichostasis Spinulosa. Proximal Roundness sically and predominantly found in the elderly and middle-aged. A second, pruritic variant has been described mostly in young adults. These lesions are most typi- cally seen on the trunk and upper arms.4 The affected follicles may contain up to 50 vellus hairs and mild perifolliculitis may be present.1 Pityrosporum and bacteria, specifically Propionibacterium acne, may be a possible etiologic factor of this dis- ease. However, the precise cause of TS is still unknown.5 Although there is no cure for TS, several treatment regimens have been tried with Figure 2 Figure 5 varying success. Keratolytic preparations Close-up of Trichostasis Spinulosa Distal Shredding
KEEHAN, WAY, MATTHEWS 39 Pulsed Diode Laser. Dermatol Surg 2003; 29: 85-88. 4. Strobos, M.A., Jonkman, M.F. Trichostasis spinulosa: itchy follicular papules in young adults. Int J Dermatol. 2002; 41: 643-646. 5. Chung, T.A, Lee, J.B., Jang, H.S., et al. A clinical, microbio- logical, and histopathological study of trichostasis spinu- losa. J Dermatol. 1998; 25: 697-702. 6. Elston, D.M., White L.C. Treatment of Trichostasis Spinu- losa with a Hydroactive Adhesive Pad. Cutis 2000; 66: 77-78.
40 TRICHOSTASIS SPINULOSA: A COMMONLY OVERLOOKED ENTITY Hypertrophic Lichen Planus and Lupus Erythematosus Overlap Syndrome: A Case Report and Review
Michelle Endicott, D.O.* *3rd year resident, Case Western Reserve University, University Hospitals of Cleveland
ABSTRACT
Lichen planus-lupus erythematosus (LP-LE) overlap syndrome is an uncommon and a difficult condition to diagnose. The diagnosis depends on the presence of clinical, histologic, and/or immunologic features of both diseases occurring simultaneously. LP-LE overlap syndrome usually has a chronic course. Treatment options include the use of retinoids, dapsone, hydroxychloro- quine and thalidomide however the course tends to be chronic. A case of LP-LE overlap syndrome is presented along with a review of the literature
& E, which revealed a hypertrophic improved after a six week course of Case Report: lichenoid dermatitis with features of both terbinafine. A 55-year-old Caucasian male pre- lupus erythematosus and hypertrophic sented to the clinic complaining of a pruritic lichen planus. A second 4mm punch Discussion rash on his scalp, upper extremities, chest, biopsy for direct immunofluorescence, was and back for approximately thirty years. also performed from the right arm of non- Lichen planus –lupus erythematosus He believed the rash began while he was lesional sun-protected skin. The direct (LP-LE) overlap syndrome is a condition serving in Vietnam. In the preceding year, immunofluorescence showed granular IgM that has clinical, histopathologic, and/or he had developed hyperkeratotic nails of along the basement membrane consistent immunofluorescent patterns of both dis- the right hand and scaling of his right palm. with lupus erythematosus. The patient had eases at the same time. Lichen planus and His rash had been unsuccessfully treated a total of six previous biopsies that were lupus erythematosus are not uncommon in the past as psoriasis with topical/intrale- obtained and reviewed. Two years prior he diseases, however they rarely occur sional corticosteroids, acitretin, and had underwent two biopsies one from a together.1 There has been approximately cyclosporine. Several years prior to his pre- verrucous plaque from the left arm and the 50 cases of LP-LE overlap syndrome sentation, he had undergone one treatment second from an eczematous patch on the reported in the literature.2 of broadband UVB phototherapy that right abdomen. The left arm was consistent Previous case reports of LP-LE overlap resulted in a cutaneous burn. He admitted with hypertrophic lichenoid dermatitis with syndrome comprise a very heterogeneous to being extremely sensitive to the sun. He features of both hypertrophic lichen planus group with some having features favoring also believed his condition became worse and verrucous lupus erythematosus and LE or LP. The clinical features of LP-LE in the summer. the second from the right abdomen overlap syndrome have included various His past medical history was significant showed interface dermatitis more consis- features including violaceous papules and for a positive RPR test with a titer of 1:4 for tent with lupus erythematosus. Interest- plaques on the dorsal acral skin, follicular several years, however his confirmatory ingly, his first biopsy from four years prior plugging, verrucoid plaques with atrophy, test, mircohemagglutination test (MHATP) showed clearly lichen planus from a viola- and mucous involvment.1 While others was repeatedly negative. He denied ceous plaque on his back. have reported hair loss, nail involvement headaches, joint pain, kidney problems, Complete blood count, basic metabolic and photosensitivity to be prominent clini- sexually transmitted diseases, fever, night panel, thyroid panel, HIV, hepatitis panel cal features.3 Several reports have shown sweats, fatigue, or weight loss. He had a and liver function tests were within normal a predilection for acral skin and oral history of depression /anxiety and neck limits. As previously stated, he had a posi- mucous. There are several different sys- pain for which he took sertraline (Zoloft) tive RPR (1:4 titer) but a negative MHATP. temic abnormalities that have been associ- and ibuprofen. The patient had no medica- A negative ANA (repeated twice) and a ated with LP-LE overlap syndrome. For tion allergies. He did not abuse alcohol, positive SSA. Also he had a negative SSB, example, Jamison et al reported a patient tobacco, or any other illicit drugs. He Smith, and RNP antibodies. His urinalysis with LP-LE overlap syndrome with low C4 denied having any family members with was completely normal. A KOH prepara- and mixed cryoglobulinemeia.4 In sum- skin problems, connective tissue disease, tion of the scale from the right palm was mary, many different clinical and systemic or autoimmune disorders. positive for hyphae consistent with tinea features are noted in patients making the On examination there were verrucoid manum. diagnosis difficult. hyperkeratotic plaques symmetrically Hydroxychloroquine 200mg twice a day In a few case reports, the passage of involving the chest, back, upper extremi- was instituted after obtaining a negative time allowed for one to diagnosis LE or ties. He had both hyperpigmented and glucose-6-phosphate dehydrogenase. He lichen planus. During the course of dis- hypopigmented patches along the vertex of was referred for ophthalmology consult ease, systemic lupus erythematosus has the scalp with atrophy centrally. There was prior to starting the medication. He was also declared itself in a few case reports a diffuse erythema of the malar and fore- instructed to use sun-protection including with the presentation of additional serologic head regions. The oral and genital mucosa physical blocker sunscreen and sun-avoid- and noncutaneous manifestations.1 was found to be normal. There were five ance. Initially he felt the medication helped, It is important to differentiate between hyperkeratotic, yellow dystrophic nails with however after six months there was little lupus erythematosus and lichen planus scaling on the right hand palm. improvement except for decrease in pruri- because it has an effect on treatment and A 4mm punch biopsy was performed on tus. A trial of thalidomide is being consid- prognosis of patients. Therefore, physi- the patient’s right arm and it was sent for H ered. His tinea manum and onychomycosis cians must try to distinguish them by using
GALICZYNSKI, JR., LIM, GREENBERG 41 all diagnostic tests available.1 LP and LE display some similar histologic features however there are a few findings that favor one diagnosis over the other. For example, colloid bodies are more numerous in lichen planus along with basement membrane cleft formation (Max-Joseph spaces). In lupus erythematosus, basement mem- brane thickening is a common feature.5 Immunofluorescence can sometimes be helpful. A linear band of fibrinogen at the basement membrane zone is consistent with lichen planus. Whereas, granular deposits of immunoglobulins at the base- ment membrane zone is consistent with lupus erythematosus.1 However, as in our patient this distinction is not always possi- ble thus the diagnosis of LP-LE overlap syndrome was made. This disease overlap syndrome tends to have a chronic course and be very treat- ment resistant. Various treatment options have been tried including systemic retinoids, cyclosporine, dapsone, hydroxy- chloroquine, and thalidomide.6
References: 1. Camisa C, et al. Use of indirect immunofluorescenece in the lupus erythematosus/lichen planus overlap syndrome: an additional diagnostic clue. J Am Acad Dermatolo 1984;11:1050-58. 2. Inaloz HS, et al. Lupus erythematosus-lichen planus over- lap syndrome with scarring alopecia. J Eur Acad Dermatol Venereol 2000;15:171-4. 3. Ahmed Ar, et al. Coexistence of lichen planus and systemic lupus erythematosus. J Am Acad Dermatolo 1982;7:478- 83. 4. Jamison TH, Cooper NM, Epstein WV: Lichen planus and discoid lupus erythematosus. Arch Dermatol 1978;114:1039-42. 5. Kim H, Pomeranz MK. Lupus erythematosus and lichen planus overlap syndrome. J Drugs Dermatol 2004;3:311- 2. 6. Grabbe S, Kolde G. Coexisting lichen planus and subacute cutaneous lupus erythematosus. Clin Exp Dermatol 1995; 20:249-54.
42 LICHEN PLANOPILARIS: A CASE PRESENTATION AND REVIEW OF THE LITERATURE Nationwide 24 hour Turn-around-Time on all routine specimens All malignant melanoma cases are phoned to your office upon diagnosis Expert "in-house" billing services with toll-free numbers for direct patient inquiry "Rush" results faxed to you immediately Every biopsy read by our board certified dermatopathologists: • Evangelos Poulos, M.D. • Raymond L. Barnhill, M.D. • Andrew Hanly, M.D. SERVICE COMMITMENT:
GLOBAL PATHOLOGY Contact us and put us to the test call us toll free# 1.866.825.4422 LABORATORY SERVICES 16250 N.W. 59th. Ave, Suite 201 Miami Lakes, Florida 33014 Nationwide 24 hour Turn-around-Time on all routine specimens All malignant melanoma cases are phoned to your office upon diagnosis Expert "in-house" billing services with toll-free numbers for direct patient inquiry "Rush" results faxed to you immediately Every biopsy read by our board certified dermatopathologists: • Evangelos Poulos, M.D. • Raymond L. Barnhill, M.D. • Andrew Hanly, M.D. SERVICE COMMITMENT:
GLOBAL PATHOLOGY Contact us and put us to the test call us toll free# 1.866.825.4422 LABORATORY SERVICES 16250 N.W. 59th. Ave, Suite 201 Miami Lakes, Florida 33014 Lichen Planopilaris: A Case Presentation and Review of the Literature
Edward M. Galiczynski, Jr., MS-III, Lake Erie College of Osteopathic Medicine, Scott J.M. Lim, D.O., Assistant Professor-Lake Erie College of Osteopathic Medicine, Michael R. Greenberg, M.D., M,B.A., Medical Director-Lock Haven University Department of Physican Assistant Studies
ABSTRACT
A sixty-nine year old female presented to the office with a one year history of scalp pruritis, scaling erythematous plaque-like lesions and cicatricial hair loss. Dermatological evaluation and biopsy resulted in the diagnosis of lichen planopilaris (LPP). LPP is a rare, progressive inflammatory condition of unknown etiology that causes irreversible scalp hair loss. Early diagnosis and treat- ment is paramount in order to prevent scarring from occurring. This case study reviews the clinical presentation, histopathology, differential diagnosis, and treatment options of LPP.
primary scarring alopecias, where the hair Case Report: follicle is the principal target of destruction, A sixty-nine year old female presented to and secondary scarring alopecias, where the office with a one year history of scalp the follicular damage is a secondary con- pruritis, scaling erythematous plaque-like sequence to impingement of the follicular lesions and cicatricial hair loss (see photos unit.2 1, 2, and 3). She had been treated with The differential diagnosis of primary cephalexin 500mg twice daily and diflo- scarring alopecias includes lichen planopi- rasone 0.05% topical cream without relief. laris (LPP), pseudopelade, and discoid Her past medical history was significant for lupus erythematosus. hyperlipidemia. She denied any history of Lichen planopilaris is a rare inflammatory diabetes, psoriasis, eczema or other der- condition that causes permanent scalp hair Figure 1 matological conditions. She had been tak- loss. The pathogenesis of LPP is poorly ing simvastatin for hyperlipidemia. She had understood. Patients initially present with no known drug allergies. Her past surgical erythema, perifollicular scaling and hyperk- history was positive for a total hysterec- eratotic follicular papules. The hair follicles tomy with bilateral salpingoophorectomy are subsequently destroyed, yielding and cholecystectomy. Her family history atrophic, irregular, angular or polygonal revealed diabetes mellitus (type 2), coro- shaped patches of alopecia with similar fol- nary artery disease and skin cancer. She licular papules at the periphery of the patch denied the use of tobacco products or con- of alopecia. Symptoms vary from moderate sumption of alcohol. Physical exam to severe scalp itching, pain, burning and revealed perifollicular erythema, papu- discomfort. Lesions of LPP may be insidi- losquamous plaques, diffuse hair thinning ous or fulminant, involving focal or wide- and cicatricial alopecia noted predomi- spread areas of the scalp. Lichen planus in nately at the vertex of the scalp. No other other areas of the body including mucous Figure 2 cutaneous or oral lesions were present. membrane and nails may occasionally pre- (melanophages).In more developed Longitudinal ridging of the nails was evi- cede, occur simultaneously or follow scalp lesions, perifollicular fibrosis and epithelial dent (see photo 4). Anti-nuclear antibody involvement. LPP is reported more fre- atrophy at the level of the infundibulum and (ANA) was negative. A punch biopsy was quently in women with the onset varying isthmus are characteristic findings. Dam- taken at two sites revealing telogen hair fol- 3 from late childhood to the seventh decade. age to the hair bulge, the site where stem licles with cystic dilation surrounded by a The course of the disease is slowly pro- cells of the hair follicle are currently lichenoid infiltrate of lymphocytes and histi- gressive and patients usually retain accepted to reside, results in permanent ocytes at the level of the dermal-epidermal enough hair to cover the affected scalp scarring alopecia. Immunofluorescence in junction. The inflammatory infiltrate demon- with meticulous hair styling. The diagnosis active stages shows cytoid body staining strated vacuolar degeneration involving the of LPP is made histologically. The usual by anti-IgM and/or anti-IgA, IgG and rarely follicular epithelium and increased fibrosis histologic features of lichen planus are C3 at the level of the dermal-epidermal in the reticular dermis. The diagnosis of found particularly surrounding the hair folli- junction.4 lichen planopilaris was made and the cles and other epidermal appendages The clinical triad of scarring alopecia, patient was subsequently treated with topi- including: benign acanthosis of the epider- loss of pubic and axillary hairs and the pro- cal corticosteroids (clobetasol). Her symp- mis, hypergranulosis, orthokeratotic hyper- gressive development of horny follicular toms have been well controlled with keratosis, a moderate to severe band-like papules variously located is known as the occasional exacerbation. infiltrate of lymphocytes and histiocytes as Graham-Little syndrome.4 well as vacuolar degeneration at the level Discussion of the dermal-epidermal junction with many The clinical presentation of cytoid bodies (apoptotically necrotic ker- pseudopelade of Brocq (PB) is similar to Scarring alopecias are due to permanent atinocytes). Frequently there is the pres- LPP. There is controversy over the etiol- damage to essential parts of the hair follicle ence of melanin pigment incontinence with ogy of PB. PB may represent either a dis- or destruction of the entire hair follicle.1 the presence of melanin-containing tinct entity (i.e., an idiopathic primary They are classified into the categories of macrophages in the inflammatory infiltrate scarring alopecia) or the terminal stage of
LAD, LIN, WAY 45 of treatment is to alleviate symptoms and Potent topical or intra-lesional glucocorti- to impede progression. Intralesional and/or coids are the first-line treatment of LPP. Group I and II topical steroids are used as Antimalarials and retinoids have been used the initial treatment for localized LPP. In with some success. Although anecdotally instances of rapid progression, oral corti- effective in cases of LPP, the use of costeroids may be considered to limit the thalidomide is not recommended due to acute inflammation. Topical glucocorticoids potential adverse consequences. relieve itching; nevertheless, the lesions Cyclosporin and immunomodulating resolve slowly. Antimalarials (hydroxy- agents including tacrolimus and pime- chloroquine) and retinoids (isotretinoin) crolimus may be used in severe, refractory may be effective in the long-term treatment cases. Further research is needed in order of LPP, requiring months to years for to provide physicians with a better under- improvement and resolution.7 standing of the etiology of LPP, and thus Cyclosporine, a calcineurin inhibitor that provide superior treatment of this condition. acts by suppressing gene transcription of IL-2, has been successful in treating References: severe and refractory lichen planus of the 1. Habif TP. Clinical Dermatology: A Color Guide to Diagnosis skin, and has produced sustained remis- and Therapy. 4th edition. 8,9,10,11 sion in numerous patients with LPP. St. Louis, Mo: Mosby; 2004. While the mechanism of action of 2. Headington, John T et al. Clinical Aspects of Hair Disor- ders. Cicatricial Alopecia. cyclosporine in lichen planus is unknown, Dermatology Clinics 1996;14: 773-782. cyclosporin is presumed to involve the 3. Mirmirani P, Willey A, Price VH et al. Short course of oral cyclosporine in lichen selective inhibition of T-helper cells and planopilaris. J Am Acad Dermatol. 2003; 49(4):667-71. down-regulation of cytokines responsible 4. Elder D, Elenitsas R, Jaworsky C, Johnson B Jr. Lever's 9,15 Histopathology of the Skin, for T-cell adhesion to keratinocytes. 8th edition. Philadelphia; Lippincott-Raven, 1997. Figure 3 There have been a few cases of thalido- 5. Moretti S, Amato L, Massi D, Bianchi B, Gallerani I, Fabbri P et al. Evaluation of mide induced remission of lichen planopi- inflammatory infiltrate and fibrogenic cytokines in laris.17 Thalidomide most likely exerts its pseudopelade of Brocq suggests beneficial effects in patients with LPP by the involvement of T-helper 2 and 3 cytokines. Br J Derma- tol. 2004 Jul;151(1):84-90. affecting tissue cytokine concentrations 6. Petropoulos, Peter, Ferri, Fred. Discoid Lupus. Instant such as TNF-α down-regulation.16 How- Diagnosis and Treatment. W.B. Saunders Co., 2003. ever, benefit-to-risk analysis is essential 7. Tan, E, Martinka, M, Ball, N, Shapiro, J. et al. Primary Cica- due to the potentially adverse effects asso- tricial Alopecias: Clinicopathology of 112 Cases. J Am Acad Dermatol 2004; ciated with thalidomide - most notably ter- 50:1. atogenecity. A recent study suggests that 8. Higgins EM, Munro CS, Friedmann PS, Marks JM et al. thalidomide is ineffective in treatment of Cyclosporin A in the treatment of lichen planus. Arch Dermatol 1989;125:1436. 17 LPP. 9. Ho VC, Gupta AK, Ellis CN, Nickoloff BJ, Voorhees JJ et al. Treatment of severe One study analyzed the phenotype of lichen planus with cyclosporin. J Am Acad Dermatol Figure 4 the inflammatory infiltrate present in scar- 1990;22:64-8. ring alopecia.5 The histology, direct 10.Pigatto PD, Chiappino G, Bigardi A, Mozzanica N, Finzi AF et al. Cyclosporin A for various forms of cicatricial alopecia such as immunofluorescence (DIF) and immuno- treatment of severe lichen planus. Br J Dermatol lichen planopilaris (LPP) or discoid lupus histochemistry of lichen planopilaris 1990;122:121-3. 5 11.Mozzanica N, Cattaneo A, Legori A, Pigatto P, Finzi AF et erythematosus (DLE). revealed a prominent infiltrate of CD3+ al. Immunohistologic Early lesions of discoid lupus erythe- cells with a high CD4+/CD8+ ratio, variable evaluation of the effect of cyclosporin treatment on the lichen planus immune matosus are similar to LPP and numbers of macrophages, mast cells and infiltrate. J Am Acad Dermatol 1991; 24:550-4. pseudopelade of Brocq.2 Late lesions of fibroblasts always fewer than lymphocytes. 12.Levell NJ, Munro CS, Marks JM et al. Severe lichen planus Interferon (INF)-gamma was also present.5 clears with very low-dose discoid lupus erythematous (DLE) are cyclosporin. Br J Dermatol 1992;127:66-7. more pronounced and clinically diagnostic. This data suggests that T-helper cells may 13.Reiffers-Mettelock J et al. Acute lichen planus treated by Clinical inspection and skin biopsy usually be involved in the pathogenesis of LPP. Sandimmune (cyclosporin). Dermatology 1992;184:84. establish the diagnosis of DLE. A combina- Therefore, a trial of immunomodulator 14.Oliver GF, Winkelmann RK. Treatment of lichen planus et tion of diffuse scaling, telangiectases and agents such as topical tacrolimus or pime- al. Drugs 1993; 45:56-65. 15.Brown MD, Gupta AK, Ellis CN, Rocher LL, Voorhees JJ et mottled hyperpigmentation within areas of crolimus may be a reasonable therapeutic al. Therapy of scarring are characteristic. Histologically, modality in recalcitrant LPP. dermatologic disease with cyclosporin A. Adv Dermatol 1989;4:1-28. DLE is usually characterized by a more 16.George S.J., Hsu S. et al. Lichen planopilaris treated with prominent vacuolar degeneration at the Conclusion thalidomide. J Am Acad dermal-epidermal junction with epidermal Dermatol 2001;45:965-6. 17.Jouanique C. et al. Thalidomide is ineffective in the treat- atrophy, prominent follicular plugging and Lichen planopilaris is a rare inflammatory ment of lichen planopilaris. patchy superficial perivascular and band- condition of uncertain etiology that causes J Am Acad Dermatol: 2004; 51(3): 480. like infiltrates of lymphocytes and histio- irreversible scalp hair loss. Like other scar- cytes. As the disease process progresses, ring alopecias, LPP involves either destruc- plugged follicles are absent, and the skin tion of the hair follicle or scarring of the becomes smooth, atrophic and scarred.3 reticular dermis. Due to the progressive Immunoflourescent studies are not useful.1 nature of LPP, prompt diagnosis and treat- ANA may be positive in 20% of patients ment is essential in order to prevent scar- with isolated DLE.6 ring. Cutaneous biopsy is essential for the The treatment of patients with LPP is a diagnosis of LPP. The primary objective of challenge and may not change the ultimate therapy is to alleviate symptoms, and to outcome of the disease. The primary focus impede or slow progression of the disease.
46 LICHEN PLANOPILARIS: A CASE PRESENTATION AND REVIEW OF THE LITERATURE Herpes Simplex and HIV Infection: A Case Report and Review of the Literature
Frank T. Armstrong, DO*, Marya Cassandra, DO**, Richard Miller, DO, FAOCD*** * Board certified in dermatology and internal medicine and is in private practice at Bay Dermatology and Cosmetic Surgery in Port Richey, Florida. **Third year dermatology resident from NOVA Southeastern University (Sun Coast Hospital) in Largo, Florida ***Dr. Miller is a dermatologist in private practice at Bay Dermatology and Cosmetic Surgery in Port Richey, Florida. Program director of the NOVA Southeastern University/Sun Coast Hospital dermatology residency program
ABSTRACT
Herpes progenitalis is a common infection most frequently caused by herpes simplex virus 2 (HSV-2). In the early 1980’s chronic perianal herpetic ulcers came to the forefront, largely due to the impending human immunodeficiency virus (HIV) epi- demic. Genital herpes and other genito-ulcerative diseases (GUDs) are clearly risk factors for concomitant HIV infection. In immunocompetent patients, a reactivation of an HSV infection typically heals within one to two weeks. In contrast, severely immunosuppressed patients, such as those with advanced HIV infection, present with a more chronic course. We describe a case of recalcitrant genital herpes manifesting as the initial presentation of HIV disease. A review of the literature was also performed on PubMed using the keywords: HIV and herpes simplex.
Case Report: A 37 year-old African-American male was admitted to the hospital for evaluation and treatment of purulent ulcerations in the genital region of three months duration. He had been treated by his primary care physician several times on an outpatient basis with topical clotrimazole and betamethasone dipropionate as well as oral antibiotics. A previous inconclusive biopsy report revealed “a non-specific Figures 1 acute and chronic inflammatory infiltrate Multiple, well demarcated, punched with benign sweat gland proliferation”. out ulcers that coalesce in the The patient denied any history of illicit periscrotal and perianal areas. drug use, unprotected sexual encounters, homosexual behavior, sexually transmitted improved and was discharged on acyclovir. diseases, blood transfusions, or tattoos. He He was scheduled for follow-up with the denied any specific past medical conditions infectious disease service to commence or surgical procedures. The review of sys- highly active anti-retroviral therapy tems was unremarkable except for the (HAART) and prophylaxis against other painful ulcers in the groin. opportunistic infections. Physical examination showed multiple, well demarcated, punched out ulcers that Comment coalesced in the periscrotal and perianal areas (figures 1 and 2). Painless, inguinal, The herpes virus contains double Figures 2 nonsupperative lymphadenopathy was pre- stranded DNA that replicates in the cell Multiple, well demarcated, punched sent bilaterally. The rest of the cutaneous nucleus and is characterized by the ability out ulcers that coalesce in the exam was unremarkable. Laboratory to produce latent but lifelong infection. Epi- periscrotal and perianal areas. examination revealed a white blood cell demiologic surveys suggest that HSV-2 is count of 3.4 X 103; otherwise, the remain- the most common cause of genital ulcera- and other genito-ulcerative disease der of the hemogram and metabolic profile tions among the sexually transmitted dis- (GUDs) are actually risk factors for HIV was within normal limits. A bacterial cul- eases.1 It is estimated that currently in the acquisition.4,5,6,7,8 It is possible that a preex- ture of the ulcerations grew normal flora, United States, 23% of adults are infected isting HSV infection could increase the the RPR was non-reactive, and a viral cul- with HSV-2, of which of up to 20% are pathogenicity of HIV since the two viruses ture was not yet obtained. completely asymptomatic.2 may act as cofactors.9 This concept is Empirically, the patient was treated with In the setting of HIV infection, the clinical termed reciprocal enhancement. Ker- systemic azithromycin and acyclovir and presentation of anorectal diseases may be atinocytes, unlike macrophages and T topical tepid burrows solution compresses. atypical. In fact, unusual features of her- helper cells, lack the CD4 molecule that is Biopsies that were obtained from the bor- pes simplex or varicella infections should the required receptor for entry of HIV-1 der and center of the ulcers was consistent prompt one to consider an underlying HIV infection. Heng et al was the first to report with consistent a herpes virus infection (fig- infection.3 an in-vivo co-infection of HIV and HSV-1 in 10 ure 3). HIV serologies were positive, and Although there is debate in the literature, keratinocytes and macrophages. They the CD4 count was 234 The patient the majority of studies suggest that HSV-2 demonstrated that the virions in the co-
ARMSTRONG, CASSANDRA, MILLER 47 ciclovir are effective antiviral therapies for 3. Crowe SM. Unusual features of heres simplex or zoster 15 infection that suggest HIV infection. Med H Aust HSV. Foscarnet has successfully been 1993;158(3):186-7. used as an alternative in acyclovir resistant 4. Dickerson MC, Johnston J, Delea TE, White A, Andrews E. The causal role for genital ulcer disease as a risk factor cases; however, foscarnet resistant strains for transmission of human immunodeficiency virus. An have also been isolated. Spermicides such application of the Bradford Hill criteria. Sex Transm Dis as nonoxynol-9 and gramicidin have also 1996;23(5):429-40. 5. Keet IP, Lee FK, van Griensven GJ, Lange JM, Nahmias A, shown anti-HSV and anti-HIV activity but Coutinho RA. Herpes simplex virus type 2 and other geni- are not recommended as sole prevention tal ulcerative infections as a risk factor for HIV-1 acquisi- tion. Genitourin Med 1990;66(5):330-3. strategies. Specifically, identifying and 6. Kingsley LA, Armstrong J, Rahman A, Ho M, Rinaldo CR Jr. counseling the asymptomatic carrier of No association between herpes simplex virus type-2 seropositivity or anogenital lesions and HIV seroconver- HSV is necessary if we are to decrease the sion among homosexual men. J Acqui Immune Defic transmission of genital herpes and poten- Syndr 1990;3(8):773-9. tial HIV co-infection. 7. Chen CY, Ballard RC, Beck-Sague CM, Dangor Y, Radebe F, Schmid S, Weiss JB, Tshabalala V, Fehler G, Htun Y, Figure 3 Morse SA. Human immunodeficiency virus infection and genital ulcer disease in South Africa: the herpetic connec- Histology reveals multinucleated giant Conclusion tion. Sex Transm Dis 2000;27(1):30-1. cells, ballooning degeneration, and 8. Moriuchi M, Moriuchi H. Herpes Simplex Virus infection Since the emergence of HIV in the early induces replication of human immunodeficiency virus type ground glass nuclei. 1. Virology 2000;278(2):534-40. 1980’s, the prevalence, presentation, and 9. Griffiths PD. Herpesviruses and AIDS. Scand J Infect Dis infected cells were larger, morphologically pathogenicity of GUDs, including HSV, Suppl 1996;100:3-7. atypical, and appeared to be hybrids of one have changed dramatically. An emphasis 10. Heng MC, Heng SY, Allen SG. Co-infection and synergy of human immunodeficiency virus-1 and herpes simplex another. Since AIDs patients have been should be placed on treating any underly- virus-1. Lancet 1994;29;343(8892):255-8. reported to shed more HSV, to acquire ing STD since any GUD may carry an 11. Mole L, Ripich S, Margolis D, Holodniy M. The impact of active herpes simplex virus infection on human immunod- more chronic HSV infections, and to have increased rate of transmission of HIV. Our eficiency virus load. J Infect Dis 1997;176(3):766-70. produced multiple acyclovir resistant focus should be on early identification and 12. Koelle DM, Wald A. Herpes simplex virus: the importance of asymptomatic shedding. J Antimicrob Chemother strains this questions the need for incorpo- treatment of the asymptomatic shedding of 2000;45. rating chronic suppressive treatment for HSV in AIDS patients and to continue to 13. Stewart JA, Reef SE, Pellett PE, Corey L, Whitley RJ. Her- HSV-2 in the treatment of AIDS.11,12,13,14 work towards new antiviral therapies and pesvirus infections in persons infected with human immunodeficiency virus. Clin Infect Dis 1995;21 Suppl Treatment modalities for HSV and HIV vaccines. 1:S114-20. have focused on anti-viral therapies and 14. McGrath BJ, Newman CL. Genital herpes simplex infec- tions in patients with the acquired immunodeficiency syn- safe sex practices. Unfortunately, no effec- References: drome. Pharmacotherapy 1994;14(5):529-42. tive vaccines are available for HSV or HIV. 15. Corey L. Herpes simplex virus infections during the decade 1. Da Rosa-Santos OL, Goncalves Da Silva A, Pereira AC Jr. since the licensure of acyclovir. J Med Virol 1993; Suppl Complicating matters is the emergence of Herpes simplex virus type 2 in Brazil: sero-epidemiologic 1:7-12. acyclovir resistant strains of HSV. In most survey. Int J Dermatol. 1996;35(11): 794-6. 2. Odum RB, James WD, Berger TG. Viral Diseases. Andrews’ instances, acyclovir, valacyclovir, and fam- Diseases of the Skin. 9th Ed. Philadelphia, PA: WB Saun- ders Co; 2000. p. 473-482.
48 HERPES SIMPLEX AND HIV INFECTION: A CASE REPORT AND REVIEW OF THE LITERATURE X-Linked Ichthyosis
Tara H. Lawlor, D.O.* , Donald J. Adler, D.O.** *Lehigh Valley Hospital-Muhlenberg, Second Year Dermatology Resident, Allentown, PA **Lehigh Valley Hospital Dermatology Residency Clinical Educator, Doylestown, PA
ABSTRACT
A case report of an adult male with X-linked ichthyosis is presented along with the pathogenesis, histopathology, differential diagnoses, laboratory evaluations and treatments for the disease. X-linked ichthyosis is a clinically mild eruption due to a genetic disorder of keratinization and is recessively inherited with incidence second to ichthyosis vulgaris. It is found in males at birth and is due to a steroid sulfatase deficiency. Scaling is found in a distinct distribution and extracutaneous manifestations are possi- ble. Typically, hyperkeratosis and a normal to thickened granular layer are seen on dermatohistopathology. There are numerous ways to make the diagnosis in affected patients and carriers and these are reviewed. Treatment is aimed at eliminating and preventing scale.
On physical examination diffuse adher- Introduction ent, plate-like brown scales were noted on X-linked ichthyosis is an interesting der- the trunk, posterior and lateral neck and matological disease process which has extremities with accentuation over the been studied extensively. In 1966, Wells extensor surfaces and relative sparing of and Kerr classified the various ichthyoses. the flexures. His face, palms and soles In 1976 steroid sulfatase (STS) deficiency were spared. See Figure 1. was identified by Jobsis et al and in 1978, Laboratory data from our patient Shapiro et al showed the relationship included a peripheral blood fluorescence in between X-linked ichthyosis and a STS situ hybridization (FISH) study positive for deficiency.1,2,3 a STS deficiency. This study was per- The skin manifestations typically develop formed using molecular cytogenetics. A at birth or early infancy with light scaling DNA FISH probe using cultured T lympho- which progresses to larger, dark scales cytes from the peripheral blood of our affecting the extensor and sometimes patient and a STS probe specific for the flexor regions of the extremities in addition short arm, p portion, of the X22 chromo- to preauricular areas, neck and upper some was applied. Using the STS probe trunk. The palms and soles are generally which hybridizes within band Xp22.3, a uninvolved. Asymptomatic corneal opaci- lack of hybridization to the X chromosome ties and cryptorchidism as well as delayed was shown. This was consistent with a labor in mothers of affected patients are microdeletion specific for X-linked associated features.4 ichthyosis. See Figure 2. Peripheral blood FISH study for Kallman Case Report syndrome was negative showing a normal pattern of hybridization at band Xp22.3. A thirty-two year old Caucasian male Serum lipoprotein electrophoresis including Figures 1a & 1b presented to the office for treatment of “dry serum cholesterol, triglycerides, chylomi- Diffuse adherent, plate-like brown skin all my life”. He described a lifelong crons, beta lipoproteins, pre-beta lipopro- scales on trunk and extremities with history of diffuse, dry and scaling skin on teins, and alpha lipoproteins was also accentuation over extensor surfaces his trunk and extremities noted to be worse performed and showed a normal pattern. in the winter months. His birth history was Urology and ophthalmology consults were extracutaneous manifestations are possi- 5 unremarkable for any prolonged or difficult obtained and were both within normal lim- ble. labor and he had no history of unde- its. Mild, light colored scaling is seen in the scended testes. However, the patient and A punch biopsy from the right leg neonatal period. Over the ensuing weeks, his wife did have difficulty conceiving for showed thickened and compact hyperker- the scales become yellow-brown, polygo- approximately one year prior to presenta- atosis and hypergranulosis. See Figure 3. nal and firmly adherent eventually pro- tion. gressing to large, dark scales often giving The patient’s past medical and surgical Discussion the skin a dirty appearance. The abdomen history included a unilateral herniorrhaphy. is usually more involved than the back and His family history included a nephew with X-linked ichthyosis is a clinically mild the scales are more prominent over the similar skin findings. He had no medication skin eruption due to a genetic disorder of extensor surfaces, pre-auricular areas, allergies and took no oral medications. He keratinization. It is the second most com- neck and upper trunk with or without flex- had been using over the counter moisturiz- mon form of ichthyosis after ichthyosis vul- ural involvement. Generally, sparing of the ers and emollients with minimal benefit. garis. X-linked ichthyosis affects between palms and soles is seen and hair and nails He smoked one pack of cigarettes per day one in 2,000 and 6,000 males and has no are normal. The condition generally and had approximately four drinks per racial or geographic predilections. It typi- improves in the summer and worsens in 1 week. The patient worked as a material cally develops at birth or early infancy usu- the winter. food handler. ally between two and six weeks of age and In 1966, Wells and Kerr classified the
LAWLOR, ADLER 49 tion as well as hypoplasia of the penis and mal to thickened granular layer, and mild to scrotum have also been reported. Other moderate acanthosis. Ultrastructurally, an phenotypical abnormalities are rarely seen increased number of keratohyaline gran- including short stature, mental retardation, ules and desmosomes persist into the stra- chondrodysplasia punctata (a form of tum corneum along with increased dwarfism), and Kallmann syndrome numbers of melanosomes which may (hypogonadotrophic hypogonadism and account for the dark coloration of scales.12 anosmia). The latter two processes have The main differential diagnoses of X- genes with large deletions that map to the linked ichthyosis include other hereditary Xp22.3 location.4 disorders of cornification such as ichthyosis X-linked ichthyosis is due to a genetic vulgaris, lamellar ichthyosis, congenital disorder of keratinization leading to a reten- ichthyosiform erythroderma and bullous Figure 2 tion ichthyosis. It is caused by a deficiency ichthyosiform erythroderma. Distinction of Fluorescence in situ hybridization of the STS enzyme resulting from abnor- the disorders of cornification is based on (FISH) study positive for STS defi- malities in its coding gene. The STS gene family history, onset and course of the dis- ciency. The internal control and is mapped to the distal part of the short ease, cutaneous findings, noncutaneous enzyme presence should both occur arm of the X chromosome, specifically manifestations and histopathology. It is at the centromere location of the X22 Xp22.3. 90% of X-linked ichthyosis patients important to remember that climatic condi- chromosome with the green dot as have a complete deletion of the gene and tions can modify skin manifestations in 10% have a point mutation or partial dele- ichthyosis complicating the diagnosis.1 control and red dot as enzyme gene 1,2,3 presence. Since only the green dot is tion of the STS gene. One case in the lit- Ichthyosis vulgaris is the most common seen at the arrow, this was positive for erature reported a patient with somatic and ichthyosis and affects 1 in 250 newborns or 5 a STS gene deletion. germinal mosaicism of the STS gene in a 1% of the population . It is autosomal dom- carrier and offered DNA slippage as the inant and appears in the first month of life possible mechanism for this mosaicism. with fine, white scales over the extensors, The origin of the X chromosome with the with flexural and intertriginous sparing, ker- deletion of the STS gene was shown to be atosis pilaris, atopy and palmoplantar the grandfather of the proband.7 hyperkeratosis and hyperlinearity. In X- STS is a membrane bound microsomal linked ichthyosis these features are not enzyme capable of hydrolyzing sulfated seen. It generally improves with age steroid hormones and cholesterol sulfate. whereas X-linked ichthyosis worsens with Its activity is usually measured with dehy- age.On histopathology, mild to moderate droepiandrosterone sulfate (DHEA) as a compact hyperkeratosis with a decreased substrate.8 It is present in many tissues or absent granular layer reflecting including the placenta, liver, kidneys, decreased or absent filaggrin, is important adrenals, ovaries, fibroblasts, epidermal is making the diagnosis. This disorder is cells, leukocytes, hair bulbs and testicular due to retention of scale. The genetic Figure 3 tissue.9 This enzyme normally has increas- cause in ichthyosis vulgaris seems to be a H & E of right leg showing thickened ing activity at the stratum corneum-granular keratohyaline defect that may affect the and compact hyperkeratosis and layer junction where it hydrolyzes choles- matrix protein of the stratum corneum.13 hypergranulosis (20x) terol sulfate and sulfated steroid hormones. The clinical distinction between X-linked In normal epidermis, cholesterol sulfate ichthyosis and ichthyosis vulgaris may be various ichthyoses. In 1976 steroid sulfa- decreases from 6% in the granular layer to difficult because they share many clinical tase deficiency was identified by Jobsis et 3% in the stratum corneum. In patients with features although they arise from different al and in 1978, Shapiro et al showed the X-linked ichthyosis, the STS deficiency genetic defects.1,5 Overlap is frequent mak- relationship between X-linked ichthyosis results in levels of cholesterol sulfate in the 1,2,3 ing the diagnosis challenging. Wells and and a STS deficiency. stratum corneum approaching 12-30%. Jenning reported specific diagnostic criteria Extracutaneous manifestations are pos- This increase in cholesterol sulfate along used to differentiate ichthyosis vulgaris sible in X-linked ichthyosis patients. with decreased cholesterol in the stratum from X-linked ichthyosis. These included: Affected males and female carriers may corneum leads to persistent keratinocyte family history of ichthyosis, age of onset, have comma shaped corneal opacities on adhesion and abnormal desquamation.9,10 cutaneous manifestations (color and size the posterior capsule or Descemet’s mem- The measurement of STS levels differ- of scales, site of maximal involvement and brane. These opacities are asymptomatic entiates X-linked ichthyosis from other presence of palmoplantar involvement), and do not affect visual acuity. They may ichthyosis types and identifies X-linked ocular involvement and histopathology.11 In present in adulthood in 24% or more of ichthyosis carriers. The enzyme is normally a paper reported by Cuevas-Covarrubias, female carriers and 50-100% of affected produced by the placenta where sulfated a sample of 66 unrelated Mexican patients male patients and are detectable by slit steroid precursors are converted to estro- with ichthyosis was studied. Clinical criteria lamp examination. The presence of corneal gens during pregnancy. A deficiency leads included familial pedigree, age of onset, opacities is helpful in making the to low estrogen levels and difficulty initiat- affected areas of the skin, characteristics of diagnosis.6 During the birth of the affected ing labor or slowed labor leading to a scale, and associated features. Assays of patient, prolonged labor and failure to higher number of women requiring STS activity in leukocytes and amplification progress may be seen due to placental Cesarean sections, especially in primi- of the 5’3’ ends of the STS gene using STS deficiency. In addition, affected male paras. The course of pregnancy and fetal PCR were performed. Patients all had patients have an increased risk of cryp- development appear to be normal except similar distribution of scaling and two were torchidism and testicular cancer with for skin findings in the newborn.11 classified as ichthyosis vulgaris due to reports of such cancer presenting without atopy and palm-sole hyperlinearity yet 1 The histopathology of X-linked ichthyosis undescended testes. Abnormalities of is nonspecific but typically shows mild to proved to be X-linked ichthyosis by assays. sperm count and abnormal sexual matura- moderate compact orthokeratosis, a nor- According to the authors, atopy and palm-
50 X-LINKED ICHTHYOSIS sole hyperlinearity should not be trait spe- lipoproteins. Additional methods for diagno- delayed labor in a mother with a previous cific for ichthyosis vulgaris nor should they sis include amplification of the 5’ 3’ ends of born X-linked ichthyosis child, an obstetrics exclude the possible diagnosis of X-linked the STS gene using PCR because most of or geneticist consultation for higher risk ichthyosis. These results emphasize the the patients have a complete deletion of delivery in future pregnancies may be war- use of laboratory studies to definitively con- this gene.5,10 Maternal urine can be used to ranted. firm X-linked ichthyosis as a diagnosis. detect high levels of sulfated estrogen pre- Using STS activity, X-linked ichthyosis may cursors and low levels of estriol. Amniotic Conclusion be differentiated from ichthyosis vulgaris by fluid analysis may be used prenatally to the enzymatic activity being absent.5 measure placental sulfatase activity and X-linked ichthyosis is usually a clinically Other considerations in the differential elevated DHEAS, a STS substrate.4 mild eruption due to a genetic disorder of diagnosis include lamellar ichthyosis which keratinization. It develops at birth or in early is autosomal recessive and presents as a Treatment infancy and may be associated with extra- collodion baby at birth. Later, large quadri- cutaneous manifestations. Patients may lateral plate-like scales involving flexures, The aim of treatment for X-linked present at a later age, as in our case, with palms and soles develop. There is an ichthyosis is prevention and elimination of complaints of dry skin. The condition is increased incidence of ectropion. On scales. Topical keratolytics such as ammo- caused by a deficiency of STS that result histopathology severe compact hyperker- nium lactate contain lactic acid, an alpha from abnormalities in its coding gene. A atosis with a normal granular layer is seen. hydroxy acid with keratolytic action which lack of this enzyme results in increased This is a retention ichthyosis due to muta- results in disadhesion of corneocytes. levels of cholesterol sulfate. Accumulation tions in the gene encoding the enzyme Other treatments include emollients, of cholesterol sulfate is believed to cause transglutaminase.1 hydrating agents, and topical retinoids. persistent keratinocyte adhesion, which Congenital ichthyosiform erythroderma is Lubrication and emollients which may manifests as abnormal desquamation. also autosomal recessive and presents as soften the skin and preparations containing Diagnosis is made in a variety of ways and a collodion baby at birth. Fine, white salicylic acid may provide help by removing treatment is directed towards the preven- scales are seen over the entire body, with the scales but results are typically unsatis- tion and elimination of scales. The patient erythroderma, and increased alopecia. It is factory. Systemic retinoids may be effective in this case presentation responded well to also due to a transglutaminase 1 defi- but are only used in the most severe topical keratolytics applied once or twice a ciency. On histopathology moderate com- cases. day. pact hyperkeratosis, focal parakeratosis, The bioactive form of vitamin D3 has and a normal granular cell layer or dimin- been shown to modulate epidermal prolif- References: ished granular cell layer under parakerato- eration and differentiation. Calcipotriol is a 1. Cuevas-Covarrubias SA et al. Accuracy of the clinical diag- sis are seen. synthetic vitamin D analogue with the nosis of recessive X-linked ichthyosis vs. ichthyosis vul- garis. J Dermatol 1996;23:594-97. Bullous ichthyosiform erythroderma is an capacity for binding to the vitamin D recep- 2. Shapiro LJ et at. X-linked ichthyosis due to steroid sulfatase autosomal dominant inherited disorder tor and stimulating epidermal differentia- deficiency. Lancet 1978;1:70-2. tion. A study by Kragballe et al used 3. Wells RS, Kerr CB. Clinical features of autosomal dominant which presents in a neonate with erythro- and sex-linked ichthyosis in an English population. Brit derma, scaling and bullae at birth and pro- calcipotriol ointment versus placebo twice Med J 1966;1:947-50. daily for 12 weeks in patients with disor- 4. Paller AS. Laboratory tests for ichthyosis. Dermatol Clin gresses to intertriginous verrucous, large 1994;12(1):99-107. and dark scales over time. On histopathol- ders of keratinization. They concluded that 5. Cuevas-Covarrubias SA et al. Are atopy and palm-sole short term treatment (12 weeks) of cal- hyperlinearity clinical tools in the differential diagnosis ogy it shows compact hyperkeratosis, vari- between ichthyosis vulgaris and X-linked ichthyosis? J able parakeratosis, vacuolization of the cipotriol ointment up to 100g/wk is moder- Dermatol 1998;25:556-57. granular and upper spinous layers, and ately efficacious, well-tolerated and safe in 6. Sever RJ et al. Eye changes in ichthyosis. JAMA adult patients (over 12) with various 1968;206:2283-86. hypergranulosis with irregular and large 7. Cuevas-Covarrubias SA. Somatic and germinal mosaicism keratohyaline granules. Abnormalities of ichthyoses. Although the study was limited for the steroid sulfatase gene deletion in a steroid sulfa- to 67 patients with various ichthyoses, the tase deficiency carrier. J Invest Dermatol 2002;119:972- the intermediate filament proteins keratin 1 75. and 10, and tonofilaments associated with authors suggested the possible investiga- 8. Nomura K et al. A study of the steroid sulfatase gene in fam- 14,4 tion of combination therapy with calcipotriol ilies with X-linked ichthyosis using polymerase chain reac- desmosomes lead to acantholysis. tion. Acta Derm-Venereol 1995;75:340-42. and retinoids to observe potential synergis- 9. Hamanaka S et al. A case of recessive X-linked ichthyosis: There are a number of ways to confirm 15 the diagnosis of X-linked ichthyosis. These tic effects and investigate their benefit. scale-specific abnormalities of lipid composition may α explain the pathogenesis of the skin manifestation. J Der- include demonstrating gene deletion, lack Topical tacalcitol (1 , 24-dihydroxyvita- matol 1997;24:156-60. of STS enzyme activity or increase in STS min D3) has been tested in Japan as an 10. Valdes-Flores M et al. Deletion of exons 1-5 of the STS alternative treatment for ichthyoses with gene causing X-linked ichthyosis. J Invest Dermatol substrate. A FISH study may be performed 2001;116(3):456-58. from peripheral blood using a STS probe. retentive hyperkeratosis. In one single- 11. Hirato K et al. Steroid sulfatase activities in human leuko- blinded study of 9 patients by Okano, the cytes: biochemical and clinical aspects. Endocrinol Japan Absence of the hybridization signal indi- 1991;38(6):597-602. cates a microdeletion of the STS gene. A medication failed to show effectiveness 12. Anton-Lamprecht I, Hofbauer M. Ultrastructural distinction against different keratinizing disorders such of autosomal dominant ichthyosis vulgaris and X-linked STS assay shows reduced or absent ichthyosis. Hum Genet 1972;15:261-4. enzyme activity in leukocytes, skin fibrob- as X-linked ichthyosis, ichthyosis vulgaris 13. Cuevas-Covarrubias SA et al. Higher prevelance of X- 16 lasts and keratinocytes in affected patients and acquired ichthyosis. linked ichthyosis vs. ichthyosis vulgaris in Mexico. Int J Dermatol 1999;38:555-60. and to a lesser degree in carriers. Elevated This patient was successfully treated 14. DiGiovanna JJ, Robinson-Bostom L. Ichthyosis: etiology, cholesterol sulfate levels in the serum of with ammonium lactate 12% cream once diagnosis, and management. Am J Clin Dermatol 2003;4(2):81-95. affected patients can be detected by chro- or twice per day and showed significant 15. Kragballe K et al. Efficacy, tolerability and safety of cal- matography or spectrophotometry but improvement in clinical scaling. cipotriol ointment in disorders of keratinization. Arch Der- matol 1995;131:556-60. serum cholesterol is normal in these Certain consultations may be of benefit 16. Okano M. Assessment of the clinical effect of topical tacal- patients. Lipid thin layer chromatography when working up a patient suspected of citol on ichthyosis with retentive hyperkeratosis. Dermatol- demonstrates increased cholesterol sulfate having X-linked ichthyosis. A urology con- ogy 2001;202:116-18. in the stratum corneum. Lipoprotein elec- sultation is important to evaluate for cryp- trophoresis may also be used since torchidism or other genital abnormalities. increased cholesterol sulfate increases the An ophthalmology consultation may iden- electrophoretic mobility of low density tify corneal opacities. In the case of
LAWLOR, ADLER 51 Merkel Cell Carcinoma: A Case Report
Norma Montiel, D.O.*, Evangeline Perez, D.O.**, Zoila Flashner, M.D.*** , Dr. Marvin S. Watsky**** *2nd year Dermatology Resident **1st year Dermatology Resident *** Clinical Assistant Professor at Touro College, St. John’s Episcopal Hospital, Far Rockaway, New York **** Director of Dermatology, St. John’s Episcopal Hospital, South Shore
ABSTRACT
Merkel cell carcinoma (MCC) is a rare neuroendocrine carcinoma that occurs most often in elderly whites on the neck, extremities, and periocular regions on sun exposed areas. Although spontaneous remissions have been reported, the prognosis is very poor. We present a case of MCC in a 68 year old Caucasian male who presented with an enlarging fibrous nodule on his leg of 3 months duration.
oncologist for treatment. The lesion was Case Report treated as a primary malignancy and wide The patient is a 68 year old Caucasian excision with sentinel node biopsy was per- male who presented to the office complain- formed. ing of a growth on his right lower leg that had been increasing in size for the last 3 Literature Review: months (Figure 1). He denied any pain or pruritis with the lesion and he denied a per- First described by Frederick Merkel in sonal and family history of skin cancer. His 1875 and by Toker in 1972 as a “trabecular medical history was significant for coronary cancer”, MCC is now considered to be the artery disease, valvular heart disease, and most aggressive cutaneous malignancy.1,2 previous strokes. His medications included Over 400 cases are reported each year in warfarin, clopidogrel, metoprolol, losartan, the United States with mortality rates 3,4 Figure 1 hydrochlorothiazide, nitroglycerin, and eze- between 25-35%. timibe. Merkel cells are of neuroendocrine origin dysplasia, Cowden’s disease, Hodgkin’s On physical examination, the patient and are found in or near the basal layer of disease, chronic lymphocytic leukemia 2,5 appeared to be well nourished and fully the epidermis. They are believed to be (CLL), and immunosuppresion.1,8 Specifi- alert and oriented. The lesion in question slow acting mechanoreceptors that provide cally, renal transplant patients have a risk was a solitary, round, hyperpigmented, information about touch and hair move- of 0.13/1,000 while HIV patients have a rel- 1 fibrous 1 cm nodule located on the lateral ment. In the neoplastic form, they are ative risk of 13.4%.1 aspect of the proximal third of his right considered a malignancy of the amine pre- lower leg. The differential diagnosis cursor and uptake decarboxylase (APUD) included neurofibroma, dermatofibroma, system.2 Names synonymous with MCC of Clinical Presentation: dermatofibrosarcoma protuberans, and the skin include trabecular carcinoma, MCC usually presents as an asympto- nodular basal cell carcinoma and a shave cutaneous APUDoma, primary small cell matic red or violaceous papule or nodule. biopsy was performed. carcinoma, and primary neuroendocrine Surface features may include a shiny 2 Findings on histopathological examina- carcinoma. appearance, telangiectasia, and tion revealed a neoplasm within the dermis ulceration.1,2,4 They are often no larger than characterized by irregular aggregates of Epidemiology 2 cm in diameter on presentation and may cells dissecting between collagen bundles have satellite lesions occurring secondary and within blood vessels. The cells had MCC is a rare form of cutaneous skin to lymphatic spread.1 large nuclei with minimal cytoplasm and cancer with an incidence of approximately nucleoli that were not conspicuous. The 0.23/100,000 in whites with most cases 1 Histology: differential diagnosis at this point included occurring in the seventh decade of life. metastatic neuroendocrine carcinoma and The incidence for blacks is one-twentieth of MCC occurs most often in the dermis 1 MCC. Immunohistochemical studies were this figure. It occurs slightly more often in and can extend into the subcutis. The performed and the neoplasm stained posi- women on sun exposed areas. Sites of basophilic tumor cells are small and tively with antibodies against pankeratin, predilection include the head and neck in monomorphic with round to oval shaped cytokeratin (CK) 20, synaptophysin, and 50% of cases, particularly the periorbital nuclei and scant cytoplasm.2,5 The triad of CK 7. Further immunohistochemical stud- region, and the extremities in 40% of vesicular nuclei with small nucleoli, abun- 6,7 ies with antibodies against endothelial cells cases. dant mitoses, and apoptosis strongly sug- failed to reveal vascular invasion. gests MCC.9 The Azzopardi phenomenon A search for a primary occult lesion as Etiology: refers to the deposition of DNA around the possible source of metastatic disease intratumoral blood vessels and has been Exposure to UVA, UVB, arsenic, and 5 was undertaken and the patient underwent reported in MCC. methoxsalen have all been implicated as a positron emission tomography (PET) scan- There are three main histological pat- cause of MCC.1 Reports by Miller indicate ning and gastrointestinal evaluation with terns of MCC - trabecular, intermediate, that UVB exposure correlates with the inci- colonoscopy which were all negative. The and small cell variant. The trabecular sub- dence of MCC.8 Higher risk patients patient was then referred to a surgical type is the least common pattern and iden- include those with congenital ectodermal
52 MERKEL CELL CARCINOMA: A CASE REPORT may be taken in cosmetically sensitive Table 11,2,7 areas as long as radiotherapy is given.12 However, if no radiotherapy is given, wide Immunohistochemical markers MCC Small cell carcinoma Lymphoma margins are required for better survival. Radiation therapy has been shown to Neuron-specific enolase (NSE) + + - reduce recurrences from 39% to 26% and CK20 + - - regional failure (nodal metastasis) from 46% to 22%.1 Radiation therapy is started Leukocyte common antigen - - + at 45-50 Gys in 20 to 25 divided fractions Thyroid transcription factor (TTF-1) - + - as soon as the excisional wound heals.1 Stage II disease is treated with wide local excision of the primary tumor and
1,4 regional lymph node dissection. If neces- Table 2 Staging for Merkel cell carcinoma sary, radiation at doses of 50-60 Gys are used to debulk nodal masses. Surgery is Stage Description tailored to the patient and is based on the size and location of the nodes and the con- IA Disease confined to skin and 2 cm in diameter Radiation Oncology Group (TROG) treated II Involvement of regional lymph nodes 53 high risk patients with synchronized chemoradiotherapy and adjuvant III Metastatic disease chemotherapy which resulted in a three year survival of 76%.13 The role of chemotherapy in the treatment of MCC, tified by round to polygonal shaped cells Staging is based on the size of the pri- however, still remains elusive. that are compactly arranged around mary tumor, nodal involvement, and metas- Stage III disease occurs in 28-70% of 2,4 adenexal structures. The intermediate tasis (Table 2). Stage I accounts for patients at initial presentation.1 In patients type is the most common histological type 70-80% of cases, stage II 10-30%, and with good bone marrow reserve and renal 1 and is recognized by less compact cells stage III 1-4%. function, the platin agents, carboplatin and that have a greater number of mitoses and Elective lymph node dissection (ELND) etoposide are favored and have resulted in necrosis. This subtype is more aggressive is recommended in the absence of clini- 44% of patients having a complete than the trabecular subtype. The small cell cally positive nodes for high risk patients response to therapy and 11% having a par- subtype is as aggressive as the intermedi- characterized by lesions greater than 2 cm, tial response. Other studies have shown ate subtype. It mimics other types of small high mitotic rates (more than 10 mitoses this combination to have a 60% response cell carcinoma having sheets and clusters per high power field), histological evidence rate compared to the cyclophosphamide, 4 of cells. of lymphatic permeation, and small cell his- oxorubicin (or epirubicin), and vincristine SCC may be associated with MCC. One tological patterns.1 For areas with indeter- combination which has shown a 75.5% pattern contains a grenz zone separating minate lymphatic drainage (i.e. tumors on response rate.1,14 Further studies are the superficial SCC from dermal MCC and the back), sentinel lymph node biopsy is required. In addition, for those patients the second shows SCC in nests sur- recommended over ELND.4 with ulcerating, bleeding, or fungating rounded by typical MCC.10 masses, radiation therapy can be used pal- Because of the large differential associ- Differential Diagnosis: liatively. ated with the histology of MCC including small cell carcinoma and lymphoma, The differential diagnosis of MCC New Treatments: immunohistochemistry is utilized for defini- includes basal cell carcinoma (BCC), ame- tive diagnosis (Table 1).1,2 CK 20 is highly lanotic melanoma, SCC, and cutaneous Nerve growth factor inhibitor and Bcl-2 specific for MCC and differentiates this lymphoma.1, 2 antisense oligonucleotides are the newest from small cell carcinoma.11 The use of this chemotherapeutic agents presently being marker in sentinel node biopsy is sensitive Treatment: studied.12 However, with reports of sponta- but not 100% specific. Thyroid transcription neous remission even in stage III disease, factor-1 (TTF-1), absent in MCC, is a new Stages I and II are treated for curative research is focusing more on immunother- marker that may be useful in differentiation intent while treatment of stage III is pallia- apy.12 from small cell carcinoma where it is pre- tive.1 In stage I localized disease, accept- sent.2,7 Other features include reactivity of able treatment is achieved with wide Prognosis: enolase, CK 8, 18, 19, 20, and chroma- excision and radiotherapy. Recent studies granin A. The neoplasm is TTF-1, S-100, have indicated that optimal treatment is Poor prognostic signs include nodal dis- HMB-45, and NK 1/CB negative (Table 1).7 achieved via Mohs surgery with adjuvant ease (median survival is 13 months vs. 40 radiotherapy.12 One study showed that months if nodes are not involved), metasta- Staging: patients treated with wide excision had a sis (median survival 9 months), male sex, recurrence rate of 32%, whereas those tumor size greater than 2 cm, age older Once the patient has been diagnosed treated by Mohs had a recurrence rate of than 60 years, and lack of radiotherapy.1,5 with MCC, the staging work up includes only 8%. However, in cases where Mohs The prognosis of lesions in the lower CBC, serum electrolytes, and CT scan of surgery may require a large excision, radio- extremities may also be relatively poorer the chest, the latter also serving to rule out therapy, as an adjunct to wide excision since these lesions are often under treated small cell lung carcinoma.1 Radiolabelled may be sufficient as the tumor is exquis- because of less tolerance to radiation and somatostatin analogue (octreotide) scintig- itely radiosensitive.1 Acceptable margins for greater difficulty in repairing wide excisions raphy has a greater sensitivity than CT for excision of a primary tumor is 2.5 to 3 cm in this site.1 detecting metastases.1 though some suggest that smaller margins
MONTIEL, PEREZ, FLASHNER 53 5Suarez C, Rodrigo JP, Ferlito A, Devaney KO, Rinaldo A. Recurrence: Conclusion: Merkel Cell carcinoma of the head and neck. Oral Oncol 2004 Sep;40(8):773-9. Local recurrence occurs in approxi- Merkel cell carcinoma, although a rare 6Ratner D, Nelson BR, Brown MD, et al. Merkel Cell CA, J Am Acad Dermatology. 1993;29:143-56. mately 20-44% of patients within 4 months neoplasm, must be considered in those 7Usui Y, Rao NA. Merkel cell carcinoma of the eyelid: report of of excision. Regional lymph node dissec- patients with risk factors because of its a case with immunohitochemical study. Jpn J Ophthalmol 2004 May-Jun;48(3):306-8. tion and radiation therapy are options for aggressive behavior. Its relatively benign 8Agnew KL, Ruchlemer R, Catovsky D, Matutes E, Bunker these patients and those who have clinical appearance can often delay diag- CB. Cutaneous findings in chronic lymphocytic leukaemia. Br J Dermatolol. 2004 Jun;150(6):1129-35. reached their maximum tolerated dose of nosis and increase the likelihood of local 5A. Miller radiation or have had complete nodal dis- spread and metastasis. A high index of 9Haag M, Glass LF, Fenske NA: Merkel cell carcinoma: Diag- section. For patients who can neither have suspicion is required and a biopsy, at the nosis and treatment. Dermatol Surg 21:669-683, 1995. 10Al-Ahmadie HA, Matasim DF, Matema GK. A case of further radiation or nodal dissection, very least, is warranted for these unassum- intraepidermal Mercal cell carcinoma within squamous cell chemotherapy may be an option.4 ing lesions especially in elderly patients carcinoma in-situ: Merkel cell carcinoma in situ? Am J Dermatolpathol 2004 Jun;26(3):230-3 complaining of a rapid growth on sun 11Su LD, Lowe L, Bradford CR, et al: Immunostaining for exposed skin areas. cytokeratin 20 improves detection of micrometastatic Follow-up: Merkel cell carcinoma in sentinel lymph nodes. J Am Acad Dermatol 46:661-666, 2002. Patients diagnosed with MCC should be 12Mendenhall WM, Mendenhall CM, Mendenhall NP. Merkel followed closely with visits every 3 months References: cell carcinoma. Laryngoscope. 2004 May;114(5):906-10. 1Poulsen M. Merkel-cell carcinoma of the skin. Lancet Oncol 13Poulsen M, Rischen D, Walpole E, et al. High risk Merkel for the first three years followed by annual 2004;16:54-57. cell carcinoma of the skin treated with synchronous carbo- appointments. Each visit should consist of 2Bickle K, Glass LF, Messina JL, Fenske NA, Siegrist K. plastin/etoposide and radiation. J Clin Oncology 2003; a full detailed physical exam and a review Merkel Cell carcinoma: a clinical, histopathologic and 21:4371-76 immunohistochemical review. Semin Cutan Med Surg. 14Lehrer MS, Hershock D, Ming ME. Merkel cell carcinoma. of systems. Laboratory and radiological 2004Mar;23(1):46-53. Curr Treat Options Oncol. 2004 Jun;5(3):195-9. studies are ordered when clinically war- 3Perdikis G, TerKonda SP. Pigmented skin lesions of the 11 upper extremity. Hand Clin 2004 Aug;20(3):283-91. ranted. 4www.cancer.gov/cancertopics/pdq/treatment/Merkel cell/helathprofessional/page1
54 MERKEL CELL CARCINOMA: A CASE REPORT Unilateral Laterothoracic Exanthem-A Case Report
Gandhari Warner, D.O.*, Jonathan Stuart Crane, D.O.**, Ronald P. Benjamin, M.D.***, Patricia Hood, PA-C ****, Carla DiBenedetto, PA-C.***** * Family Medicine Resident at New Hanover Regional Medical Center, Wilmington, NC. **Atlantic Dermatology Associates P.A., 1104 Medical Center Drive, Wilmington, N.C. 28401, (910) 251 9944 ***Atlantic Dermatology Associates P.A., 1104 Medical Center Drive, Wilmington, N.C. 28401, (910) 251 9944 ****Atlantic Dermatology Associates P.A., 1104 Medical Center Drive, Wilmington, N.C. 28401, (910) 251 9944 *****Atlantic Dermatology Associates P.A., 1104 Medical Center Drive, Wilmington, N.C. 28401, (910) 251 9944
ABSTRACT
Unilateral laterothoracic exanthem (ULE), also known as asymmetric periflexural exanthem of childhood (APEC), is a disease of probable viral origin characterized by unilateral onset and predictable progression. The disease was first described in 1962 by Brunner in a paper entitled, “A new papular erythema of childhood” (1). Thirty years later, Bodemer and Prost described 18 patients with a similar unilateral rash and named the disease Unilateral Laterothoracic Exanthem (2). Case reports concur that onset is always unilateral and frequently localized to the axilla, laterothoracic region and flank. The rash commonly progresses in a centrifugal pattern, becoming bilateral while maintaining an asymmetric appearance. A 12 month old male presented to our office with scattered, mildly erythematous, scarlatiniform papular lesions on the left arm, left thorax, left leg and left palm. With the existence of so many nonspecific viral eruptions in childhood, the subjective report of unilateral onset is often times the clini- cians’ key to diagnosis.
Introduction Historical Perspective Prior to receiving its name, unilateral lat- erothoracic exanthem was first described in 1962 by Brunner et al in a paper entitled, “A new papular erythema of childhood”. They spoke of a newly described, erythe- matous eruption, primarily unilateral, noted in children between the ages of 6 months and 5 years.1 Similar unilateral lesions were independently reported by Dr. William Laur in the same year during a dermatol- Figure 1 ogy presentation at the 1962 Texas Med- ical Association meeting. He described 175 cantly from case to case but has been patients with a patch of discrete, papular, reported to last anywhere from 2 weeks to pink, lichenoid lesions often appearing on 12 weeks. The illness resolves sponta- one side of the thorax and extending into neously without treatment. the axillary region. He proposed the name Clinical Description lichen miliaris.3 Thirty years later in 1992, Bodemer and Prost coined the term Unilat- Lesions most commonly arise on the eral Laterothoracic Exanthem (ULE) to trunk or axilla but in rare cases may begin 4 Figure 2 describe the disease. They described erup- on the extremities or in the groin region. tions in 18 children, initially unilateral and Regardless of initial localization, eruptions Many children have upper respiratory localized close to the axilla, which had ultimately will advance to involve the tho- 3 symptoms or gastrointestinal symptoms characteristic features.2 rax. Spread is centrifugal with approxi- mately 70% of cases advancing to the including fever, malaise, vomiting, and diar- Definition contralateral side.6 The eruptions maintain rhea in association with the eruptions. One study reported that 77% of the 48 children Unilateral laterothoracic exanthem is a an asymmetric appearance throughout the disease course with the side of onset being studied had infectious symptoms before or disease of unknown etiology occurring pri- 4 dominantly affected. Involvement of the during the outbreak. Regional lym- marily in children between 6 months and 5 phadenopathy and mild pruritis are also years of age and identifiable by its distinct hands, feet and face, although rare, has been noted.3 common findings. No significant laboratory eruptions with unilateral onset. abnormalities have been found to be asso- Eruptions are usually small erythema- 4 Etiology tous papules, scarlatiniform in appearance ciated with the disease. 5 Unilateral laterothoracic exanthem has but poorly demarcated. Initially morbiliform no known cause but is speculated by some in nature, these mildly pruritic lesions Histologic Description progress to eczematous plaques.4 A dis- investigators to have a viral etiology.2 The Skin biopsies show mild to moderate disease affects girls more commonly than tinct halo surrounding the papules is con- perivascular, predominately lymphocytic, boys (2:1) and usually occurs in late winter sidered by some researchers to be a key 3, 4 infiltrate composed primarily of T lympho- and spring. Duration of illness varies signifi- diagnostic feature.
WARNER, CRANE, BENJAMIN, HOOD, DIBENEDETTO 55 Scattered, mildly erythematous, scarla- In our patient, the characteristic unilat- tiniform papular lesions were observable eral onset, age, seasonal predominance, unilaterally on the left arm (figure 2), left lat- rash appearance and clinical features were eral thorax extending to the left flank, left observed. The lesions remained unilateral leg and left palm. The left side was largely throughout the entire four week duration of affected but the right was spared. Affected the illness. areas had atopic appearing skin. Follow up examination revealed com- Conclusion plete resolution of the unilateral laterotho- racic exanthem. Total disease duration The differential diagnosis for unilateral was four weeks with spontaneous resolu- laterothoracic exanthem includes many tion. common skin eruptions. Among others, it is not uncommon for unilateral laterothoracic Discussion exanthem to be mistaken for scabies, Although the etiology of unilateral lat- atopic dermatitis, tinea corporis, or scarlet erothoracic exanthem is unknown, the pro- fever. Although all are very treatable, each posed theories of viral origin seem entity has its own distinctive treatment regi- appropriate. Viral exanthems are very com- men and time course. With a definitive mon in childhood and most often diagnosis of unilateral laterothoracic exan- harmless.8 The young age of the affected them, parents can avoid using unneces- population, its seasonal affliction, and its sary prescriptions and be assured of the associated viral symptoms like lym- illness’ harmless nature and spontaneous phadenopathy, upper respiratory tract resolution. It is likely that the incidence of Figure 3 infections and fever are all suggestive of a unilateral laterothoracic exanthem is much viral cause.2 In addition, researchers report higher than what is currently reported in the cytes (specifically CD 4+ T cells).4, 3, 5 The broad spectrum antibiotics to be an ineffec- literature. Although it is considered a harm- infiltrate surrounds and involves the eccrine tive treatment.2 Spontaneous resolution less illness, the importance to differentiate ducts but spares the secretory coils.6 without the aid of steroids, creams, antibi- it from other viral exanthems of childhood Differential Diagnosis otics, or antihistamines is inevitable will accumulate significance as we learn although the extensive variability of time more about its etiology. Unilateral laterothoracic exanthem can course makes complete resolution unpre- be easily mistaken for scabies, scarlet dictable.4 No long term recurrences have References: fever, contact dermatitis, tinea corporis, mil- been reported. 1. Brunner MJ, Rubin L, Dunlap FE. A new papular erythema iaria, Gianotti-Crosti syndrome, atypical of childhood. Archives of Dermatology. 1962. 85: 539- 4, 7 The term unilateral laterothoracic exan- 540. pityriasis rosea, and atopic dermatitis. It 4 them can be misleading. Although the 2. Bodemer C, de Prost Y. Unilateral laterothoracic exanthem is commonly diagnosed as a nonspecific unique distinction of this disease is its obvi- in children: A new disease? The Journal of the American drug or viral eruption. Academy of Dermatology. 1992. 27: 693-696. ous onset on one side of the body, the 3. Laur WE. Unilateral laterothoracic exanthem in children [let- diagnosis is commonly missed. Often times ter]. The Journal of the American Academy of Dermatol- ogy. 1993. 29: 799-800. Case Report children do not present to the practitioner 4. McCuaig CC, Russo P, Powell J, et al. Unilateral laterotho- until the rash has significantly spread. With racic exanthem. The Journal of the American Academy of A 12 month old male presented in April as many as 70% of the cases having bilat- Dermatology. 1996. 34: 979-984. 2005 with a rash of 16 days duration. An 5. Maroon M, Billingsley EM. Unilateral laterothoracic exan- eral involvement, the likelihood of a child them [letter]. The Journal of the American Academy of erythematous rash began on the left leg presenting with a nondistinct bilateral rash Dermatology. 1994. 30:1045. and then spread to the left thorax. (figures 6. Odom, RB, James WD, Berger TG. Andrew’s Diseases of is very high.6 A good history, revealing uni- 1 & 3) The lesions were mildly pruritic at the Skin-Clinical Dermatology. Ninth Edition. 2000. 961- lateral onset, and a high index of suspicion 962. onset but itching had resolved by presenta- 7. Harper J, Oranje A, Prose N. Textbook of Pediatric Derma- are often necessary to accurately diagnose tion in our office. After several days, the tology. 2000. Vol. 1. 350. unilateral laterothoracic exanthem. Unilat- 8. Bjorge Nelson JS, Seabury Stone M. Update on selected rash became dry and bumpy. The patient eral laterothoracic exanthem typically viral exanthems. Current Opinion in Pediatrics. 2000. had been using mometasone furoate 12:359-364. spares the face, hands, feet and genitals cream prescribed by his pediatrician three although rare cases involving these areas days prior. This treatment was largely have been reported.3, 4 unsuccessful.
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