Journal of the American Osteopathic College of Dermatology Journal of the American Osteopathic College of Dermatology

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

Earl U. Bachenberg, D.O. Richard Miller, D.O. Lloyd Cleaver, D.O. Ronald Miller, D.O. Eugene Conte, D.O. Evangelos Poulos, M.D. Monte Fox, D.O. Stephen Purcell, D.O. Sandy Goldman, D.O. Darrel Rigel, M.D. Gene Graff, D.O. Robert Schwarze, D.O. Andrew Hanly, M.D. Michael Scott, D.O. Cindy Hoffman, D.O. Eric Seiger, D..O David Horowitz, D.O. Brooks Walker, D.O Charles Hughes, D.O. Bill Way, D.O. Daniel Hurd, D.O. Schield Wikas, D.O. Mark Lebwohl, M.D. Edward Yob, D.O. Jere Mammino, D.O.

2002-2003 OFFICERS President: Robert F. Schwarze, DO President-Elect: Stanley E. Skopit, DO First Vice-President: Ronald C. Miller, DO Second Vice-President: Richard A. Miller, DO Third Vice-President: Bill V. Way, DO Secretary-Treasurer: James D. Bernard, DO Immediate Past President: Cindy F. Hoffman, DO Trustees: Daniel S. Hurd, DO Jere J. Mammino, DO Brian S. Portnoy, DO Robert J. Signore, DO Executive Director: Rebecca Mansfield, MA

AOCD 1501 E Illinois Kirksville, MO 63501 800-449-2623 FAX: 660-627-2623 www.aocd.org

COPYRIGHT AND PERMISSION: written permission must be obtained from the Journal of the American Osteopathic College of Der- matology for copying or reprinting text of more than half page, tables or figures. Permissions are normally granted contingent upon similar permission from the author(s), inclusion of acknowledgement of the original source, and a payment of $15 per page, table or figure of reproduced material. Permission fees are waived for authors wishing to reproduce their own articles. Request for permission should be directed to JAOCD c/o AOCD PO Box 7525 Kirksville, MO 63501 Copyright 2003 by the Journal of the American Osteopathic College of Dermatology Printed by: Stoyles Graphics Services, Mason City, IA 50401 Journal of the American Osteopathic College of Dermatology

2 Journal of the American Osteopathic College of Dermatology

Volume 1, Issue 1 April 2003 CONTENTS

Letter From The JAOCD Editors ...... 4 Letter from the President of the AOCD...... 5 Patient Assessment in the Treatment of Premenstrual Acne Flare with Vitamin B6 Therapy: A Two-Year Retrospective Study...... 6 Bill V. Way, D.O., Rick Lin, M.P.H.D.O., Dan J. Ladd Jr., D.O. Squamous Cell Carcinoma of the Lip ...... 10 Jay S. Gottlieb, D.O., F.O.C.O.O. Phakomatoses ...... 15 Kellie Mosley, D.O., Stanley E. Skopit, D.O., F.A.O.C.D. Mid-dermal Elastolysis: A Case Report and Literature Review ...... 18 Matthew B. Doppelt, D.O., Stanley E. Skopit, D.O., F.A.O.C.D. A Rare Case of Bleomycin Induced Flagellate Hyperpigmentation Presenting Histopathologically as an Urticarial Drug Hypersensitivity Reaction ...... 23 Risa Gorin, D.O., Charles Gropper, M.D., Cindy Hoffman, D.O., Damian DiCostanzo, M.D. Cutaneous Manifistations of Sarcoidosis...... 26 Steven Israel Moreno, D.O., Stanley E. Skopit, D.O., F.A.O.C.D. Therapeutic Perspectives in Dermatology #1 ...... 30 James Q. Del Rosso, D.O., F.A.O.C.D. Necrobiotic Xanthogranuloma: A Case Report and Literature Review ...... 34 Robin I. Shecter, D.O., Brad P. Blick, D.O., M.P.H., David Tenzel, M.D., Neal Penneys, M.D., PhD., and Steven M. Abrams, M.D. Furuncular Cutaneous Myiasis ...... 37 Jere J. Mammino, D.O. Cutaneous Anthrax and Bioterrorism ...... 41 Peter A. Vitulli, D.O., Stanley E. Skopit, D.O., F.A.O.C.D. Porokeratosis Palmaris et Plantaris Disseminata: A case report ...... 43 Eric Adrien Adelman, D.O. Cutaneous Manifestations of Biological Terrorism...... 47 Stephen G. Mallette, D.O., David Harowitz, D.O., Mark Horowitz, D.O. First Documented Case of Fournier’s Gangrene After Dilatation and Curettage ...... 55 Alpesh D. Desai, D.O., Tejas D. Desal, D.O., David Horowitz, D.O., Mark Horowitz, D.O. Stevens-Johnson Sydrome: Treatment with Intravenous Immunoglobulin, A Case Report and Review ...... 58 Charmaine Jensen, D.O., Schield Wikas, D.O., Monte Fox, D.O. Epidermotropic Metastatic Malignant Melanoma (EMMM)Ða pathological variant of melanoma...... 68 Julian O. Moore, D.O., Rao N. Saladi, M.D., Neal B. Shultz, M.D., Mark G. Lebwohl, M.D., Robert G. Phelps, M.D.

3 Letter From The JAOCD Editors

Jay S. Gottlieb, D.O. Stanley E. Skopit, D.O. James Q. DelRosso, D.O.

It is with great pride, excitement and anticipation that our dream of launching our College's first journal, the JAOCD, has come to fruition in this inaugural edition. This journal will hopefully serve several functions. The mission of the Journal of the American Osteopathic College of Dermatology serves to better the continuing education needs of the AOCD members, residents and the dermatology community at large. The JAOCD will be a vehicle for our residents throughout the country to have the opportunity for their required papers to be published during their residency program. The Journal will provide our dermatology colleagues, as well, the ability to report on interesting and rare disorders of the integumentary system.

We will cover topics that will be academically challenging. We will include such areas as dermatologic therapeutic modalities, original presentation of research, brief opinions, a review of dermatology affiliated clinical studies, brief individual case reports of unusual interest, basic science as it relates to dermatology, articles emphasizing cutaneous surgery, dermatopathology, cosmetic dermatology, pharmaceutical dermatology, editorials, letters to the editors, and finally Pearls and anecdotes in dermatology.

At this time we must extend our sincere appreciation to our Founding Spon- sors. These six companies, without hesitation, stepped up to the plate to back our efforts. We look forward to a long and mutually beneficial relationship with each one. Our deepest thank you goes to Allergan Skin Care, Connetics Cor- poration, Global Pathology Laboratory Services, Novartis Pharmaceuticals Corporation, Medicis-The Dermatology Company and 3M Pharmaceuticals who have made the financial commitment to see that our dream has been ful- filled.

Get information about the JAOCD at www.aocd.org or e-mail us at [email protected].

Fraternally yours in Dermatology,

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 5 Patient Assessment in the Treatment of Premenstrual Acne Flare with Vitamin B6 Therapy: A Two-Year Retrospective Study

Bill V. Way, D.O.,* Rick Lin, D.O., M.P.H.,** Dan J. Ladd Jr., D.O.***

Abstract Premenstrual acne flare (PAF) is a common condition among female acne patients. Vitamin B6 is used by some physicians to treat this condition. This study provides statistical data in support of Vitamin B6 therapy for the treatment of premenstrual acne flare. There are 67 female participants in this study. Among the 57 patients in the 100mg treatment group, 19 patients (33%) per- ceive no response while 38 patients (66%) experience positive response. Among the 21 patients in the 200mg treatment group, 5 patients (24%) did not experience any improvement of their premenstrual acne flare, while 16 patients (76%) experienced improvement with the treatment. The results of 100 mg treatment group (p<0.001) and 200 mg treatment group (p<0.001) were both statistically significant against the baseline rating. The use of Vitamin B6 in the treatment of premenstrual acne flare provides both clinically and statistically significant results.

Introduction tions, other researchers found that prog- months of taking the increased dose, the esterone administration exacerbated the treatment is declared ineffective for this It is estimated that up to 60-70% of PAF.8 patient and other treatment options are females experience an exacerbation of explored at that time, such as oral contra- acne shortly prior to their menses.1 The While the use of Vitamin B6 (pyridox- ceptive pills. ine) for the treatment of PAF may not be use of Vitamin B6 (pyridoxine) in the treatment of this condition has been used by conclusively supported by the scientific The treatment protocol is also summa- clinicians for more than 25 years. Very literature, it has been used by clinicians rized in FIGURE 1. few studies regarding this treatment have since the 1970s.3 The only reported been published during this period of clinical result of this therapy was done in Criteria for Inclusion time.2,3 1974 by Snider and Dieteman in the form of a letter to the editor of Archives of This is a retrospective chart study con- The possible physiologic mechanism of Dermatology.3 This letter has been ducted among all female patients diag- premenstrual acne flare (PAF) is that prior referenced by many consumer health nosed with PAF between the 2 years to menses, progesterone exerts its books, alternative medicine publications, period of June 1, 1998 to June 1, 2000. influence and leads to such phenom- and internet websites as the scientific In order to be included in the study, the enon.4 This explanation is consistent with basis for Vitamin B (pyridoxine) therapy patient will need to have at least one (1) 6 follow-up visit after the initial diagnosis research performed with Vitamin B6 in the treatment of PAF. (pyridoxine) and its role in the expression and treatment of PAF. If the symptoms of steroid hormones, such as proges- The purpose of this study is to evaluate are not completely controlled at the first 5 follow-up visit, one (1) additional follow-up terone. The biologically active form of the efficacy of Vitamin B6 (pyridoxine) vitamin B can modulate and decrease treatment for the condition of PAF. The visit will be required to collect the data 6 subsequent to the Vitamin B (pyridoxine) the transcriptional response to proges- results of this study will provide additional 6 terone.5 This blunts the effect proges- data for this therapy. dosage increase. terone has on the body, and theoretically Methods Another reason for exclusion will be alleviates the symptoms of premenstrual incomplete or inconclusive patient subjec- acne flare. Treatment Protocol tive data in the chart. Also for patients who initiate the treatment but failed to It should be noted that the role of prog- The Duncanville Dermatology Clinic esterone in PAF is not conclusive. There have adequate follow-up data, their has incorporated a standardized research charts will not be included in this study. is research in the literature that conflicts treatment protocol for PAF for the past 2 with the progesterone effect theory. years. When a patient presents for treat- Collection of Data and Definition of Some researchers found that sub-physio- ment of acne, she will be routinely Treatment Response logic daily doses ranging from 5-25 mg of screened for PAF. If she presents with progesterone did not worsen PAF. On the the symptoms of PAF, she would be put The clinical severity of the patient's contrary, it improved the patient's on Vitamin B (pyridoxine) 100mg daily for PAF will be assigned a numerical rating of 6,7 6 condition. In contrast to these observa- 3 months. If premenstrual acne flaring 1 (none to minimal), 2 (moderate), 3 symptoms decrease, the patient will be (severe). The assignment of this numeri- *Kirksville College of Osteopathic Medicine, Dept of advised to maintain the current dose. If cal value will be based on the subjective Dermatology, Texas Division descriptions of the patient in the chart fol- **Kirksville College of Osteopathic Medicine, Dept of PAF shows no improvement, the patient Dermatology, Texas Division will be asked to increase the daily Vitamin lowing appropriate visits. Duncanville ***Kirksville College of Osteopathic Medicine, Dept of B (pyridoxine) dose to 200 mg. If the Dermatology Clinic uses a set of stan- Dermatology, Texas Division 6 patient still shows no improvement after 3 dardized subjective evaluation as part of

6 (The Journal of the American Osteopathic College of Dermatology, Vol. 1, No. 1, pp 6-0, June 2003) their dictation system. The numerical rating of severity is assigned based on this system as summarized in TABLE 1. When one of the descriptors is used in the chart for patients visiting for PAF, the appropriate clinical rating is assigned to that patient for that visit. The evaluation of the patient at the initial treatment will be collected as the baseline in which to be used in comparison with the results of the treatment. At the first follow-up visit following the 100

mg of Vitamin B6 (pyridoxine) treatment, the results from patients who are compli- ant with the treatment will be used as the experimental group. For the other group who did not start the treatment as instructed, their evaluation will be used as the result of the control (non-treatment) group. If the clinical rating of 1 (minimal symptoms) is not achieved at this follow- up visit, the treatment of 100 mg of Vita-

min B6 (pyridoxine) is declared a failure. Patients who failed the 100 mg Vitamin B6 (pyridoxine) treatment, their dosage of

Vitamin B6 (pyridoxine) would be increased to 200 mg at the first follow-up visit. If a patient did not return for the second follow-up visit after the dose increase, this patient will be excluded from the 200 mg treatment group. How- ever, the response from 100 mg treatment will still be used as part of the 100 mg treatment results. On the second follow-up visit, their subjective evaluation will once again be assessed a numerical rating. The clinical rating of this patient in response to the

200 mg Vitamin B6 (pyridoxine) treatment will be compared to her 100 mg response in order to determine whether there is an improvement of her condition from the dose increase. TABLE 1: Clinical evaluation rating assignment based on the qualifying phrase used in the description of premenstrual acne flare Statistical Analysis Clinical Evaluation Rating (3) severe Clinical ratings of the patients are sum- “No Improvement.” marized as meansÐStandard Deviations. ”Does flare more with menstrual cycle.” Differences between group means and ”She does have cycle flares.” the baseline rating were assessed with ”Flares with her menses.” the two-tailed paired t-test; the null ”She still has cycle flares” hypothesis of no difference is tested. ”Her acne flares prior to her menstrual cycle.” Analysis of Variance (ANOVA) is used to compare the group means of control, 100 Clinical Evaluation Rating (2) moderate mg, and 200 mg treatment groups. “Condition has been improving but not completely.” ”Some improvement but she continues to breakout especially with menstrual cycle.” Association between treatment and ”History of occasional premenstrual acne.” non-treatment groups was evaluated with Chi-square analysis and Fisher Exact Clinical Evaluation Rating (1) minimal Test. Both 100 mg and 200 mg Vitamin “Completely cleared.” B 6 (pyridoxine) treatment groups are ”Patient states she has minimal flare with menstrual cycles.” tested against expected value of the con- ”Has no menstrual cycle flares at this time.” trol (non-treatment) group. ”Premenstrual acne has decreased when taking Vitamin B6.” ”Patient not having problems with present program.” The data is analyzed using Microsoft ”Had no flare ups since last visit.” Excel. Statistical significance is indicated by P value of less than 0.05. All reported

WAY, LIN, LADD 7 TABLE 2: Patients’ subjective response to Non-treatment, Vitamin B6 100 mg Two-tailed Fisher Exact Test shows positive association with treatment in both treatment, and Vitamin B6 200 mg treatment. the 100 mg treatment group versus the No Improvement Improvement Total non-treatment group (p=0.001). And for Non-treatment 9 (90%) 1(10%) 10 200 mg treatment group and non-treatment group, the Fisher Exact Test also 100 mg Treatment 30(53%) 27(47%) 57 shows the positive association with treat- 200 mg Treatment 5(24%) 16(76%) 21 ment (p<0.001) Discussion P values are two-tailed. All reports will treatment group, 4 patients (8%) failed include aggregated data only. treatment (Clinical rating:1) and 3 patients The results of this study demonstrate that Vitamin B (Pyridoxine) therapy (6%) did not achieve complete resolution 6 Results of the symptoms (Clinical rating:2). The decreases the acneiform leisions on other 42 patients (86%) are satisfied with patients who suffer PAF. Up to 74% of This study is derived from a population the treatment (Clinical rating:3). The the patients who are treated experienced of patients at Duncanville Dermatology mean clinical rating of the 200 mg treat- complete control of PAF symptoms within Clinic who had the diagnosis of PAF. ment group is 2.78 with stand deviation of 6 months after treatment with 100mg or There are a total of 67 patients participat- 0.56 200mg daily. This study is similar to the ing in the study. These patients' ages design of Snider and Dieteman in 1974.3 range from 13 to 50 years old. All of Overall, total of 42 out of 57 patients In their study, the patients were put on them are pre-menopausal. The average (74%) experience near-complete control 50mg of Vitamin B6 daily and the improve- age is 26.19 years old with a standard of PAF from either 100 mg or 200 mg Vit- ment is based on a standardized patient deviation of 11.91. The ethnicity of this questionnaire.(3) Their study was not fol- amin B6 (Pyridoxine) treatment after 3 to 6 sample breaks down into 48 Whites, 12 months of initiation of the therapy. lowed by any additional studies in the use Blacks, of Vitamin B6 in the treatment of PAF. It 6 Hispanics, and 1 Asian. In order to compare the means of the was our intention in this study to provide control group, 100 mg treatment group, more data for the Vitamin B6 (Pyridoxine) All patients in the study are receiving and 200 mg treatment group, Student's Vitamin B6 (pyridoxine) treatment for the t-test was performed separately. The first time. The initial clinical ratings of 1 result of the non-treatment group was not (severe), 2 (moderate), 3 (minimal) were statistically significant from the baseline averaged for all 67 patients to use as the clinical rating prior to the treatment. baseline evaluation. The baseline mean (p=0.95) The confidence interval of the is 1.09 with standard deviation of 0.28. difference between means of control group and the baseline is (-0.21) to The 10 patients in the non-treatment (0.19). The results of the 100 mg treat- group have the mean clinical rating of 1.1 ment group yield a p-value of less than with standard deviation of 0.32. 0.001, and are thus statistically signifi- Among the 57 patients in the 100 mg cant. Confidence interval of the differ- treatment group, 19 patients (33%) per- ence between the baseline and 100 mg ceive no response (Clinical rating:1) while treatment group rating is (0.82) to (1.28). 38 patients (66%) experience positive The 200 mg treatment group has a statis- therapy on PAF. response. Among the 38 positive respon- tically significant p-value of less than The US recommended daily allowance ders, 11 patients (30%) experience some 0.001 when compared to the baseline. Confidence interval of the difference is (RDA) of Vitamin B is 1.6-2.0 mg per improvement and received clinical rating 6 day.9 Taking high doses of more than of 2 (moderate symptoms). 27 patients (1.53) to (1.85). 500mg of Vitamin B daily can lead to tox- (47%) are satisfied with the treatment and 6 Repeat Measure Analysis of Variance icity, which manifests in the form of experience minimal or no PAF. They is also performed to compare the control peripheral neuropathy. Typical symptoms receive the clinical rating of 3 (minimal group, 100 mg treatment group, and 200 are tingling (pins and needles), clumsi- symptoms). The mean clinical rating of mg treatment group. Results show signif- ness and numbness. These signs are 100 mg treatment group is 2.14 with a icant differences among 3 groups reversible when the high dose intake of standard of deviation of 0.92. (p<0.001). Vitamin B6 is stopped. The US's Institute Among the 49 patients in the 200 mg of Medicine has concluded that 500 mg/day represents the lowest-observed- adverse-effect-level (LOAEL) for Vitamin TABLE 3: Statistical analysis of the clinical ratings among different groups B6 intake. This report also arrives at a Baseline Non- 100 mg 200mg no-observed-adverse-effect-level Treatment Treatment (NOAEL) of 200 mg/day.10 In our study,

all patients on Vitamin B6 treatment, be it Sample size (n) 67 10 57 21 100 mg or 200 mg, were all monitored for Rating 1 0 0 27 14 signs of toxicity. In the two year period included in this study, no signs of periph- Rating 2 5 1 11 3 eral neuropathy were reported. The treat- Rating 3 62 9 19 4 ment protocol of the Duncanville Mean Rating 2.93 2.9 1.86 1.52 Dermatology Clinic includes that if any patients were to complain of the signs of Standard Deviation 0.26 0.32 0.91 0.81 Vitamin B6 toxicity during this treatment, the treatment would stop immediately.

8 ASSESSMENT IN TREATMENT OF PREMENTSTRUAL ACNE The results of this study support the author to alleviate the symptoms of PAF.3 References efficacy of Vitamin B6 in controlling No study on the use of prednisone for the 1. Cunliffe WJ, ed. Acne. Chicago, IL Yearbook Medical Pub- patient's PAF. As with all studies, there treatment of PAF has been published. It lishers; 1989 wwwwwwwwwwwwwwwwwwwww. 2. Fisher DA. Desideratum dermatologicum—cause and are intrinsic biases in the study that can- may be worthwhile to compare pred- control of premenstrual acne flare. Int J Dermatol. 2000;39(5):334-6. not be eliminated. Due to the nature of nisone therapy with Vitamin B6 therapy in the retrospective chart study design, we a prospective double blind clinical study 3. Snider BL, Dietenman DF. Pyridoxine therapy for premenstrual acne flare. Arch Dermatol. were unable to collect data on placebo in the future. 1974;110(1):130-1. effect. Consequently, we are unable to 4. Pochi PE. Acne in premature ovarian failure. Re-estab- Another possible future study would be lishment of cyclic flare-ups with methoxyprogesterone account for the placebo effect in this acetate therapy. Arch Dermatol. 1974; 109: 556-557 treatment study. to explore the unanswered role of Vitamin 5. Tully DB, Allgood VE, Cidlowski JA. Modulation of steroid receptor-mediated gene expression by vitamin B . B6 in the control of PAF. We suspect that 6 FASEB J. 1994;8(3):343-9 Another difficulty of this study is the fact there maybe relationship between Vita- 6. Jarret A. The effects of progesterone and testosterone on that the non-treatment (control) group is min B and progesterone level. The surface sebum and acne vulgaris. Br J Dermatol. 6 71:102-116, 1959 derived from a relatively smaller group of future study design can measure the 7. Newman BA, Feldman FF: Adult premenstrual acne: An patients than the other treatment group. progesterone levels in groups of patients entity suggesting corpus luteum dysfunction. Arch This is also inevitable because of the ret- that are on1 no treatment,2 placebo, and 3 Dermatol. 69:356-363, 1954 8. Nillius SJ, Johansson EDB. Plasma levels of rospective nature of this study. A rela- Vitamin B6 . This will allow a clearer progesterone after vaginal, rectal, or intramuscular tively small number of the patients did not demonstration of the relationship between administration of progesterone. Am J Obstet Gynecol. 110:470-477. 1971 start the Vitamin B6 (Pyridoxine) treatment Vitamin B6 intake and progesterone levels 9. Recommended Dietary Allowances. National Academy of as compared to the patients who did initi- in the blood stream. Sciences;10th ed., 1989 ate the therapy. However, part of the 10. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, analysis of the data was done by repeat Although our study provides statistically and Choline (2000), pp. 541-565: Index, Nat'l Academy measure analysis of variance. This elimi- and clinically significant results in the use Press 2000. nated the use of the control group in the of Vitamin B6 for the treatment of PAF, analysis and does provide a statistical repeated clinical trial study is warranted. significance in this study. The lack of placebo control and the relatively small study sample can be over-

In addition to the use of Vitamin B6, sub- come by a prospective study design. It physiologic doses of prednisone (5 mg) can also be used as part of future meta- have been recommended by another analysis to confer a more definitive result.

WAY, LIN, LADD 9 Squamous Cell Carcinoma of the Lip

Jay S. Gottlieb, D.O., F.O.C.O.O.*

With approximately 4,300 cases of lip majority of these occurred on the upper utilized. The use of nasolabial flaps can cancer resulting in 100-150 deaths per lip. Melanoma infrequently involves the be considered and used unilaterally or year in the United States, the topic of lip lips. bilaterally for reconstruction of the entire cancer is timely. The lip is the most length of the lip. Resection of large lip frequent site for cancer of the oral cavity. Squamous cell carcinoma of the lip is cancers can require total lip reconstruc- If treated early, the prognosis is excellent. typically a crusted ulceration, which tion. Prognostic indicators which may herald bleeds easily. Occasionally the patient an aggressive disease and a poor has been treated with antibiotics and may Infiltrating squamous cell carcinoma of outcome will be discussed. even report having had some improve- the lip may require resection of bone and ment. The lesion only later develops into adjacent soft tissue. If cheek tissue is The incidence of lip cancer in the a palpable mass. Actinic changes are inadequate for closure then regional flaps United States is 1.8 per 100,000. Patients usually visible on the lip and on other are preferable to distal flaps. Since large typically present in their 7th or 8th exposed area of the head and neck. lip cancers will required the adjuvant use decade. All reported series demonstrate Leukoplakia of the lip may be seen. of radiation therapy, reconstruction that the disease occurs more frequently in Enlarged palpable lymph nodes, if should be directed toward closing the males. There is a male to female ratio present, are most likely inflammatory in defect and covering exposed bone. This that approaches 79:1 for cancer of the nature rather than suggesting metastatic will help achieve early wound healing. lower lip and 5:1 for the upper lip. disease. An enlarged lymph node must The forehead flap has also been used to always be addressed. Hypesthesia of the accomplish lip reconstruction. Both Many factors have been implicated in lip must make the physician consider the bipedicaled and unilaterally based flaps lip cancer. Sunlight is a major contributor possibility of perineural invasion. can be used. The visor flap has been to the development of lip cancer. The lip utilized for near total lip reconstruction. is prone to sun damage because it lacks When treating cancer of the lip the pri- Other flaps available for reconstruction of a pigmented layer for protection. mary goal is eradication of the cancer. the anterior oral cavity include the Cigarette and pipe smoking also play a Consideration is also given to preserving trapezius myocutaneous flap, the role. A positive serology to syphilis was oral competence and an adequate buccal pectoralis myocutaneous flap, the implicated in some early studies, with the sulcus, minimizing the surgical deformity, deltopectoral flap as well as the incidence nearing 20%. More recent and restoration of a cosmesis. Primary latissimus dorsi flap. papers report not more than a 3% surgical excision offers the advantage of association. Poor oral hygiene results in eradication of disease, pathological About 10% of patients with lip cancer persistent irritation and possibly lip survey of margins and reconstruction of will present with local metastasis. An cancer. The use of alcohol has been the defect in a single stage. additional 15% will subsequently develop associated with the development of local node metastasis. If local node carcinoma of the lip as well as other sites A T1 or small T2 lesion of the lip can metastasis is confirmed the five year in the oral cavity. Mouthwashes that be excised with a 6-10mm margin and survival approaches 50%. The survival contain alcohol have also been result in a defect less than 1/2 the length rate for treatment of the initial neck implicated. The lower lip is the most of the lip and can be closed primarily. The metastasis by elective neck dissection frequent location of lip cancer and is resulting defect from excising the middle and for salvage for the subsequent devel- found between 90 and 96%. The upper lip of the upper lip may require excision of opment of neck nodes is essentially the is involved between 1.3 and 7.7% of the perialar skin. same. Since less than 10% of patients time and the commissure is involved in with T1 or T2 lip cancers develop neck 1 to 2%. Lip augmentation is generally required metastasis, most authors do not feel that when 1/2 to 2/3 of the length of the lip is a neck dissection is empirically indicated. The incidence of squamous cell carci- resected. The Abbe flap can be used. It In the clinically negative neck, when the noma of the lip approaches 95%. They is a full thickness flap from the opposite tumor size approaches T3 and T4, then are most frequently of the well-differenti- lip which is pedicled at the vermillion sentinel node sampling procedure should ated variety. Basal cell carcinoma may border and may be used to reconstruct be performed for biopsy. extend onto the labial surface. Basal cell defect of either the upper or lower lip not carcinoma is twice as common on the involving the commissure. If the com- If the patient presents with lip carci- upper lip and is the most frequent missure is involved then the Estlander noma and has positive unilateral neck neoplasm in that location. Salivary gland flap from the opposite lip can be used to nodes, a radical neck dissection is tumors of the lip have been reported. Of reconstruct the defect. The myocuta- indicated. If the patient presents with a these, about 20% were malignant. The neous innervated flap may also be used. large midline tumor or a large tumor that approaches the midline, consideration If more than 2/3 of either the upper or should be given to performing a contralat- *Associate Clinical Professor- Department of Surgery the lower lip is resected an adjacent eral node sampling procedure. If the Nova Southeastern University cheek tissue flap is required. Several patient has a confirmed regional metasta- College of Osteopathic Medicine cheek advancement flaps have been

10 (The Journal of the American Osteopathic College of Dermatology, Vol. 1, No. 1, pp 10-12, June 2003) sis, it should be treated postoperatively with radiotherapy. The extent of disease at the time of presentation determines the patient’s prognosis. The five-year cure rate for T1 and T2 lesions without cervical metastasis approaches 90%. This excellent cure Figure 1 rate can be achieved with either surgery or irradiation. The five-year survival falls to 60% for T3 lip cancers and to 40% for T4 lip cancers. If metastatic disease is present in the neck, the five-year survival rate falls to 50%. There are several prognostic indicators for squamous carcinoma of the lip. The prognosis of carcinoma of the upper lip and commissure is worse then the prognosis for the lower lip. The five-year survival is 10 to 20% lower than for the lower lip. Cervical metastasis, especially when large, bilateral or fixed indicate a poor prognosis as does the presence of Figure 2 distant metastasis. A worse prognosis is seen with poorly differentiated squamous cell carcinoma as well as with melanoma. Recurrent squamous cell carcinoma at the site of the initial resection carries a worse prognosis and suggests an aggressive tumor. The presence of bony mandibular involvement has a five-year survival rate of 29%. Case Presentation A 65 year old white male presented to the dermatology clinic with a three-month history of a progressively enlarging lower lip mass. He reported a nonhealing, painless ulceration in that location where he had some dental procedure performed Figure 3 3 years prior. He admitted to smoking three packs of cigarettes per day for the past 39 years and consumed alcohol reg- ularly. Past medical history was otherwise unremarkable. On exam he was found to be a thin white male with a large amount of diffuse actinic skin damage in the head and neck area. Examination revealed a firm, non- perineural invasion of the right two cases. Arch Intern Med 128:609-611, 1971. tender 1cm mass in his right lower lip mental nerve. For this reason he is to Bernier JL, Clark ML: Squamous cell carcinoma of the lip: A critical statistical and morpological analysis of 835 cases. which extended to the midline. There was undergo radiotherapy postoperatively. Milit Surg 109:379-384, 1951. no cervical adenopathy. His laboratory Brown RG, Poole MD, Calami PM, Bakamjian VY: Bibliography Advanced and recurrent squamous carcinoma of the lower lip. values were normal. Amer J Surg 132:492-497, 1976. Ashley FL, McConnell DV, Machida R, Sterling HE, Gal- loway D, Grazer F: Carcinoma of the lip: A comparison of five Burget GC, Menick FJ: Aesthetic restoration of one-half of A punch biopsy was performed which year results after irradiation and surgical therapy. Am J Surg the upper lip. Plast Reconstr Surg 78:583-592, 1986. revealed invasive well differentiated squa- 110:549-544, 1965. Burkel CC: Cancer of the lip. Can Med Assoc J 62:28-36, mous cell carcinoma. Subsequently he Bailey B: Management of carcinoma of the lip. Laryngo- 1950. underwent a full thickness resection of scope 87:250-260, 1977. Cross JE, Guralnick E, Dadland EM: Carcinoma of the lip: Baker SR: Current management of cancer of the lip. A review of 563 case records of carcinoma of the lip at the 35% of his lower lip. Surgical margins Oncology 4:107-120, 1991. Pondville Hospital. Surg Gynecol Obstet 87:153-168, 1948. were free of tumor. Reconstruction was Baker SR: Risk factors in multiple carcinomas of the lip. David MC: On the etiology of cancer of the lower lip. Plast carried out employing a W-Plasty. His Otolaryngol Head Neck Surg 88:248-251, 1980. Reconst Surg, 52:151-154, 1973. Baker SR, Krause CJ: Cancer of the lip, in Suen JY, Myers Del Regato JA, Sala JM: The treatment of carcinoma of postoperative course was unremarkable. EN (eds): Cancer of the Head and Neck. New York, Churchill the lip. Radiology 73:839-847, 1989. (FIGURES 1,2,3,) The final pathology Livingston, 1981, pp 280-300. Eckert CT, Petry JL: Carcinoma of the lip. Surg Clin North reported invasive well differentiated squa- Baker SR, Krause CJ: Carcinoma of the lip: Laryngoscope Am 24:1064-1069, 1944. mous cell carcinoma with all surgical mar- 90:19-27, 1990 Fitzpatrick PJ: Cancer of the lip. J Otolaryngol 13:32-36, Berger HM, Goldman R, Comick HC, Waisman J: Epider- 1989. gins clear. There was, however, moid carcinoma of the lip after renal transplantation: Report of Gladstone WS, Kerr HD: Epidermoid carcinoma of the

GOTTLIEB 11 lower lip: Results of radiation therapy of the local lesions. Am J of the lip. Can Med Assoc J 90:670-679, 1964. Schreiner BF, Christy CJ: Results of irradiation treatment Roentgenology 79:101-114, 1958. Mahoney LJ: Resection of cervical lymph nodes in cancer of cancer of the lip. Analysis of 636 cases from 1926-1936. Gullanne PJ, Martin GF: Minor and major lip of the lip: Results in 123 patients. Can J Surg 12:40-43, 1969. Radiology 39:293-307, 1942. reconstruction J Otolaryngol 12:75-81, 1983. Marshall KA, Milton TEZ: Indications for neck dissection in Spira M, Hardy B: Vermilionectomy. Plast Reconstr Surg Heller KS, Shah JP: Carcinoma of the lip. Am J Surg carcinoma of the lip. Am J Surg, 133:216-217, 1977. 33:39-46, 1964. 138:600-603, 1979. Martin HE: Cheiloplasty for advanced carcinoma of the lip. Szpak CA, Stone MJ, Frenkel EP: Some observations Hendricks JL, Mendelson BC, Woods JE: Invasive carci- Surg Gynecol Obstet 54:914-922, 1932. concerning the demographic and geographic incidence of car- noma of the lower lip. Surg Clin North Am 57:839-844, 1977. Martin HE, MacComb WS, Blady JV: Cancer of the lip. cinoma of the lip and buccal cavity. Cancer 40:343-350, 1977. Hornback NB, Homayooni S: Carcinoma of the lower lip: Ann Surg 114:226-235, 1941. Teichgraeber JF, Larson DL: Some oncologic considera- Treatment results at the University of Indiana Hospitals. Can- Mazzola RF, Lupo G: Evolving concepts in lip reconstruc- tions in the treatment of lip cancer. Otolaryngol Head Neck cer 41:352-357, 1978. tion. Clin Plast Surg 11:583-617, 1984. Surg, 98:589-592, 1988. Jesse RH: Extensive cancer of the lip: Surgical therapy. Modlin J: Neck dissection in cancer of the lower lip. Five- Ward GE, Hendrick JW: Results of treatment of carcinoma Arch Surg 94:509-516, 1967. year results in 179 patients. Surgery 28:404-410, 1950. of the lip. Surgery 27:321-327, 1950. Jorgensen K, Elbrond O, Andersen AP: Carcinoma of the Molnar L, Ronay P, Tapolcsanyi L: Carcinoma of the lip: Webster JP: Crescent peri-alar cheek excision for upper lip: A series of 869 cases. Acta Radiol 12:177-190, 1973. Analysis of the material of 25 years. Oncology 29:101-112, lip flap advancement with a short history of upper lip repair. Ju DM: On the etiology of cancer of the lower lip. Plast 1974. Plast Reconstr Surg 16:434-439, 1955. Reconstr Surg 52:151-154, 1973. Owens OT, Calcaterra TC: Salivary gland tumors of the Wilson JSP, Walker EP: Reconstruction of the lower lip. Karapandzic M: Reconstruction of lip defects by local arte- lip. Arch Otolaryngol 108:45-47, 1982. Head Neck Surg 4:29-44, 1981. rial flaps. Br J Plast Surg 27:93-97, 1974. Petrovich Z, Kuisk H, Tobochnik N, Hittle R, Barton R, Wookey H, Ash C, Welsh WK, Mustard RA: The treatment Keller AZ: Cellular types, survival, race, nativity, occupa- Jose LS: Carcinoma of the lip. Arch Otolaryngol, 105:187-191, of oral cancer by combination of radiotherapy and surgery. Ann tions, habits, and associated diseases in the pathogenesis of 1979. Surg 134:529-537, 1951. lip cancer. Am J Epidemiol 91:486-499, 1970. Richard GE: The radiologic treatment of cancer 1929- Yarington CT, Larrabee WF: Reconstruction following lip Lore JM, Kaufman S, Grabau JC, Popvic DN: Surgical 1936, IV. Carcinoma of the lips. Can Med Assoc J 35:490-501, resection. Otolaryngol Clin North Am 16:407-421, 1983. management and epidemiology of lip cancer. Otolaryngol Clin 1936. Yonkers AJ, Yarington CT: Cancer of the lip. Laryngo- North Am 12:81-95, 1979. Sack JC, Ford CN: Metastatic squamous cell carcinoma of scope 81:625-630,1971. MacKay EN, Sellers AH: A statistical review of carcinoma the lip. Arch Otolaryngol 104:282-285, 1978.

12 SQUAMOUS CELL CARCINOMA OF THE LIP 13 14 Phakomatoses

Kellie Mosley, DO*, Stanley E. Skopit, D.O., F.A.O.C.D.**

Phakomatoses The patients also have multiple café au segmental hypertrophy, cystic lesions in lait spots. Also, approximately one-fourth cancellous bones, cortical bones or The phakomatoses are neurocuta- of the patients under 6-years-old have pedunculated from the bone and scallop- neous diseases. They are a group of Lisch nodules which are found in the ing of the posterior vertebral body. The hereditary disorders which occur sponta- irises. These nodules are also found in exact cause of these changes is not neously, which lesions involve the 94% of older patients.3 known, however, segmental hypertrophy nervous system and the skin.1 from increased vascular supply has been Phakomatosis is derived from the Greek The hallmark of the neurofibromatosis implemented. word phakos which means “mother spot”. is the café au lait macule. It is a uniformly The mother spots will be malformative pigmented, light brown macule, round or Generalized osteomalacia has also and dysplastic lesions found most often in oval with irregular or uneven borders. been described in patients with AF. the brain, the skin and the viscera of the The macules are most often present at Absence of the greater or lesser wing of patient. The masses or tumors which birth or by the time the patient reaches the sphenoid bone and congenital bowing develop from the mother spots are his/her first birthday. The diagnostic of the bones of the leg and pseudoarthro- termed phakomas. These included a marker for Type 1 neurofibromatosis is sis are classic, but unusual skeletal find- spectrum of proliferative activity, which the finding of six (6) or more café au lait ings in neurofibromatosis.7 were benign and other malignant neo- macules of at least 1.5-cm in diameter.4 plasms. Phakomatosis include tuberous Histologically, neurofibromas are found sclerosis, von Recklinghausen’s disease Axillary freckling or Crowe’s sign may to have faintly eosinophilic, thin, wavy- (neurofibromatosis), von Hippel-Lindau’s often occur usually on the neck, but may type spindle cells which have a spindle- disease (angiomatosis retinae), ataxia also involve the inguinal region extending shaped nucleus. Mast cells are greatly telangiectasia, basal cell nevus syn- to the peritoneal area. There may also be increased in the background matrix.8 drome, nevus sebaceous, and Sturge- marked hyperpigmentation of the skin Weber syndrome.2 present along with xanthogranulomas. While laboratory tests are helpful in identifying the complications of This paper will review four of the more Many organ systems may also be neurofibromatosis, there are no specific common neurocutaneous diseases, involved in neurofibromatosis. Endocrine laboratory tests for the disorder. The including neurofibromatosis, tuberous disorders occur such as acromegaly, diagnosis of neurofibromatosis is made in sclerosis, von Hippel-Lindau’s disease cretinism, hyperparathyroidism, patients when two or more of the follow- and Sturge-Weber disease. myxedema and pheochromocytoma. ing criteria are present: Patients with neurofibromatosis Type 1 Neurofibromatosis 1) Six or more café au lait macules are four times more likely to develop with greatest diameter greater than malignancies than the general population. There are two forms of neurofibro- 5-mm in pre-puberty patients and Malignant peripheral nerve sheath tumors matosis which have been described greater than 15 in post-puberty develop in approximately 5% of patients including neurofibromatosis 1 (NF1) and patients. with NF1, which usually occurs after 10- neurofibromatosis 2 (NF2). 2) Two or more neurofibromas of any years of age. However, it has been noted type or one plexiform neurofibroma. Neurofibromatosis or von Reckling- that younger children are also affected. 3) Freckling in the axillary or inguinal hausen’s disease is inherited autosomal Osteocytomas are the most common region. dominantly and encompasses develop- intracranial tumor involving the optic 4) A distinctive osseous lesion mental changes in the skin and in the nerves, the hypothalamus, brain stem including sphenoid dysplasia or nervous system. Type 1 neurofibromato- and the cerebellum. thinning of the longbone cortex with sis encompasses approximately 85% of or without pseudoarthrosis. the cases and is termed classic Seizures, dementia and mental retar- 5) Optic leioma. neurofibromatosis. Cutaneous manifesta- dation, along with a variety of intracranial 6) Two or more Lisch nodules. tions of neurofibromatosis includes malignancies may also occur. Melanoma, 7) A parent, sibling or offspring with neurofibromas which measure a few however, does not appear to be a true neurofibromatosis Type 1 on the millimeters to a few centimeters in association. basis of the above criteria.9 diameter. These are widely distributed. In neurofibromatosis, approximately There is no treatment available for 40% of patients have abnormalities of the neurofibromatosis except for excision of * Nova Southeastern University/College of Osteopathic Medi- bone. These skeletal abnormalities vary cine and Surgery the neurofibromas. There have been North Broward Hospital District from asymptomatic, erosive-type changes deaths reported from intracranial Fort Lauderdale, FL resulting from pressure from adjacent meningiomas and gliomas, peripheral ** Program Director neurofibromas to painful pathologic nerve scar sarcomas and other Nova Southeastern University/College of Osteopathic Med- fractures. The most common skeletal malignancies. The disease is exacer- icine and Surgery manifestation is kyphoscoliosis.5,6 North Broward Hospital District bated during pregnancy and treatment Fort Lauderdale, FL Additional radiographic findings include resistant hypertension also occurs. The

(The Journal of the American Osteopathic College of Dermatology, Vol. 1, No. 1, pp 15-17, June 2003) 15 literature suggests obtaining a baseline penetrance and a spontaneous mutation bromas. The prognosis for tuberous scle- MRI of the brain and spinal cord, along rate of approximately 60%. This is due to rosis is good except for a rare incidence with a baseline ophthalmologic examina- a deletion on chromosome 9.13,14 The of premature death due to status epilepti- tion. The prognosis favors a shortened presenting features usually are mono- cus or a malignant brain tumor. Differen- life span secondary to clonic seizures seen in infancy with men- tial diagnosis would include nevus neurofibrosarcoma, pheochromocytoma tal retardation developing in depigmentosis, nevus anemicus, vitiligo, or vascular or CNS tumor complications. approximately 50-80%. The earliest char- idiopathic guttate hypomelanosis or There is a noted great variation in sever- acteristic finding is the ash-leaf or hyper- hypomelanosis of Ito.20 ity of this disease.10 pigmented macule that is polygonal in shape, and this usually develops before Sturge-Weber Syndrome Neurofibromatosis 2 the adenoma sebaceum. Adenoma sebaceum is a nodular rash seen on the Sturge-Weber syndrome or encephalo- (Bilateral Acoustic Neurofibromatosis) face, particularly in the nasolabial folds, facial angiomatosis includes nevus flam- which develops between one and five- meus of the face which is present at birth This is also inherited autosomal domi- and ipsilateral meningeal angiomatosis nantly. The incidence is 1 in 35,000 with years-of-age. Other skin manifestations include angiofibromas, which occur in the which involves the posterior parietal, tem- males equaling females and is seen in all poral and occipital lobes.21 This usually races. The symptoms frequently appear trunk, the gingiva and periungual region. Shagreen patches, which are connective occurs unilateral, but may also be bilat- at 15 to 25years of age. The genetic and eral in up to 25-30% of people. Additional phenotypic characteristics of NF2 are dis- tissue nevi, also occur along with retinal nodular hamartomas.15 clinical features include seizures, mental tinct from those of NF1, with the NF2 retardation, hemiparesis, and ipsilateral 10 gene being located on chromosome 22. The pathognomonic central nervous glaucoma.22 Sturge-Weber syndrome has The characteristic feature of NF2 is bilat- system lesions of tuberous sclerosis been hypothesized to be due to a cere- eral vestibular schwannoma. Also, café include hamartomas and astrocytic bral vascular abnormality which occurs au lait spots and cutaneous neurofibro- tumors which involve the cerebral cortex between 4-8 weeks of gestation. mas are less common in NF2 than are in and the ventricular borders. The cortical Seizures will occur clinically in approxi- NF1. Plexiform neurofibromas and Lisch lesions which are termed tubers are mately 90% of the cases. nodules are also rarely seen in NF2. made of astrocytes, neurons and dysplas- Schwannoma is a central nervous system tic cells with astrocytic and neuronal fea- The cutaneous lesion is a simple capil- tumor, usually of low grade malignancy tures. The four main intracranial lary angioma of the dermis. This usually and occurring with increased frequency in manifestations of tuberous sclerosis are involves the upper eyelid or supra-orbital NF2. Pre-senile cataracts or lens opacity cortical tubers, subependymal nodules, region and is localized to the region of the develop in approximately 50% of NF2 subependymal giant cell astrocytomas cutaneous distribution of the ophthalmic patients. The tumors may be complicated division of the trigeminal nerve. This is and white matter abnormalities. The 23 by deafness, tinnitus, poor balance, common histological finding in all of these present at birth. headache, muscular wasting and under- lesions is the presence of giant cell which water disorientation.11 Neurofibromatosis Angiomatosis of the choroid of the eye show a spectrum of varying differentia- is usually seen in approximately 35-50% 2 can be diagnosed when the following tions into a neuronal or astrocytic ele- characteristics are present: of the cases. This may lead to increased ment. Cortical tumors are firm lesions intraocular pressure which results in 1) Bilateral cranial nerve mass visual- and involve the gray matter and underly- buphthalmos. ized with either CT or MRI. ing white matter. The cortex is iso intense with gray matter but there is high The leptomeningeal angiomatosis usu- 2) A first-degree relative with NF2. signal on T-2 weighted images, and there ally lies over the ipsilateral occipital lobe are underlying white matter due to gliosis with varying degrees of extension over 3) And either a unilateral nerve mass or edema.16 Another common finding in the parietal or temporal lobes. This or any two of the following: neurofi- adults is sclerosis of the bones of the involves the thin-walled vessels which are broma, glioma, meningioma, skull. Bony sclerosis has also been iden- confined to the pia. There is a loss of nor- schwannoma (osteo or capsular) tified in the lumbosacral spine and pelvis, mal superficial cortical veins which results cataract or lens opacity at a young the phalanges of the hands and feet, and in shunting to the deep venous system. age. rarely the ribs.17 The incidence of Contrast CT or MRI demonstrates exten- intracranial calcification increases from sive leptomeningeal angiomatosis.24 The Management includes referral to a approximately 15% in infants to 60% in pathnomonic radiographic feature is the neurologist or neurosurgeon with surgical children age 10 to 14-years-old.18 The presence of opaque double-contoured debulking of the tumors or referral to classic radiographic features of tuberous sinusoidal lines that follow the convolu- other specialists as warranted along with sclerosis often times are completely tions of the brain. This radiographic fea- examination of a first-degree relative. asymptomatic. Mental development does ture represents calcium deposits in the Prognosis includes progressive deteriora- not correlate well with the presence or outer layers of the cerebral cortex in the tion with loss of hearing, ambulation and absence of intracranial lesions.19 region of the meningeal angiomatosis. sight. Death is usually due to tumors in They are usually seen only after the age the CNS which occur approximately 20 Laboratory evaluation includes wood’s 25 12 of 2-years-old. Other radiologic findings years after onset of symptomatology. light examination, transfontanelle ultra- which have been reported include a thick- sound, CT/MRI of the brain, EEG, fundo- Tuberous Sclerosis ened cranium, an elevated petrous bone scopic exam, renal ultrasound and with ipsilateral enlargement of the human echocardiogram in infancy. Manage- cranium.26 Differential diagnosis would Tuberous sclerosis is an autosomal ment would include referral to an appro- dominant disorder. The diagnosis is include periorbital hemangioma and priate specialist such as a salmon patch. Laboratory evaluation based on clinical, radiological and patho- neurosurgeon/neurologist for removal of logical findings. It presents classically would include MRI with gadolinium and brain tumors, or referral to a laser special- EEG if MRI is positive. Management with a triad of mental retardation, epilepsy ist for CO2 laser excision of facial angiofi- and adenoma sebaceum. It has a low would be a referral to a dermatologist for

16 PHAKOMATOSES a pulsed dye laser treatment and also a capillary malformations of the head and sis, tuberous sclerosis, and Sturge-Weber syndrome. Arch Dermatol 1993; 129(2)L219-226 referral to an ophthalmologist and neurol- neck including capillary angiomas. 12. Martuza RL, Eldridge R. Neurofibromatosis 2 (bilateral ogist if seizures are present. The course Approximately 10-20% of cerebellar acoustic neurofibromatosis) N Eng J Med 1990; 113(1):39-52. of the disease is dependent on the sever- hemangioblastomas produce erythropoi- 13. Roach ES, Smith M, Huttenlocher P, et al. Diagnostic ity and extent of the cerebral and ocular etin which are accompanied by a criteria: Tuberous sclerosis complex. J Child Neurol 7: lesions present. Prognosis is a reflection secondary polycythemia.30 Diagnosis 221-224, 1992. 14. Stefansson K: Tuberous sclerosis. Mayo Clin Proc of the difficulty in controlling the seizures. would include cerebellar tumors. Labora- 66:868-872, 1991 (editorial) This could be reflected in an increased tory evaluation would include a CT or MRI 15. Romanowski CAJ, Cavallin LIB (1998) Neurofibromatosis types I and II: radiological appearance. Hosp Med 59: frequency of mental retardation over scan of the brain and spinal cord, abdom- 134-9. time.27 inal CT, MRI scan, a VMA level, serum 16. Romanowski CAJ, Cavallin LIB (1998) Neurofibromatosis types I and II: radiological appearance. Hosp Med 59: catecholamine level and a complete 134-9. Von Hippel-Lindau Syndrome blood cell count. Management would 17. Green GJ. The radiology of tuberose sclerosis. Clin include referral to ophthalmology, neuro- Radiol 1968;19:135-47. VHL, also known as, CNS angiomato- 18. Fitz CR, Harwood-Nsh DCF, Thompson JR. surgeon and neurologist, along with urol- Neuroradiology of tuberous sclerosis in children. sis is an autosomal dominant disease ogist. The prognosis is grim with this Radiology 1974;110:635-42. with incomplete penetrance. Approxi- being a progressively fatal disease with 19. Teplick JG. Tuberous sclerosis. Extensive roentgen find- mately 1 in 40,000 of the general ings without the usual clinical picture: a case report. death occurring by the fourth decade. Radiology 1969;93:53-5. population are affected, and it is due to a Hematuria is usually the common pre- 20. Kwiatkowski DJ, Short MP. Tuberous sclerosis. Arch defect in chromosome 3.28 Clinical Dermatol 1994; 130:348-353. senting sign. Premature death is sec- 21. Alexander GL, Norman RM. The Sturge-Weber presentation is usually by the fourth ondary to the progressive growth of CNS syndrome. Bristol: John Wright & Sons, Inc, 1960. decade of life. The pathogenesis is 22. Alexander GL, Norman RM. The Sturge-Weber hemangioblastomas or metastatic renal syndrome. Bristol: John Wright & Sons, Inc, 1960. unknown. Retinal hemangioblastomas cell carcinoma.31,32 23. Romanowski CAJ, Cavallin LJB. Tuberous sclerosis, von with secondary visual impairment and Hippel-Lindau disease, Sturge-Weber syndrome review. Hosp Med 1998;Vol. 59, No. 3, pg. 230. blindness if untreated, is the characteris- BIBLIOGRAPHY 24. Romanowski CAJ, Cavallin LJB. Tuberous sclerosis, von tic lesion. Other lesions seen include a Hippel-Lindau disease, Sturge-Weber syndrome review. 1. Gomez MR (ed): Neurocutaneous Diseases. Boston, renal cyst, renal cell carcinoma in approx- Hosp Med 1998; Vol. 59, No. 3, pg. 230. Butterworths, 1987. 25. Peterman AF, Hayles AB, Dockerty MB, et al. imately 25-40% of the patients, pheochro- 2. Gomez MR (ed): Neurocutaneous Diseases. Boston, Encephalotrigeminal angiomatosis (Sturge-Weber Butterworths, 1987. disease): clinical study of thirty-five cases. JAMA mocytoma seen in approximately 10% of 3. Goldberg NS: Neurofibromatosis. Adv Dermatol 1996, 29 1958;167:2169-76. the patients and pancreatic cysts. The 11:179. 26. Enzman DR, Hayward RW, Norman D, et al. Cranial criteria proposed by Melmon and Rosen, 4. Goldberg NS: Neurofibromatosis. Adv Dermatol 1996, computed tomographic scan appearance of Sturge-Weber 11:179. disease: unusual presentation. Radiology 1977;122:721-4. frequently used for the diagnosis of Von 5. Hunt JC, Pugh DG. Skeletal lesions in neurofibromatosis 27. Paller AS. The Sturge-Weber syndrome. Dermatology Hippel-Landau disease: two or more cen- Radiology 1961; 76:1-19. 1987;4:300-304. 6. Holt JF, Wright EM. The radiologic features of tral nervous system hemangioblastomas 28. Romanowski CAJ, Cavallin LJB. Tuberous sclerosis, neurofibromatosis. Radiology 1948;51:647-64. von Hippel-Lindau disease, Sturge-Weber syndrome or a single central nervous system 7. Holt JF, Wright EM. The radiologic features of review. Hosp Med 1998;Vol. 59, No. 3, pg. 228. hemangioblastoma in association with the neurofibromatosis. Radiology 1948;51:647-64. 29. Romanowski CAJ, Cavallin LJB. Tuberous sclerosis, 8. Levene LJ. Bone changes in neurofibromatosis. Arch von Hippel-Lindau disease, Sturge-Weber syndrome visceral manifestation of the disease. Intern Med 1959; 103:570-80. review. Hosp Med 1998;Vol. 59, No. 3, pg. 228. With a family history of retinal or central 9. National Institute of Health Consensus Development 30. Melmon KL, Rosen SW: Lindau’s disease. Review of the Conference, Neurofibromatosis. Arch Neurol 45:575-578, literature and study of a large kindrid. Am J. Med 36:595- nervous system hemangioblastoma, only 1988. 617, 1964. one hemangioblastoma visceral lesion is 10. Truhan AP, Filipek PA. Magnetic resonance imaging. Its 31. Maher ER, Moore AT. Von Hippel-Lindau disease. Br J role in the neuroradiologic evaluation of required for the diagnosis. There is cuta- Ophthalmol 1992;76(12): 743-745. neurofibromatosis, tuberous sclerosis, and Sturge-Weber 32. Karsdorp N, et al.: Von Hippel-Lindau’s disease: new neous involvement seen in approximately syndrome. Arch Dermatol 1993; 129(2)L219-226. strategies in early detection and treatment. Am J Med 11. Truhan AP, Filipek PA. Magnetic resonance imaging. Its 1994, 97:158. 81:625-630, 1971. 5% of the cases, which would involve role in the neuroradiologic evaluation of neurofibromato-

MOSLEY, SKOPIT 17 Mid-dermal Elastolysis: A Case Report and Literature Review

Matthew B. Doppelt, D.O.*, Stanley E. Skopit, D.O.,F.A.O.C.D.**

A 37 year-old female presented to the office distressed over subtle wrinkling of her abdominal skin. A punch biopsy was performed to aid in the diagnosis. Microscopically, elastic tissue stains revealed a well-defined mid-dermal absence of elastic tissue. The diagnosis of idiopathic mid-dermal elastolysis was made. This disease is rarely reported in the literature and what follows is a case report and review of the other documented cases.

Case Report History

A 37 year-old female presented to the office complaining of a subtle wrinkling on her abdomen that had been slowly progressing over the course of a year. As an actress she was quite distraught with anticipation that this rash might continue to evolve causing further “disfigurement.” She denied any prior rash in the areas Fig.1. Fine wrinkles on abdomen char- affected and her past medical history was acteristic of MDE. Fig. 4. Elastic stain (EVG) demon- completely non-contributory. She also strates absence of elastic outlined to denied any history of cosmetic surgery the mid-dermis. such as breast augmentation or liposuc- tion. There were no altered sensations such as pruritus, burning, or numbness at the affected sites. She had sought treatment from a naturopathic physician who prescribed various herbal remedies; none of which helped the condition. She had also applied an over-the-counter steroid cream for one month without benefit. Physical Examination Fig. 2. Magnified view of MDE wrinkles In general, the patient was well-nour- ished, well-hydrated and somewhat anx- ious. Initial superficial inspection failed to Fig 5. High power magnification (EVG) reveal any rash. However, when the lines demonstrates the absence of inflam- of skin tension were relaxed, large, poorly matory cells or granuloma formation. defined patches of fine skin wrinkling and yellowish papules could be observed on diagnosis of mid-dermal elastolysis was the abdomen and to a lesser extent the made. lower back, forearms, and medial thighs The CBC, CMP and UA were all within (Fig. 1 & 2). Mild hyperelasticity of the normal limits. Autoimmune blood work skin on the neck and the bilateral antecu- was performed. The only positive was an bital fossa was noted. ANA 1:160 in the speckled pattern. The Investigations anti-smooth muscle, antimitochondrial, anti-SS-A/-SS-B, RNP, anti-SM, antihis- A three-millimeter punch biopsy was Fig. 3 Three-millimeter punch biopsy tone, antichromatin, anti-DSDNA antibod- taken from a representative area of the specimens from a lesion in figure 1. ies were all negative. The rheumatoid abdomen. H&E staining revealed disor- Disorganized collagen bundles identi- factor was also negative and the sedi- ganized collagen bundles in the mid-retic- fied in the mid-reticular dermis (H & mentation rate and complement levels E). were normal. * Nova Southeastern University/College of Osteopathic Medicine and Surgery, North Broward Hospital District, Fort After the patient was given the diagno- Lauderdale, FL ular dermis (Fig. 3). Elastic van Gieson sis she utilized the Internet to learn more ** Program Director; Nova Southeastern University/College of stain demonstrated loss of elastic fibers in about this disease. Even though she Osteopathic Medicine and Surgery, North Broward Hospital denied any history of tick bites or charac- District, Fort Lauderdale, FL the mid-reticular dermis (Fig. 4 & 5). A

18 (The Journal of the American Osteopathic College of Dermatology, Vol. 1, No. 1, pp 18-20, June 2003) teristic rash, she had a Lyme titer per- diagnostic criteria for SLE and never had Diagnosis, Prognosis, and formed. Interestingly, this was “positive the characteristic rash of Lyme’s disease. Treatment Kirsner and Flanaga reported two female patients with MDE who also had positive The astute dermatologist should sus- DISCUSSION ANAs and false-positive Lyme titers.10 pect MDE based upon the unique clinical At 32 weeks of age elastic fibers are One of their cases was attributed to presentation of fine wrinkling and/or follic- well-developed. They are thickest in the silicone mammoplasty. In one case ular protrusions of skin primarily overlying dermis and become thinner as they reported in the European literature, the abdomen and arms. A punch biopsy approach the epidermis. Elastic fibers of Hashimoto’s thyroiditis was associated with microscopic examination utilizing the dermis consist of two components: with the development of MDE.7 Others9,19,21 elastic tissue staining should be per- microfibrils (15%, electron-dense) and the have implicated the role of UV light as the formed. Histologically a distinct band of matrix elastin (85%, electron-lucent). wrinkling tends to occur in photodistrib- elastolysis confined exclusively to the mid Microfibrils are aggregated at the periph- uted areas, including Bannister2 who dermis will confirm the diagnosis. Addi- ery of the elastic fiber, and are also pre- reported two males with widespread per- tionally, it may prove beneficial to perform sent within the elastin as strands. Elastic sistent reticulate erythema concentrated screening tests for autoimmune, collagen- fibers are significantly changed during within chronically sun damaged skin. vascular, endocrine, and hematological maturation and exposure to UV light. The However, only six of the thirty-four diseases to identify otherwise subclinical microfibrils, which confer elasticity, are described cases have known previous disease states. While MDE tends to be slowly lost as they mature. Additionally, inflammatory conditions. progressive, no internal organ involve- the physiologic turnover of elastic tissue Pathogenesis ment has been reported. The specific is markedly decreased in mature tis- pathophysiologic process has yet to be sues.12 Elastin degradation may be Several pathogenic mechanisms of clearly elucidated and as such, there is markedly increased in various disease MDE have been postulated. These no known effective treatment. However, states. Polymorphonuclear elastases are include decreased elastic fiber production because of the predominant photodistrib- among the most powerful elastolytic (UV light playing a considerable role), an ution of the wrinkling, it is logical to enzymes and probably play a role in post- autoimmune process causing destruction encourage patients to adopt protective inflammatory elastolysis.13 of elastic fibers,10 and an inflammatory measures against UV radiation. process. Additionally, the use of colchicine and Demographics retinoic acid have been recommended Shelley and Wood18 hypothesized that but have shown little benefit.1,20 Oral and Shelley and Wood first described mid- 16 18 the cause of the disorder in their patient topical steroids have proven ineffective. dermal elastolysis (MDE) in 1977. It is was immune elastolysis. Autoimmune described as a rare, acquired disorder diseases have been associated with MDE Conclusion characterized histologically by a band-like including rheumatoid arthritis,17 Hashimo- absence of elastic tissue confined exclu- 7 3 We have presented a case of a rarely to’s thyroiditis, and lupus. This coupled reported disease known as MDE in a 39 sively to the mid-dermis. A Medline with reports of positive ANAs and “false- search ranging from 1977 until the year-old Caucasian female. This disease positive” Lyme titers lends support to an is characterized clinically by slowly present day utilizing the identifiers “mid- immune mediated mechanism of MDE. dermal” and “elastolysis” was performed. progressive, very fine wrinkling of the skin After reviewing the articles a total of Snider, et al., opined that MDE and/or follicular protrusions usually over thirty-two cases have been reported with appears to fall in a spectrum of elastolytic the abdomen and arms. Histologically, it this being the thirty-third.1-22 Only four of disorders that also includes cutis laxa, is characterized by the destruction and the cases reported were males. The anetoderma, perifollicular elastolysis, and loss of elastic fibers confined exclusively average age at presentation was thirty- actinic granuloma.19 Although MDE was to the mid-dermis. While several patho- nine with the vast majority of cases originally described as a non-inflamma- genic mechanisms of MDE have been ranging between thirty and fifty. The tory condition, multiple reports have postulated, the specific histogenesis of oldest patient was seventy-nine and the demonstrated the presence of inflamma- this disease is still poorly understood. At youngest patient was fifteen. tory infiltrates and elastic fiber phagocyto- present, there are no known effective sis supporting an inflammatory treatments. Hopefully, through further Clinical Presentations: Clinically, MDE hypothesis of MDE pathogenesis.3,9,18 reports, a common unifying theme may is characterized by diffuse fine wrinkling Neri, et al.,13 have performed the most in become apparent that will explain its of the skin with a predilection for the trunk depth investigation as to a potential pathogenesis. Once this is known, and upper extremities. Yellow to white inflammatory pathogenesis of MDE. They perhaps we will have more effective papules and plaques as well as perifollic- undertook a pathological and ultrastruc- treatment options. ular papules have also been described. tural study of five cases of MDE. A lym- Acknowledgments Shelley and Wood’s case was that of a 42 phocytic perivascular infiltrate was year-old female with fine wrinkles on the 18 present in all five patients with three of The author thanks Drs. Evangelos trunk and arms. In their case, there was five showing histiocytes among collagen Poulos and Andrew Hanly at Global an urticarial event that lasted for more bundles. Additionally, all five cases Pathology for their expertise in der- than a year and preceded the wrinkling by revealed mononuclear cells often show- matopathology, and their assistance in seven years. They believed MDE repre- ing phagocytized elastic fibers. Subse- providing the histopathologic images con- sented a post-inflammatory event related quently, the authors surmised that the tained within this report. to the antecedent urticarial event. The elastolysis in MDE is most likely a post- youngest case, a 15 year-old female inflammatory phenomenon. References developed MDE in areas clinically 1. Agha A, Hashimoto K, Mahon M. Mid-dermal elastolysis: diagnosed five years previously with None of the theories that have been case report and review of the literature. J Dermatol 1994;21:760-6. 22 granuloma annulare. In 2001, Boyd and advanced specifically addresses why, or 2. Bannister MJ, Rubel DM, KossarMid-dermal King described MDE in two patients with how the elastolytic process remains con- elastophagocytosis presenting as a persistent reticulate 3 erythema. Austral J Dermtol 2001;42:50-4 lupus erythematosus. Our patient has a fined to the mid-dermis. 3. Boyd AS, King LE. Mid-dermal elastolysis in two patients positive ANA and Lyme titer, but no other with lupus erythematosus. Am J Dermatopathol 2001;23(2):136-8.

DOPPELT, SKOPIT 19 4. Brenner W, Gschnait F, Knorad K, et al. Non-inflamma- process in mid-dermal elastolysis. J Am Acad Dermatol 17. Rudolph RI. Mid-dermal elastolysis. J Am Acad Dermatol tory dermal elastolysis. Br J Dermatol 1978;99:335-8. 1992;27:832-4. 1990;22:230-6. 5. Brod BA, Rabkin M, Rhodes AR, et al. Mid-dermal 11. Maghraoui S, Grossin M, Crickx B, et al. Mid-dermal 18. Shelley WB, Wood MG. Wrinkles due to idiopathic loss of elastolysis with inflammation. J Am Acad Dermatol elastolysis. J Am Acad Dermatol 1992;26:882-884. mid-dermal elastic tissue. Br J Dermatol 1977;97:441-5. 1992;26:882-4. 12. Lever WF, ed Histopathology of the skin. Philadelphia: 19. Snider RL, Lang PG, Maize JC. The clinical spectrum of 6. Crivellato E. Disseminated nevus anelasticus. Int J Lippincott Ð Raven, 1997:43-44. mid-dermal elastolysis and the role of UV light in its Dermatol 1986;25:171-173. 13. Neri I, Patrizi A, Fanti PA, et al. Mid-dermal elastolysis: a pathogenesis. J Am Acad Dermatol 1993;28:938-42. 7. Gamblicher T, Linhart C, Wolter M. Mid-dermal elastolysis pathologic and ultrastructural study of five cases. J Cutan 20. Sterling JC, Coleman N, Pye RJ. Mid-dermal elastolysis. associated with Hashimoto’s thyroiditis. J Eur Acad Pathol 1996;23:165-9. Br J Dermatol 1994;130:502-6. Dermatol Venereol 1999;12:245-9. 14. Rae V, Falanga V. Wrinkling due to mid-dermal 21. Trueb RM, Burg G. Idiopathic mid-dermal elastolysis. 8. Harmon CB, Su WPD, Gagne EJ, et al. Ultrastructural elastolysis: report of a case and review of the literature. Dermatology 1993;187:62-6. evaluation of mid-dermal elastolysis. J Cutan Pathol Arch Dermatol 1989;125:950-1. 22. Yen A, Tschen J, Raimer S. Mid-dermal elastolysis in an 1994;21:233-8. 15. Roa BK, Endzweig CH, Kagen MH, et al. Wrinkling due to adolescent subsequent to lesions resembling granuloma 9. Kim JM, Su WPD. Mid-dermal elastolysis with wrinkling; mid-dermal elastolysis: two cases and literature review. annulare. J Am Acad Dermatol 1997;37(5):870-2. report of two cases and review of the literature. J Cutan Med Surg 2000;4:40-4. J Am Acad Dermatol 1992;26:169-73. 16. Rothfleisch J. Mid-dermal elastolysis. Dematol Online J 10. Kirsner RS, Falanga V. Features of an autoimmune 2001;7(1):15

20 MID-DERMAL ELASTOLYSIS

A Rare Case of Bleomycin Induced Flagellate Hyperpigmentation Presenting Histopathologically as an Urticarial Drug Hypersensitivity Reaction

Risa Gorin, D.O.*, Charles Gropper, M.D*, Cindy Hoffman, D.O.**, Damian DiCostanzo, M.D.***

Abstract

A case of flagellate hyperpigmentation after administration of bleomycin in a patient with Hodgkin’s Lymphoma is described. Clinically and histologically, the eruption was consistent with an urticarial drug hypersensitivity reaction. This is the second reported case in which bleomycin-induced flagellate hyperpigmentation was found to have these histological findings. A review the of the literature was performed, and the various clinical and histopathological features for this distinctive eruption is discussed.

Case Report Our differential diagnosis at that time taining antineoplastic antibiotic derived was post-inflammatory hyperpigmenta- from the soil fungus Streptomyces verticil- A 27 year-old Hispanic male was tion, primary cutaneous lymphoma, lus.1-5 It has antitumor, anti-bacterial, and referred to the dermatology clinic by his metastatic disease, urticarial drug reac- antiviral properties. It works by inhibiting hematologist for evaluation of a pruritic tion, and bleomycin-induced hyperpig- incorporation of thymidine into DNA eruption of 3 months duration. The mentation. A clinical diagnosis of resulting in single and double stranded patient’s past medical history was signifi- bleomycin-induced flagellate hyperpig- breaks and subsequent DNA degrada- cant for Stage IIb Hodgkin’s Lymphoma mentation was made. The patient was tion. that was diagnosed 4 months prior to pre- advised to complete his course of oral prednisone and antihistamines and was Bleomycin was initially isolated in 1965 sentation by a biopsy of a mediastinal in Japan by Umezawa.1, 2, 4, 6 Today, it is a mass. Prior to this, the patient was other- given fluocinonide 0.05% ointment for additional symptomatic relief. In addition, commonly used systemic chemothera- wise healthy, took no medications on a peutic agent used in the treatment of daily basis, and reported no drug aller- a 3-mm punch biopsy was performed from one of the hyperpigmented streaks various neoplasms’ including non-Hodgk- gies. One month after diagnosis, he was in’s lymphoma, Squamous Cell started on a chemotherapeutic regimen of on his trunk. Microscopic analysis revealed a superficial perivascular and Carcinoma (head, neck, skin, mucosa, doxorubicin, bleomycin, vinblastine, and cervix, vulva, penis, and larynx), dacarbazine (ABVD) every 2 weeks. He interstitial mixed cell infiltrate with numerous eosinophils and slight epidermal Testicular Carcinoma, and Hodgkin’s stated that the eruption began within 24 disease. It is widely distributed through- hours of his first treatment with ABVD, spongiosis consistent with an urticarial drug hypersensitivity reaction. Also noted out the body and is degraded by a was progressively worse after subse- hydrolase enzyme present in tissues. quent treatments, and never fully was an increased number of melanophages in the dermis. However, the skin and lungs do not resolved. The pruritic eruption was recal- possess this hydrolase enzyme allowing citrant to oral prednisone and antihista- In support of a diagnosis of urticarial accumulation of the drug in these mines. drug hypersensitivity reaction was the locations.1, 3, 5, 6 This is considered to be At the time of presentation to the der- finding of a significant blood eosinophilia. the reason why the majority of side matology clinic, a comprehensive cuta- The blood eosinophils were 1.6% (refer- effects occur in the lungs and skin in the neous examination revealed multiple ence range, 0 to7.0%) after his first treat- form of pulmonary fibrosis and hyperpig- linear hyperpigmented streaks coalescing ment but than ranged from 8.5% to14.3% mentation, respectively.1 during his next 5 treatments. into patches on his trunk and upper Like many other chemotherapeutic extremities, erythematous, edematous On follow-up examination 3 weeks agents, bleomycin has been reported to urticarial papules and plaques on his later, the hyperpigmented streaks and cause a variety of mucocutaneous trunk and proximal interphalangeal joints erythematous nodules and papules per- reactions including alopecia, mucositis, bilaterally, mild edema distally in his sisted but his upper extremity joint edema hypersensitivity reactions, onychodystro- upper extremities and hands, and diffuse had improved. He reported a burning phy, onycholysis, Beau’s lines, radiation non-scarring alopecia. There were no oral sensation from the fluocinonide 0.05% enhancement, radiation recall, lesions. ointment and discontinued its use. His neutrophillic eccrine hidradenitis, eccrine pruritus persisted, and therefore, he was squamous syringometaplasia, and 7-9 Department of Dermatology, Saint Barnabas Hospital, Bronx, maintained on antihistamines for sympto- sclerodermatous changes. Aside from New York, matic relief. One week prior to his follow- the mucocutaneous reactions, bleomycin An affiliate of New York College of Osteopathic Medicine of up visit, the ABVD was discontinued as is cardiac and pulmonary toxic. However, New York Institute of Technology. * Dermatology Resident he experienced clearing of his mediasti- there is virtually no gonadal toxicity or risk ** Director of the Dermatology Residency Program nal mass and adenopathy. for myeloid malignancies associated with *** Professor of Dermatopathology. 9 Corresponding Author: Risa Gorin, D.O., c/o St Barnabas its use. Local reactions caused by Hospital, 183rd Street and 3rd Avenue, Bronx, NY 10457; Comment extravasation of the drug into adjacent 718-960-6517; email: [email protected] No funding was received for this project. Bleomycin is a cytostatic, sulfur-con- soft tissue or veins during infusion include

(The Journal of the American Osteopathic College of Dermatology, Vol. 1, No. 1, pp 23-25, June 2003) 23 chemical cellulites and ulceration.7 A distinctive “flagellate” hyperpigmentation frequently occurs and is unique to bleomycin. Bleomycin induced flagellate hyperpigmentation occurs in 8 to 38% of patients and was first reported in 1971 by Moulin et al.1, 5, 6, 11 Guillet and Guillet reported an occurrence of cutaneous hyperpigmentation in 66% of patients studied in their series.12 Hyperpigmenta- tion has been reported after intramuscular, 13 intravenous,6,14 intraperitoneal,15 and intrapleural1,3 administration of the bleomycin. Onset of the eruption varies from 24 hours to 9 weeks after Figure 3B. Superficial perivascular administration and after cumulative doses and interstitial mixed cell infiltrate with ranging from 60 mg to 285 mg, but has numerous cosinophils and slight epi- been observed to occur after as little as dermal spongiosis (H&E, original mag- 15 mg.2, 5, 6 nification x 100). reaction patterns have been reported in A review of the literature demonstrates biopsy specimens of previously reported a variety of clinical and histopathologic cases. Epidermal changes have included presentations. The eruption typically focal vacuolar degeneration of the basal occurs on the upper trunk, limbs, and layer,1,11 dyskeratosis and necrosis of epi- face and is extremely pruritic. Clinically, dermal keratinocytes and eccrine epithelium,1,4 melanin distribution in the upper Figure 3A. Superficial perivascular horny layers,12 irregular acanthosis and and interstitial mixed cell infiltrate with spongiosis,5 and full thickness epidermal numerous cosinophils and slight acantholysis.13 Dermal changes reported epidermal spongiosis (H&E, original include perivascular pigmentary inconti- magnification x 40). nence and extravasation of erythrocytes,13 lymphocytic vasculitis,3 moderate papil- include dermatomyositis,11 painful inflam- lary dermal edema1,11 and a fixed-drug matory nodules on the extremities, warty type reaction pattern.1 Yamamoto et al. hyperkeratotic plaques on the fingers, reported thickened collagen bundles and erythema multiforme, digital gangrene, a deposition of amorphous homogenous Raynauds phenomenon and blisters.5-8 material in the upper dermis consistent with sclerodermatous changes suggest- The precise mechanism for bleomycin- ing that bleomycin influences dermal Figure 1. Multiple linear hyperpig- induced hyperpigmentation is unknown. fibroblasts as well.14 Lastly, in 1999 mented streaks coalescing into The hyperpigmentation is reversible when Rubeiz, et al reported the first case of an patches with erythematous edematous the drug is discontinued, but may persist urticarial allergic drug reaction histologi- urticarial papules and plaques on the up to six months or more,4, 9, 16 and may cally.2 My patient demonstrates similar right upper extremity. recur on re-challenge.6 No treatment is clinical and histological findings. necessary only symptomatic care.1 Some authors theorize that the hyperpigmented Bleomycin-induced flagellate hyperpig- lesions arise as a result of local trauma mentation is a unique and distinctive from scratching or pressure allowing the occurrence. Although varying clinical and drug to leak out of dilated blood vessels.11 histological findings have been reported, However, many authors have been one of the rarest histolopatholoigcal unsuccessful in reproducing the lesions findings is that of an urticarial hypersensi- by these means.3,8,13 Several other theo- tivity reaction. Our patients’ clinical and ries have been proposed and include histopathological presentation was inflammatory oncotaxis,5 direct or indirect consistent with this rare variant. cytotoxic effects on keratinocytes and Corresponding with the histologic eccrine epithelium,4,12 increased findings, his laboratory data revealed a melanocyte stimulating hormone secre- significant blood eosinophilia consistent tion, and stimulation of melanocytes by with an urticarial drug hypersensitivity adrenocorticotrophic hormone.6 Also reaction. Figure 2. Multiple hyperpigmented implicated in the pathogenesis of hyper- linear streaks coalescing into patches pigmentation is the increased transfer of Further case reports of this rare on the knee. melanin. In support of this, electon histological presentation of bleomycin microscopy has revealed decreased epi- induced flagellate hyperpigmentation are lesions include linear microvesicular dermal turnover and a prolonged contact needed to better elucidate the exact bands,12 urticarial papules and plaques,12 between melanocytes and keratinocytes mechanism for this unique cutaneous erythematoviolaceous macules evolving .14 While the number of melanocytes was finding. into papules,15 and patchy pigmentation in not increased, an increase in the number References: 9 pressure areas and palmar creases. of melanosomes present in keratinocytes 1. Nigro MG, Hsu S. Bleomycin-induced flagellate Less common clinical presentations was seen.1,13A variety of histopathological pigmentation. Cutis. 2001; 68(4):285-286.

24 A RARE CASE OF BLEOMYCIN INDUCED FLAGELLATE HYPERPIGMENTATION 2. Rubeiz NG, Salem A, Dibbs R, Kibbi AG. Bleomycin- 1994;131:700-702. Baseil. Cutaneous pigmented stripes and bleomycin induced urticarial flagellate drug hypersensivity. 7. Koppel, RA, Boh EE. Cutaneous reactions to treatment. Archives of Dermatology. 1986;122(4):381-382 International Journal of Dermatology. 1999;38:140-141. chemotherapeutic agents. The American Journal of the 13. Rademaker M, Thomas RH, Meyrick Lowe DG, Munro DD 3. Duhra P, Ilchyshyn A, Das RN. Bleomycin-induced Medical Sciences. 2001; 321(5):327-335. Linear streaking due to bleomycin. Clinical and flagellate erythema. Clinical and Experimental 8. Hood AF. Cutaneous side effects of cancer chemotherapy Experimental Dermatology. 1987;12(6):457-459. Dermatology. 1991;16(3):216-217. The Medical Clinics of North America. 1986; 70(1):187- 14. Yamamoto T, Yokozeki H, Nishioka K. Dermal sclerosis in 4. Templeton SF, Solomon AR, Swerlick RA. Intradermal 209. the lesional skin of ‘flagellate’ erythema (scratch bleomycin injections into normal human skin. Archives of 9. Susser WS, Whitaker-Worth DL, Grant-Kels JM. dermatitis) induced by bleomycin. Dermatology. Dermatology. 1994; 130:577-583. Mucocutaneous reactions to chemotherapy. Journal of the 1998;197:399-400 5. Cortina P, Garrido JA, Tomas JF, Unamuno P, Armijo M. American Academy of Dermatology. 1999;40:367-398. 15. Zaki I, Haslam P, Scerri L. Flagellate erythema after ‘Flagellate’ erythema from bleomycin. With 10. Abeloff, MD, Clinical Oncology, 2nd ed. Philadelphia, PA: intraperitoneal bleomycin. Clinical and Experimental histopathological findings suggestive of inflammatory Churchill Livingston, Inc.; 2000. Dermatology. 1994;19:366-367. oncotaxis. Dermatologica. 1990; 180(2):106-109. 11. Gomez CP, Sanchez-Aguilar D, Pereiro M Jr, Toribio J. 16. Lazar AP, Lazar P. Streaky pigmentation in a patient with 6. Mowad CM, Nguyen TV, Elenitsas R, Leyden JJ. Flagellate erythema and dermatomyositis. Clinical and acquired immune deficiency syndrome (AIDS). Cutis. Bleomycin-induced flagellate dermatitis: a clinical and Experimental Dermatology. 1998;23(5):239-240. 1988;42(5):397-398. histopathological review. British Journal of Dermatology. 12. Guillet G, Guillet MH, de Meaux H, Gauthier Y, Sureve-

GORIN, GROPPER, HOFFMAN, DICOSTANZO 25 Cutaneous Manifistations of Sarcoidosis

Steven Israel Moreno, D.O.*, Stanley E. Skopit, D.O., F.A.O.C.D.**

Abstract

Sarcoidosis is a multisystem disorder of unknown cause that is characterized by its pathologic hallmark, the noncaseating granuloma. Since its first recognition as a clinical entity, sarcoidosis has been known to induce secondary derangement of normal tissue as well as organ anatomy and function with prominent cutaneous involvement. The cutaneous manifestations of sarcoidosis often enable the dermatologist to be the first physician to make the diagnosis. This paper reviews the pathogenesis, cutaneous polymorphisms, systemic involvement, diagnosis, and treatment for cutaneous sarcoidosis to further enhance the dermatologist’s understanding of this complex condition.

Introduction severity of disease according to race and increased susceptibility to sarcoidosis.13,32 ethnic background. A number of studies Further genetic studies through the use of Sarcoidosis is a multisystem disorder indicate that cases affecting African polymerase chain reaction (PCR) of unknown cause that is characterized Americans have a tendency to be more restriction fragment polymorphism have by its pathologic hallmark, the acute and severe than in other races. pinpointed the HLA-DRB1 locus to deter- noncaseating granuloma. Since its first Cases affecting Caucasians tend to be mine susceptibility to sarcoidosis.14,32 recognition as a clinical entity, sarcoidosis asymptomatic and chronic, with a more has been known to induce secondary favorable prognosis.5,32 Definitive identification and proof of an derangement of normal tissue as well as infectious agent are still lacking. The organ anatomy and function with Pathogenesis association of tuberculosis and sarcoidosis remains controversial. prominent cutaneous involvement. The The cause of sarcoidosis remains 15,32 cutaneous manifestations of sarcoidosis Popper et al found that 11 out of 35 obscure for a number of reasons, cases of sarcoidosis lung tissue had often enable the dermatologist to be the including the heterogeneity of first physician to make the diagnosis. mycobacterial DNA sequences. Kon and manifestations of the disease, overlap duBois16,32 found acid-fast forms of This paper reviews the pathogenesis, with other diseases, and insensitive and bacteria grew from the blood of 19 of 20 nonspecific diagnostic tests that lead to cutaneous polymorphisms, systemic 6 patients with sarcoidosis. However, involvement, diagnosis, and treatment for misclassification of the disease. There Richter et al,17,32 by coding for 16S cutaneous sarcoidosis to further enhance are many postulations as to the origin of ribosomal RNA, present in all the dermatologist’s understanding of this sarcoidosis, including immunologic, mycobacterial species, found none complex condition. genetic, infectious, and environmental. detectable in 23 lung tissue samples from patients with sarcoidosis. Therefore, Epidemiology The development of noncaseating granulomas is thought to be the result of studies for the detection of mycobacteria Sarcoidosis occurs worldwide, local presentation of an antigen by have been shown to be inconclusive. A affecting people of all races, both sexes, macrophages to CD4 T lymphocytes.7,32 multicenter study supported by the and all ages. It has a bimodal peak, first The T-cells then act in a twofold manner: National Institutes of Health, named between the ages of 25 to 35 and then in in antigen recognition and in amplification ACCESS (A Case-Controlled Etiologic women aged 45 to 65 years.1,32 Interest- of the local cellular immune response.7,32 Study of Sarcoidosis), is currently ingly, cases of sarcoidosis present most The production of CD4 T-cell derived underway to search for possible commonly in the winter and early spring cytokines enhance lymphocyte prolifera- infectious agents as the cause of months.2,32 Worldwide incidence of tion to induce granuloma formation.8,32 sarcoidosis.18,32 sarcoidosis ranges from 1 case to 64 Thus, a highly focused antigen-driven, Suggestions of environmental triggers cases per 100,000 population with the overexuberant cellular immune response 9,32 for the origin of sarcoidosis include higher annual incidence reported among occurs within the target organ. In inorganic antigens including clay, talc, African Americans, the Irish, and addition, the recruitment of CD4 T-cells pine, pollen, oxalosis, and beryllium.16,19,32 Scandinavians.3,32 African American from the peripheral blood causes the 10, 32 Occupational associations have been women between the ages of 30 and 39 development of anergy. There is also health care workers,20,32 firemen, 21,32 and years were found to have the highest a resultant hypergammaglobulinemia 22,32 4,32 navy personnel on aircraft carriers. annual incidence of 107/100,000. from a nonspecific induction of polyclonal Interestingly, sarcoidosis is found to be B-cell immunoglobulin.11 Perhaps more important than varia- more common in nonsmokers than tions in incidence are the differences in A genetic origin is supported by the smokers.23,32 presence of familial clusters of Cutaneous Manifestations sarcoidosis.12,32 In the United States this *Resident in Dermatology Nova Southeastern University /College of Osteopathic Medicine/North Broward Hospital occurs more commonly among African The first case of sarcoidosis was District Americans. Associations through reported by Hutchinson more than a ** Program Director-Dermatology Nova Southeastern serologic studies have shown patients century ago. This first description University/College of Osteopathic Medicine/North Broward Hospital District with certain class I and II HLA alleles corresponded to a patient with lupus found on chromosome 6, may have pernio, and for a long time it was believed

26 (The Journal of the American Osteopathic College of Dermatology, Vol. 1, No. 1, pp 26-29, June 2003) that the disease was limited to the skin. appearance is not specific, but skin Lung manifestations occur in nearly all On average, 25% of sarcoidosis cases biopsies are diagnostic.26 cases of sarcoid.27,32 Lung disease is have cutaneous involvement that can mainly granulomatous involvement of occur at any stage, however, most often Subcutaneous Sarcoidosis. Also interstitial areas, affecting alveoli, blood cutaneous involvement occurs at onset of known as Darier-Roussy sarcoid, it vessels, and bronchioles. In 10% to 15% the disease.6 For this reason the consists of a few 1 to 3 deep-seated, of patients there is irreversible fibrosis dermatologist will often be the first to painless, firm, mobile nodules on the and severe disability.11 consider a diagnosis of sarcoidosis. trunk and extremities without epidermal involvement.25 Intrathoracic and peripheral lymphatic Cutaneous lesions are classified as adenopathy is common. Up to 90% of specific, when histologic examination Scar Sarcoidosis. Sarcoid lesions may patients present with hilar and/or paratra- shows the typical sarcoid granulomas, or develop in old scars. Previously flat scars cheal adenopathy.11 nonspecific. Common specific sarcoido- may raise up and develop a red or purple hue resembling keloids. The pathogene- Hematologic changes are seen in up sis skin lesions manifest as macu- 28,32 lopapules, plaques, subcutaneous sis is unknown. to 40% of cases, manifesting as leukope- nodules, infiltrative scars, and lupus nia, lymphocytopenia, and an elevated Plaques. Flat-surfaced and slightly sedimentation rate.31,32 pernio.24 Maculopapular lesions are the elevated plaques appear with greatest most common cutaneous manifestations frequency on the cheeks, limbs, and trunk The liver and spleen are involved of sarcoidosis. The most important symmetrically. Involvement of the scalp between 50% and 80% of the time. nonspecific skin lesion is erythema may lead to alopecia.26 Hepatic granulomas may cause jaundice, nodosum (EN), and its association with and splenomegaly is associated with a hilar lymphadenopathy, also called Ichthyosiform Sarcoidosis. This form poor outcome because of its association Lofgren syndrome, the most resembles ichthyosis vulgaris with fine 26 with extensive fibrotic changes in other characteristic form of sarcoidosis.25 scaling on the distal extremities. organs.32 Specific Cutaneous Manifestations: Alopecia. Alopecia due to sarcoidosis Musculoskeletal involvement has been is seen in two settings. Plaques may reported to occur in up to 39% of patients, Maculopapular Sarcoidosis. This is involve the scalp leading to a scarring the most common form of cutaneous sar- including bone cysts, osteolytic lesions, hair loss. More rarely, circular lesions chronic myopathy and arthritis.32 coidosis. They are usually red-brown to appear on the scalp resembling alopecia purple papules and measure less than 1 areata.26 Ocular manifestations are present in cm.25 They are commonly found on the 30% to 50% of cases. Sarcoidosis face, lips, nape of the neck, upper back Morpheaform Sarcoidosis. Very rarely, classically presents as acute anterior and shoulders.24 In time the lesions invo- lesions present as generalized plaques, uveitis. Other lesions include lacrimal lute to faint macules. but may be localized and be gland enlargement, iritis, conjunctival accompanied by dermal fibrosis resem- nodules, and scleral plaques. There is a Annular Sarcoidosis. Papular lesions bling morphea. Skin biopsies will demon- 26 definite threat of blindness and all may coalesce or be arranged in annular strate noncaseating granulomas. 32 patterns. Central clearing with hypopig- patients need eye examinations. mentation, atrophy, and scarring may Mucosal Sarcoidosis. Lesions in the Involvement of the upper respiratory occur. These lesions favor the head and mouth are characterized by pinhead- tract is found in 5% to 20% of cases and neck and are usually associated with sized papules that may be grouped or 26 can present as lupus pernio. There can chronic sarcoidosis.26 fused together to form a flat plaque. be granulomatous invasion of nasal and Hypopigmented Sarcoidosis. Hypopig- Nonspecific Cutaneous oral mucosa, larynx and pharynx, salivary mentation may be the earliest sign of Manifestations: glands, tonsils, and tongue. Parotid sarcoidosis. Favoring the extremities, gland enlargement is found in 6% of Erythema Nodosum in Sarcoidosis. cases.32 these lesions vary from a few millimeters EN is the most common nonspecific to more than a centimeter in diameter. cutaneous finding and considered the Cardiac manifestations occur in 5% of Often, a palpable dermal component is at cases and may have serious sequelae 26 hallmark of acute sarcoidosis. When the center of the lesion. associated with bilateral hilar adenopathy, such as sudden cardiac death, heart 6 Lupus Pernio. This is the most char- migratory polyarthritis, fever, and iritis, it block, cardiomyopathy, or pericarditis. 29,32 acteristic skin lesion of sarcoidosis, It is is called Lofgren’s syndrome. EN is Neurologic manifestations occur in 5% most common in African American associated with a good prognosis, with to 10% of cases. The most common is a women and is the hallmark of fibrotic the sarcoidosis involuting within 2 years 30,32 self-limited cranial nerve VII palsy, but all disease.27,32 Lesions are typically of onset in 83% of cases. cranial nerves can be affected. Other violaceous, and smooth with shiny Other nonspecific changes seen with problems include aseptic meningitis, plaques on the head and neck, especially sarcoidosis are calcifications, prurigo, and seizures, space-occupying masses, the nose, cheeks, lips, forehead, and erythema multiforme. peripheral neuropathy, stroke, and ears. Lesions may be disfiguring and myasthenia gravis. Neurologic manifes- involve underlying bone. Lupus pernio Systemic Involvement tations are associated with a higher coexists with chronic fibrotic sarcoidosis mortality rate.32,33 of the upper respiratory tract, with nasal, In patients with sarcoidosis one third pharyngeal, and laryngeal involvement, can present with nonspecific constitu- Endocrine manifestations such as pulmonary fibrosis, chronic uveitis, and tional complaints including fever, fatigue, hypercalcemia occur in up to 17% of bone cysts.25,27,32 and weight loss. Sarcoidosis should be cases. Diabetes insipidus can result from included in the differential of a fever of pituitary involvement, while hyperthy- Ulcerative Sarcoidosis. Affecting unknown origin. Other symptoms can be roidism can result from thyroid primarily young African American women, associated with the specific organ system involvement.32 this type is very rare. Lesions favor the affected. lower extremities. The clinical Renal involvement can result in diffuse

MORENO/SKOPIT 27 interstitial nephritis which may lead to specificity.13,32 avoid long-term corticosteroid-induced renal insufficiency.18,32 side effects. The agents most often used Laboratory evaluation of a suspected are antimalarials, methotrexate, azathio- Gastrointestinal involvement is rare, patient with sarcoidosis includes liver and prine, chlorambucil, cyclophosphamide, however, it most commonly presents in renal function tests, complete blood 27,32 32 and cyclosporine. The data on the stomach as an ulcer or mass. count, erythrocyte sedimentation rate, immunosuppressive agents are largely serum calcium and angiotensin-convert- Because of the many different presen- anecdotal from case reports and have not ing-enzyme (ACE) levels. However, been proven to be efficacious by tations of sarcoidosis, several syndromes elevated ACE levels are no longer con- have been discovered. Lofgren’s randomized controlled studies.6 This is sidered specific for the diagnosis of also true for therapies for specific syndrome, frequent among Irish, sarcoidosis.13,32 Scandinavian, and Puerto Rican female cutaneous sarcoidosis. patients consists of acute sarcoidosis, Additional clinical evaluation should The indication for treating cutaneous EN, migratory polyarthritis, fever, and include pulmonary function tests, sarcoidosis is disfigurement.18,32 Chronic iritis. Darier-Roussy sarcoidosis is the electrocardiography, slit-lamp eye cutaneous lesions, particularly lupus presence of subcutaneous nodules of the examination, and tuberculin/anergy 13,32 pernio and plaques, which may cause trunk and extremities. Waldenstrom testing. scarring, may require oral steroid syndrome is the combination of fever, Patients found to have sarcoidosis treatment. Alternative oral therapies that parotid enlargement, anterior uveitis, and have been reported to be successful with facial nerve palsy. Mikulicz’s syndrome is should be monitored for resolution or progression of the disease and for new cutaneous sarcoidosis include hydroxy- bilateral sarcoidosis of the parotid, chloroquine (200-400 mg/day), chloro- submandibular, and lacrimal glands.11 organ involvement, since all patients are at risk for clinical deterioration in their quine (250-500 mg/day), methotrexate Diagnostic Evaluation condition. (15 mg/week in 3 divided doses at 12 hour intervals), allopurinol (100-300 There are no definitive diagnostic Differential Diagnosis mg/day for several months), thalidomide blood, skin, or radiologic imaging tests The clinical and histopathologic (300 mg/day for 4 months), isotretinoin (1 specific for sarcoidosis, hence it is a mg/kg/day), minocycline (200 mg/day for diagnosis of exclusion.13,32 The diagnosis differential diagnosis for specific cutaneous sarcoidosis consists of lupus 12 months), PUVA, and melatonin (50 of sarcoidosis is based on the presence mg/day).32 of compatible clinical, radiological, and vulgaris, leprosy, atypical mycobacterial pathological information. At baseline the infections, syphilis, localized foreign body Non-oral therapies for limited examination should include a complete reactions, tattoo-induced granulomatous cutaneous sarcoidosis have included history with emphasis on occupational reactions, necrobiosis lipoidica, superpotent topical corticosteroids, and environmental exposure. The granuloma annulare, granulomatous topical steroid with hydrocolloid occlusive emphasis during physical examination rosacea, metastatic Crohn’s disease, dressing, intralesional triamcinolone (5-10 deep fungal infection, and lupus miliaris mg/ml repeated monthly), intralesional should be placed on the skin, lungs, eyes, 36 nerves, liver, and heart. disseminatus faciei. chloroquine (50 mg/ml monthly), and Treatment carbon dioxide or pulsed dye laser. When sarcoidosis is suspected, a Surgical approaches have consisted of biopsy of the involved organ system is The heterogeneity of the manifesta- dermabrasion, grafting, and plastic indicated, such as the skin, lung, or tions of sarcoidosis, its uncertain clinical surgery for lupus pernio.32 salivary glands, to obtain histologic course, and the potential side effects of confirmation of noncaseating granulomas, treatment compound the challenge of Prognosis and tissue culture to rule out bacterial, clinical management. There are few firm The prognosis of patients with mycobacterial, and fungal origin. guidelines regarding whether or when to cutaneous sarcoidosis depends mainly on Histologic examination shows well- initiate treatment. As a general rule, oral- the extension and severity of systemic demarcated islands of epithelioid cells corticosteroids are indicated as the first involvement. Up to 60% of patients with with occasional giant cell formation and line treatment for severe ocular, sarcoidosis experience spontaneous neurologic, cardiac, or pulmonary resolution, and an additional 10% to 20% no necrosis. There is a sparse 13,32 lymphocytic infiltrate concentrated sarcoidosis. of patients have resolution with corticos- 32,37 peripherally around the noncaseating Corticosteroids remain the mainstay of teroid use. Some types of specific epithelioid granulomas. Giant cells are therapy despite the lack of well controlled cutaneous lesions, particularly plaques more common in older lesions and often clinical trials to show that these agents and lupus pernio, are more persistent, contain Schaumann bodies (altered improve patients’ long-term outcome. and are associated with more severe lysosomes) or stellate asteroid bodies The correct dose, the value of daily as pulmonary and extrathoracic involvement. (entrapped collagen). Neither are specific opposed to alternate-day therapy, and the Nevertheless, the presence of specific for sarcoidosis, as they have been appropriate duration of therapy are cutaneous lesions taken as a whole does observed in other granulomas, such as unknown. Current protocols suggest the not have prognostic significance. How- tuberculosis, leprosy, and berylliosis.32,34 use of 30 to 40 mg of prednisone daily for ever, the presence of EN is the best inde- 8 to 12 weeks, with gradual tapering of pendent predictive factor of a good Radiographic diagnosis is initiated by prognosis of sarcoidosis.25 chest radiography. Gallium-67 scans the dose to 10 to 20 mg every other day may contribute by demonstrating gallium over a period of 6 to 12 months.(13, 32) Relapses as treatment is withdrawn uptake by granulomas in the parotid and However, severe systemic involvement are frequent, especially in African lacrimal glands, called the panda sign, or requires a dose of 1 mg/kg per day for 4 American patients, who tend to have to 6 weeks followed by a slow taper over more severe and prolonged symptoms.18,32 uptake by the bilateral hilar lymph nodes, 11 called the lambda sign.32,35 However, 2 to 3 months. The disease is chronic in 10% to 20% of gallium scanning adds little true patients, but only 1% to 5% will eventually In chronic disease nonsteroidal 27,32 diagnostic value because of their lack of immunosuppressive agents are used to die of the disease. Up to 10% of

28 CUTANEOUS MANIFESTATIONS OF SARCOIDOSIS patients with cardiac and neurologic Harrison’s Principles of internal medicine. New York: systemic disease. Arch Dermatol 1997;133:882-8. McGraw-Hill; 1998. P. 1922-8. 26. Sarcoidosis. Odom RB, James WD, Berger TG, et al disease will die of their illness. Death 12. Rybicki BA, Harrington D, Major M, Simoff M, editors. Andews’ diseases of the skin: clinical dermatology. from sarcoidosis is mostly due to failure Popovich J Jr, Maliarik M, et al. Heterogeneity of familial Philadelphia: W.B. Saunders; 2000. P.896-903. risk in sarcoidosis. Genet Epidemiol 1996;13:23-33. 27. Anonymous. Statement on sarcoidosis: joint statement of of vital organs, specifically the lungs and 13. Ishihara M, Ohno S. Genetic influences on sarcoidosis. the American Thoracic Society (ATS), the European heart.6 Eye 1997;11:155-61. Respiratory Society (ERS) and the World Association of 14. Ishihara M, Inoko H, Suzuki K, Ono H, Hiraga Y, Ando H, Sarcoidosis and Other Granulomatous Disorders adopted References et al. HLA class II genotyping of sarcoidosis patients in by the ATS board of directors and by the ERS executive Hokkaido by PCR-RFLP. Jpn J Ophthalmol committee, February 1999. Am J Respir Crit Care Med 1. Chesnutt AN. Enigmas in sarcoidosis. West J Med 1996;40:540-3. 1999;160:736-55. 1995;162:519-26. 15. Popper HH, Klemen H, Hoefler G, Winter E. Presence of 28. Caro I. Scar sarcoidosis. QQQQ 1983;32:531-3. mycobacterial DNA in sarcoidosis. Hum Pathol 29. Okamato H, Mizuno K, Imamura S, Nagai S, Izumi T. 2. Fite E, Alsina JM, Mana J, Pujol R, Ruiz J, Morera J. 1997;28:796-800. Erythema nodosum-like eruptions in sarcoidosis. Clin Exp Edemiology of sarcoidosis in Catalonia: 1979-1989. 16. Kon OM, du Bois RM. Mycobacteria and sarcoidosis. Dermatol 1994;19:507-10. Sarcoidosis Vasc Diffuse Lung Dis 1996;13:153-8. Thorax 1997;52(Suppl 3):S47-51. 30. Neville E, Walker AN, James DG. Prognostic factor 3. Reich JM, Johnson R. Incidence of clinically identified 17. Richter E, Greinert U, Kirsten D, Rusch-Gerdes S, predicting the outcome of sarcoidosis: an analysis of 818 sarcoidosis in a northwest United States population. Schluter C, Duchrow M, et al. Assessment of patients. Q J Med 1983;52:525-33. Sarcoidosis Vasc Diffuse Lung Dis 1996;13:173-7. mycobacterial DNA in cell and tissues of mycobacterial 31. Lower EE, Smith JT, Martelo OJ, Baughman RP. The 4. Rybicki BA, Major M, Popovich J Jr., Maliarik MJ, Iannuzzi and sarcoid lesions. Am J Respir Crit Care Med anemia of sarcoidosis. Sarcoidosis 1988;5:51-5 MC. Racial differences in sarcoidosis incidence: a 5-year 1996;153:375-80. 32. English JC, Patel PJ, Greer KE. Sarcoidosis. J Am Acad study in a health maintenance organization. Am J 18. Johns CJ, Michelle TM. The clinical management of Dermatol 2001;44:725-43. Epidemiol 1997;145:234-41. sarcoidosis: a 50-year experience at the Johns Hopkins 33. Chapelon C, Ziza JM, Piette JC, Levy Y, Raguin G, 5. Edmonstone WM, Wilson AG. Sarcoidosis in Caucasians, Hospital. Medicine 1999;78:65-111. Weschsler B, et al. Neurosarcoidosis: signs, course and Blacks and Asians in London. Br J Dis Chest 19. El-Zaatari FA, Naser SA, Markesich DC, Kalter DC, treatment in 35 confirmed cases. Medicine 1985;79:27-36. Engstand L, Graham DY. Identification of Mycobacterium 1990;69:261-76. 6. Newman LS, Rose CS, Maier LA. Sarcoidosis. N Engl J avium complex in sarcoidosis. J Clin Microbiol 34. Shapiro PE. Noninfectious Granulomas. In: Elder D, Med 1997;336:1224-34. 1996;34:2240-5. Elenitas R, Jaworsky C, Johnson B, et al, editors. Lever’s 7. Grunewald J, Olerup O, Persson U, Ohrn MB, Wigzell H, 20. Edmonstone WM. Sarcoidosis in nurses: is there an histopathology of the skin. Philadelphia: Lippincott-Raven; Eklund A. T-cell receptor variable region gene usage by association? Thorax 1988;43:342-3. 1997.P.322-6. CD4+ and CD8+ T cells in bronchoalveolar lavage fluid 21. Kern DG, Neill MA, Wrenn KS, Varone JC. Investigation of 35. Sulavik SB, Spencer RP, Palestro CJ, Swyer AJ, and peripheral blood of sarcoidosis patients. Proc Natl a unique time-pace cluster of sarcoidosis in firefighters. Teirstein AS, Goldsmith SJ. Specificity and sensitivity of Acad Sci USA 1994;91:4965-9. Am Rev Respir Dis 1993;148:974-80. distinctive chest radiographic and/or 67Ga images in the 8. Agostini C, Costabel U, Semenzato G. Sarcoidosis news: 22. Anonymous. Sarcoidosis among US Navy enlisted men noninvasive diagnosis of sarcoidosis. Chest immunologic frontiers for new immunosuppressive 1965-1993. MMWR Morb Mortal Wkly Rep 1993;103:403-9. strategies. Clin Immunol Immunopathol 1998;88:199-204. 1997;46:539-43. 36. Rabinowitz OL, Zaim MT. A clinicopathologic approach to 9. De Rose V, Trentin L, Crivellari MT, Cipriani A, 23. Douglas JG, Middleton WG, Gaddie J, Petrie GR, granulomatous dermatoses. J Am Acad Dermatol Gialgroni GG, Pozzi E, et al. Release of prostaglandin E2 Choo-Kang YF, Prescott RJ, et al. Sarcoidosis: a disorder 1996;35:588-600. and leukotriene B4 by alveolar macrophages from patients common in nonsmokers. Thorax 1986;41:787-91. 37. Peckham DG, Spiteri MA. Sarcoidosis. Postgrad Med J with sarcoidosis. Thorax 1997;52:76-83. 24. Sharma OP. Sarcoidosis of the skin. In: Freedberg IM 1996;72:196-200.da 10. Bansal AS, Bruce J, Hogan PG, Allen RK. An assessment Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz SI, of peripheral immunity in patients with sarcoidosis using et al, editors. Fitzpatrick’s Dermatology in general measurements of serum vitamin D3, cytokines and soluble medicine. New York: McGraw-Hill; 1999. P.2099-106. CD23. Clin Exp Immunol 1997;110:927. 25. Mana J, Marcoval J, Graells J, Salazaar A, Pyri J, Pujol R. 11. Crystal RG. Sarcoidosis. 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MORENO/SKOPIT 29 Therapeutic Perspectives in Dermatology #1 Focus on Reviews from Current Literature related to Pharmacotherapy

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

This feature provides reviews of selected references related to the pharmacologic treatment of dermatologic disorders. Emphasis is placed on discussion of specific disease state indications, drug actions, reactions and interactions. The overall goal of this feature is to provide clinically useful information that will be of valued assistance to the practi- tioner. The review in this issue focuses on treatment of common dermatoses.

The Role of Topical Sulfacetamide twice daily.4 Both treatment groups exhib- in inflammatory lesions counts was 10%/Sulfur 5% in the Treatment of ited statistically significant reduction in noticed in the active treatment group; the Rosacea. papule counts and erythema at all follow- patients treated with benzoyl peroxide 5% up points. A significant reduction in over- wash as monotherapy demonstrated a Clinical studies have evaluated the all rosacea severity was observed at 39% reduction in inflammatory lesions as anti-inflammatory benefit of topical week 8. Although the sulfacetamide compared to < 10 % lesion reduction in sulfacetamide 10%/sulfur 5% for the 12 1-3 10%/sulfur 5% cleanser alone demon- the placebo vehicle group. Microbio- treatment of rosacea. In one multicenter strated efficacy as monotherapy, com- logic assessment of treated patients (n = open-label study (n = 54), twice daily bined use with metronidazole 0.75% gel 16) demonstrated a 46 % reduction in P. application of sulfacetamide 10%/sulfur provided maximum benefit. Treatment acnes organism counts after 2 weeks of 5% lotion used over a period of 8 weeks was well tolerated in both study groups. A treatment with benzoyl peroxide wash demonstrated a 43% mean reduction in separate investigator-blinded patient pref- alone.12 erythema and an 81% mean reduction in erence study compared the tolerability inflammatory lesion counts when com- A 12-week, controlled, investigator- .2 and acceptance of sulfacetamide pared to baseline evaluations An 8 week 10%/sulfur 5% cleanser (n = 25) versus blinded study of male (n = 22) and female double-blinded trial (n = 94) compared an established commercially available, (n = 34) adult patients with moderate sulfacetamide 10%/sulfur 5% lotion ver- non-lipid facial cleanser (n = 25). Compa- facial inflammatory acne evaluated the sus placebo vehicle. The active treatment rable results were demonstrated in all clinical impact and tolerability of group exhibited a 65% decrease in combining a benzoyl peroxide cleanser tested categories which included tolerabil- 10 counts of inflammatory lesions by week 4 ity, irritation and product aesthetics.5 and topical retinoid therapy. The and 78% by week 8, as compared to 44% combination of benzoyl peroxide 6% by week 4 and 36% by week 8 in the The Role of Benzoyl Peroxide Cleansers cleanser used in the morning and placebo vehicle group. A significant in the Treatment of Acne Vulgaris. tretinoin 0.1% microsphere gel in the decrease in facial erythema was also evening (n = 30) was compared to noted in the actively treated study arm; Topical benzoyl peroxide continues to application of tretinoin 0.1% microsphere erythema reduction was reported as 66 % be a “workhorse” of acne therapy due to gel alone in the evening (n = 26). Both at week 4 and 83% at week 8, compared its ability to reduce inflammatory lesions, groups were given a gentle non-lipid to 33% at week 4 and 31% at week 8 in potentiate the effect of antibiotic therapy facial cleanser to be used in morning and 1 and reduce emergence of antibiotic-resis- vehicle-treated patients. An investigator- 6-9 evening, except during the morning in blinded comparative trial of sulfacetamide tant Propionibacterium acnes strains. P. those patients using the benzoyl peroxide 10%/sulfur 5% lotion (n = 31) and acnes organisms resistant to benzoyl 6% cleanser. Evaluation parameters metronidazole 0.75% gel (n = 32) demon- peroxide have not been identified. included inflammatory (papules, pustules) strated similar efficacy rates based on Informal surveys completed by the author and non-inflammatory (comedonal) lesion investigator evaluations and patient suggest that although dermatologists counts, acne severity, severity of acne- assessments of improvement after 8 accept the clinical benefits of benzoyl associated erythema and conventional weeks of therapy.3 Local tolerability of peroxide “leave on” formulations such as indices of irritation (ie. dryness, scaling, both medications was comparable and gels, the clinical efficacy and P.acnes erythema, peeling). significant systemic adverse reactions suppression achieved with some benzoyl were noted. peroxide cleanser formulations have not By endpoint at week 12, patients using been fully appreciated. The ability of the combination protocol of benzoyl In an 8 week trial of patients with topical benzoyl peroxide gel and cleanser peroxide 6% gel and tretinoin 0.1% moderate rosacea, sulfacetamide formulations to suppress P. acnes microsphere gel demonstrated 58.5 % 10%/sulfur 5% cleanser (n = 15) was organisms and reduce inflammatory acne reduction in inflammatory lesions, 44.1% used twice daily, alone or in combination lesions has been evaluated and reduction in non-inflammatory lesions, with metronidazole 0.75% gel (n = 15) confirmed.6,9-15 In a vehicle-controlled, 54.5% reduction in overall acne severity double blind study evaluating the impact based on lesion counts and 47.5% of benzoyl peroxide 5% wash (n = 75) reduction in acne-associated erythema. Clinical Assistant Professor used twice daily over a period of 12 The group treated with tretinoin 0.1% Department of Dermatology University of Nevada School of Medicine weeks, a statistically significant reduction microsphere gel alone exhibited 29.8% Las Vegas, Nevada

30 (The Journal of the American Osteopathic College of Dermatology, Vol. 1, No. 1, pp 30-33, June 2003) intravenous infliximab 5mg/kg at presentation, after 2 weeks and again at 6 weeks. Just prior to the second infusion, persistent erythematous patches with complete absence of pustules were noted. Continued improvement resulted in reduction in the dosages of methotrexate, acitretin and prednisone at the point in time when the third infusion was administered (4 weeks after the second infusion). At follow-up 4 weeks after the third infusion (10 weeks after starting therapy), complete clearance of psoriasis was Figure 1: Comparative % reduction in observed. At follow-up 6 weeks later (10 inflammatory acne lesions: benzoyl weeks after the third infusion), complete Figure 2A: Diffuse plaque psoriasis peroxide 6% cleanser/tretinoin 0.1% remission persisted and all other systemic involving the lateral trunk (pre- microsphere combination versus and topical therapies were discontinued treatment) tretinoin 0.1% microsphere alone. by this time point. Marked improvement of ungual dystrophy was also noted with sig- reduction in inflammatory lesions, 48.9% nificant new growth of disease-free finger- reduction in non-inflammatory lesions, nails observed within the first 10 weeks of 30.7% reduction in overall acne severity initiating therapy. No adverse reaction and 18.2% reduction in acne-associated were observed. erythema (see Figure 1). Other than Corticosteroid Foam Formulations reduction in non-inflammatory lesions, and Treatment of Psoriasis Involving Non- which was comparable in both treatment Scalp Regions. arms, the combination treatment regimen proved to be statistically superior to The efficacy of both the betametha- tretinoin 0.1% microsphere gel alone. The sone valerate 0.12 % and clobetasol pro- number of patients experiencing signifi- pionate 0.05 % foam formulations have cant irritation was minimal and compara- been confirmed in double-blind, placebo- ble in both treatment groups. No dropouts controlled clinical studies of adult patients occurred in either study arm due to treated for moderate to severe scalp pso- Figure 2B: Close-up of Figure 2A adverse events related to drug usage. riasis.18,19 Betamethasone valerate 0.12 % This study demonstrates that benzoyl foam used for the treatment of adult peroxide 6% cleanser provides an addi- patients (n = 37) with psoriasis involving tive benefit when used in combination the trunk and extremities was shown to with topical retinoid therapy by reducing be effective, with statistically significant inflammatory acne lesions and decreas- improvement in composite psoriasis ing acne-related erythema. The use of the severity scores demonstrated in a 12 benzoyl peroxide cleanser did not interef- week, split-body, placebo-comparison ere with the activity or efficacy of the topi- study.20 Statistically significant superiority cal retinoid and was not associated with a in efficacy has also been confirmed with significant increase in irritation. clobetasol propionate 0.05 % foam as compared to placebo foam vehicle for the Infliximab Therapy and Pustular treatment of adult patients with mild to Psoriasis. moderate nonscalp psoriasis (n = 81).21 Several new therapies are under In a double-blind, placebo controlled evaluation for the treatment of psoriasis Figure 2C: Marked clearance of psori- study of adult patients (n = 279) with non- vulgaris. The “big 4 biologic agents” that asis after 2 weeks of treatment with scalp plaque psoriasis affecting up to 20 have currently emerged from this general clobetasol propionate 0.05% foam % body surface area, clobetasol propi- class of compounds includes etanercept, applied twice daily (follow-up one onate 0.05 % foam proved to be highly efalizumab, infliximab and alefacept.16 week after completion of therapy) effective.22 Patients were treated for 2 These agents have been studied predom- weeks, with the final follow-up evaluation inantly for patients affected with diffuse, completed at week 4 (2 weeks after com- comparable to the evaluations completed moderate to severe psoriasis vulgaris pletion of therapy). After 2 weeks of ther- by the study investigators. No significant (chronic plaque psoriasis). A recent report apy, 71 % in the clobetasol propionate local or systemic reactions were noted in discusses the successful use of infliximab 0.05 % foam group and 22 % in the patients involved in either study arm. therapy in a patient with severe pustular placebo foam group demonstrated com- psoriasis.17 A 39 year-old Caucasian male Oral Antifungal Therapy and Tinea plete or almost complete disease clear- with chronic severe psoriasis demonstrat- Versicolor. ance by physician global evaluation. At ing limited control with intramuscular follow-up 2 weeks after completion of Tinea versicolor is a common methotrexate, acitretin and corticosteroid therapy, efficacy was sustained in 57 % of superficial fungal infection caused by therapy (oral prednisone, topical patients undergoing active treatment certain commensal yeast species from triamcinolone acetonide 0.1%) presented compared to 17% in the placebo-treated the genus Malassezia. A double-blind with severe, generalized pustular arm (see Figures 2A, 2B, 2C). Patient study evaluated the comparative efficacy psoriasis. Treatment was initiated with assessment of response proved to be of oral ketoconazole and oral fluconazole

DEL ROSSO 31 for the treatment of tinea versicolor in topical imiquimod 5% cream.32-36 sions. Clinical and histologic clearance of adult patients (n = 100).25 Patients greater Currently approved by the Food and Drug actinic keratoses was achieved in 80% of than 15 years of age were included if Administration for the treatment of exter- patients treated with topical imiquimod. tinea versicolor affected at least 25% of nal genital verrucae cause by human the trunk region, with diagnosis based on papilomavirus, imiquimod has been Based on currently available studies clinical examination, direct microscopy shown to facilitate immunologic disease and clinical experience with the use of (potassium hydroxide preparation) and recognition and natural response.37-41 topical imiquimod for treatment of Wood’s light evaluation. Study patients Studies evaluating imiquimod have epithelial malignancy (actinic keratoses, were randomized to receive either single demonstrated (a) an increase in Th-1 basal cell carcinoma, squamous cell dose fluconazole 300 mg (2 x 150 mg cytokine response with local induction of carcinoma in situ), it is important to allow capsules) repeated once in 7 days or the synthesis and release of multiple for reduction in application frequency or short rest periods off of therapy in order single dose ketoconazole 400 mg (2 x cytokines including interferon-alpha, 33,44 200 mg tablets) repeated once in 7 days. tumor necrosis factor-alpha, multiple to reduce associated inflammation. It Follow-up evaluations were completed interleukins (IL-1, IL-6, IL-8, IL-10, IL-12), has been suggested that imiquimod over a duration of 12 weeks from the macrophage inflammatory proteins and differs from topical 5-fluorouracil in that initiation of therapy, with efficacy macrophage chemotactic protein (b) induction of severe inflammation is not evaluated by clinical and mycologic enhancement of Langerhans cell required with imiquimod therapy in order to achieve clearance of actinic keratosis assessment. Cure rates were statistically migration to regional lymph nodes 44,45 comparable at all follow-up points (week promoting the activation and recruitment lesions. This is likely due to differences 2, 4, 8 and 12) and were optimal at week of targeted T lymphocytes and (c) indirect in mechanism of action. 8, with cure observed in 90% of the effects including stimulation of the release A pilot evaluation of topical imiquimod patients treated with fluconazole and 88% of interferon-gamma and downregulation “cycle therapy” has been completed in of those treated with ketoconazole. At of Th-2 cytokine response with inhibited patients (n = 25) presenting with 5 Ð 20 week 12, mycologic cure rates declined production of interleukins Ð4 (IL-4) and Ð5 AKs in designated anatomic regions. 33,36 slightly; potassium hydroxide preparation (IL-5).37-41 Studies have demonstrated the A “cycle” consisted of the application of negativity was 82% in fluconazole-treated presence of cytokine release and imiquimod 5% cream 3 times per week patients and 78% in patients treated with activated T-lymphocytes infiltrating tumor for 4 weeks followed by 4 weeks off of ketoconazole. An attempt to correlate the in both naturally regressing and therapy. If persistent actinic keratoses resolution of “reversed” skin color (hypo- interferon-treated basal cell carcinoma were noted at follow-up, a maximum of 3 or hyperpigmentation) with mycologic and squamous cell carcinoma in situ, treatment cycles were utilized in this initial cure at post-treatment follow up revealed findings that are likely to relate at least study. Evaluation at 4 weeks post-therapy no correlation at week 2, with correlation partially to the mode of action of after a single cycle demonstrated present during follow-up visits completed imiquimod when used to treat epithelial clearance in approximately 50% of during weeks 4 through 12. The treatment malignancies, including actinic patients. A second treatment cycle regimens were safe and well tolerated in keratoses.40-43 demonstrated clearance in an additional 95% of study patients with few mild A preliminary report of 6 male patients one-third of patients. Case reports of adverse effects observed. Fatigue was patients treated long-term with topical reported in 2 patients treated with presenting with up to 10 actinic keratoses affecting the scalp demonstrated imiquimod for actinic keratoses affecting ketoconazole and 1 patient treated with the forehead and dorsum of the hands fluconazole, headache and “rash” were complete clearance with imiquimod 5% cream applied 3 times per week for a noted continued improvement and noted in 2 patients treated with 32 maintenance of lesion clearance with ketoconazole and diarrhea was reported duration of 6 Ð 8 weeks. The frequency of application was reduced to twice a twice weekly application over a period of in 1 patient treated with fluconazole. The 9 months.44 relationship of these reported adverse week upon the development of significant events to the specific study drug are not local inflammation at treatment sites. The References: cases were described as recurrent after entirely clear. No severe adverse 1 Sauder D, Miller R, Gratton, et al. The treatment f reactions or significant changes in prior treatment with other modalities (ie. rosacea: the safety and efficacy of sodium sulfacetamide laboratory profiles completed at week 2 cryotherapy, topical 5-fluorouracil). 10% and sulfur 5% lotion is demonstrated in a double- Follow-up examinations ranging over time blind study. J Dermatol Treat 1997;8:79-85 (complete blood cell count, liver profile, 2. Davis GF, Glazer SD, Medansky RS. Successful treatment renal parameters) were reported during periods of 2 Ð 12 months confirmed of rosacea with a novel formulation of sodium clinical and histologic remission of the sulfacetamide 10% and sulfur 5% topical lotion. the study. J Geriatr Dermatol 1994;2:140-144 treated lesions. Mild, reversible erythema 3. Lebwohl MG, Medansky RS, Russo CL, et al. The Topical Imiquimod and Actinic and pruritus were noted and were comparative efficacy of sodium sulfacetamide 10%/sulfur 5% lotion and metronidazole 0.75% gel in the treatment of Keratosis Therapy. interpreted as an anticipated reaction dur- rosacea. J Dermatol Treat 1995;3:183-185 ing the course of therapy. 4. Swinyer L. Evaluation of a novel sodium sulfacetamide Several effective options are available 10% and sulfur 5% prescription cleanser for the treatment for the treatment of actinic keratoses, A vehicle-controlled, blinded trial of rosacea (poster P-147). American Academy of Dermatology 59th Annual Meeting March 2-7, 2001, including liquid nitrogen cryotherapy, topi- examined the treatment of actinic Washington, DC cal 5-fluorouracil, topical diclofenac 5% keratoses using imiquimod 5% cream 5. Stewart D. Assessment of tolerability of a prescription 33-35 sodium sulfacetamide 10%/sulfur 5% facial cleanser in gel, topical retinoid therapy, photody- applied 3 times per week (n = 36). The adult subjects with rosacea (poster P-148). American namic therapy and various surgical and endpoint of the study was defined as the Academy of Dermatology 59th Annual Meeting March 2-7, 26-30 2001, Washington, DC ablative options. Treatment selection is time point where clearance of lesions was 6. White G. Acne therapy. Adv Dermatol 1999;14:29-58 dependent on many variables, including observed, with a maximum duration of 12 7. Leyden JJ, Kaidbey K, Gans EH. The antimicrobial effect physician experience and perceptions of weeks. In approximately half of the in vivo of minocycline, doxycycline and tetracycline in humans. J Dermatol Treat 1996;7:223-225 efficacy, number and location of lesions, - actively treated patients, the application 8. Leyden JJ. Current issues in antimicrobial therapy for anticipated reactions and patient frequency was reduced to once or twice a treatment of acne. JEADV 2001;15(S):51-55 26,31 9. Leyden JJ. The evolving role of Propionibacteriumcnes preferences. An additional therapy week upon the appearance of application in acne. Sem Cutan Med Surg 2001;20:139-143 under evaluation proven to be effective in site-related inflammatory reactions, which 10. Shalita AR, Rafal ES. Tolerability and efficacy review of benzoyl peroxide 6% cleanser used in combination with the management of actinic keratosis is included erythema and superficial ero- tretinoin 0.1% gel versus tretinoin 0.1% gel used alone for

32 THERAPEUTIC PERSPECTIVES IN DERMATOLOGY the treatment of moderate inflammatory acne vulgaris. nonscalp regions. J Cutan Med Surg (submitted for of multiple actinic keratoses with imiquimod 5% cream; a Medicis, Data on file, 2002 (submitted for publication) publication) placebo controlled study. Poster presentation. American 11. Swinyer LJ, Baker MD, Swinyer TA, et al. A comparative 23. Borelli D, Jacobs PH, Nall L. Tinea versicolor: epidemio- Academy of Dermatology 60th Annual Convention. New study of benzoyl peroxide and clindamycin phosphate for logic, clinical and therapeutic aspects. J Am Acad Orleans, USA, February 2002 treating acne vulgaris. Brit J Dermatol1988;119:615-622 Dermatol 1991;25:300-305 36. Salasche S, Levine N, Morrison L. Cycle therapy of actinic 12. Mills OH, Rafal E, Hino P, et al. Evaluating the efficacy of 24. Sunenshine PJ, Schwartz RA, Janniger CK. Tinea keratoses of the face and scalp with 5% topical imiquimod: benzoyl peroxide wash. Galderma Laboratories, Inc., Data versicolor. Int J Dermatol 1998;37:648-655 an open label trial. Jour Am Arch of Dermatol (in press). on file, 2002 25. Farshchian M, Yaghoobi R, Samadi K. Fluconazole versus 37. Tyring SK. Immune-response modifiers: a new paradigm in 13. Warner GT, Plosker GL. Clindamycin/benzoyl peroxide ketoconazole in the treatment of tinea versicolor. the treatment of human papillomavirus. Curr Therapeut gel: a review of its use in the management of acne. Am J J Dermatol Treat 2002;13:73-76 Res 2000;61:584-596 Clin Dermatol 2002;3:349-360 26. Dinehart SM. The treatment of actinic keratoses. 38. Miller R. Imiquimod stimulates innate and cell mediated 14. Gans EH, Christensen M, McCullough JL. A study of J Am Acad Dermatol 2000;42:S25-S28 immunity which controls virus infections and tumors. benzoyl peroxide gel containing zinc lactate and glycolic 27. Drake LA, Ceilly RI, Cornelison RL, et al. Guidelines of Int J Dermatol 2002;41(S1):3-6 acid for treatment of acne. Cosmetic Dermatol care for actinic keratoses. Committee on guidelines of 39. Pearson GW, Langley RGB. Topical imiquimod. 2002;15:33-36 care. J Am Acad Dermatol 1995;32:95-98 J Dermatol Treat 2001;12:37-40 15. Kligman A. Comparison of topical benzoyl peroxide gel 28. Wolf JE, Taylor JR, Tschen E, et al. Topical 3.0% 40. Tyring S, Conant M, Marini M, et al. Imiquimod: an oral minocycline, oral doxycycline and a combination for diclofenac gel in 2.5% hyaluronan gel in the treatment of international update on therapeutic uses in dermatology. suppression of P. acnes in acne patients. J Dermatol Treat actinic keratoses. Int J Dermatol 2001;40:709-713 Int J Dermatol 2002;41:810-816 1998;9:187-191 29. Weiss J, Menter A, Hevia O, et al. Effective treatment of 41. Dahl M. Imiquimod: a cytokine inducer. J Am Acad 16. Weinberg JM. Tipping the scales: biologic therapy 2002. actinic keratosis with 0.5% fluorouracil cream for 1, 2, or 4 Dermatol 2002;47:S205-208 Cutis 2002;70:262-268 weeks. Cutis 2002;70(2S):22-29 42. Salasche S. Imiquimod 5% cream: a new treatment 17. Elewski BE. Infliximab for the treatment of severe pustular 30. Jeffes EW, McCullough JL, Weinstein GD, et al. Photody option for basal cell carcinoma. Int J Dermatol psoriasis. J Am Acad Dermatol 2002;47:796-797 namic therapy of actinic keratoses with topical aminole 2002;41(S1):16-20 18. Franz TJ, Parsell DA, Halualani RM, et al. Betamethasone vulinic acid hydrochloride and fluorescent blue light. J Am 43. Mackenzie-Wood A, Kossard S, DeLauney J. Safety and valerate foam 0.12%: a novel vehicle with enhanced Acad Dermatol 2001;45:96-104 efficacy trial evaluating imiquimod 5% cream in Bowen’s delivery and efficacy. Int J Dermatol 1999;38:628-632 31. Del Rosso JQ. Actinic keratoses: evaluating management disease with once-daily application. J Am Acad Dermatol 19. Franz TJ, Parsell DA, Myers JA, et al. Clobetasol strategies. Skin & Aging 2002;10:48-54 2001;44:462-470 propionate foam 0.05%: a novel vehicle with enhanced 32. Stockfleth E, Meyer T, Benninghoff B, et al. Successful 44. Persaud A, Lebwohl M. Imiquimod cream in the treatment delivery.Int J Dermatol 2000;39:521-5 treatment of actinic keratosis with imiquimod cream 5%: a of actinic keratoses. J Am Acad Dermatol 2002;47:S236- 20. Stein LF, Sherr A, Solodkina G, et al. J Cut Med Surg report of six cases. Br J Dermatol 2001;144:1050-1053 239 2001;5:303-307 33. Flowers F. Imiquimod in the treatment of actinic keratoses 45. Epstein E. Does intermittent “pulse” topical 5-fluorouracil 21. Lebwohl M, Sherer D, Washenik K, et al. A randomized, and other intraepithelial neoplasms. Int J Dermatol therapy allow destruction of actinic keratoses without double blind, placebo-controlled study of clobetasol 2002;41(S1):12-15 significant inflammation? J Am Acad Dermatol propionate 0.05% foam in the treatment of nonscalp 34. Edwards L. Therapeutic response of actinic keratoses to 1998;38:77-80 psoriasis. Int J Dermatol 2002;41:269-274 the immune response modifier, imiquimod 5% cream. 22. Gottlieb AB, Ford RO, Spellman MC. The safety and Poster presentation. American Academy of Dermatology efficacy of clobetasol propionate 0.05% foam in the 58th Annual Convention. San Francisco, US, March 2000 treatment of mild to moderate plaque-type psoriasis on 35. Stockfleth E, Ulrich C, Meyer T, et al. Successful treatment

33 DEL ROSSO Necrobiotic Xanthogranuloma: A Case Report and Literature Review

by Robin I. Shecter, D.O., Brad P. Glick, D.O., M.P.H., David Tenzel, M.D., Neal Penneys, M.D., PhD., and Steven M. Abrams, M.D.

Background: Necrobiotic xanthogranuloma (NXG) is a rare disease which predominantly affects the periorbital region and is frequently associated with a paraproteinemia and lymphoproliferative diseases. To date, only approximately seventy-six cases have been described in the literature. An 84-year old female presented to the ophthalmologist with a three month history of two orange/yellow plaques on the right periorbital area with similar lesions on the chest and back. An incisional biopsy was performed on the right upper eyelid lesion and was consistent with the diagnosis of neorobiotic xanthogranuloma. Subsequently, a similar lesion appeared on the left periorbital area a few months later. This article will discuss this patient’s case in detail. Additionally, a review of the literature will be discussed including the laboratory abnormalities and systemic disorders associated with NXG. Histopathologic findings will be depicted along with the current treatment modalities. The course and prognosis of the disease will also be reviewed.

glucose 105 mg/dL, cholesterol 153 mg/dL, triglycerides 495 mg/dL, total Case Presentation: keratitis, scleritis, episcleritis, or anterior protein 5.7 g/dL, with 3.4 g/dL of albumin. uveitis. Motility was intact and there was The serum electrophoresis demonstrated An 84-year old white female presented no diplopia. An incisional biopsy was to the ophthalmologist in August, 2002 a paraprotein spike in the alpha globulin taken from one of the lesions on the right region; immunoelectrophoresis showed with a three month history of two firm, upper eyelid. Histologic examination nontender, non-pruritic orange/yellow this to be a monoclonal IgG K-type with revealed a granulomatous process probable polyclonal IgG, as well. The plaques on the right upper and lower eye- consisting of many foamy histiocytes, lids. The patient also had similar non- patient refused to have a bone marrow multinucleated giant cells (touton and biopsy or a metastatic bone marrow pruritic nodules and plaques involving the foreign body type) and associated with chest and back. The lesions on the right survey to check for multiple myeloma and necrobiotic collagen and cholesterol other lymphoproliferative disorders. periorbital area gradually increased in clefts. Acid fast and PAS stains, did not number and size, which caused the demonstrate organisms. Control stains Discussion: patient to seek medical attention. The were performed. The lesions on the right patient would only reveal the periorbital upper and lower eyelids were then Neorobotic xanthogranuloma (NXG) lesions at the ophthalmology office. The was first recognized as a separate entity surgically excised with tumor margins 3 patient’s past medical history was consis- free. by Kossard and Winkelmann in 1980. tent with hypertension, hyperlipidemia, NXG is a rare disease. As mentioned and breast cancer, which was diagnosed The physical examination performed at previously only approximately seventy-six several years ago. The past surgical his- the patient’s primary care physician was cases have been reported in the litera- tory and family history are noncontribu- within normal limits except for the ture.1 The age of onset of NXG ranges tory to this case. cutaneous abnormalities described from seventeen to eighty-five years and previously. In particular, there were no the disease does not have a sex predilec- The patient had a complete visual associated cardiac abnormalities nor tion.4 examination on the first visit which hepatosplenomegaly noted on the revealed a visual acuity of 20/30 OD and examination. NXG is a histiocytic disorder often 20/25 OS. Orange/yellow “xanthelasma- associated with immunoglobulin G (IgG) like deposits” were present on the right Approximately three months later on paraproteinemia and various other upper eyelid and also on the right lower October 31, 2002, the patient developed systemic laboratory findings.4 It is an eyelid. There were no orbital masses. another lesion, a yellow /orange papule, inflammatory histiocytoxanthomatosis There was no conjunctival involvement, on the left upper lid (Figure 1a), which involving the dermis and subcutaneous Robin I. Shecter, D.O., Correspondent: Dermatology Res- was surgically removed with tumor tissue primarily of the face and often the ident, Wellington Regional Medical Center/Lake Erie College margins free. There was no evidence of eyelids and less frequently of the trunk of Osteopathic Medicine, West Palm Beach, Florida, Fax (954) 3 321-9726, Tel (954) 321-9780, Email: [email protected] recurrent lesions on the right periorbital and extremities. The distinctive Brad P. Glick D.O., M.P.H., Dermatology Residency Director area at this visit. The visual examination cutaneous lesions show some similarities Wellington Regional Medical Center/Lake Erie College of Osteopathic Medicine, West Palm Beach, Florida remained without significant abnormali- of both xanthomatous and necorobiotic David Tenzel, M.D., Oculoplastics and Reconstructive Surgery ties. processes.4 The orange/yellow color of Aventura, Florida NXG lesions is similar to the color of Neal Penneys, M.D., PhD., Dermatopathology, AmeriPath, Laboratory findings included the fol- Fort Lauderdale, Florida classic xanthoma, while the atrophy and Steven M. Abrams, M.D., Hematology/Oncology, Lauderhill, lowing values: hemoglobin 16.3 g/dL, telangiectasia seen in NXG give the Florida hematocrit 46.0%, WBCs 4,200 ul, fasting lesions an appearance that is somewhat

34 (The Journal of the American Osteopathic College of Dermatology, Vol. 1, No. 1, pp 34-36, June 2003) similar to that of necrobiosis lipoidica.5 The differential diagnosis of NXG also includes: granuloma annulare, multicentric reticulohistiocytosis, lipid proteinosis, primary localized amyloidosis, juvenile xanthogranuloma and Erdheim-Chester disease which can present with “xanthoma-like” lesions of the eyelids.3,11 Before NXG was recognized as a distinct disease entity, histologic examination often labeled NXG lesions as “atypical necrobiosis lipoidica”.6 Clinically, the lesions appear either as firm superficial, waxy yellow/orange papules or plaques with prominent telangiectasia, as deep violaceous plaques, or as flesh-colored nodules. The lesions may ulcerate and undergo some degree of scarring and even Figure 1a An orange yellow papule of necrobiotic xanthogranuloma on the hemorrhagic necrosis.2 The periorbital left upper eyelid of this 84-year old female patient. region is the most frequently involved area, followed by the trunk, the other 7 in patients with NXG include chronic areas of the face and extremities. A lymphocytic leukemia and amyloidosis of case of NXG with involvement of the the liver.4 Involvement of the internal lacrimal gland and episclera only, without organs with NXG lesions has been skin lesions has been documented.4 The 3 reported occasionally but is probably oral mucosa is occasionally involved. In under-reported. There has been no addition hepatoslenomegaly is observed reported association of breast cancer and in approximately twenty percent of 3 NXG in the literaure. It has also been patients. recommended that a search for cardiac When the lesions are periorbital, they involvement be undertaken in NXG are often bilaterally symmetric and can patients.10 Echocardiography and produce a wide range of symptoms, such dynamic cardiac imaging are recom- 4 mended.10 Finally, other associated dis- as pain and blurred vision. Ulceration is Figure 1b Hematoxylin and Eosin not an uncommon feature of NXG eases include arthropathy, hypertension, neuropathy, primary biliary cirrhosis, and stain (H & E stain) at 100x magnifica- lesions. The incidence of ulceration has tion. Histologic findings shows a been reported as high as forty-three Graves’ disease.3 4 diffuse granulomatous infiltrate with percent. Histopathologic findings in NXG show cholesterol clefts and touton giant There have been many laboratory a granulomatous infiltrate involving the cells. abnormalities reported in patients with whole dermis and the subcutis. The NXG. The most characteristic finding is a mixed infiltrate is composed of lympho- paraproteinemia, usually of the IgG cytes, epithelioid cells, foamy cells and type.8,9 This was present in our patient. numerous bizarre giant cells of either the IgA paraproteinemia has been reported touton or foreign body type. Cholesterol as well but much less frequently. A clefts occur in the necrobiotic areas in serum protein electrophoresis is therefore one-third of biopsies and one-half of biop- mandatory in the search for a paraprotein sies show lymphoid nodules, usually spike in patients with NXG.2 Other fre- found around the areas that have numer- quently reported laboratory abnormalities ous plasma cells (Figures 1b,1c,1d). include elevated ESR, decreased CH50, Leukocytoclasis has been reported decreased C3 and C4 levels, anemia and rarely.2 It has been found that NXG leukopenia. Cryoglobulinemia has been cases that are poor in lipid and giant cells found in forty percent of cases.3 Elevated are analogous histologically to the early Figure 1c ( H&E stain) at 200x magnifi- serum lipid and glucose levels have been presentation of juvenile xanthogranuloma cation. Histologic findings of necrobi- noted occasionally.9 Although it may not in which touton giant cells and xanthoma- otic xanthogranuloma shows a help differentiate these patients from tisation are absent.1 lymphoid follicle with touton giant cells. those displaying necrobiosis lipoidica, a Immunohistochemical studies of NXG clinical and laboratory examination to rule shows that infiltrates are CD15 and CD4 out diabetes mellitus is indicated.2 positive and CD1a and S-100 negative.3 There are many treatments used to Patients with NXG should be investi- Ultrastructurally, cells are rich in lipid treat NXG, each with varying degrees of gated for malignancies of the hematologic droplets. success. A combination of chlorambucil or melphalan with oral corticosteroids is or lymphoproliferative type, in particular Cholesterol clefts and myeloid bodies multiple myeloma. Plasmocytosis of the one of the most commonly used therapies are similar to those observed in juvenile for NXG.2 Interferon alfa-2b is another bone marrow is frequent is patients with 1 xanthogranuloma. 12 NXG but the occurrence of multiple treatment that has shown good results. myeloma is still a relatively rare finding.4 Therapy: Other treatments utilized with varying Other disorders reported less commonly degrees of success include: cyclophos-

SHECTER, GLICK,TENZEL, PENNEYS, ABRAMS 35 lesions of NXG.4 Finally, surgical excision potentially life-threatening systemic condi- of NXG lesions usually results in relatively tions, its recognition by the physician is rapid recurrence. However, there has extremely important. been a report of a surgical excision of a References: single NXG lesion that has not recurred 1. Spraul, C.W., et al. Bilateral necrobiotic xanthogranuloma by one year follow-up.4 of the eyelids with associated paraproteinemia: Case report and review of the literature. Klin Monatsb Augenheilkd 2002; 219 (1-2): 55-58. Course and Prognosis: 2. Codere, F. et al. Necrobiotic xanthogranuloma of the eyelid. Archives of Ophthalmology 1983; 101: 60-63. The pathogenesis of NXG as well as 3. Freedberg, Irwin et al., Editors. Fitzpatrick’s Dermatology its link to paraproteinemia is unclear. The in General Medicine (Fifth Edition). The McGraw-Hill Companies, Inc. 1999; 1899-1902. course of NXG is usually progressive and 4. Russo, G. Necrobiotic xanthogranuloma with locally destructive. Prognosis of NXG Scleroderma. Cutis 2002; 70 (6) 311-316.. 5. Finan, M.C., et.al. Necrobiotic xanthogranuloma with depends on the severity of the disease, paraproteinemia. A review of 22 cases. Medicine 1986; Figure 1d ( H&E stain) at 400x magnifi- the extracutaneous involvement, and 65: 376-388. cation. Histologic findings of necrobi- 2 6. Kossard, S. Necrobiotic xanthogranuloma with visceral tumors. paraproteinemia. Journal of the American Academy of otic xanthogranuloma shows a In conclusion, we have presented an Dermatology. 1980; 3: 257-270. cholesterol cleft and multinucleated 7. Mehregan, D. A., et al. Necrobiotic xanthogranuloma. 84 year old female who was diagnosed Archives of Dermatology 1992; 128: 94-100. giant cells. with necrobiotic xanthogranuloma of the 8. Fortson, J.S., et al. Necrobiotic xanthogranuloma with IgA paraproteinemia and extra cutaneous involvement. phamide, methotrexate, nitrogen mustard, eyelid. Necrobiotic xanthogranuloma is a American Journal of Dermatopathology 1990; 12: rare disorder that is associated with 579-584. adrenocoricotropic hormone, systemic 9. Scuphan, R.K., et al. Necrobiotic xanthogranuloma with corticosteroids, intralesional corticos- paraproteinemia and often with plasma paraproteinemia. Archives of Dermatology 1989; 113: teroids, azathioprine, plasmaphoresis, cell and lymphoproliferative disorders 1389-1391. 10. Umbert J., et al. Necrobiotic xanthogranuloma with 4,12 including multiple myeloma. We have and radiation therapy. Extracorpeal cardiac involvement. British Journal of Dermatology 1995; photophoresis has been tried without any presented a review of the literature on 133: 438-443. 4 necrobiotic xanthogranuloma. As previ- 11. Weedon, D. Skin Pathology Second Edition, Churchill appreciable results. Ulcerations Livingstone Publishing, 2002; 1073-1074. associated with NXG have been treated ously discussed, because necrobiotic 12. Finelli, L.G. et al. Plasmapheresis, a treatment modality xanthogranuloma may result in for necrobiotic xanthogranuloma. Journal of the American with thalidomide and etretinate with Academy of Dermatology. 1987; 17: 351-354. limited improvement.7 These medications dysfunction of the eyelids or extraocular however, do not help the xanthomatous muscles, and is associated with

36 NECROBIOTIC XANTHOGRANULOMA Furuncular Cutaneous Myiasis

Jere J. Mammino, DO

Myiasis is the infestation of tion with a central 0.2 cm pore (Fig. 1). mammalian tissues by dipterous (two- Pressure on the lesion caused some winged fly) larvae. The skin is the most slight serosanguineous fluid to be common site, but other areas can be expressed. Myiasis was suspected, so involved, including ocular, auricular, the pore was covered with a thick layer of gastrointestinal, and genitourinary. bacitracin ointment and she was asked to Cutaneous myiasis may present in one of return in an hour. On reexamination a three ways: a superficial infection of white parasite could be seen inside the larvae (maggots), a dermal slowly pore. The central area of the lesion was migrating erythematous patch, or as a injected with 2% Lidocaine and a 0.5 cm furuncle. This article describes the furuncular form of cutaneous myiasis, and reports a recent case.

Case Reports Fig. 3. Close up photo of the D. A 24-year-old white woman presented hominis third instar larva. with a slowly enlarging tender nodule on her scalp. Her history is significant for traveling to the Central American country of Belize on vacation five weeks prior. She did much hiking and exploring of the countryside. On the plane back, she felt a small irritated bump on her scalp which she assumed was a mosquito bite. Over the course of a month this slowly enlarged which prompted a visit to her family physician. He astutely realized this presentation was unusual for an abscess so referred her for dermatologic consulta- Fig. 2. The extracted larva, released tion. after incision and firm pressure Fig. 4. The human botfly, D. hominis. Physical examination revealed a mildly tender 2 cm area of erythematous indura- incision was made over the pore. Firm areas. It is a common parasitic infesta- pressure was applied around the lesion tion in endemic areas from central Mexico and the larva was expressed (Fig. 2). through Central and South America.2 Prophylactic antibiotics were prescribed, Cases have been reported in Canada and and she had a full recovery in a few days. the United States from travelers who The larva measured 1.3cm in length return from these areas. The botfly has and was elongate in appearance. The both wild and domestic animals and birds body had narrow belts of sparsely set, as its normal hosts, although humans posteriorly pointing spines. The anterior occasionally can become infected. In end possessed prominent mouth-hooks Africa, a similar type of furuncular and the posterior end was narrowed (Fig. cutaneous myiasis is caused by the 3). Consulting a parasitology text1 con- tumbu fly.3 firmed this to be a mature third instar The human botfly has a fascinating larva of Dermatobia hominis, a common and complicated life cycle (Fig. 5). The type of botfly in the western hemisphere. female fly can produce eggs but have no Fig. 1. The lesion with the small cen- Discussion direct means of introducing them into a tral punctum. host. Instead the female captures This presentation of furuncular another species of biting arthropod, cutaneous myiasis in this patient is typical usually mosquitoes, and by holding its of the human botfly, Dermatobia hominis wings with her legs she glues 15 to 30 (Fig. 4). The flies are found in the forest eggs on its abdomen (Fig. 6).2 She will Advanced Dermatology, 1410 W. Broadway, Suite 205, Oviedo, FL 32765407-359-2100 (w), 407-359-5445 (f), doc- and jungle areas especially around rivers then repeat many times over the next 8 to [email protected] and streams, and along the coastal 9 days producing 100 to 400 eggs. If an

(The Journal of the American Osteopathic College of Dermatology, Vol. 1, No. 1, pp 37-38, June 2003) 37 ment of the larva or small bubbles as the larva breaths. The patient’s symptoms may range from mild pruritus to intermittent or constant sharp pain. Different treatment methods have been described to remove the larva. The native method involves introducing tobacco juice and squeezing tightly.6 If the punctum is wide, an effective method is to occlude this opening causing the larva to migrate out of the skin as it attempts to breathe. Substances described as being effective include petroleum jelly, pork fat, nail polish, adhesive tape, chewing gum, bee’s wax, butter and mineral oil.2 Incising the lesion, as in our patient, is fast effective method. A small incision is made over the punctum and firm pressure with fingers or the ends of two tongue depres- sors can usually express the larva. This technique is similar to the removal of a pilar cyst on the scalp. Surgical excision with debridement of the cavity is required only if the above methods fail. Once the larva is removed, the site heals quickly Fig. 5. Life cycle of D. hominis. leaving a small pigmented scar that fades over time. follicle, or through intact skin4. The larvae are now safe to feed and grow, establish- In our age of more common interna- ing a boil-like pouch below the dermis. A tional travel, the health professional must small opening is kept open to allow it to maintain a higher degree of suspicion to intermittently breathe through its respira- make an accurate diagnosis of cutaneous tory tube. The larva undergoes three myiasis. Key points to assist in this diag- moltings in the next 5 to 12 weeks reach- nosis include one or more non-healing ing a size of 2 cm or more in length.5 It lesions on exposed skin, drainage from a then enlarges the pore and falls to the central punctum, a white structure visible ground, spending 2 to 4 weeks in the soil in the punctum, symptoms of tenderness, to pupate. Finally an adult fly emerges pruritis, or movement, and a history of completing the life cycle. recent travel to an endemic area. Fig. 6. The insect vector carrying the Clinically lesions of myiasis are found References botfly’s eggs. on exposed skin, most commonly the 1. Brown HW. Basic Clinical Parasitology, 4th ed. New York: extremities, back, or scalp. Within 24 Appleton-Century-Crofts; 1975. 2. Purych D. Dermatobia hominis. Microbiology Public Health. insect vector cannot be found, the eggs hours of a larva entering, a small erythe- http://www2.provlab.ab.ca/bugs/webbug/parasite/botfly.htm. are deposited on plant leaves which may matous papule appears. This gradually Accessed December 29, 2002. 3. Ockenhouse CF et al. Cutaneous Myiasis Caused by the come in contact with a host. enlarges to form a furuncle-like lesion up African Tumbu Fly. Arch Dermatol 1990; 126:199-202. to 3 cm in diameter surrounded by a 4. Arosemena RS et al. Cutaneous Myiasis. JAAD 1993; The insect vector is not harmed by larger area of induration. In the center a 28:254-256. carrying the eggs. When it bites a warm 5. Kevin J, Rahman M. A Traveler With Nonhealing Skin Nod- 2 to 3 mm breathing hole or punctum can ules. Cleveland Clinic J of Med 2002; 69: 524-528. blooded animal, the heat from the be seen with serous, serosanguineous, or 6. Moschella SL, Hurley HJ. Dermatology, 2nd ed. Philadel- mammal causes the larvae to hatch and seropurulent exudate given off. Examina- phia: Saunders; 1985. escape from their eggshells. These tion of the punctum may reveal move- burrow into the skin via the bite, a hair

38 FURUNCULAR CUTANEOUS MYIASIS

40 Cutaneous Anthrax and Bioterrorism

Peter A. Vitulli, D.O.,* Stanley E. Skopit, D.O., F.A.O.C.D.**

The name Anthrax is derived from the undercooked contaminated meat. have been reported. The primary lesion Greek word for coal, Anthracis, and refers Symptoms appear 2-5 days after of the skin is usually a painless, prurific to the typical black escar seen on the skin ingestion of endospores. Endospores papual that appears 3-5 days after of affected areas. presumably enter the mucosal lining exposure to the endosporeand in 28-36 resulting in ulceration and subsequent hours undergoes central necrosis and Bacillus Anthracis is a spore forming mesenteric lymhangitis of the upper and drying leaving a characteristic dark gram + bacillus that is found in soil. lower gastrointestinal tract. Fever, brown-black eschar which is surrounded Endospores can survive for decades abdominal pain, acites, melena, by an indurate, swollen area with since they are very resistant to drying, hematemisis, meningitis, shock and death vesicles. Regional lymph glands become heat, and ultraviolet radiation. Bacillus have been reported with mortality rates enlarged and supprative. These lesions Anthracis is an endemic infection in 50-60% in treated Gastrointestinal are typically painless and non purulent. If animals. Anthrax. Inhalation Anthrax is rare in these lesions are painful and pustular this Naturally occurring infection generally nature and is the most serious form of usually indicates secondary infection with results from contact with contaminated anthrax with mortality rates of 70-90%. It staphylococcus or streptococcus, or a fluids, hides, wool, leather, or occurs after inhalation of endospores different etiology other than anthrax. In contaminated meat, from the infected from contaminated animal hides or prod- severe cases fever, extensive local animals, usually Herbivors, via ucts. Symptoms usually develop in 10 edema, and shock may occur. days but may take up to 6 weeks to endospores and has been called wool- Mortality rate is 20% for untreated 5 develop after exposure. Early symptoms sorters disease . Endospores are intro- cases and <1% for treated cases. Anthrax duced into the body by abrasion include fever, non-productive cough, myalgias, malaise, and pluritic chest pain, Meningitis can complicate all forms of (cutaneous), inhalation (respiratory), or anthrax and is nearly always fatal. ingestion (gastrointestinal) anthrax and all resembling a viral upper respiratory are phagocytes by macrophages and tract infection which can make early diag- Histopathology of Cutaneous Anthrax carried to regional lymph nodes. nosis difficult. Early in disease course shows epidermal necrosis and pandermal Endospores germinate inside chest radiographs show a widened medi- inflammation With narcotizing vasculitis, macrophages and become vegetative astinum 3 which is evidence of hemor- numerous gram + thick bacilli are present. bacteria. The vegetative bacteria are then rhagic mediastinitis and pleural effusions. released from the macrophages, multiply Usually Inhalation Anthrax causes So why was anthrax chosen as a in the lymphatic system, enter the blood mediastinitis than pneumonia. bioterrorist agent. Anthrax has a history stream causing massive septicemia. This as a biological agent and was used by the Symptoms progress rapidly over 24-72 Japanese Army in Manchuria in 1940.1 is mediated mostly via edema toxin and hours with increasing fever, dyspnea, lethal toxin. Anthrax is odorless, tasteless, and shock , and death, with mortality rates virtually invisible. It is relatively inexpen- Edema toxin increases levels of between 70-90%. Early diagnosis and sive. The accidental aerosolized release intracellular CAMP. Increased intracellu- treatment are key to survival and is often of anthrax from a military microbiology lar CAMP levels cause disruption of difficult, requiring a large index of facility in Sverdlousk in the former Soviet water hemostasis and results in massive suspicion. Union in 1979 resulted in at least 79 edema as seen in cutaneous anthrax. Cutaneous Anthrax 1 in nature cases of anthrax infection and 68 deaths. accounts for 95% a anthrax infections in This demonstrated the lethal potential of Lethal toxin stimulates macrophages anthrax aerosols.2 to release Tumor Necrosis Factor ? (TNF) the United States prior to 9/11/01. and Interleukin 1B (IL1B). Increased Anthrax infections in the United States In 1993 a report by the US Congres- levels of TNF and IL1B result in shock prior to 9/11/01 is rare with less than 10 sional Office of Technology Assessment and death.1 Clinically Anthrax presents as cases in the last 20 years. Patients often estimated between 130,000 and 3 million Gastrointestinal, Inhalation, and Cuta- have an occupational history of contact deaths could follow the aerosolized neous forms. Gastrointestinal anthrax with animals or animal products. Most release of 100kg of the anthrax spores has never been reported in the United common areas of involvement are areas upwind of the Washington D.C. area- States and is the result of ingestion of of the skin not protected by clothing, lethality matching or exceeding the hydro- where spores can land and be introduced gen bomb.2 by cut or abrasion, such as the head, An economic model developed by the *Resident in Dermatology, Nova Southeastern University/Col- neck, and extremities.Human to human lege of Osteopathic Medicine North Broward Hospital District transmission has not been documented. CDC suggested a cost of 26.2 billion per **Program Director, Nova Southeastern University/College of A few cases of transmission by insect bite 100,000 persons exposed.2 Based on the Osteopathic Medicine/North Broward Hospital District cost and lethal nature of anthrax it is an

(The Journal of the American Osteopathic College of Dermatology, Vol. 1, No. 1, pp 41-42, June 2003) 41 excellent biological weapon which would * First line: Ciprofloxacin 500mg p.o. rifampin, vancomycin, penicillin, cause public panic, social disruption, bid for 60 days ampicillin, chloramphenacol, mass casualties and marked economic * Alternative: Doxycycline 100mg p.o. imipenem, clindamycin, or clory loss.4 bid for 60 days thromycin should be used * Amoxicillin 500mg p.o. tid if a patient concomitantly Since 9/11/01 their have been 11 can not take a flouroquialone or cases of confirmed Inhalation Anthrax, 0 * Pregnant women: Same treatment as tetracycline class drug adults (Ciprofloxacin or tetracycline cases of confirmed Gatrointestinal * For extensive lesions: Extensive Anthrax , and 12 cases of Cutaneous is not recommended during edema, signs of systemic involv- pregnancy but may be indicated for Anthrax - 4 suspected and 8 confirmed, ment, or hand and neck lesions, the the most recent, 3/12/02, being a lab life threatening illness treatment is the same as for an * Immunocomprimised persons same worker in Texas who was testing samples inhalation anthrax infection from Florida and New York.6 as children and adult recommenda- * Pregnant women should receive the tions Clinicians in the post 9/11 era must same treatment as adults. Note * Pediatric treatment: Ciprofloxacin have a high index of suspicion for the ciprofloxacin or tetracycline is not 10mg/kg IV q 12 hours (max diagnosis of anthrax and initiate early recommended during pregnancy but 400mg/dose) for 60 days or treatment. If Anthrax is suspected, the may be indicated for life threatening Doxycycline : > 45kg - 100mg IV q 12 following is the Cutaneous Anthrax illness. hours for 60 days 45kg - 2.2mg/kg IV management. * Immunocomprimised persons q 12 hours for 60 days in addition, or should receive the same treatment 2 antimicrobials including rifampin, Algorithm: Diagnosis of Cutaneous as adults Pediatric Recommenda- vancomycin, penicillin, ampicillin, Anthrax tions chloramphenacol, imipenem, clin * Notify the Department of Health * Pediatric Treatment: Ciprofloxacin damycin, or clorythromycin should be regarding suspected Anthrax cases 15mg/kg q 12 hours max dose 1 gm used concomitantly for any additional instructions before /day in children for 60 days In Conclusion, as a dermatologist in doing diagnostic tests * Doxycycline is also a first line the post 9/11 era we have to have a high * Swab exudates for gram stain and alternative pending sensitivities ñ if > index of suspicion for the diagnosis of culture than 8 years and >45kg ñ same as anthrax. If a suspicious lesion is noted, * Obtain two 4mm punch biopsyís, one adult dose. If < 45kg 2.2mg/kg q 1st notify the Health Department and do for permanent sections ( formalin ) 12 hours for 60 days the appropriate diagnostic studies based and one for non-bacterial static (ster * Note: Ciprofloxacin may cause on the Health Departments recommenda- ile saline) or in a bacterial culturette arthropathy in children and doxycy- tions and initiate early treatment. * Draw 5ml of blood in a red topped or cline may cause dental pigmentation serum separator tube, label tube R/O in children 5 References Anthrax save serum at ñ70 degrees The following are treatment guidelines for 1. Dixon T, Meselson M, Guillemin J, Hanna P. NEJM; centigrade 7 1999:341;814-826 inhalation anthrax infection. 2. Inglesby T, Henderson D, Bartlett J, Eitzen E. Friedlander * Draw 5mls of blood in a purple top A, Hauer J, McDade J, Osterholm M, OíTool tube. This tube should be refriger- * Adult treatment: Ciprofloxacin T, Perl T, Russel P, Tonat K. Anthrax as a Biological 400mg IV q 12 hours and switch to Weapon JAMA. 1999;281:1735-1745 ated and held for potential PCR 3. Lever. Histopathology of the Skin , 8th Edition:488-/889 4 testing by the CDC p.o. when clinically appropriate for a MMWR 10/26/01: 150(42):909-919 * Obtain blood cultures for febrile or total treatment duration of 60 days: 5. Andrews. Diseases of the Skin, 9th Edition:323 6. MMWR Morbidity and Mortality Weekly Report, 2002 June hospitalized patients or Doxycycline 100mg IV q 12 hours 7:51(22):42 * Notify lab regarding suspected and switch to p.o. when clinically 7. Inglesby T et al. Anthrax as a biological weapon, 2002. Anthrax appropriate for a total treatment JAMA 2002;17: 2236-2252 duration of 60 days. In addition 1 or The following are treatment Guidelines for 2 other antimicrobials including Cutaneous Anthrax 7

42 CUTANEOUS ANTHRAX AND BIOTERRORISM Porokeratosis Palmaris et Plantaris Disseminata: A case report

Eric Adrien Adelman, D.O.*

Introduction the course of the last decade these histological hallmark of porokeratosis the lesions have increased in number and cornoid lamella. Below the cornoid there Porokeratosis is a group of chronic distribution to include her entire palms were vacuolated keratinocytes and disorders of keratinization that has an and soles with sporadic lesions on decrease in the thickness of the granular autosomal dominant inheritance, and is bilateral lower extremities. The lesions cell layer. characterized by a common histological are most troublesome to the patient picture of an epidermal ridge formed by a visually, although a few lesions are Treatment thickened column of abnormal painful and itch at which point the patient Due to the patient’s age, diffuse nature keratinocytes called a cornoid lamella. shaves the specifically painful lesions of disease process, and the possibility of The porokeratosis disorders are classified with a kitchen knife causing relief for a reproduction, the patient will await into five disease processes: (1) Poroker- period of time. The patient has been treatment with the only proven efficacious atosis of Mibelli; (2) Disseminated superfi- increasingly frustrated due to previously long-term control of the disease, oral cial actinic porokeratosis; (3) failed attempts at finding a diagnosis. retinoids.v In the interim, the patient has Porokeratosis palmaris et plantaris dis- The patient’s mother, who is sixty- been using Tazorac 0.05% cream and seminata; (4) Punctate porokeratosis; keratolytics with moderate results and, (5) Linear porokeratosis.1 three, also has a history of similar undiagnosed lesions on her palms and relieving pain in select areas. Porokeratosis palmaris et plantaris soles. The mother first saw the Discussion disseminata was first discovered by Guss development of this disease process in et al,IV in 1971 based on findings of eight her early twenties, with slow progression The first porokeratosis discovered was members from four generations who had over the last forty years. The mother’s in 1893 by Mibelli and Resphighi and multiple porokeratoses on the palm, lesions are not as pronounced as her classically named Porokeratosis of soles, and trunk. It was found that this daughters. The patient’s younger brother, Mibelli. This type is characterized by a disease process occurred most twenty-four, began developing scaling plaque-like formation of irregular atrophic commonly in the young teens and early plaques a few years ago on his palms patches with a well-demarcated twenties. It had a familial aspect with and soles. The mother and brother of the hyperkeratotic border. It occurs early in transmission in an autosomal dominant patient were unable to be examined due life, is autosomal dominant like all the fashion, and began on the palms and to geographic location, but were porokeratosis types, is slowly soles, unlike any form of porokeratosis interviewed via phone. Both deny pain or progressive, persists indefinitely, and is classified. Clinically the lesions are itching of lesions. The patient’s father usually localized and found on practically bilateral, symmetrical, and mostly uniform has no history of the disease process and any body surface. The second disorder in nature. The lesions are seen on both grandparents of the mother were unable of porokeratosis was described in 1966 sun-exposed and non-sun exposed skin to be evaluated due to both dying at a by Chernosky, called disseminated with the more hyperkeratotic representa- very young age of unknown causes. superficial actinic porokeratosis (DSAP).vi tive lesions on the palms and soles. This The type occurs in an older population, is disease process has been documented to Physical examination reveals exten- most prominent in sun-exposed areas, occur most often on the palms, soles and sive scaling annular and gyrate 2 to 3 mm and is more generalized with multiple trunk, although there have been plaques with hyperkeratotic scaling bor- superficial and relatively uniform documented cases involving all skin and ders on bilateral soles and upper ankles. hyperkeratotic papules. DSAP is often mucosal surfaces.1 The plaques have a hyperpigmented found bilaterally and in a symmetric depressed or atrophic center. Bilateral fashion. This type of porokeratosis, Case Report palms show scaling annular and gyrate unlike the others is found more commonly plaques with a lesser degree of central ii A 28 year-old female with no prior past in women. Linear porokeratosis is depression and hyperkeratotic borders. medical history presented to our office found from birth to adulthood, consists of The remainder of the physical examina- with complaints of multiple scaling lesions that mimic porokeratosis of Mibelli tion was without consequence. plaques on bilateral palms, soles, and and is seen exclusively in a unilateral and shins. The patient first developed a few Histological findings linear fashion. It has the highest risk of of these lesions in her mid- teens on the group for developing malignancy, and small areas of her palms and soles. Over The biopsies taken showed classical is most commonly found on the distal representations of porokeratosis with extremities.iii Punctate porokeratosis is

*Eric Adrien Adelman, New York College of Osteopathic acanthosis, orthokeratosis, and a mildly usually associated with linear or the Medicine, Doctorate of Osteopathic Medicine, 1998, Miami dense inflammatory infiltrate in the Mibelli forms of porokeratosis showing University of Ohio, Bachelor of Science, 1993, 1770 Meridian dermis. The epidermis showed multiple plaques or a linear distribution of Ave. Apt. 206, Miami Beach, Florida 33139, (954) 224-1027, [email protected] currently a resident in Dermatol- columns of parakeratotic cells reaching hyperkeratotic discrete lesions. ogy, Nova Southeastern University/College of Osteopathic above the uniform orthokeratosis, the Medicine/North Broward Hospital District According to Guss et aliv in 1971 and

(The Journal of the American Osteopathic College of Dermatology, Vol. 1, No. 1, pp 43-44, June 2003) 43 McCallister et alvi patients with Poroker- and sulfur-salicyclic acid creams had no the reported findings of porokeratosis atosis palmaris et plantaris disseminata effect. The use of Fluorouracil improved palmaris et plantaris. The historical, experienced exacerbation of symptoms pain and decreased hyperkeratosis, but physical, and histologic findings define it including pain and itching during the had little other effects.iv Topical retinoids from other specific porokeratoses. The summer months, and had less hyperkera- showed reduction in hyperkeratotic rarity of this disorder and limited treat- totic plaques on areas of the trunk and lesions.ix The only modality that has ment options, along with its possible extremities. In our patient’s case the less shown long-term beneficial response and propensity as a precursor to squamous hyperkeratotic areas of the disease possible protective effects against cell carcinoma, leave us with a challenge presented on her palms, and as far as malignancy is the oral retinoids. Although for the present and future. she can remember our patient has not there is documentation showing excellent experienced this summer phenomenon. results with retinoid therapy, there also References have cases where retinoids have i. Patrizi A, Passarini B, Minghetti G, Masina M:Porokearto There are many theories on the cause sis palmaris et disseminata: An unusual clinical present- worsened the disease.x The dosage tion. J Am Acad Dermatol 1989:21:415-8. of porokeratosis palmaris et plantaris varies per patient and relapse occurs ii. Freedberg I, Eisen A, Wolff K, Austen K, Goldsmith L, disseminata. Reed and Lanai believed Katz S, Fitzpatrick T: Porokeratosis. Fitzpatrick’s Dermatol soon after the medication is stopped. in General Medicine 5th Edition Volume 1 624-9 1999. that the cornoid lamella of the poroker- Although retinoid therapy is conflicting, it iii Odom R, James W, Berger T: Anndrew’s Diseases of the atoses was due to abnormal clones of Skin, Clinical Dermatology 9th Edition 713-16,2000. seems to be the best therapy at this time. iv Guss SB, Osbourn RA, Lutzner M: Porokeratosis keratinocytes causing an increased plantaris, palmaris, et Disseminata: A third type of turnover of epidermal cells. The tendency Squamous cell carcinoma has been porokeratosis. Arch Dermatol 104:366-373, 1971. of this abnormality could possibly be reported in multiple cases of porokerato- v Marschalko M, Somlai: Porokeratosis Plantaris, Palmaris, et Disseminata. Arch Dermatol: 122:890-91;1986. iv,x either inherited or due to actinic exposure sis palmaris et plantaris. The cause of vi McCallister R, Estes S, Yarbrough C: Porokeratosis or unrelated reason. Because Wade and this is not known at this time, but is Plantaris, Palmaris, Et Disseminata: Report of a case and viii treatment with isotretinoin. J Am Acad Dermatol 13:598- Ackerman observed cornoid lamella in theorized to be due to a high rate of 603, 1985. inflammatory and neoplastic disorders, abnormal DNA-ploidy in abnormal viii Wade TR, Ackeman AB: Cornoid Lamellation: A histologic reaction pattern. Am J Dermatolpathol 2:5-15,1980. they proposed that cornoid lamella were keratinocytes of porokeratosis, and by ix Shaw J, White C: Porokeratosis plantaris palmaris et expressions of disordered epithelial phenotypic features of overexpression of disseminata: J Am Acad Dermatol11:454-60,1984. metabolism. The status is still unclear. p53.x x Seishima M, Izumi T, Oyamda Z, Maeda M: Squamous celll carcinoma arising from lesions of porokeratosis pal maris et plantaris disseminata: Eur J Dermato 10:478-80, As far as treatment is concerned, most Conclusion 2000. attempted modalities have been inadequate in results. Topical steroids This patient’s case in consistent with

44 POROKERATOSIS PALMARIS ET PLANTARIS DISSEMINATA IN THE TREATMENT OF ACNE...

Patient treated with TAZORAC ® Cream 0.1% q.d. The difference is in the results.

BASELINE WEEK 12 These unretouched photographs represent actual clinical experience with TAZORAC ® Cream 0.1%. However, as with all medications, results may vary.

FAST By week 4, a significantly greater reduction in comedones, 21% vs 14% for vehicle (P ≤ .05)1 POTENT 46% reduction in open and closed comedones by week 12 vs 27% for vehicle (P ≤ .001)1 41% reduction in inflammatory acne by week 12 vs 27% for vehicle (P = .01) 1 ELEGANT Tolerability of TAZORAC ® Cream 0.1% proven to be comparable to Differin®gel 0.1% in a 4-week study of healthy volunteers 2

Because retinoids may cause fetal harm when administered to a pregnant woman, TAZORAC® Cream is contraindicated in women who are or who may become pregnant. Women should use adequate birth control measures when TAZORAC® Cream is used. TAZORAC® Cream 0.1% is indicated for acne vulgaris. The most frequent adverse events reported during clinical trials for the treatment of acne vulgaris were seen in 10% to 30% of patients and included, in descending order, desquamation, dry skin, erythema, and burning sensation.

1. Data on file, Allergan, Inc. [TAZORAC® Cream vs vehicle in acne.] 2. Data on file, Allergan, Inc. [Leyden data, TAZORAC® Cream vs Differin® .] Please see adjacent page for brief summary of prescribing information.

Think power. Think cream. TAZORAC is a registered trademark owned by Allergan, Inc. Differin is a registered trademark owned by Galderma Laboratories, L.P. ©2003 Allergan, Inc., Irvine, CA 92612 4941391 Printed in USA 01/03 TAZORAC® (tazarotene) Cream, 0.1% BRIEF SUMMARY (For full prescribing information, see package insert) rats showed no indications of increased carcinogenic risks. Based on pharmacokinetic data from a INDICATIONS AND USAGE: TAZORAC® (tazarotene) Cream 0.1% is indicated for the topical treat- shorter term study in rats, the highest dose of 0.125 mg/kg/day was anticipated to give systemic expo-

ment of patients with acne vulgaris. sure in the rat equivalent to 2.0 times the maximum AUC0-24h seen in acne patients treated with 0.1% tazarotene cream at 2 mg/kg/cm2 over 15% body surface area in a controlled pharmacokinetic study. CONTRAINDICATIONS: Retinoids may cause fetal harm when administered to a pregnant woman. In evaluation of photo co-carcinogenicity, median time to onset of tumors was decreased, and the number of tumors increased in hairless mice following chronic topical dosing with intercurrent expo- In rats, tazarotene 0.05% gel administered topically during gestation days 6 through 17 at sure to ultraviolet radiation at tazarotene concentrations of 0.001%, 0.005%, and 0.01% in a gel for- 0.25 mg/kg/day resulted in reduced fetal body weights and reduced skeletal ossification. Rabbits mulation for up to 40 weeks. dosed topically with 0.25 mg/kg/day tazarotene gel during gestation days 6 through 18 were noted with single incidences of known retinoid malformations, including spina bifida, hydrocephaly, and A long-term topical application study of up to 0.1% tazarotene in a gel formulation in mice terminated at 88 weeks showed that dose levels of 0.05, 0.125, 0.25, and 1.0 mg/kg/day (reduced to heart anomalies. Systemic exposure (AUC0-24h) to tazarotenic acid at topical doses of 0.25 mg/kg/day tazarotene in a gel formulation in rats and rabbits represented 4.0 and 44 times, respectively, the maxi- 0.5 mg/kg/day for males after 41 weeks due to severe dermal irritation) revealed no apparent carcino- mum AUC in acne patients treated with 0.1% tazarotene cream at 2 mg/cm2 over 15% body surface genic effects when compared to vehicle control animals; untreated control animals were not com- 0-24h pletely evaluated. Systemic exposure (AUC ) at the highest dose was 13 times the maximum AUC area in a controlled pharmacokinetic study. 0-12h 0-24h seen in acne patients treated with 0.1% tazarotene cream at 2 mg/cm2 over 15% body surface area in a As with other retinoids, when tazarotene was given orally to experimental animals, developmental controlled pharmacokinetic study. delays were seen in rats; and teratogenic effects and post-implantation loss were observed in rats and Tazarotene was found to be non-mutagenic in the Ames assays using Salmonella and E. coli and did rabbits at doses producing 3.5 and 85 times, respectively, the maximum exposure (AUC0-24h) seen in acne patients treated topically with 0.1% tazarotene cream at 2 mg/cm2 over 15% body surface area in not produce structural chromosomal aberrations in a human lymphocyte assay. Tazarotene was also a controlled pharmacokinetic study. non-mutagenic in the CHO/HGPRT mammalian cell forward gene mutation assay and was non-clasto- genic in the in vivo mouse micronucleus test. In a study of the effect of oral tazarotene on fertility and early embryonic development in rats, decreased number of implantation sites, decreased litter size, decreased number of live fetuses, and No impairment of fertility occurred in rats when male animals were treated for 70 days prior to mating decreased fetal body weights, all classic developmental effects of retinoids, were observed when and female animals were treated for 14 days prior to mating and continuing through gestation and lac- female rats were administered 2 mg/kg/day from 15 days before mating through gestation day 7. A low tation with topical doses of tazarotene gel up to 0.125 mg/kg/day. Based on data from another study, the systemic drug exposure in the rat would be equivalent to 2.0 times the maximum AUC observed incidence of retinoid-related malformations at that dose were reported to be related to treatment. That 0-24h in acne patients treated with 0.1% tazarotene cream at 2 mg/cm2 over 15% body surface area in a con- dose produced an AUC0-24h that was 11 times that observed in acne patients treated with 0.1% tazarotene cream at trolled pharmacokinetic study. 2 mg/cm2 over 15% body surface area. No impairment of mating performance or fertility was observed in male rats treated for 70 days prior to mating with oral doses of up to 1.0 mg/kg/day tazarotene. That dose produced an AUC that was Systemic exposure to tazarotenic acid is dependent upon the extent of the body surface area treated. IN 0-24h 6.3 times the maximum AUC observed in acne patients treated with 0.1% tazarotene cream at PATIENTS TREATED TOPICALLY OVER SUFFICIENT BODY SURFACE AREA, EXPOSURE COULD BE 0-24h 2 IN THE SAME ORDER OF MAGNITUDE AS IN THESE ORALLY TREATED ANIMALS. Although there 2 mg/cm over 15% body surface area. may be less systemic exposure in the treatment of acne of the face alone due to less surface area for No effect on parameters of mating performance or fertility was observed in female rats treated for application, tazarotene is a teratogenic substance, and it is not known what level of exposure is 15 days prior to mating and continuing through day 7 of gestation with oral doses of tazarotene up to required for teratogenicity in humans. 2.0 mg/kg/day. However, there was a significant decrease in the number of estrous stages and an There were three reported pregnancies in patients who participated in the clinical trials on acne with increase in developmental effects at that dose (see CONTRAINDICATIONS). That dose produced an AUC that was 11 times the maximum AUC observed in acne patients treated with tazarotene cream 0.1%. Two of the patients were found to have been treated with tazarotene cream and 0-24h 0-24h 2 the other had been treated with vehicle. One of the patients who was treated with tazarotene cream 0.1% tazarotene cream at 2 mg/cm over 15% body surface area. elected to terminate the pregnancy. The other gave birth to an apparently normal, healthy child at Reproductive capabilities of F1 animals, including F2 survival and development, were not affected by 36 weeks gestation. Seven pregnant women who were inadvertently exposed to topical tazarotene dur- topical administration of tazarotene gel to female F0 parental rats from gestation day 16 through lacta- ing other clinical trials subsequently delivered healthy babies. As the exact timing and extent of expo- tion day 20 at the maximum tolerated dose of 0.125 mg/kg/day. Based on data from another study, the

sure in relation to the gestation times are not certain, the significance of these findings is unknown. systemic drug exposure in the rat would be equivalent to 2.0 times the maximum AUC0-24h observed in 2 TAZORAC® Cream is contraindicated in women who are or may become pregnant. If this drug is used acne patients treated with 0.1% tazarotene cream at 2 mg/cm over 15% body surface area. during pregnancy, or if the patient becomes pregnant while taking this drug, treatment should be dis- Pregnancy: Teratogenic Effects: Pregnancy Category X: continued and the patient apprised of the potential hazard to the fetus. Women of child-bearing poten- See CONTRAINDICATIONS section. Women of child-bearing potential should use adequate birth-con- tial should be warned of the potential risk and use adequate birth-control measures when TAZORAC® trol measures when TAZORAC® Cream is used. The possibility that a woman of childbearing potential Cream is used. The possibility that a woman of child-bearing potential is pregnant at the time of insti- is pregnant at the time of institution of therapy should be considered. A negative result for pregnancy tution of therapy should be considered. A negative result for pregnancy test having a sensitivity down test having a sensitivity down to at least 50 mIU/mL for hCG should be obtained within to at least 50 mIU/mL for human chorionic gonadotropin (hCG) should be obtained within 2 weeks 2 weeks prior to TAZORAC® Cream therapy, which should begin during a normal menstrual period. prior to TAZORAC® Cream therapy, which should begin during a normal menstrual period. (see also There are no adequate and well-controlled studies in pregnant women. Although there may be less PRECAUTIONS: Pregnancy: Teratogenic Effects). systemic exposure in the treatment of acne of the face alone due to less surface area for application, TAZORAC® Cream is contraindicated in individuals who have shown hypersensitivity to any of its tazarotene is a teratogenic substance , and it is not known what level of exposure is required for terato- components. genicity in humans. WARNINGS: Nursing mothers: Pregnancy Category X. See CONTRAINDICATIONS section. Women of child-bearing potential After single topical doses of 14C-tazarotene gel to the skin of lactating rats, radioactivity was detected in should be warned of the potential risk and use adequate birth-control measures when TAZORAC® milk, suggesting that there would be transfer of drug-related material to the offspring via milk. It is not Cream is used. The possibility that a woman of child-bearing potential is pregnant at the time of insti- known whether this drug is excreted in human milk. Caution should be exercised when tazarotene is tution of therapy should be considered. A negative result for pregnancy test having a sensitivity down administered to a nursing woman. to at least 50 mIU/mL for hCG should be obtained within 2 weeks prior to TAZORAC® Cream therapy, Pediatric Use: which should begin during a normal menstrual period. The safety and efficacy of tazarotene cream have not been established in patients with acne under the PRECAUTIONS: age of 12 years. General: TAZORAC® Cream should be applied only to the affected areas. For external use only. Avoid Geriatric Use: contact with eyes, eyelids, and mouth. If contact with eyes occurs, rinse thoroughly with water. Tazarotene cream for the treatment of acne has not been clinically tested in persons Retinoids should not be used on eczematous skin, as they may cause severe irritation. 65 years of age or older. Because of heightened burning susceptibility, exposure to sunlight (including sunlamps) should be ADVERSE REACTIONS: avoided unless deemed medically necessary, and in such cases, exposure should be minimized dur- In human dermal safety studies, tazarotene 0.05% and 0.1% creams did not induce allergic contact ing the use of TAZORAC® Cream. Patients must be warned to use sunscreens (minimum SPF of 15) sensitization, phototoxicity, or photoallergy. and protective clothing when using TAZORAC® Cream. Patients with sunburn should be advised not to The most frequent adverse reactions reported during clinical trials with TAZORAC® Cream 0.1% in the use TAZORAC® Cream until fully recovered. Patients who may have considerable sun exposure due to treatment of acne, occurring in 10-30% of patients, in descending order included desquamation, dry their occupation and those patients with inherent sensitivity to sunlight should exercise particular cau- skin, erythema, and burning sensation. Events occurring in 1 to 5% of patients included pruritus, irri- tion when using TAZORAC® Cream and ensure that the precautions outlined in the Information for tation, face pain, and stinging. Patients subsection of the full package insert are observed. OVERDOSAGE: ® TAZORAC Cream should be administered with caution if the patient is also taking drugs known to be Excessive topical use of TAZORAC® Cream 0.1% may lead to marked redness, peeling, or discomfort photosensitizers (e.g., thiazides, tetracyclines, fluoroquinolones, phenothiazines, sulfonamides) (see PRECAUTIONS: General). because of the increased possibility of augmented photosensitivity. TAZORAC® Cream 0.1% is not for oral use. Oral ingestion of the drug may lead to the same adverse Some individuals may experience excessive pruritus, burning, skin redness or peeling. If these effects effects as those associated with excessive oral intake of Vitamin A (hypervitaminosis A) or other occur, the medication should either be discontinued until the integrity of the skin is restored, or the retinoids. If oral ingestion occurs, the patient should be monitored and appropriate supportive mea- dosing should be reduced to an interval the patient can tolerate. However, efficacy at reduced fre- sures should be administered as necessary. quency of application has not been established. Weather extremes, such as wind or cold, may be more Rx only irritating to patients using TAZORAC® Cream. U.S. Patent Number 5,089,509 Drug Interactions: Concomitant dermatologic medications and cosmetics that have a strong drying effect should be avoided. It is also advisable to “rest” a patient’s skin until the effects of such preparations subside before use of TAZORAC® Cream is begun. Carcinogenesis, Mutagenesis, Impairment of Fertility: ® Registered trademarks of Allergan, Inc. A long term study of tazarotene following oral administration of 0.025, 0.050, and 0.125 mg/kg/day to ©2003 Allergan, Inc., Irvine, California 92612, USA Printed in USA 46 Cutaneous Manifestations of Biological Terrorism

Stephen G. Mallette, D.O.,* David Horowitz, D.O., ** Mark Horowitz, D.O. ***

Abstract his paper is intended to discuss the biological agents and diseases and their cutaneous manifestations that are designated as Category A by the CDC. Category A is defined as agents that pose a high risk to national security because they can be easily disseminated from person to person, result in high mortality rates and have the potential for major public health impact, might cause public panic and social disruption, and require special action for public health preparedness. In light of the recent terrorist attacks the CDC recommends that healthcare providers must be prepared to address these pathogens rarely seen in the United States. 1

Anthrax History Three types of the disease occur in Pathogenesis and Clinical humans: inhalational, cutaneous, and Research on anthrax as a biological Manifestations. gastrointestinal with cutaneous being the weapon began more than 80 years ago. most common form. Wool sorters were Cutaneous anthrax occurs following Anthrax has been used, unsuccessfully, historically at greatest risk for inhalational deposition into the skin with previous cuts by the terrorist group Aum Shinrikyo on at disease. Until the 2001 attacks, no cases or abrasions making one more least 8 occasions without result in illness. of inhalational disease were reported. susceptible to infection. After the spore An accidental release in Sverdlovsk in Cutaneous anthrax is the most common germinates in skin tissue, toxin production 1979 resulted in 79 cases of anthrax and naturally occurring form. Until the anthrax results in local edema followed by ulcer 68 deaths. The aerosol is odorless and attacks of 2001 there were 224 cases of formation by the second day. 1 to 3 mm invisible and can travel many kilometers cutaneous anthrax reported between vesicles may appear that discharge clear before disseminating. The WHO in 1970 1944 and 1994. Gastrointestinal anthrax fluid containing numerous organisms. released a report estimating the theoreti- is the least common form with most of the This is followed by painless, black eschar cal aircraft release of 50 kg of anthrax reported cases occurring in Africa and formation with extensive local edema. over an urban population of 5 million Asia. It follows the ingestion of insuffi- The eschar dries, loosens, and falls off in would result in 250,000 causalities, of ciently cooked meat. 2 the next 1 to 2 weeks. Lymphadenopathy which 100,000 would die without treat- can occur with associated systemic ment. In 1993 a report by the U.S. Con- Microbiology. symptoms. Without antibiotic therapy, the gressional Office of Technology mortality rate has been reported as high Assessment estimated that between Anthrax infection is caused by Bacillus anthracis, a large aerobic, encapsulated, as 20%; however, with antibiotic 130,000 and 3 million deaths could follow treatment death is rare.4 the aerosolized release of 100 kg of gram-positive, square ended rod that 3 anthrax spores upwind of the Washington forms spores in unfriendly environment. Inhalational anthrax occurs following D.C. area which is a lethality matching or It is derived from the Greek word for coal, deposition of spore-bearing particles into exceeding that of a hydrogen bomb. 17 ancthrakis, because of the coal like skin alveolar spaces. The spores are ingested nations currently have offensive biological lesions. Spores may persist for many by macrophages and those that survive weapon programs but it is not known how years in cutaneous products of these ani- are transported to the mediastinal lymph many are working with anthrax. Iraq has mals and in pastures where they live. nodes where germination may occur up acknowledged producing anthrax Spores can be grown readily on all ordi- to 60 days later. Once the germination weapons. nary laboratory media at 37 degrees occurs, disease follows rapidly. The Celsius with a “jointed bamboo-rod” bacteria release toxins leading to Epidemiology. cellular appearance and a unique “curled- hemorrhage, edema, and necrosis. The hair” colonial appearance. The spores Anthrax can be acquired through disease has two stages. The first stage will germinate in nutrient rich environ- contact of anthrax containing animals or has a spectrum of nonspecific symptoms ments and from spores only after the animal products. The disease most such as fever dyspnea, cough, headache, supply is exhausted. Reservoirs of commonly occurs in herbivores, which and chest pain. This stage can last from infection have been virtually eliminated in are infected by ingesting spores from soil. hours to a few days. The second stage the United States due to vaccination and Animal vaccination programs have dra- develops abruptly with fever, dyspnea, animal control programs but imported matically reduced animal mortality. diaphoresis, and shock. Chest X-ray animal products introduce spores into shows a widened mediastinum consistent selected industrial environments. Up until with lymphadenopathy. Up to half of the recently infections in the United States patients develop hemorrhagic meningitis *Stephen G. Mallette, D.O., 2nd Year Dermatology were limited to persons working in animal with delirium and obtundation. The mor- Resident, Western University COMP, Torrance, CA, product-associated industries, particularly 2nd PaperSubmitted tality rate before the development of criti- **Program Director: David Horowitz, D.O. individuals handling raw materials in wool cal care units was 89%. ***Program Director: Mark Horowitz, D.O. factories.

(The Journal of the American Osteopathic College of Dermatology, Vol. 1, No. 1, pp 47-52, June 2003) 47 Gastrointestinal anthrax occurs due to Smallpox which are the monkeypox, vaccinia, and deposition and germination of spores in cowpox. Only smallpox is readily the GI tract. Two forms may occur: oral- Smallpox represents a serious threat if transmitted from person to person. pharyngeal form and lower GI form. The used as a biological weapon because of oral-pharyngeal has oral or esophageal its case-fatality rate of 30% or more Pathogenesis and Clinical ulcers with regional development of among unvaccinated persons and the Manifestations. lymphadenopathy, edema, and sepsis. absence of specific therapy. In today’s Smallpox is an acute exanthematous The lower GI form presents with nausea, highly susceptible, unvaccinated, mobile disease caused by infection with poxvirus vomiting, and malaise which progresses population smallpox would be able to variolae. The main clinical features of to an acute abdomen or sepsis. widely and quickly spread through this this disease are a 3-day prodromal illness country. Diagnosis. and a generalized centrifugal rash with History. rapidly successive papules, vesicles, If cutaneous anthrax is suspected, a pustules, umbilication, and crusting within Gram stain and culture of vesicular fluid Smallpox was probably first used as a 14 days. Through vaccination policies should be obtained. If the Gram stain is weapon during the French and Indian and intensive case finding eradication of negative or the patient is taking antibiotics Wars (1754-1767) by British forces in smallpox was officially announced in already, punch biopsy should be North America. Soldiers distributed 1979. Until the advent of the Jennerian performed and specimens sent to a blankets that had been used by smallpox vaccination, smallpox was a major threat laboratory with the ability to perform patients with the intent of initiating with widespread attack rates, persistent immunohistochemical staining or outbreaks among American Indians. infection within a community, and a high polymerase chain reaction assays. Blood Epidemics did occur killing more than mortality rate. The poxvirus variola cultures should be obtained and 50% of affected tribes. The threat of infection follows contact with another antibiotics should be initiated pending smallpox being used as a weapon was infected human being primarily by confirmation of the diagnosis of greatly diminished when in 1796 Edward respiratory transmission but skin cutaneous anthrax. The differential Jenner demonstrated that an infection inoculation and fomite spread may also diagnosis must include tularemia, scrub caused by cowpox protected against play a role. Following contact, an typhus, rickettsial spotted fevers, rat bite smallpox. Many people were vaccinated asymptomatic period of 12 to 13 days fever, ecthyma gangrenosum, arachnid with cowpox inoculation. Smallpox was with massive viral replication occurs. The bites, and vasculitides. eradicated in 1977. Many research labs virus following introduction via the retained stocks of variola virus including respiratory tract, undergoes local In cases of inhalational anthrax chest the United States and the USSR. The multiplication in the respiratory mucosa x-ray should be obtained. The most variola virus can be released by an and regional lymphoid tissue. Viremia useful microbiologic test is the standard aerosol method and due to the stability of occurs which spreads the virus widely blood culture which will show growth the virus wide dissemination would be throughout the reticuloendothelial system, within to 24 hours. Sputum culture and possible. Also the infectious dose is where massive multiplication occurs. A Gram stain are unlikely to be diagnostic. small.5 second veremia then occurs which begins Treatment. Epidemiology. the onset of prodromal illness with spread to organs and tissues and primary Treatment for cutaneous anthrax is There were two principal forms of manifestation in the skin. Ciprofloxacin 500mg twice daily for 60 smallpox, variola major and a milder form days or Doxycycline 100mg twice daily for variola minor. Variola major predomi- An influenzal illness shortly after 60 days in adults and pregnant women. nated throughout the world through the contact has been described as an illness For children more than 8 years of age or 19th century. Smallpox is spread from contact. A history of contact is essential. 45kg, a dose of ciprofloxacin 10-15mg/kg person to person, primarily by droplet A vaccination history and interval to every 12 hours or doxycycline 100mg nuclei or aerosols expelled from the symptoms are very important, as the every 12 hours is recommended. For oropharynx of infected persons and by disease pattern may be altered. Prior to children less then 45kg or less then 8 direct contact. There are no animal onset of skin lesions, a prodromal period years of age, 2.2mg/kg every 12 hours is vectors or reservoirs and the virus can of 3 days’ duration occurs characterized the recommended dose.2 For inhalational spread through clothing and bed linens. by apprehension, sudden prostrating anthrax, treatment with ciprofloxacin The transmission of smallpox does not fever, severe headache, back pain, and 400mg every 12 hours or doxycycline occur until the onset of the rash by which vomiting. A prodromal rash is not 100mg every 12 hours IV with change to time the affected person is confined to uncommon; it is a macular and papular or oral forms when clinically appropriate for bed due to prodromal illness restricting petechial, and when it occurs in the 60 days is recommended. There were 22 characteristic “swimming trunk” distribu- contact to household residents. The 7 cases confirmed or suspected cases that patient is most infectious from the onset tion, it is felt to be pathognomonic. resulted from the anthrax attacks of 2001. of the rash through the first 7 to 10 days The disease may take several Eleven of these cases were inhalational of rash. The age of distribution has been courses. In the nonvaccinated, a discrete anthrax, of which 5 died. The remaining historically children since in the past the pox eruption is the most frequent form of 11 were cutaneous anthrax infection. adults had been immunized or already illness. Severe forms of the disease are Anthrax can be delivered as the letter contracted the disease as children. This associated with confluent eruptions attacks were or in aerosol form giving the of course would change since immuniza- and/or cutaneous hemorrhage. ability for larger area coverage. tions have stopped.6 Infrequently variola may occur without The U.S. anthrax vaccine, named Microbiology. eruption, or with just a few pocks. A flat anthrax vaccine absorbed (AVA), is an erythematous macular rash may precede inactivated cell-free product. It is licensed Smallpox is a DNA virus and a the appearance of tense, deep-seated to be given in 6 dose series. It is made member of the genus orthopoxvirus. The papules that rapidly vesiculate. These from cell-free filtrate of a nonencapsu- virion has a brick-shaped structure with a lesions are firm and more deep-seated lated attenuated strain of B anthracis.2 diameter of 200nm. This group contains than those of chickenpox. The rash may 3 other members that can infect humans be sparse, or individual vesicles may

48 CUTANEOUS MANIFESTATIONS OF BIOLOGICAL TERRORISM become confluent to form large patches. with best efforts aimed at prevention with Generalized vaccinia follows primary As the lesions mature, the classic the Jennerian vaccination. Thiosemicar- vaccination in which the virus becomes “pustule” occurs. These lesions do not bazone and antivariola or antivaccina blood-borne and lesions appear 6 to 9 contain bacteria, and the cloudiness serum and immune globulin failed in the days after vaccination and were few in represents accumulated white blood cells, therapy of established smallpox. Care number or generalized. This condition is debris, and protein. Central umbilication should be supportive and prevention of usually self-limited but in severe cases is characteristic and eventually the lesion secondary bacterial infection a must. The VIG can be used. crusts over and heals with scar formation. overall mortality of smallpox is 25 percent This is the classic appearance of the with confluent disease representing a Inadvertent inoculation occurs from disease. Those with previous vaccination greater risk than discrete eruptions. close contacts or autoinoculation to face, may present with variations such as flat Fulminant smallpox is universally fatal, as mouth, eyelid, and genitalia. Most lesions disklike appearance or may undergo are the hemorrhagic forms of the illness. heal without incident, but VIG may be resolution without passing through Since the aerosol release of smallpox to used. vesiculopustular stage. There are two as little as 50 to 100 persons would There are 5 groups at risk for the hemorrhagic forms of the disease; one in rapidly spread in a now highly susceptible above complications: 1. Persons with which hemorrhage occurs in association population, the infected would rapidly eczema or exfoliative skin condition; with prodromal symptoms but death expand to 10 to 20 times the first 2. Persons with leukemia, lymphoma, or supervenes before any of the generation. Therefore, vaccination within generalized malignancy receiving therapy characteristic skin lesions can occur; and the first few days of exposure and even that causes immunosuppression; 3. HIV a second, characterized by hemorrhage as late 4 days can prevent or ameliorate patients; 4. Hereditary immune disorders; into preexisting lesions. Both have subsequent illness. and 5. Pregnant women. VIG may be almost universally fatal outcomes, the first Also of note are the vaccine given simultaneously with vaccination in within a week and the second after 8 to these individuals.5 12 days. Other common secondary complications. Vaccine can be safely physical findings are ulceration of the administered to persons of all ages, from Tularemia birth onward. The vaccination is cornea, laryngeal lesions with symptoms The causative agent of tularemia is of obstruction in the upper part of the performed using a bifurcated needle that is dipped into an ampule of reconstituted Francisella tularensis and is one of the airway, central nervous system most infectious pathogenic bacteria involvement with encephalitis or acute vaccine. This needle is then rapidly stroked onto the arm 15 times in 5mm known requiring inoculation or inhalation psychotic behavior, and, less commonly, of as few as 10 organisms to cause osteomyelitis, pneumonia, and orchitis. 8 diameter. After 3 days a red papule appears at the site and becomes disease. Tularemia is widely considered Diagnosis. vesicular on about the 5th day. On the a dangerous potential biological weapon 7th day it becomes the Jennerian pustule, because its extreme infectivity, ease of Histopathology shows deep vesicles a whitish, umbilicated, multilocular, dissemination, and substantial capacity to with leukocyte infiltration. Also typical containing turbid lymph and surrounded cause illness and death. cytoplasmic inclusion bodies have been by an erythematous areola that may con- (9) History. described known as Guarnieri’s bodies. tinue to expand for 3 more days. This Differential diagnosis should include can be associated with fever and Tularemia was first described as a chickenpox, coagulation disorders, lymphadenopathy. The pustule dries and plaguelike disease of rodents in 1911 typhus, and in the preeruptive phase of falls off in about 3 weeks. and, shortly thereafter, was recognized as a potentially severe and fatal illness in the disease must be distinguished from Complications. dengue, measles, enterovirus, and other humans. It has been studied for military febrile illnesses. Rapid laboratory means Postvaccinial encephalitis occurs at a purposes in both the east and west. It of diagnosis include light microscopic rate of 1 in 300,000. One fourth of these has been suggested that tularemia identification of elementary bodies with cases are fatal. Between 8 and 15 days outbreaks affecting tens of thousands of appropriate stains, electron microscopic after vaccination, encephalitic symptoms Soviet and German soldiers on the identification of virus in vesicular fluid or developed such as fever, headache, eastern European front during World War scrapings from the base of a papule or vomiting, drowsiness, and sometimes II may have been the result of intentional early vesicle, and fluorescent antibody spastic paralysis, meningitic signs, coma, use. Following the war research was staining of the virus from same material. and convulsions. Recovery is either developed to study the use of tularemia All of these tests yield rapid results but complete or with residual paralysis and as a weapon in the United States, Soviet definite diagnosis can be achieved only other CNS symptoms. There is no Union and other countries. In 1969, a by isolation of the virus in the treatment. World Health Organization expert embryonated egg or in appropriate tissue committee estimated that an aerosol culture systems and specific identification Progressive vaccinia (Vaccinia Gan- dispersal of 50 kg of virulent F tularensis of the virus by neutralization with variola grenosa) can occur in primary or revacci- over a metropolitan area with 5 million or vaccinal antiserum. Smallpox is best nees. It was frequently a fatal inhabitants would result in 250,000 diagnosed by clinical picture and complication in those with immune incapacitating casualties, including adequate history of exposure, observa- deficiency syndromes. The vaccinial 19,000 deaths.10 lesion failed to heal and progresses to tion of an approximately 2-week Epidemiology. incubation period followed by a severe 3 skin necrosis spreading to bones and day prodrome, ultimately terminating in a viscera. VIG has been used for this Tularemia is mostly a rural disease typical rash with centrifugal distribution problem. and occurs throughout much of North and all lesions in the same stage of Eczema vaccinatum occurs in which America and Eurasia. In the United development. vaccinial skin lesions extended over States human cases have been reported from every state except Hawaii; however Treatment. areas currently afflicted with eczema. VIG was therapeutic. most cases occur in south central and Treatment for the disease is limited western states. In Eurasia the disease is

MALLETTE 49 widely endemic with the greatest Clinical Manifestations. Histopathology shows granulomatous numbers of human cases reported in formation with central necrosis and northern and central Europe. Natural Primary disease presentations include nuclear dust. There is a nonspecific reservoirs of infection include mammals ulceroglandular, glandular, oculoglandu- inflammatory infiltrate associated with the such as voles, mice, water rats, squirrels, lar, oropharyngeal, pneumonic, typhoidal, granulomatous reaction.13 rabbits, and hares that acquire infection and septic forms. The onset of tularemia through bites by ticks, flies, and is usually abrupt, with fever, headache, The differential of the primary lesion mosquitoes or through contaminated chills and rigors, generalized body aches, should include furuncle, paronychia, environments such as water, soil, and coryza and sore throat. Nausea, ecthyma, anthrax, P multocida infection, vegetation. Humans can become vomiting, and diarrhea sometimes occur. or sporotichosis. The regional adenopa- infected by various modes including bites Sweats, fever and chills, progressive thy suggests cat-scratch disease, plague, by arthropods, handling infectious animal weakness, malaise, anorexia, and weight meliodisis, Eastern hemisphere spotted tissue or fluids, direct contact with or loss characterize the continuing illness. fever, or lymphogranuloma venereum. ingestion of contaminated water, food, or Without antibiotics the overall mortality The febrile illness must be differentiated soil and inhalation of infective aerosols. rates range from 5% to 15% and fatality from Lyme disease, Rocky Mountain rates as high as 30% to 60% were spotted fever, or community pneumo- All ages and sexes are equally 11 susceptible with those who hunt, trap, reported for untreated forms of the nias. pneumonic and severe systemic forms of handle infected animals, and farm having Treatment. a higher incidence. No person-to-person disease. transmission has been documented. The ulceroglandular type begins with a IV Streptomycin is the drug of choice Less than 200 cases were reported in the primary papule or nodule that rapidly with Gentamicin being an acceptable United States in the 1990s with most ulcerates at the site of infection. This can alternative. Treatment should be occurring in June through September occur from contact with tissues or body continued for ten days. Other treatments when arthropod transmission is most fluid of infected mammals via abrasion or include tetracyclines, ciprofloxacin, and common.11 scratch or by bites of a tick such as chloramphenicol. These all may also be used in children. Short courses of F tularensis could be used as a Dermacentor andersoni or of a deer fly Chrysops dicalis. The primary ulcer is gentamicin may be used in pregnant weapon in a number of ways, but experts women. In the United States a live believe that an aerosol release would tender, firm, indolent, and punched-out, with a necrotic base that heals with scar attenuated vaccine derived from avirulent have the greatest adverse medical and live vaccine strain has been used for public health consequences. Release in formation in about six weeks. Lymphan- gitis spreads from the primary lesion. laboratory workers and is under review by a densely populated area would result in the FDA. It does not protect all recipients an abrupt onset of large numbers of The regional lymph glands become swollen, painful, and inflamed, and tend against aerosol challenges in studies and cases of acute, nonspecific febrile illness did not reduce incidence of ulceroglandu- beginning 3 to 5 days later with pleurop- to break down, forming subcutaneous nodules resembling those of sporotri- lar disease but did reduce signs and neumintis developing in a significant symptoms. Exposed persons should be proportion of cases during the ensuing chosis. Other symptoms include fever at first continuous then remissions and back treated prophylactically with 14 days of days and weeks. 10 to normal. Erythema multiforme and oral doxycycline or ciprofloxacin. Microbiology. erythema nodosum often occur as well.12 Botulism, Plague, and F tularensis is a small, nonmotile, In the typhoidal type the site of Viral Hemorrhagic Fevers aerobic, gram-negative coccovacillus. It inoculation is not known and there is no has a thin lipopolysaccharide-containing local sore or adenopathy. Persistent Botulism. Clostridium botulimum is a envelope and is a hardy non-spore-form- fever, malaise, GI symptoms, and spore-forming, obligate anaerobe whose ing organism that survives for weeks at presence of specific agglutinins in the natural habitat is soil from which it can be low temperatures in water, moist soil, hay, blood serum after the first week isolated without undue difficulty. straw, and decaying animal carcasses. It characterize this form. Also oculoglandu- Botulinum toxin exists in 7 distinct is divided into two major subspecies lar which is primary conjunctivitis and an antigenic types that have been assigned (biovars) by virulence testing, biochemical oropharyngeal form may occur. The the letters A through G. Botulinum toxin reactions and epidemiological features. oropharyngeal form occurs after ingesting is the most poisonous substance known. Type A is highly virulent in humans and infected inadequately cooked meat. The One gram of crystalline toxin, evenly animals, produces acid from glycerol, glandular type has no primary site of dispersed and inhaled, would kill more demonstrates citrulline uredise activity, infection but enlargement of regional than one million people, although and it the most common biovar isolated in lymph glands followed by generalized technical factors would make such North America. Type B is relatively involvement occurs. dissemination difficult. avirulent, does not produce acid from Diagnosis. Three forms of naturally occurring glycerol, and does not demonstrate human botulism exist: foodborne, wound, citrulline ureidase activity. A diagnosis can be made by direct and intestinal. Less than 200 hundred Pathogenesis. examination of secretions, exudates, or cases are reported annually in the United biopsy specimens using direct fluorescent States. All forms result from absorption F tularensis can infect humans through antibody or immunohistochemical stains. of toxin from mucosal surface or wound. skin, mucous membranes, GI tract, and It can also be cultured on special media It does not penetrate intact skin. Once lungs. It is a facultative intracellular containing cystine glucose blood agar or absorbed the bloodstream carries the bacterium that multiplies within other selective media.11 The most reliable toxin to peripheral cholinergic synapses macrophages. Untreated, bacilli inocu- diagnostic procedure is the agglutination at neuromuscular junctions where it binds lated into skin or mucous membranes mul- test which is positive after two weeks of irreversibly. The toxin is internalized and tiply, spread to regional lymph nodes and illness and diagnostic with a fourfold rise enzymatically blocks acetylcholine further multiply, and may then disseminate in titer. release. Symptoms include cramps, to organs throughout the body. nausea, vomiting, or diarrhea for GI trans-

50 CUTANEOUS MANIFESTATIONS OF BIOLOGICAL TERRORISM mission then progressing to an acute a presents with symptoms of other bacterial the ability of the use of plague as a febrile, symmetric, descending flaccid pneumonias and must differentiated from bioweapon.17 paralysis that always begins in bulbar such. The differential diagnosis includes musculature. Patients present with tularemia, lymphogranuloma venereum, difficulty seeing or swallowing. Other cat-scratch disease, Eastern Hemisphere Viral Hemorrhagic Fevers. symptoms include ptosis, diplopia, blurred spotted fever, and supportive lymphadeni- vision, dysarthria, dysphonia, and tis. The diagnosis can be firmly The viral hemorrhagic fevers refer to a dysphagia. Recovery results form new established by examination of Gram and clinical illness associated with fever and a motor axon twigs that sprout to Wayson-stained smears of infected bleeding diathesis caused by a virus reinnervate paralyzed muscle fibers, a material and by culture of the organism belonging to 1 of 4 distinct families which process that, in adults, may take weeks from blood, sputum, or aspirated buboes. are Filoviridae, Arenaviridae, Bunya- or months to complete. Also a convalescent passive hemagglu- viridae, and Flaviviridae. Not all of the eination titer of greater than 1:16 is viruses of these families pose a serious The use of botulinum toxin as a strongly suggestive of a diagnosis. threat as biological weapons due to their weapon began as early as 60 years ago characteristics. Those that do pose a by Japan in Manchuria on prisoners who The treatment of all forms is IM serious threat, include Ebola and Marburg were fed toxin during Japan’s occupation. streptomycin. Alternatives include viruses (Filoviridae), Lassa fever and It was used in aerosol form in the mid- chloramphenicol and tetracycline that can New World arenaviruses (Arenaviridae), 1990s in Japan by the cult Aum Shinriky be added if resistant strains are found. Rift Valley fever (Bunyaviridae), and that failed due to faulty technique and Bubonic plague if untreated has a yellow fever, Omsk hemorrhagic fever, internal sabotage. Currently Iraq has mortality rate of 30 to 70% while and Kyasanur Forest disease (Flavoviri- 19000 L unaccounted for which consti- pneumonic and septicemic plague is dae). All of the HFVs are RNA viruses tutes approximately 3 times the amount universally fatal. Early antibiotic with lipid envelopes. These diseases are needed to kill the entire population by treatment can reduce the mortality rate to described in the table below. inhalation.14 5 to 10%.15,16 The methods of diagnosing of HFVs The diagnosis of botulism is with the The first plague pandemic began in include antigen detection by antigen-cap- standard diagnostic test of specimen and Egypt in AD 541 and swept across ture enzyme-linked immunosorbent assay food with mouse bioassay in which type Europe with population losses of between (ELISA), IgM antibody detection by specific antitoxin protects mice against 50 and 60%. The second plague antibody-capture ELISA, RT-PCR, and any botulinum toxin present in the pandemic began in 1346 and killed 30 to viral isolation. The lab testing requires sample. This test yields results in 1 to 2 40 million people in Europe. The third time so a diagnosis will rely heavily on days and must be done in untreated pandemic began in China in 1855 and clinical judgment. specimen. killed more than 12 million people in India and China. In World War II Japan The treatment, as shown above, is Treatment of botulism is supportive dropped plague-infected fleas over largely supportive. Studies are currently and passive immunization with equine populated areas of China causing being done on antiviral therapies as well antitoxin. The antitoxin will not reverse outbreaks of plague. The United States as vaccines. There is a vaccine for existent paralysis but will neutralize and Soviet Union developed aerosol yellow fever called the yellow fever live existing toxin. forms of the disease eliminating the attenuated 17D vaccine which is highly Plague. unpredictable flea vector in later years. effective when administered to travelers The WHO in 1970 reported that in a to endemic areas but would be ineffective This disease occurs in 3 forms that are worst-case scenario if 50g of Y pestis for post exposure treatment due to the bubonic, bubonic-septicemic (a more were released by aerosol over a city of 5 short incubation period of yellow fever acute and severe form of bubonic plague million, 150,000 persons would develop since neutralizing antibodies take longer with bacteremia and delerium), and pneumonic plague with 36,000 deaths. It to appear. pneumonic. The plague is caused by is unknown currently if any countries have Yersinia pestis an aerobic gram-negative HFVs have been weaponized by the bacillus with “safety-pin” bipolar staining. The disease is transmitted by fleabites of Table 1 Xenopsylla cheopis and in the United States by the Diamanus montanus, Virus Disease Vector Geographic Person to Person Chrasis bacchi, and Opisocrostis hirsutus Distribution Transmission all of which are species that live on the Ebola Ebola Hemorrhagic Unknown Africa Yes host rodents such as squirrels, rats, Fever prairie dogs, chipmunks, marmots, Marburg Marburg Unknown Africa Yes skunks, deer mice, wood rats, and hares. Hemorrhagic Fever Infection can also be transmitted through contact of infected animals, humans, Lassa Lassa Fever Rodent West Africa Yes pneumonic spread and infected exudates. New World New World Rodent Americas Yes Arenaviradae Hemorrhagic fever The clinical manifestations of bubonic Rift Valley Rift Valley fever Mosquito Africa, Saudi No plaque include an initial fleabite (if Arabia, Yemen visible). Painful, tender, enlarged lymph Yellow fever Yellow fever Mosquito Africa, tropical No nodes are present in the area draining the Americas bite site. The nodes become matted Omsk Omsk hemorrhagic Tick Central Asia No (buboes) with extensive surrounding edema. Other symptoms include fever, hemorrhagic fever fever headache, nausea, vomiting, tachycardia, Kyassanur Forest Kyassanur Forest Tick India No and abdominal pain. Pneumonic plague disease disease

MALLETTE 51 In conclusion, this paper serves as a summarization of Category A agents and in the event that a healthcare provider suspects such as diagnosis they should contact both the CDC and the local health department for correct procedures. Ongoing research on therapies, diagnostic testing and vaccination will hopefully lead to lessen the threat of such attacks. Bibliography 1. Public Health Emergency Preparedness and Response. Biological Diseases/Agents Listing. Atlanta, Georgia. Centers for Disease Control and Prevention; 2002. Available at http://www.bt.cdc.gov. 2. Inglesby, Thomas V., et al. Anthrax as a biological weapon, 2002: updated recommendations for management. JAMA. 2002; 287:2236:2252. 3. Fitzpatrick TB. Dermatology in General Medicine. 5th Ed. New York: McGraw Hill, 1999: 2257-2259. 4. Odom, Richard, B. Andrews’ Diseases of the Skin. 9th Ed. Philadelphia: W. B. Saunders, 2000: 323-324. 5. Henderson, Donald A., et al. Bioterrorism: Guidelines for Medical and Public Health Management. Chicago: American Medical Association, 2002: 99-120. 6. Breman, Joel G. and Henderson, D.A. Diagnosis and management of smallpox. New England Journal of Medicine. 2002;346:1300-1307. 7. Odom, Richard B., Andrews’ Diseases of the Skin. 9th Ed. Philadelphia: W. B. Saunders, 2000: 497. 8. Fitzpatrick TB. Dermatology in General Medicine. 5th Ed. New York: McGraw Hill, 1999:2467-2473. 9. Elder, David. Lever’s Histopathology of the Skin. 8th Ed. Philadelphia: Lippincott-Raven, 1997:574. 10. Henderson, Donald A., et al. Bioterrorism: Guidelines for Medical and Public Health Management. Chicago: American Medical Association, 2002:167-190. 11. Fitzpatrick TB. Dermatology in General Medicine. 5th Ed. New York: McGraw Hill, 1999: 2263-2267. 12. Odom, Richard B. Andrews’ Diseases of the Skin. 9th Ed. Philadelphia: W. B. Saunders, 2000: 347-348. 13. Elder, David. Lever’s Histopathology of the Skin. 8th Ed. Philadelphia: Lippincott-Raven, 1997:488-489. 14. Henderson, Donald A., et al. Bioterrorism: Guidelines for Medical and Public Health Management. Chicago: American Medical Association, 2002:141-166. 15. Odom, Richard B. Andrews’ Diseases of the Skin. 9th Ed. Philadelphia: W. B. Saunders, 2000: 346. 16. Fitzpatrick TB. Dermatology in General Medicine. 5th Ed. New York: McGraw Hill, 1999: 2264. 17. Henderson, Donald A., et al. Bioterrorism: Guidelines for Medical and Public Health Management. Chicago: American Medical Association, 2002: 121-140. 18. Borio, Luciana, et al. Hemorrhagic fever viruses as biological weapons. Journal of the American Medical Association. 2002: 287; 2391-2405.

Table 2 former Soviet Union, United States and stopped production in 1992.18 Russia. Several studies show the successful infection of nonhuman pri- The VHFs’ transmission is still poorly mates by aerosol preparations of Ebola, understood. Studies continue on Marburg, Lassa, and New World are- developing rapid diagnostic techniques, naviruses. The United States discontin- therapies, and vaccines. ued its program in 1969 and Russia

52 CUTANEOUS MANIFESTATIONS OF BIOLOGICAL TERRORISM TOPICAL SUSPENSION LOPROXIntroducing

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The most common adverse reactions reported are pruritus, burning, and contact dermatitis. LOPROX TS, available in 30 and 60 mL.

T. Pedis T. Versicolor Cutaneous Candidiasis T. Cruris T. Corporis

LPX02018_ODJ_12/02 © 2002 MEDICIS® Pharmaceutical Corp. See full prescribing information andAUTHOR reference on the following page. 53 LOPROX® TOPICAL SUSPENSION Information for Patients: The patient should be told to: (CICLOPIROX) 0.77% (W/W) 1. Use the medication for the full treatment time even though signs/symptoms may FOR DERMATOLOGIC USE ONLY. have improved and notify the physician if there is no improvement after four weeks. NOT FOR USE IN EYES. 2. Inform the physician if the area of application shows signs of increased irritation (redness, itching, burning, blistering, swelling, oozing) indicative of possible sen- Rx Only sitization. ® DESCRIPTION: Loprox (ciclopirox) Topical Suspension 0.77% is for topical use. 3. Avoid the use of occlusive wrappings or dressings. Each gram of LOPROX Topical Suspension contains 7.70 mg of Ciclopirox (as Carcinogenesis, Mutagenesis, Impairment of Fertility: A carcinogenicity study in Ciclopirox Olamine) in a water miscible suspension base consisting of Purified Water female mice dosed cutaneously twice per week for 50 weeks followed by a 6-month USP, Cocamide DEA, Octyldodecanol NF, Mineral Oil USP, Stearyl Alcohol NF, drug-free observation period prior to necropsy revealed no evidence of tumors at the Cetyl Alcohol NF, Polysorbate 60 NF, Myristyl Alcohol NF, Lactic Acid USP, Sorbitan application site. The following in vitro and in vivo genotoxicity tests have been con- Monostearate NF, and Benzyl Alcohol NF (1%) as preservative. LOPROX Topical Sus- ducted with ciclopirox olamine: studies to evaluate gene mutation in the Ames Salmo- pension contains a synthetic, broad-spectrum, antifungal agent ciclopirox nella/Mammalian Microsome Assay (negative) and Yeast Saccharomyces Cerevisiae (as ciclopirox olamine). The chemical name is 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)- Assay (negative) and studies to evaluate chromosome aberrations in vivo in the Mouse pyridone, 2-aminoethanol salt. Dominant Lethal Assay and in the Mouse Micronucleus Assay at 500 mg/kg (negative). The CAS Registry Number is 41621-49-2. The following battery of in vitro genotoxicity tests were conducted with ciclopirox: a The chemical structure is: chromosome aberration assay in V79 Chinese Hamster Cells, with and without metabolic activation (positive); a gene mutation assay in the HGPRT - test with V79 Chinese Hamster Cells (negative) and a primary DNA damage assay (i.e., unscheduled DNA Synthesis Assay in A549 Human Cells (negative)). An in vitro Cell Transformation Assay in BALB/C3T3 Cells was negative for cell transformation. In an in vivo Chinese Hamster Bone Marrow Cytogenetic Assay, ciclopirox was negative for chromosome aberrations at 5000 mg/kg. Pregnancy Category B: Reproduction studies have been performed in the mouse, rat, rabbit, and monkey, via various routes of administration, at doses 10 times or more the topical human dose and have revealed no significant evidence of impaired fertility or LOPROX Topical Suspension has a pH of 7. harm to the fetus due to ciclopirox. There are, however, no adequate or well-controlled CLINICAL PHARMACOLOGY: Ciclopirox is a broad-spectrum, antifungal agent that studies in pregnant women. Because animal reproduction studies are not always pre- inhibits the growth of pathogenic dermatophytes, yeasts, and Malassezia furfur. dictive of human response, this drug should be used during pregnancy only if clearly Ciclopirox exhibits fungicidal activity in vitro against isolates of Trichophyton rubrum, Tri- needed. chophyton mentagrophytes, Epidermophyton floccosum, Microsporum canis, and Can- Nursing Mothers: It is not known whether this drug is excreted in human milk. Caution dida albicans. should be exercised when LOPROX Topical Suspension is administered to a nursing Pharmacokinetic studies in men with radiolabeled ciclopirox solution in polyethylene woman. glycol 400 showed an average of 1.3% absorption of the dose when it was applied top- Pediatric Use: Safety and effectiveness in pediatric patients below the age of 10 years 2 ically to 750 cm on the back followed by occlusion for 6 hours. The biological half-life have not been established. was 1.7 hours and excretion occurred via the kidney. Two days after application only ADVERSE REACTIONS: In the controlled clinical trial with 89 patients using LOPROX 0.01% of the dose applied could be found in the urine. Fecal excretion was negligible. Topical Suspension and 89 patients using the vehicle, the incidence of adverse reac- Autoradiographic studies with human cadaver skin showed that ciclopirox penetrates tions was low. Those considered possibly related to treatment or occurring in more into the hair and through the epidermis and hair follicles into the sebaceous glands and than one patient were pruritus, which occurred in two patients using ciclopirox suspen- dermis, while a portion of the drug remains in the stratum corneum. sion and one patient using the suspension vehicle, and burning, which occurred in one In vitro penetration studies in frozen or fresh excised human cadaver and pig skin indi- patient using ciclopirox suspension. cated that the penetration of LOPROX Topical Suspension is equivalent to that of DOSAGE AND ADMINISTRATION: Gently massage LOPROX Topical Suspension into Loprox® (ciclopirox) Cream 0.77%. Therapeutic equivalence of cream and suspension the affected and surrounding skin areas twice daily, in the morning and evening. Clini- formulations also was indicated by studies of experimentally induced guinea pig and cal improvement with relief of pruritus and other symptoms usually occurs within the human trichophytosis. first week of treatment. If a patient shows no clinical improvement after four weeks of INDICATIONS AND USAGE: LOPROX Topical Suspension is indicated for the topical treatment with LOPROX Topical Suspension the diagnosis should be redetermined. treatment of the following dermal infections: tinea pedis, tinea cruris and tinea corporis Patients with tinea versicolor usually exhibit clinical and mycological clearing after two due to Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton flocco- weeks of treatment. sum, and Microsporum canis; cutaneous candidiasis (moniliasis) due to Candida albi- HOW SUPPLIED: LOPROX® (ciclopirox) Topical Suspension 0.77% is supplied in 30 cans; and tinea (pityriasis) versicolor due to Malassezia furfur. mL bottles (NDC 99207-022-30), 60 mL bottles (NDC 99207-022-60). CONTRAINDICATIONS: LOPROX Topical Suspension is contraindicated in individuals Bottle space provided to allow for vigorous shaking before each use. who have shown hypersensitivity to any of its components. Store between 5˚ and 25˚C (41˚ and 77˚F). WARNINGS: General: LOPROX Topical Suspension is not for ophthalmic use. US Patent Pending PRECAUTIONS: If a reaction suggesting sensitivity or chemical irritation should occur with the use of LOPROX Topical Suspension, treatment should be discontinued and Prescribing Information as of May 2002 appropriate therapy instituted. Manufactured for: Reference: MEDICIS, The Dermatology Company 1. Data on file, Medicis Pharmaceutical Corporation Scottsdale, AZ 85258 by: Patheon, Inc. Missisauga, Ontario L5N 7K9 CANADA Made in Canada REG TM MEDICIS MEDICIS, The Dermatology Company®

54 First Documented Case of Fournier’s Gangrene After Dilatation and Curettage

Alpesh D. Desai, D.O., Tejas D. Desai, D.O., David Horowitz, D.O.,* Mark Horowitz, D.O.**

Abstract Fournier’s gangrene is a rapidly progressive necrotizing fasciitis of the perineum. Aggressive management is desired in order to prevent mortality. We present a case of Fournier’s gangrene in a 71-year-old female with diabetes. The etiology of her infection was due to a dilatation and curettage for post-menopausal bleeding. Gangrene Severity Index was noted to be 7, which correlated to a 78% survival rate. The patient succumbed 41 days after admission from a pulmonary embolism. This is the first reported case of Fournier’s gangrene following a dilatation and curettage to date. Dermatologists should recognize and be familiar with the signs and symptoms of Fournier’s gangrene in order to prevent morbidity and mortality.

(Key Words: Fournier’s gangrene, necrotizing fasciitis, perineum, dilatation and curettage)

Introduction Case Report associated muscle bogginess and hypertrophy. There are approximately 850 cases of A 71-year-old female was admitted to Fournier’s gangrene (FG). It was first the hospital with a chief complaint of a The following day a pelvic ultrasound described in 1883 by Jean Alfred bloody vaginal discharge that was noticed showed a uterine fibroid mass measuring Fournier, a French venerologist, as a by the patient’s family upon routine 11.8 X 17.1 cm, which had increased in a rapidly progressing gangrene of the penis bathing. The discharge was described as size from a previous study two years and scrotum that occurs in young, healthy green and malodorous. She denied any earlier. A gynecological evaluation by males.1. Today, these infections are often dysuria, nausea, vomiting, or constipa- hysteroscopy demonstrated a fundal seen in debilitated patients with comorbid tion. The patient had been experiencing uterine polyp. No evidence of hyperpla- conditions, most notably diabetes mellitus brown diarrhea a few days prior to admis- sia or fibroids were noted. There were no (DM) and alcoholism. A precipitating sion. cervical abrasions or vaginal lacerations cause is often identifiable.2 Prior to 1979, visualized. Polypectomy and D&C were there were only two cases of FG in Past medical history was significant for performed. Pathologic reports described females reported in the literature.3,4 The hypertension (HTN), congestive heart fail- endometrial cystic hyperplasia with focal incidence of FG has increased in women ure, insulin dependent diabetes mellitus, tubal metaplasia. two past cerebral vascular accidents from 1979 to 1988, with 14% of the One week post D&C, a vulvar abscess patients reported to have been women (CVA), with the most recent CVA resulting in a right-sided hemiparesis; in addition, was noted which communicated with the and this trend represents a divergence left groin toward the anterior superior from the traditional diagnostic criteria for the patient was diagnosed with peripheral 5 vascular diseases and rheumatoid arthri- iliac spine (ASIS). In addition, there were this condition. Fournier’s gangrene is multiple ulcerations on the mons pubis aggressive and has a mortality of 49% in tis (RA). Past surgical history revealed a 5 right hip replacement. Family history was and a white-green, malodorous females. This is significantly greater discharge. The patient’s temperature than male mortality. When patients with significant for HTN, IDDM, and myocar- dial infarction (MI). was 36.1 oC, pulse 140, and respiratory obstetrical causes were excluded, the rate of 24. Hematological studies overall mortality of both sexes was not Physical examination revealed the revealed a white count of 27.8 th/cm and significantly different. This suggests that patient to be 5’11’’ and 168 lbs., BP a hemocrit of 23.3%. Electrolyte levels the pathophysiology of this condition is 136/79. pulse 95, respiratory rate 20, and were as follows: sodium 133 mmol/L, similar in both sexes. We present a temperature was 36.8 oC. Head, eyes, potassium 3.8 mmol/L, bicarbonate 22 unique case of FG in a 71-year-old ears, nose, and throat examination mg/100mL, and serum creatinine 0.8 female status post dilatation and revealed bilateral cataracts and cerumen mg/100mL. Because of the notable skin curettage (D&C) with insulin dependent impaction bilaterally. The neck, heart, changes in the vulvar region, a DM (IDDM), congestive heart failure lungs, and abdomen were unremarkable. dermatology consult was obtained and a (CHF), and peripheral vascular disease An examination of the extremities diagnosis of Fournier’s gangrene was (PVD). revealed right-sided hemiparesis with the made due to edema, erythema, necrosis, right hand held in a flexed position. Left crepitus, and bullae formation. Surgical Alpesh D. Desai, D.O.20911 Earl St., Suite 300, muscle strength of upper and lower Torrance, CA 90503, 310-540-3636 (office), 310-214-9813 consult was also obtained and the patient (fax), [email protected] extremity showed weakness of 4/5. The was taken to surgery. A right radical Tejas D. Desai, D.O. genital, pelvic, and rectal examination *David Horowitz, D.O., Program Director hemi-vulvectomy was performed with **Mark Horowitz, D.O., Program Director were unremarkable. Osteopathic struc- dissection carried down to the right Coast Dermatology tural examination revealed a type II dys- femoral sheath and the upper extent to Western University of Health Sciences function on the right from T2-T12 with

(The Journal of the American Osteopathic College of Dermatology, Vol. 1, No. 1, pp 55-57, June 2003) 55 the right side of the abdomen. The surgi- cause to be an episiotomy.5 Most this case. Fecal and urinary diversion are cal wound was left open with packing. A patients are affected by severe comorbid recommended if the source of the FG is right direct, indirect, and femoral hernia states, such as IDDM, alcoholism, or believed to be genitourinary or colorectal. were also identified. intravenous drug use, all of which hinders Initially, family wishes were against the immunologic defenses.3 Although a rare implementation of a colostomy. Since the The patient was placed on metronida- condition, FG must be aggressively man- patient had total incontinence of her anal zole, fluconazole, and piper- aged due to its high morbidity and mortal- sphincter and bladder, it was critical to acillin/tazobactram, along with daily ity. The gangrene can spread rapidly into utilize rectal and urinary catheters, dressing changes with half strength Dakin the abdomen through the inguinal canal thereby preventing re-infection into the solution. Pathological reports identified or spread in between Colles’ and debrided areas. After continued the excised right vulva measuring 17.0 x Scarpa’s fascia. Symptoms of FG include discussions with the family and continued 15.0 x 5.5 cm. It was described as gelati- localized perineal pain, fever, and disori- contamination of the wound by fecal nous and purulent with no nodules, entation. Dermatologic changes are the material, the family elected for a diverting masses, or hemorrhage. The deep most apparent and should be identified colostomy. In this situation, the use of a margin of the excised tissue showed an immediately by a dermatologist. The skin colostomy appeared logical and practical; area of pus-like change consistent with changes include pale erythema, with or however, a study by Clayton et al.16 the anterior surface measuring 4.0 x 2.5 without crepitance and, subsequently, a showed a greater survival rate in patients cm. This specimen also revealed blue-to-brown ecchymotic discoloration.13 that did not undergo a colostomy necrosis, suppurative inflammation, and Pain usually is prominent early in the compared to patients that elected for this gangrenous pockets, consistent with course of this condition, but gradually is procedure. fasciitis. Cultures obtained immediately replaced by numbness and analgesia due preoperatively indicated: Enterococcus to compression and destruction of the Treatment with hyperbaric oxygen was species, alpha-hemolytic Streptococci, cutaneous nerves. In advanced stages of used because HBO facilitates phagolytic Lactobacillus species, and yeast. Vulvar the disease, prostration may be severe. function, promotes angiogenesis, and cultures revealed: Enterococcus species, Bacteremia is common, but not uniformly assists with wound healing. It also has a alpha-hemolytic Streptococci, and direct toxic effect on the anaerobic present. This patient illustrated the 17 Escherichia coli. majority of these signs and symptoms organisms by increasing free-radicals. after her D&C. One study demonstrated a zero mortality The patient received daily hyperbaric rate in 11 patients diagnosed with FG that oxygen (HBP) treatments to improve We believe that this patient’s infection underwent HBO therapy.17 Care must be granulation of the extensive debridement developed as a result of a vaginal abra- taken with diabetic patients using HBO zone for 21 days. Twenty one days post- sion from the D&C that subsequently therapy, since this procedure can cause operatively, the patient and family agreed became infected and burrowed between hypoglycemia.17 Kovalcik et al.18 reported for a diverting colostomy. A left ovarian Colles’ and Scarpa’s fascia. This site a rapid drop of fever and leukocytosis mass was discovered resulting in a left was undoubtedly complicated by her after HBO treatment was initiated. oophorectomy along with a supracervical IDDM, which resulted in susceptibility to hysterectomy. bacterial infections, defective phagocytic The extent of body surface involved is function, increased incidence of urinary not a statistical factor when assessing A radical debridement was also mortality.16,19 However, patients who are performed and a full thickness skin flap tract infections secondary to diabetic neuropathy, and small vessel disease.14 diabetic and have FG seem to have an was constructed to allow for closure of increased mortality rate of two to three the right vulvar region. Pathological Moreover, the previous CVAs contributed 15 to the maintenance of this infection by times higher. Another study showed a report noted the uterus to contain a 14.0 x 52% mortality rate in FG caused by surgi- 12.0 x 9.5 cm subserosal leiomyoma, with impairing adequate fecal and urinary function. As a result, urinary and fecal cal procedures and a significantly greater hyalinization, ischemia, and cystic mortality rate for females when compared degeneration. The endometrium showed material were constantly being introduced 5 into the abrasion site. After a review of to males. Other prognostic factors of hyperplasia without atypia. The ovary mortality include blood urea nitrogen mass was predominately adipose tissue. the literature, we could not identify a known cause of FG after D&C. (BUN) greater than 50 mg/dl upon pre- Nine days after skin flap closure, the sentation and advanced age.16 Interest- patient sustained an acute pulmonary Fournier’s gangrene is primarily a ingly, FG has a lower mortality rate when embolus resulting in her demise. multi-organism infection. Typical bacteria compared to other forms of necrotizing Discussion include E. coli, Bacteriodes, Proteus, fascitis.3

anaerobic streptococci, and Clostrid- 19 Fournier’s gangrene is a rapidly - ium.5,15 Most cases reviewed show E. coli Laor et al. created a Fournier’s Gan- progressing fasciitis of the perineum. The to be the most prevalent organism.15,16 grene Severity Index (FGSI), which is terminology used to describe these Although a study has shown no statistical based on the treatment outcomes of 30 infections have expanded over the years. significance between bacteriologic patients over a 15 year period. They Examples include synergistic gangrene, findings and mortality rate, broad used 9 parameters and denoted a score necrotizing fasciitis,6 and synergistic spectrum antibiotics must be utilized due for each parameter (Table 1). According necrotizing cellulitis.7 The initial portal of to FG’s rapid and fulminant course.16 A to this index, a FGSI score greater than 9 entry for FG most commonly occurs from reasonable choice would be the corresponds to a 75% probability of local trauma, extension of an urinary tract combined use of gentamycin and death, whereas a score of less than 9 infection, or extension of a perianal infec- metronidazole. With proper surgical corresponds to a 78% survival rate. Our tion.3 There have been many cases debridement, antibiotic therapy is not patient scored a 7 on the FGSI and, associated with other mechanisms, such necessary after 5-7 days.3 unfortunately, succumbed to a pulmonary as Crohn’s,8 rectal adenocarcinoma,9 embolus. ulcerative colitis ,10 operative procedures The ability of this patient to fight infections was severely hampered by her Although not used in the treatment such as circumcision, vasectomy, and protocol for this case, some clinicians hernia repair.13 A review of the literature IDDM. As noted, urinary and fecal control were critical issues in the management of believe in the application of unprocessed indicated the most common surgical honey. Efem20 managed 20 consecutive

56 FOURNIER’S GANGRENE AFTER DILATATION AND CURETTAGE Table 1. Fournier’s gangrene severity index High Abnormal Values Normal Low Abnormal Values

l Point Assign. +4 +3 +2 +1 0 +1 +2 +3 +4

Temp. (C) >41 39-40.9 -- 38.5-38.9 36-38.4 34-33.9 32-33.9 30-31.9 <29.9 Heart rate >180 140-179 110-139 -- 70-109 -- 55-69 40-54 <39 Resp. rate >50 35-49 -- 25-34 12-24 10-11 6-9 -- <5 Serum Na >180 160-179 155-159 150-154 130-149 -- 120-129 111-119 <110 Serum K >7 6-6.9 -- 5.5-5.9 3.5-5.4 3-3.4 2.5-2.9 -- <2.5 Serum Cr >3.5 2-3.4 1.5-1.9 -- 0.6-1.4 -- <0.6 -- -- Hemocrit(%) >60 -- 50-59.9 46-49.9 30-45.9 -- 20-29.9 -- <20 WBC >40 -- 20-39.9 15-19.9 3-14.9 1-2.9 -- <1 Serum HCO3 >52 41-51.9 -- 32-40.9 22-31.9 -- 18-21.9 15-17.9 <15 --Bold Print indicates patient’s values. These added to a FGSI score of 7. Table adapted from Laor et al. cases of FG with systemic antibiotics and 7. Stone, H.L., Martin, J.D. Synergistic necrotizing cellulitis. Conclusion Ann Surg 1972; 175: 702-11. daily application of unprocessed honey to 8. Brings, H.A., Matthews, R., Brinkman, J., et al. Crohn’s the infection site (Group A) and compared Our case of FG was unique in that it disease presenting with Fournier’s gangrene and occurred in a female after a D&C, which enterovesical fistula. Ann Surg. 1997; 63: 401-5. them to 21 similar cases of FG (Group B) 9. Gamagami, R.A., Mostafavi, M., Gamagami, A., et al. managed by traditional treatment (incision to our knowledge and review of the Fournier’s gangrene: An unusual presentation for rectal and drainage, debridement, wound literature has never been documented. carcinoma. Am J Gastroenterol 1998; 93: 657-8. 10. Ardire, L., Mrowczynski, E. necrotizing fasciitis: Case of a excision, skin grafting). Three deaths FG should be considered in any nursing dilemma. Ostomy Wound Management. 1997; occurred in Group B, while no deaths debilitated patient following a gynecologi- 5: 30-45. 11. Kohagura, K., Sesoko, S., Tozawa, M., et al. A female were recorded in Group A. In addition, cal procedure with a fever of unknown case of Fournier’s gangrene in a patient with lupus Group A patients did not have to undergo origin. Dermatologists, in particular, nephritis. Nippon Jinzo Gakkai Shi (Japanese Journal of should be familiar with the skin changes Nephrology). 1998; 40: 354-8. any extensive surgical operations and the 12. Martinelli, G., Alessandrino, E.P., Bernasconi, P., et al. associated risks (i.e., general anesthesia, associated with this condition. Proper Fournier’s gangrene: A clinical presentation of necrotizing post-operative complications, etc.). The postoperative diagnosis and recognition fasciitis after bone marrow transplantation. Bone Marrow Transplant. 1998; 22(no.10): 1023-6. actions of honey are multiple which are critical to the prevention of 13. Kearney, G.P., Carling, P.C. Fournier’s gangrene: An include the ability to chemically sterilize complications. The hallmark of treatment approach to its management. J. Urol. 1983;130 : 695-8. 14. Thorton, G.F. Infections and diabetes. Med Clin North Am infected wounds, decrease edema from has been adequate resuscitation, 1971;55: 931. the wound site, induce enzymatic drainage, debridement, and systemic 15. Fialkov, J.M., Watkins, K., Fallon, B., et al. Fournier’s antibiotics and HBO therapy. Despite gangrene with an unusual urologic etiology. Urology. debridement of necrotic tissue, and 1998;52 : 324-7. stimulate epithelialization.20 Along with its acceptance of this approach to treatment, 16. Clayton, M.D., Jackson, E.F., Sharifi, R., et al. Patients cost effectiveness and noninvasive the mortality rate of 20% to 40% has with necrotizing fasciitis of male genitalia. Surg, Gynecol, 21 and Obstet. 1990; 170: 49-55. implementation, honey may revolutionize remained constant. 17. Pizzorno, R., Bonini, F., Donelli, A., et al. Hyperbaric the treatment of FG in the future. oxygen therapy in the treatment of Fournier’s gangrene in Bibliography 11 male patients. J. Urology. 1997; 158: 837-40. Fournier’s gangrene is a rare disease, 1. Fournier, AJ. Gangrene foudroyante de la verge. 18. Kovalcik, P.J., Jones, J. Necrotizing perineal infections. Semaine Med 1883; 3: 345-7. Am Surg. 1983 49: 163-6. however, physicians and other health 2. Barkel, D.C., Villalba, M.R. A reappraisal of surgical 19. Laor, E., Palmer, L.S., Tolia, B.M., et al. Outcome care workers are vital in early recognition management in necrotizing perineal infections. Am. Surg. prediction in patients with Fournier’s gangrene. J Urol. 1986; 52: 395-7. 1995; 154: 89-92. of this condition. Delay in diagnosis or 3. Jones, R.B., Hirschmann, J.V., Brown, G.S., et al. 20. Efem, S.E. Recent advances in the management of recognition of perineal infection can be Fournier’s syndrome: necrotizing subcutaneous infection Fournier’s gangrene: Preliminary observations. Surg. deadly. There should always be a of the male genitalia. J Urol. 1979; 122: 279-82. 1993; 113(2): 200-4. 4. McCrea, L.E. Fulminant gangrene of the penis. 21. Shupak, A., Shoshani, O., Goldenberg, I., et al. suspicion of FG in a debilitated patient Clinics1945; 4: 796-829. Necrotizing fasciitis: An indication for hyperbaric with fever of unknown origin. A study of 5. Stephens, B.J., Lathrop, J.C., Rice, W.T., et al. Fournier’s oxygenation. Surg. 1995; 118(5): 873-8. gangrene: Historic (1794-1978) versus Contemporary 12 patients with FG showed that the (1979-1988) differences in etiology and clinical perineum was improperly examined importance. Am. Surg. 1993; 59: 149-154. 2 6. Rea, W.J., Wynck, W.J. Necrotizing fasciitis. Ann Surg. during the assessment of a patient. 1970; 172: 957-64.

DESAL, DESAL, HOROWITZ, HOROWITZ 57 Stevens-Johnson Syndrome: Treatment with Intravenous Immunoglobulin, A Case Report and Review

Charmaine Jensen, D.O., Schield Wikas, D.O., Monte Fox, D.O.

ABSTRACT:

Stevens-Johnson Syndrome (SJS) is a mucocutaneous disorder due to an immune-complex-mediated hypersensitivity reaction. It is characterized by prodromal symptoms followed by mucous membrane erosions then widespread vesicles arising on erythematous macules. More than fifty percent of SJS are related to drug exposure. In contrast, there are very few reports of SJS occurring after vaccination. Treatment of SJS is usually supportive. Reports of the usage of intravenous immunoglobulin in SJS are few. We report a patient who received Amiodarone, Allopurinol and influenza vaccine within one month of the onset of prodromal symptoms of SJS. Treatment with intravenous immunoglobulin resulted in significant improvement. This paper reviews SJS and how to differentiate it from Erythema Multiforme and Toxic Epidermal Necrolysis based on clinical findings. In addition, the usage of intravenous immunoglobulin in SJS will be discussed.

Stevens-Johnson syndrome (SJS) is a His past medical history was Laboratory test results were as follows: mucocutaneous disorder due to immune- complicated by oxygen and steroid WBC 3.1 (nl 4.5 Ð 11.0 K/CU MM), complex-mediated hypersensitivity dependent COPD, CAD, HTN, CVA with Platelets 142 (nl 150-450 K/CU MM), reaction. It is characterized by mucous minimal deficits, BPH, chronic renal neutrophils 33 (nl 45-75%), Band % 9 (nl membrane erosions and widespread insufficiency, gout and atrial fibrillation. 0-7%), lymph % 41 (20-40%), mono % small blisters that arise on erythematous He had no history of blistering diseases. (2-10%). BUN was 38 (nl 7-26 mg/dl) and or purpuric macules.1 It most commonly He had no known drug allergies. creatinine 1.8 (0.6-1.5 mg/dl). LFT was occurs during the second through fourth unremarkable. His chest and abdominal decades of life. It affects both sexes with Medications included Lotrel (amlodip- radiological studies were unremarkable. a male to female ratio of 2:1. The ine/benazepril), Lasix (furosemide), incidence is 0.4-1.2 per million person- Zaroxolyn (metolazone), K-dur (potas- During the course of his hospital stay, years. Treatment is usually supportive. sium chloride), Coumadin (warfarin), his fever continued to rise (Fig. 1). In The use of corticosteroid therapy is Vistaril (hydroxyzine), Proventil inhaler addition, he developed conjunctival injec- controversial.2 Reports of usage of intra- (albuterol), Imdur (isosorbide mononi- tion on day 4. At this time Neosporin venous immunoglobulin (IVIg) in SJS are trate), prednisone and Uniphyl ophthalmic drops were instituted for his few. It has been reported in an immuno- (theophylline) during the last five years. conjunctivitis and Levaquin (levofloxacin) competent adult3, two patients with AIDS4 Nineteen days prior to admission, the for the fever due to presumed infection. and fifteen pediatric cases5,6,7,8. We report patient started Allopurinol for his left toe Blood cultures were obtained. a patient with SJS who was treated with gout. Moreover, Amiodarone was added two days before having his symptoms. His oral intake had declined due to both intravenous steroids and mouth pain and dysphagia. Because he immunoglobulin with significant improve- Family history was unremarkable. was prednisone dependent and his ment. Physical exam on the day of admission oropharynx had extensive whitish-yellow- A Case Report revealed a well-developed male in no ish exudates with bloody weeping dis- acute distress with a temperature of 99.3 charge, oropharyngeal candidiasis was A 67 year old African American male Fo.. His mucous membranes were dry strongly considered. At this time, he was was admitted in the hospital for gastroen- with no ocular, oral and genital lesions. started empirically on Mycelex teritis and dehydration. He had a two day Dermatological exam was unremarkable. (clotrimazole) troches and intravenous history of recurrent nausea, vomiting, diarrhea and abdominal pain. He received an influenza vaccine two days prior to admission and he has complained of malaise since then. He has been receiving influenza vaccine yearly for five years without any problems. He denied fever, chills, cough, myalgia or cold sores.

Charmaine Jensen, D.O..Dermatology Resident, Second FIGURE 1: TEMPERATURE IN FAHRENHEIT Yea, Cuyahoga Falls General Hospital, Cuyahoga Falls, Ohio Day 4 of admission- Fever continued. Onset of ocular lesions. Levaquin was started. Schield Wikas, D.O., Dermatology, Program Director, Day 5 of admission- Onset of oral lesions. Cuyahoga Falls General Hospital, Cuyahoga Falls, Ohio Day 7 of admission- Transfer to ICU due respiratory failure. Monte Fox, D.O., Dermatology, Program Director, Rich- mond Heights Hospital, Richmond Heights, Ohio Day 8 of admission- Onset of cutaneous lesions.

58 (The Journal of the American Osteopathic College of Dermatology, Vol. 1, No. 1, pp.58-67, June 2003) Diflucan (fluconazole) after obtaining gen mask is placed, reveal epidermal bacterial and fungal throat cultures. Due detachment. He had well-defined ero- to his worsening clinical picture, Levaquin sions on his upper and lower lips with was discontinued. HIV 1 antibody was overlying hemorrhagic crusts (Fig. 3). negative by EIA screen. His buccal mucosa, gingival and His oxygen requirement increased and his clinical picture declined on the Fig. 4. Purulent erosions on scrotum seventh day. He was transferred to the intensive care unit for pending respiratory failure, difficulty swallowing and clearing his secretions. He was started on total parenteral nutrition due to his impaired alimentation. Fig. 7- Violaceous macules coalesc- On day 8, he developed a “petechial ing into patches with dusky centers on rash” on his abdomen, arms and legs. abdomen. Erosions on his scrotum were also evident and Silvadene cream was started. At this time SJS was suspected and all of his medications were all discontinued. He was started on intravenous Solume- drol 30mg every 12 hours. His “rash” oropharynx had bright red erosions continued to spread to his hands and covered with yellow exudates. His feet. His right third finger became conjunctiva were severely injected with necrotic and orthopedics was consulted yellow discharge. Genital mucosa had for debridement. purulent erosions (Fig. 4). On the tenth day, dermatology was In addition, he had widespread viola- consulted for suspected SJS. Physical examination revealed an ill-appearing, Fig. 8- Erythematous patches on plan- febrile 286lb man (Fig. 2) with multiple tar aspect of feet. erosions on erythematous base on his forehead and cheeks. He also had ill- defined violaceous patches with dusky center on his cheeks. Points of contact, such as the nasal bridge where his oxy-

Fig. 2 Ð Ill appearing 67yo male in moderate distress.

Fig. 5- Violaceous patches on arms.

Fig. 9- Erythematous patches on palmar aspect of hands.

coalesced into patches. These lesions were tender to touch. Fig.3. Hemorrhagic crust overlying His palms and soles were covered erosions on lips with ill-defined dusky to erythematous patches (Fig. 8 and 9). There were violaceous vesicles on erythematous base on his cheeks. On his forehead, there was evidence of Fig. 6- Erythematous macules with erosions with overlying crusts. (Fig. 10) dusky centers on chest. His upper back had coalescing violaceous macules with epidermal ceous patches with dusky centers on detachment. It involved less than 10% of bilateral upper and lower extremities (fig. his body surface area (BSA). Clinical 5), chest (fig. 6) and abdomen (fig. 7). diagnosis of Stevens-Johnson syndrome His right third finger had well-defined was made. Silvadene cream was erosions. Some erythematous macules discontinued. Then, he was immediately treated with IVIg 500mg/kg/day or 65

JENSEN, WIKAS, FOX 59 ethasone) solution to swish and gargle four times a day. His lips were cleansed gently with sterile normal saline. His secretions were handled by gentle suc- tioning. For symptomatic relief of his genital erosions, Burrow’s soaks and sitz bath were used. His ocular treatment consisted of pred forte and Tobrex (tobramycin) eye drops. His cutaneous erosions were gently cleansed with sterile normal saline and followed by bacitracin ointment twice a day. Skin biopsies were performed for frozen section, H&E and direct immuno- fluorescence and fresh tissue culture. Fig. 10 - Violaceous vesicles on ery- Histological examination showed inflam- thematous base on cheeks. Erosions matory cell infiltrate at the dermal-epider- with overlying crusts on forehead. mal junction Fig. 15- 24 hours after1st dose of Fungal and viral cultures from his oral, IVIg. Healing erosions on oral mucosa. genital mucosa and fresh tissue biopsy Decreased hemorrhagic crust. specimen revealed no growth. Oral and Improved conjunctival injection. third digit bacterial cultures were positive for Staphylococcus aureus. His genital cultures were positive for Staphylococcus haemolyticus. Unasyn (ampicillin/ sulbac- tam) were added for empiric treatment. Twenty four hours after IVIg treatment, he became afebrile and started feeling Fig. 11 - Inflammatory cell infiltrate at better (Fig. 14). Twenty four hours after the DEJ. the first IVIg treatment, his mucosal lesions have dramatically improved. The erosions and hemorrhagic crusts have decreased (Fig.15). His palmar and plantar lesions have also improved. (Fig. 16). However, on his abdominal and upper extremities, atypical target lesions were more apparent. Fig. 16. Improved plantar lesions 24 These are represented by round macules hours after 1st dose of IVIg. with two zones of poorly defined border and central vesiculous central zone. renal function normalized without requir- (Fig.17, 18.) ing hemodialysis. He was discharged 15 Fig. 12 - Band-like lymphocytic Infil- days after starting IVIg in stable condition. trates. He also remained afebrile. Four days (Table 1) after his IVIG treatment, TPN was discontinued since he started eating solid food. Disscussion and Clinical Unasyn was also discontinued since his right finger had improved. Because of Review his history of chronic renal insufficiency, Stevens-Johnson Syndrome was first his renal function was carefully moni- described by Stevens and Johnson in 1922 tored. His BUN and creatinine had as a new eruptive fever associated with increased to a maximum of 152 and 5.0 severe erosive stomatitis and ocular lesions respectively. At this time nephrology was in 2 children.10 The first case reported was consulted for acute renal failure. The an 8 year old febrile boy with edematous patient was treated with IV fluids and his eyelids and thick purulent discharge in his

Fig. 13 - Necrotic keratinocytes at the lower epidermis. g/day for four days. Ophthalmology, Ear/Nose/Throat, pulmonology, gastroenterology were all Fig. 14. Temperature in Fahrenheit. involved in his care. His oral mucosa was Day 10 of Admission: Intravenous immunoglobulin started. 0.5g/kg x 4 days. treated symptomatically with Vibramycin Day 11 of Admission: Mucosal lesions improving. Temperature declined. (doxycycline) liquid/mycostatin (nystatin) Day 15 of Admission: Cutaneous lesions with atypical targets. suspension/Benadryl/Decadron (dexam- Day 25 of Admission: Patient discharged to home.

60 STEVENS-JOHNSON SYNDROME eyes. Scattered diffusely on his face and Bateman described the first erythema body were multiple purple papules, some multiforme (EM) target lesion in 1814. In with necrotic centers. The other case 1956, “toxic epidermal necrolysis” was reported by Stevens and Johnson was a 7 used by Lyell to describe patients with year-old boy with fever, conjunctivitis and epidermal necrosis resulting in skin sur- hemorrhagic cutaneous lesions that were face looking scalded.11 evenly distributed on his body. The patient suffered total blindness thereafter.

Fig. 17. 24 hrs. after 1st dose of IVIg. Atypical targets with vesiculous central cone and two surrounding zones.

Table 2. Course of Stevens- Johnson Syn- drome

Fig. 18. 24 hrs after 1st dose of IVIg. Atypical targets with with illdefined borders.

Table 1. Hospital Course

Clinical Features Patients with SJS usually present with prodromal symptoms of fever, cough, sorethroat, headahe, vomiting or diarrhea (Table 2). These symptoms precede mucocutaneous lesions by 1-14 days. In our patient, his prodromal symptoms preceded his mucocutaneous lesion by 6 days. Patients most often feel ill and receive antimicrobial and anti- inflammatory treatment that may cause difficulty in determining the offending factor later on.12 In contrast, prodromal symptoms are usually absent in erythema multiforme (EM). About 90% of patients with SJS or TEN will have a sudden onset of mucosal lesions that usually precede cutaneous lesions. His mucosal lesions preceded his cutaneous lesions by 4 days. The oral cavity is most often affected, particularly the buccal mucosa, hard and soft palate and vermillion border of the lips. Patients may complain of burning sensation and soreness of the mouth. Edema and erythema then occur. Finally, blisters occur and sometimes rupture forming red erosions or ulcers. The characteristic hemorrhagic crusts cover the lips. These oral lesions are extremely painful and, if severe enough, cause difficulty swallowing and hypersalivation. Severe cases may also involve the tracheal, bronchial and gastrointestinal epithelium13 as occurred in our patient. Conjunctival involvement is present in 85% of SJS-TEN patients.14 Symptoms

JENSEN, WIKAS, FOX 61 include photophobia, burning of eyes and blindness. Conjunctival lesions may present as hyperemia, inflammation, painful erosions, and even corneal scarring.15 Genital involvement present as hemorrhagic or purulent erosions of the glans penis in males or vulva and vaginal cavity in females.12 The anus is less frequently involved. Patients may complain of dysuria. Cutaneous lesions begin as erythematous to violaceous macules that may develop into vesicles or bullae. The most frequent complaint is asthenia and skin tenderness. The lesions begin diffusely on the face, neck and central trunk areas17 that later on spread to the extremeties. Palms, soles, dorsum of hands, extensor surfaces are most 8 Fig. 19. Body surface area. Distribution of detachment in SJS-TEN. *From Bastuji commonly affected. The initial lesions et al. Clinical Classification of Cases of toxic epidermal necrolysis, Stevens-John- are irregularly shaped erythematous to son Syndrome and Erythema Multiforme. Arch Dermatol. 1993;129:92-96. violaceous macules with dusky centers. (with permission) Individual lesions represent “atypical targets” which are ill-defined purpuric Stevens-Johnson syndrome is some- macules with a central blister. These times called erythema multiforme major “atypical targets” resemble EM target causing more confusion. It has been sug- lesions, however, in SJS, only two zones gested that EM with mucosal lesions and are identified. Erythema multiforme SJS are two distinct clinical entities. If target lesions consist of three concentric classification is based only on the pattern zones. The lesions of SJS are often and distribution of skin lesions, SJS larger and flatter than target lesions. A should be used for a syndrome character- positive Nikolsky sign is also present on ized by mucous membrane erosions and erythematous areas.16 The lesions have a widespread small blisters that arise on tendency to enlarge and spread. The erythematous or purpuric maculae that lesions have a striking tendency to are different from classic targets of EM.20 coalesce.12 Confluence is widespread in TEN while only limited to chest, neck and Typical target is characterized by three face in SJS. The epidermis may detach different zones: following minimal trauma exposing oozing 1. erythematous central disc with or and intensely red dermis. Pressure without blister points such as the back and shoulders Fig. 21- SJS atypical target lesions. are common areas of epidermal 2. edematous intermediate ring *From Assier et al. Arch Dermatol detachment. Maximal disease expres- 1995; 131:541. sion is usually reached within 4 to 5 3. erythematous outer ring (Fig. 19,20 days.12 20) The etiology of SJS is most likely drug What’s in a Name? The target lesions of SJS are consid- exposure accounting for >50% of ered atypical due to the lack of the third patients. Eighty to ninety five percent of There is disagreement whether EM, concentric ring.1 (Fig. 21) The mucosal TEN cases are drug induced. More than SJS and TEN are different diseases or lesions of EM and SJS are similar. It 100 different compounds have been 19 variants within a continuous spectrum. A should be noted that SJS is usually asso- thought to cause SJS-TEN. The most recent clinical classification has been ciated with systemic symptoms and inter- frequently associated drugs are listed on proposed as follows: nal organ involvement while EM is not. Table 4.9 Other drugs have also been (Table 3). BULLOUS EM: detachment <10% of reported including phenytoin, penicillin, body surface area (BSA) nystatin (Mycostatin)21, azithromycin and SJS: detachment <10% of BSA trimethoprim-sulfamethoxazole3 , OVERLAP SJS/TEN: detachment 10-30% of dapsone, cocaine, doxycycline22, BSA Widespread pur- Fig. 20 - Erythema terbinafine23, griseofulvin24, etretinate25 puric macules or flat multiforme target ciprofloxacin26 and theophylline. The most atypical targets lesions. common drugs include co-trimoxazole, TEN with SPOTS: detachment >30% of *From Dermochromes- Fansidar-R-sulfadoxine, pyrimethamine BSA Widespread pur 1, Kingsbury J. 1914 puric macules or flat and carbamazepine. Stevens-Johnson atypical targets syndrome/Toxic epidermal necrolysis caused by drugs usually begin one-three TEN w/o SPOTS: detachment >10% of BSA Large epidermal weeks after initiation of therapy. How- sheets and without ever, rechallenge with the same or purpuric macule or related drug results in more rapid onset of target . (Fig. 19) SJS.27 It has been suggested that EM is

62 STEVENS-JOHNSON SYNDROME vaccine since they have been started less than three weeks prior to his prodromal symptoms. Levaquin was started after the onset of his oral lesions. Amiodarone is an efficacious antiarrhythmic drug that was given to the patient for his atrial fibrillation. Yung et al described a 71-yo female who developed TEN three months after commencing Amiodarone.58 Other dermatological side effects of Amio- darone include photosensitivity, allergic Table 3. Comparison of Clinical Features of EM and SJS-TEN rash and blue-gray discoloration. Allop- urinol has been associated with SJS. Patients with chronic renal failure are sus- Table 4. Drugs associated with Stevens-Johnson Syndrome and Toxic Epidermal ceptible to developing severe reactions Necrolysis. from Allopurinol. Chan et al suggests that a lower dose of Allopurinol should be given to renally compromised patients.59 Our patient also received an influenza vaccine less than 24 hours prior to his prodromal symptoms. Rechallenge may have resulted in a more rapid onset of SJS. However, a link between SJS and vaccines has not been established. Pathogenesis: The pathogenesis of SJS is unclear. There is evidence that SJS is immune complex-mediated. Adhesion molecules and HLA-DR antigens expressed by keratinocytes direct cytotoxic T cells in

Table 5. Other Causative Factors

*Together these drugs account for approximately two thirds of the cases attributed to drugs in large series in France, Germany and the United States. #This drug is no longer marketed. SOURCE: Roujeau JC, Stern R, Severe Adverse Cutaneous Reactions to Drugs. N Eng J Med 1994; 331:1272-1285. mostly related to herpes while SJS was SJS/TEN and vaccination cannot be almost always related to drugs.20 established by this study.”33 The patient who received the influenza vaccine was Less commonly, SJS is due to 24 year old female developed SJS the infection such as herpes simplex virus, same day she received the vaccine. Our Mycoplasma pneumoniae, influenza, patient received influenza vaccine and lymphogranuloma venereum, histoplas- developed prodromal symptoms the mosis, Epstein-Barr virus, enterovirus, same day. He had received yearly 29 varicella and cholera (Table 5). Other influenza vaccine for 7 years without any etiologies include malignancy and problems. However, it is very difficult to idiopathic. The SJS association with identify the causative factors of his SJS malignancy is usually due to post since he had been on other drugs that DTP, diphtheria, tetanus, whole cell 60 radiation therapy for underlying cancer have been reported to cause SJS pertussis, Hib, Haemaphilus influenza or methotrexate for underlying including Allopurinol, Amiodarone and type b; MMR. measles, mumps, 61 non-Hodgkin’s lymphoma . Very few Theophylline. However, Allopurinol was rubella: OPV, oral polio vaccine. reports of SJS after vaccination have started 19 days prior to prodromal * A causal link cannot be established. been reported including measles symptoms. Amiodarone was started 2 30,31 immunization and small pox days prior to prodromal symptoms. The the destruction of keratinocytes.34 32 vaccinations . Ball et al identified six patient had been on Theophylline for Evidence also shows immune complex probable cases of SJS/TEN after about 5 years. In addition, for his fever, deposition, namely granular IgM and C3, vaccination (hepatitis B (2), influenza (1), he received Levaquin six days after on superficial cutaneous vasculature in varicella (1), (Haemophilus influenzae receiving immunization. Therefore, this EM.35 Clinical manifestations of SJS type b/ measles, mumps and rubella complicated the clinical picture even mimick Kawasaki disease and toxic shock vaccines) (1), (Diphtheria, tetanus, more. syndrome both of which are associated pertussis, H. influenza type b, rubella and with high-titer antibodies directed against oral polio vaccines) (1). However, it was Our patient’s SJS was most likely due superantigens. It is then possible that stated that “a causal link between to Amiodarone, Allopurinol or influenza SJS may at least partly, be mediated by

JENSEN, WIKAS, FOX 63 dysfunctional immune stimulation caused talization for TEN in a burn unit.40 Persis- aeruginosa, Staphylococcus aureus or by superantigen production and therefore tent erosions may occur in the oral Candida albicans. Fortunately, our amenable to IVIG therapy.36 However, it mucosa resulting in chronic dysphagia. patient did not develop sepsis. He was has been proposed that it may be linked admitted back to the hospital 5 months to abnormal detoxification of the offending later for cardiac problems. drug.37 Associations with HLA-B12 also suggests genetic susceptibility.38 The mortality rate of SJS is about 5-15%41,57 but about 30% for TEN.41 Histopathology Factors that suggest poor prognosis include old age, increased BUN Epidermal injury may present as sat- concentration, neutropenia and telite-cell necrosis. It may progress to extensive cutaneous and visceral eosinophilic necrosis of the basal and involvement. Our patient had all factors: suprabasal layers. In TEN, there is evi- 67yo, neutropenia, elevated BUN, dence of full-thickness epidermal necrosis extensive cutaneous involvement and and subepidermal split above the base- visceral insult (tracheobronchial and ment membrane. There is scant amount alimentary tract). Interestingly, prognosis of inflammation in the dermis. is not affected by the dose or type of the culprit drug.9 In addition, HIV infection Differential Diagnosis Fig. 22- 5 months after IVIg treatment. does alter prognosis. The differential diagnosis includes Hyperpigmented patches on abdomen generalized fixed drug eruption with its ill Management defined large erythematous patches, Management of SJS is multidiscipli- bullae or erosions, staphylococcal nary. (Table 7). First, withdrawal of sus- scalded skin syndrome especially in pected drug(s) should be done. All drugs, infants and pemphigus vulgaris with its especially those initiated within one oral lesions. Direct immunoflourescence month of reaction should be suspected.9 can rule this out. Erythema multiforme Because patients with SJS suffer from can be ruled out by causative factors, typical target lesions and absence of Table 6. COMPLICATIONS OF SJS internal organ involvement. Kawasaki disease with conjunctivial injection and sloughing of hands and feet can mimick SJS. Acute onset paraneoplastic pemphigus, acute graft versus host disease, viral exanthems and exfoliative dermatitis are also good considerations. Fig. 23 - 5 months after IVIg treat- Workup ment. No residual lesions on palms. Laboratory workup should include complete blood count since patients with SJS/TEN are usually lymphopenic and anemic. Neutropenia also suggests a poor prognosis. Electrolytes should be checked since epidermal fluid losses is common. Renal function should be monitored since prerenal azotemia is another common finding as seen in our patient. Bacterial colonization and sepsis need to be ruled out so cultures of blood, urine, wounds and sputum should be done. Sequelae/Prognosis Fig. 24 - 5 months after IVIg treatment. Complications of SJS are numerous. fluid and electrolyte imbalance, loss of Beau’s lines. Horizontal ridges on Cutaneous complications include scar- skin barrier and hypermetabolic state, nails. ring, hyper/hypopigmentation and in their hydration status should be closely severe cases and abnormal nail growth. monitored. The initiation of intravenous- Our patient had ill-defined hyperpig- Our patient’s oral mucosa completely fluid replacement is of prime importance. mented patches 5 months after his SJS resolved. Ocular complications of SJS Patients may even need to be transferred episode. (Fig. 22) His palms and soles include corneal ulceration and even blind- to burn or intensive care unit. had no residual lesions. (Fig. 23) Our ness. Other mucosal complications Oral care is also critical. patient had evidence of transverse ridges include respiratory failure from tracheo- Benadryl/decadron (dexamethasone)/vis- on all his nails consistent with Beau’s bronchial shedding, esophageal cous lidocaine and Nystatin (mycostatin) lines (Fig. 24) strictures, vaginal stenosis, and penile mouthwash for symptomatic relief is usu- scarring.18 The most feared complication ally helpful. If esophageal involvement is The regrowth of the epidermis usually is sepsis, which is the most frequent severe enough to interfere with eating, takes about three weeks. Interestingly, it cause of death. (Table 6) Septicemia is total parenteral nutrition may be war- is usually the typical length of the hospi- usually caused by Pseudomonas

64 STEVENS-JOHNSON SYNDROME ranted. Aspiration pneumonia can be matory properties.42 Treatment with immunocompetent patient using 1g/kg for avoided by frequent, yet careful, suction- cyclosporine43, cyclophosphamide44 and the first dose then 60g for the second ing of oropharyngeal secretions. When plasmapheresis45 have reported. Granu- dose.3 (Table 9) tracheobronchial sloughing is experi- locyte colony stimulating factor has been enced, patients with SJS may undergo reported for the treatment of SJS-TEN The mechanism of action of IVIG is respiratory failure and require endotra- with neutropenia.46 (Table 8) unclear. Its immunologic properties pro- cheal intubation. tect against excessive inflammation and Why use intravenous immunglobulin? immunologic destruction.48 Proposed Due to common involvement of the The first reported us of intravenous mechanisms of action of IVIG are as fol- conjunctiva, erythromycin ointment is immunoglobulin for SJS was in 1998. lows: beneficial. Ophthalmology is often Most of the reported uses of IVIg treat- 1. Inhibition of cytokine production and involved to perform slit lamp examination ment for SJS are in children. Morici et al action and therefore downregulating and monitor corneal ulceration to prevent used IVIg in 6 children and compared the cell surface molecules50 blindness. 2. Increased T-cell suppressor activity51 Table 8. Reported Systemic Treat- Skin care is of great importance to pre- 3. Prevention of C3 binding to target ment for STEVENS-JOHNSON SYN- cells52 vent bacterial colonization and eventual DROME sepsis. Topical care may include hydro- 4. Providing anti-idiotypic antibodies to 53 colloid or gauze dressings. Avoidance of autoantibodies sulfonamide-containing topical agents 5. Fc receptor blockade of mononu- should be done. Debridement of necrotic clear phagocytes.54 skin should not be performed before disease activity ceases.12 Succesful reported dermatological uses of IVIG include idiopathic thrombo- Since patients with SJS usually com- cytopenic purpura, Kawasaki disease, plain of asthenia, pain control should be Wegener’s vasculitis, juvenile rheumatoid appropriately given. Avoidance of adhe- arthritis, dermatomyositis, bullous sive products and any trauma to skin pemphigoid and pemphigus vulgaris, should be considered. outcome with SJS patients treated with pemphigus foliaceus, herpes gestationis, Treatment with corticosteroids is at corticosteroids.5 A single infusion rate of graft vs. host disease, pyoderma best controversial. Patterson et al36 claim 1.5-2 g/kg IVIg was used. The IVIg group gangrenosum, toxic epidermal necrolysis that early use of high-dose steroids may and Stevens-Johnson syndrome.(Table 10) The few indications licensed by the have a favorable influence. Others claim had a shorter duration of fever. Moudgil that corticosteroids contribute to Food and Drug Administration for high et al treated 2 children with IVIg with dose IVIg are chronic lymphocytic increased mortality rates due to immuno- dramatic improvement.6 A 4 1/2 month suppresion and secondary infection. leukemia, graft vs. host disease, post old infant was treated with a single bolus bone marrow transplantation, idiopathic Other anectodal treatments for EM of IVIg 400mg/kg with a 24 hour include thalidomide due to its anti-inflam- thrombocytopenic purpura, pediatric regression of cutaneous and mucosal human immunodeficiency virus and 49 lesions. Amato et al Kawasaki syndrome.55 Intravenous Table 7. Management of STEVENS-JOHNSON treated a 22-month old girl SYNDROME immunoglobulin is prepared by cold with IVIg and steroids with ethanol fractionation from the pooled improvement. Sanwo et al plasma of up to 20,000 donors per advocated for the use in batch.56 patients with AIDS and Stevens-Johnson since There are disadvantages to using IVIG has a potent anti- IVIG, namely cost and adverse effects. inflammatory activity with- The cost ranges from $50/g to $100/g. out the risk of further Reported doses of IVIG for the treatment immunosuppression.47 of SJS include a single dose of 2 g/kg or Brett et al reported a bene- 4 doses of 0.4-0.5 g/kg. (Table 11) ficial role of IVIg in the Intravenous immunoglobulin is also treatment of SJS in an Table 9. Reported uses of IVIg for SJS treatment

JENSEN, WIKAS, FOX 65 associated with adverse effects. including In addition, he was on Allopurinol, fever, chills, lower back pain, nausea and Amiodarone, Theophylline and Levaquin vomiting. It is also associated with car- all of which have been known to cause diac symptoms such as chest pain, tachy- SJS. All of the suspected culprit drugs Q cardia and hypotension and hypertension. were discontinued except for his systemic Q Patients usually experience these symp- steroids and oxygen which he is

Table 10 Dermatological uses of IVIg Table 12. Adverse effects of IVIg

Fig. 26 Ð 5 months after IVIg infusion References: 1 Assier H, Bastuji-Garin S, Revuz J, Roujeau J-C. Erythema Multiforme with Mucous Membrane Involvement and Stevens-Johnson Syndrome are clinically Different Disorders With Distinct Causes. Arch Dermatol. 1995; 131:539-543. 2 Patterson R, Miller M, Kaplan M, Doan T, Brown J, Detjen P et al: Effectiveness of early therapy with corticosteroids in Stevens-Johnson syndrome: experience with 41 cases and a hypotheses regarding pathogenesis. Ann Allergy 1994; 73:27-34. 3 Brett AS, Phillips D, Lynn AW. Intravenous Immunoglobulin Therapy for Stevens-Johnson Syndrome. Southern Medical Journal, 2001;94: Table 10 Dermatological uses of IVIg dependent on for his chronic obstructive 342-343. 4 Sanwo M, Nwadiuko R, Beall G: use of intravenous i pulmonary disease. He was treated with mmunoglobulin in the treatment of severe cutaneous four doses IVIg with improvement during drug reactions in patients with AIDS. J Allergy Clin Immunol 1996; 98:1112-1115. the first 24 hours (Fig. 25) and with 5 Morici MV, Galen WK, Shetty AK, Lebouef RP, minimal sequela after 5 months (Fig. 26). Gouri TP, Cowan GS et al. Intravenous Immunoglobulin Therapy for Children with Stevens- Johnson Syndrome. J Rheumatol 2000;27:2494-7. 6 Moudgil A, Porat S, Brunnel P, Brunnel P, It is unclear if his response was solely Jordan SC: Treatment of Stevens-Johnson syndrome with pooled human intravenous immune globulin. Clin toms within 30 to 60 minutes of infusion. due to IVIg treatment, IV solumedrol or Pediatr 1995; 34:48-51. 55 Fortunately, our patient did not have merely the natural progression of his 7 Amato GM, Travia A, Ziino O: The use of intravenous high-dose immunoglobulins (IVIG) in a case of any of these adverse effects. disease. However, he was started on IV Stevens-Johnson Syndrome. Pedatr Med Chir 1992; More serious but rare adverse effects solumedrol 48 hours before IVIg without 14:555-556. improvement. Overall, he responded well 8 Straussberg R, Harel L, Ben-Amitai D, Cohen D, Amir include anaphylaxis, acute renal failure J. Carbamazepine Induced Stevens Johnson and aseptic meningitis. Anaphylaxis is to IVIg despite his adverse effect of Syndrome Treated with IV steroids and IVIG. Pediatr reversible acute renal failure. Neurol 2000;22:231-233. more common in patients who are IgA 9 Roujeau JC, Stern RS: Severe adverse cutaneous deficient patients with anti-IgA antibodies. Intravenous immunoglobulin should be reactions to drugs. N Engl J Med 1994; 331: further studied for the treatment of SJS- 1272-1285. IgA deficient IVIg is available for such 10 Stevens AM, Johnson FC. A New Eruptive Fever patients. There is a question of whether TEN and other dermatological diseases. Associated with Stomatitis and Ophthalmia: Report of IVIg causes a prothrombotic tendency two cases in children: AJDC 1922;24:526-533. 11 Lyell A. Toxic epidermal necrolysis: an eruption 55 due to its high solute load. Acute renal resembling scalding of the skin. Br J Dermatol 1956; failure from IVIg is also believed to be 68:355-361. caused by its high solute load inducing 12 Freedberg IM, Eisen AZ, Wolff K, Austen KF. Q Q Fitzpatrick’s Dermatology in General Medicine, 5th injury to the proximal tubule.55 Fortu- Edition, Mc Graw Hill 1999, p. 647. 13 Roupe G, Ahlmen M, Fagerberg B, Suurkula M. Toxic nately, this is usually reversible. This was epidermal necrolysis with extensive mucosal erosions evident in our patient. His renal function of the gastrointestinal and respiratory tracts. Int Arch returned to baseline with the usage of Allergy Appl Immunol 1986;80:145-51. 14 Wilkins J, Morrison L, White CR Jr. Oculocutaneous intravenous fluids without requiring manifestations of the erythema multiforme/Stevens- hemodialysis. The etiology of his acute Johnson/toxic epidermal necrolysis spectrum. Dermatol Clin 1992;10:571-82. renal failure remains to be determined. In 15 Binaghi M, Kosos M, Saiag P, Roujeau JC, Coscas G. additon to IVIg, he was also on Solume- Atteinte oculaire au cours du syndrome de Lyell: drol and total parenteral nutrition, both of incidence, evolution, pronostic. Ophtalmologie Fig.1 Pre-IVIg infusion 1988;2:121-2. which can cause renal adverse effects on 16 Freedberg IM, Eisen AZ, Wolff K, Austen KF et al. an already renal compromised patient. Fitzpatrick’s Dermatology in General Medicine, 5th Edition, Mc Graw Hill 1999, p. 649. Aseptic meningitis is usually seen from 10 17 Odom RB, James WD, Berger TG. Andrews’ Dis hours to 7days after high dose IVIG ther- eases of the Skin, 9th Edition, 2000; Chap. 7:148. apy. Patients who suffer from this com- 18 Parrillo S, Parrillo CV. Stevens-Johnson Syndrome. Q Q EMedicine Journal 2001;2:1-10 monly recover. 55 (Table 12) 19 Bastui-Garlin S, Rzany B, Stern R, Shear N, Naldi L, Roujeau J-C . Clinical Classification of Cases of Toxic Epidermal Necrolysis, Stevens-Johnson Syndrome, In summary, our patient had SJS-TEN and Erythema Multiforme. Arch Dermtol. overlap with severe mucosal involvement 1993;129:92-96. 20 Kingsbury J. Erythema Multiforme. Dermochromes-1. of three sites: oral, ocular and genital. Rebman 1914. The etiology remains to be determined. 21 Garty B-Z. Stevens-Johnson Associated with Nystatin Treatment. Arch Dermatol. 1991;127: He was exposed to influenza vaccine and 741-742. shortly thereafter experienced prodromal Fig. 25- 24 hrs. after 1st IVIg 22 Curley RK, Verbov JL. Stevens-Johnson syndrome flu-like symptoms and subsequent SJS. infusion due to Tetracyclines-a case report (doxycycline) and

66 STEVENS-JOHNSON SYNDROME review of the literature. Clin Exp Dermatol 1987; Roujeau J-C, Bagot M. Metabolic predisposition to 53 Kaveri SV, Dietrich G, Kazatchkine MD. Can 12:124-125. cutaneous adverse drug reactions. Arch Dermatol intravenous immunoglobulin treatment regulate 23 Todd P, Halpern S, Munro DD. Oral terbinafine and 1995. 131:544-551. autoimmune responses? Semin Hematol 1992;29 erythema multiforme. Clin Exp Dermatol 1995;20: 38 Roujeau J-C, Huynh TN, Bracq C et al. Genetic (3 suppl 2):64-71. 247-248. Susceptibility to toxic epidermal necrolysis. Arch 54 Debre M, Bonnet MC, Fridman WH, Carosella E, 24 Rustin MHA, Bunker CB, Dowd PM, Robinson TWE. Dermatol 1987;123: 1171-1173. Philippe N, Reinert P. et al. Infusion of Fy fragments Erythema multiforme due to griseofulvin. Br J 39 Westly ED, Wechsler HL. Toxic epidermal necrolysis: for the treatment of children with acute immune Dermatol 1989; 120:455-458. granulocytic leukopenia as a prognostic indicator. thrombocytopenic purpupra. Lancet 1993;342:945- 25 David M, SandbankM, Lowe NJ. Erythema Arch Dermatol 1984;120:721-726. 949. multiforme-like eruptions associated with etretinate 40 Jordan MH, Lewis MS, Jeng JG, Rees JM. Treatment 55 Jolles S, Hughes J, Whittaker S. Dermatological therapy. Clin Exp Dermatol 1989;14:230-32. of toxic epidermal necrolysis by burn units: another Uses of High-dose Intravenous Immunoglobulin. Arch 26 Win A, Evers ML, Chmel H. Stevens-Johnson market or another threat? J Burn Care Rehabil 1991; Dermatol 1998;134:80-86. syndrome presumably induced by ciprofloxacin. Int J 12: 579-81. 56 Cohn EJ, Strong LE, Hughes WL. Preparation and Dermatol 1994; 33:512-514. 41 Revus J, Penso D, Roujeau JC, et al. Toxic properties of serum and plasma proteins: a system for 27 Revus J, Penso D, Roujeau JC. Toxic epidermal epidermal necrolysis: clinical findings and prognosis the separation into fractions of the protein and necrolysis: clinical findings and prognosis in 87 in 87 patients. Arch Dermatol 1987; 123:1160-5. lipoprotein components of biological fluids. J Am patients. Arch Dermatol 1987; 123:1160-5. 42 Moisson YF, Janier M, Civatte J. Thalidomide for Chem Soc. 1946;68:459-475. 28 Assier H, Bastuji-Garin S, Revuz J, Roujeau J-C. recurrent erythema multiforme. Br J Dermatol 57 Chan HL, Stern RS, Arndt KA. The incidence of EM, Erythema Multiforme with Mucous Membrane 1992;126: 92-93. SJS and TEN: a population based study with Involvement and Stevens-Johnson Syndrome are 43 Renfro L. Drug-induced toxic epidermal necrolysis particular reference to reactions caused by drugs clinically Different Disorders With Distinct Causes. treated with cyclosporin. Int J Dermatol 28:441, 1989. among outpatients. Arch Dermtol 1990;126:43-47. Arch Dermatol. 1995; 131:539-543. 44 Heng MCY . Efficacy of cyclophosphamide in toxic 58 Yung A, Agnew K, Snow J, Oliver F. Two unusual 29 Choy AC, Yarnold PR, Brown JE, Kayaloglou GT, epidermal necrolysis: Clinical and pathophysiological cases of toxic epidermal necrolysis. Australas J et al. Virus induced erythema multiforme and aspects. J Am Acad Dermatol 1991;25:778. Dermatol 2002; 43(1):35-8. Stevens-Johnson syndrome. Allergy Proc 45 Chaidemenos G : Plasmapheresis in toxic epidermal 59 Chan HL, Ku G, Khoo OT. Allopurinol associated 1995;16:157-61. necrolysis. Int J Dermatol 1997;36:218. hypersensitivity reactions: cutaneous and renal 30 Galili S. A mild form of Stevens-Johnson syndrome 46 Goulden V. Recombinant granulocyte colony-stimu- manifestations. Aust N Z J Med 1977; 7 (5): 518-22. following measles immunization. Isr J Med Sci lating factor in the management of toxic epidermal 60 Ridgway HB, Miech DJ. Erythema multiforme 1967;3:903-905. necrolysis. Br J Dermatol 1996;21:317. (Stevens-Johnson Syndrome) following deep 31 Hazir T, Saleem M, Abbas KA. Stevens-Johnson 47 Viard I, Wehrli P, Bullanil : Inhibition of Toxic radiation therapy. Cutis 1993; 51 (6):463-4. Syndrome following measles vaccination. J Pak Med epidermal necrolysis by blockage of CD 95 with 61 Cuthbert RJ, Craig JI, Ludlam CA. Stevens-Johnson Assoc 1997; 47: 264-5. human intravenous immunoglobulin. Science 1998; syndrome with methotrexate treatment for 32 Lane JM, Ruben FL, Abrutyn E, Miller JD. Deaths 282; 490-493. non-Hodgkins lymphoma. Ulster Med J 1993 Apr; 62 attributable to smallpox vaccination, 1959— 48 Dwyer JM. Manipulating the immune system with (1):95-7. 1966,1968.JAMA 1970; 212:441-4. immune globulin. N Eng J Med 1992;326:468-472. 33 Ball R, Ball L, Wise R, Braun M, et al. 49 Cazzola G, Nicolussi M, Carraro F, Cavalieri S, Stevens-Johnson after vaccination. Reports to the Grazziani MS. High dose IVIg in SJS. Helv paediati vaccine Adverse Event Reporting System. Ped Inf Acta, 1986;41:87-88. Dis J 2001;20: 219-223. 50 Leung DY. Cotran RS. Kurt-Jones E, Burns JC, Disclosure: 34 Norris DA. Cytokine modulation of adhesion Newburger JW, Pober JS. Endothelial cell activation Figure 20: This figure was obtained from Dermochromes- molecules in the regulation of immunologic and high interleukin-1 secretion in the pathogenesis of Volume I, Dr. Kingsbury. It is a cast model. It was published in cytotoxicity of epidermal targets. J Invest Dermatol acute Kawasaki disease. Lancet 1989;2:1298-302. 1914 by Rebman Company in New York, NY. I made numer- 1990; 95 (suppl) 111S-120S. 51 Ballow M. White W. Desbonnet C. Modulation of in ous attempts to contact the company via letters, telephone and 35 Kazmierowski JA, Wuepper KD. Erythema vitro synthesis of immunoglobulin and the induction of internet. Unfortunately, the company no longer exists. 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JENSEN, WIKAS, FOX 67 Epidermotropic Metastatic Malignant Melanoma (EMMM) Ð a pathological variant of melanoma.

Julian O. Moore 1, D.O., Rao N. Saladi 2, M.D., Neal B. Shultz 3, M.D., Mark G. Lebwohl 4, M.D.,Robert G. Phelps 5, M.D.

Abstract Epidermotropic metastatic malignant melanoma (EMMM) is a pathological variant of melanoma, which can histologically simulate a primary melanoma or melanocytic nevus. A 51 year old female presented 6 years ago with a 1.3mm, Clark level IV melanoma of the scalp. Since then, the patient presented with an almost identical histology in the areola, eyebrow, face, ear and scalp. The histology of these lesions showed atypical non-pigmented melanocytes in the epidermis and dermis with minimal lateral extension in the epidermis. Immunohistochemical analysis revealed HMB-45 expression superficially in the dermis with diminished expression deep in the dermal layers. Ki-67 staining was confined only to the superficial melanocytes. CD34 and Factor VIII showed staining around the capillaries without evidence of intravascular melanocytes. The histopathology of epidermotropic metastatic malignant melanoma may be problematic, simulating primary melanoma or a melanocytic nevus. However, clinical history coupled with melanocytic markers is helpful in distinguishing it from other melanocytic lesions.

Introduction monomorphous. The lesions are usually which the majority were epidermotropic well circumscribed and vertically oriented. metastatic malignant melanomas. The Epidermotropic metastatic malignant Thinning of the epidermis by aggregates patient had no early evidence of multi melanoma (EMMM) is a pathological of atypical melanocytes and nests within organ or systemic involvement despite variant of melanoma. The diagnosis of the dermis may occur. Inward turning of very vigorous evaluation including CAT EMMM can be particularly problematic the rete ridges at the periphery of the scan and lymph node dissection. After because the histopathological appear- lesion can be seen. Considerable upward six years the patient was found to have ance can simulate primary melanoma or pagetoid extension of melanocytes, developed pulmonary metastases. even a melanocytic nevus.1 The mitotic figures and both epidermal and metastases of malignant melanomas dermal nests are characteristic of Clinical History usually extend from the dermis to epidermotropism. There can be invasion A 51 year old female presented 6 subcutaneous fat with sparing of the of blood vessels and lymphatics.6 years ago with a 1.3 mm, Clark level IV overlying epidermis. However, in rare Patients with EMMM characteristically primary melanoma of the mid parietal instances metastatic melanomas can scalp for which she underwent wide invade superficially and exhibit present first with primary melanoma and subsequently develop multiple cutaneous excision with margin evaluation. Over the epidermotropism. In such cases, ensuing years (3-6 years) the patient has delineating a primary lesion from a metastases which can simulate primary metastatic lesion with epidermal lesions. They are often multiple, involvement can be difficult.2,3 Epider- symmetric and less than 3 to 4mm in size motropism has been seen in various and can occur from months to years after types of cutaneous carcinomas (breast, the primary lesion. Patients have often neuroendocrine) including metastatic been described with multiple skin lesions, melanoma.4,5 Usually there is no host paradoxically without any other systemic response but fibrosis or inflammatory involvement. While long survival times infiltrates can be seen. The melanocytes with skin involvement only, are not comprising the tumors are often relatively uncommon, metastasis to other organs usually indicates a poor prognosis. 1. Department of Dermatopathology, Post Doctoral Epidermotropic metastases from internal Research Fellcon, Mt. Sinai Hospital and School of malignancies are exceedingly rare, Medicine. 2. Department of Dermatopathology, Post Doctoral however, epidermotropic metastatic Research Fellow, Mt. Sinai Hospital and School of breast carcinoma, and intraepidermal Medicine. involvement from metastasizing 3. Department of Dermatopathology, Mt. Sinai Hos- pital and School of Medicine. adenocarcinomas of the rectum, vagina, 4. Chairman-Department of Dermatopathology, Mt. urethra, cervix and bladder have been Sinai Hospital and School of Medicine. 7 5. Director-Dermatopathology, Mt. Sinai Hospital and reported. School of Medicine. Address of correspondence and reprints request to We report a 51 year old female with a Robert G. Phelps, Director of Dermatopathology, One history of a primary melanoma of the Gustave L. Levy Place, Box: 1194, New York, NY-10029. Phone: (212) 241 6064. Fax: 212-534-7491. scalp who subsequently developed at Figure 1. Excision of scalp lesion with E-mail: [email protected]. least 14 regional skin metastases, of multiple epidermotropic metastases.

68 (The Journal of the American Osteopathic College of Dermatology, Vol. 1, No. 1, pp 68-70, June 2003) presented on follow up examination with multiple pigmented lesions, of almost identical histology in the areola, eyebrow, face, ear, with the scalp showing a predominance of these recurrent lesions. Generally these lesions were less than 4 mm in diameter and none of them arose in sites previously associated with preexisting melanocytic nevi. Most of the scalp lesions were located midline in the parietal scalp, extending across the Figure 4. mid-frontal scalp region adjacent to the initial excision (Figure 1). The clinical appearance of the lesions were macular and flesh colored. The lesions had irregular borders and focal areas of Figure 2 darker pigmentation. The biopsies showed distinctive atypical epithelioid non-pigmented melanocytes in the epidermis as well as the dermis and confirmed epidermotropic malignant melanoma. Multiple diagnostic evaluations including lymph node dissection and CAT scans were performed, and failed to reveal any evidence of systemic disease Figure 4 and 5. Immunohistochemistry initially. Since the diagnosis of of HMB-45 and Ki-67 in EMMM epidermotropic metastatic malignant confining to superficial dermis. No melanoma had been established, all the Intravascular involvement was seen. lesions were excised. Multiple lesions on the scalp were treated with wide re-exci- Figure 3.Atypical epithelioid and non- demonstrate evidence of intravascular sion scalp reductions and skin grafts. Her pigmented melanocytes invading epi- invasion by melanocytes. only other known medical history included dermis and superficial dermis. Waldenstrom’s macroglobulinemia. There Discussion was no documented family history of identical histopathology. There were The pathological tenants of epider- melanoma or dysplastic nevus syndrome. atypical non-pigmented epithelioid motropic metastatic malignant melanoma After six years the patient was found to melanocytes in the epidermis and dermis have been well established over the have developed pulmonary metastases. with areas of limited lateral extension in years, yet definitive diagnosis remains a Methods the epidermis (Figure 2). The lesions dauntingly difficult task. At the heart of were asymmetrical and exhibited a this diagnostic dilemma lies the fact that All the biopsies taken from the patient pagetoid spread of atypical melanocytes epidermotropic metastatic malignant were preserved in formalin fixed paraffin in the epidermis as well as nests of melanoma bears striking histologic embedded blocks at the Mount Sinai melanocytes in the dermis (Figure 3). The resemblance to primary melanomas and histology laboratory. The blocks were nests in the dermis were irregular in melanocytic nevi. Historically, this distinc- collected and serial sections were shape and size. The nuclei of the cells tion was rendered “clear cut” in 1953 by obtained and stained with hematoxylin were hyperchromatic or vesicular with Allen and Spitz,8 who felt that the and eosin for light microscopic examina- small nucleoli. Sparse melanin was identi- absence of junctional changes in the tion. All sections were evaluated with fied in a few cells. Occasional mitotic fig- overlying epithelium was conclusive evi- markers to confirm the nature of the ures were found. Adenexal involvement dence for a dermal lesion to be consid- melanoma. We studied each of the by atypical melanocytes was also seen. ered metastatic or locally recurrent. Some biopsies with antibodies against prolifera- No maturation of melanocytes was twenty five years later, the Allen and Spitz tion markers Ki-67, HMB-45 and vascular observed with descent in the dermis. theory was reexamined by Kornberg and markers CD34 and Factor VIII. An There was no vascular involvement. Ackerman9. Kornberg et al. described avidin-biotin immunoperoxidase tech- Some of the lesions extended deep in the four patients with multiple epidermotropic nique was used to stain the sections. dermis. Many of the lesions were small metastatic melanoma lesions that and identical to a benign nevus. included the presence of junctional Histopathology 10 Immunohistochemistry nests, which directly defied the initial Most of the scalp lesions were located theory of Allen and Spitz. Kornberg and midline in the parietal scalp, extending The patient’s biopsies were examined Ackerman developed and discussed across the mid-frontal scalp adjacent to and demonstrated close correlation with three specific histologic features that the scar from prior resections. There was the epidermal and dermal staining pattern favored the diagnosis of EMMM. These a 3x3 mm lesion proximal to the helix of often associated with a melanocytic three features included (1) thinning of the the right ear. The other lesions were nevus. HMB-45 was expressed superfi- epidermis by aggregates of atypical found on the areola, face and eyebrow. cially in the dermis with diminished melanocytes within the dermis often All skin biopsies of the patient were expression in the deep dermal layers associated with widening of the dermal reviewed under light microscope to (Figure 4). Ki-67 staining was confined papillae and elongation of inward turning compare cytological architecture of the only to the superficial melanocytes (Fig- rete ridges at the periphery of the speci- various sections obtained from this ure 5). CD34 and Factor VIII staining was men; (2) atypical melanocytes within the patient. Virtually all the biopsies showed seen around the capillaries but did not intradermal endothelial-lined spaces, and (3) a zone of atypical melanocytes within

MOORE, SALADI, SHULTZ, LEBWOHL, PHELPS 69 the dermis equal to or broader than that This phenomenon has been described in perils associated with misdiagnosis are within the epidermis. While this classifica- nevi and as well in invasive melanomas clear. A good clinical history and tion remains very useful to date, it is lim- with paradoxical maturation. It is difficult conscientious follow up coupled with ited in the sense that the literature to speculate, but this pattern may be immunohistochemical evaluation of supports other cases that may deviate related to the indolent clinical course of biomarkers and histopathological analysis slightly from these tenants. Heenan and these tumors in this patient. Epider- is paramount in making an accurate Clay1 described a case of epidermotropic motropic metastatic malignant melanoma diagnosis. metastatic malignant melanoma in a 51 showing strong expression confined year old male that demonstrated multiple superficially to epidermal cells has been References 10,11,15 1. Heenan PJ, Clay CD. Epidermotropic metastatic areas of extensive epidermal involve- reported by other authors. Our results melanoma simulating multiple primary melanomas. Am ment. Other authors have also postulated correlated closely with the literature J Dermatopathol. 1991; 13: 396-402. that the pathologic criteria of epider- showing this intense preferential 2. Mehregan DA, Bergeon MT, Mehregan DR. Epidermotropic metastatic malignant melanoma. Cutis. motropic metastases does not always expression characteristic of EMMM 1995; 55: 225-7. conform exactly to the classical enabling us to distinguish the metastases 3. Kato T, Dmitsu T, Tomita Y et al. New primary malignant melanoma, Epidermotropism and Indian- file stereotypic characterization offered by from nevi. Ruhhoy et al. touted this arrangement of metastatic tumor cells in a case with Kornberg and Ackerman. Abernathy et phenomenon of Ki-67 expression to be intransit metastases of acral type of malignant melanoma. Dermatologica 1986; 173: 95-100. al.11 reported two cases in which the the most helpful feature in establishing 4. Requena L, Sangueza M, Sangueza OP et al. patients not only had epidermotropic the difference between EMMM lesions Pigmented mammary Paget disease and pigmented metastases resembling primary and benign nevi.15 Expression of CD34 epidermotropic metastases from breast carcinoma. Am J Dermatopathol 2002 Jun;24(3):189-98. melanoma, but also many lesions that and Factor VIII were assessed to 5. Gillham SL, Morrison RG, Hurt MA. Epidermotropic exhibited exclusive epidermal determine the degree of vascular involve- neuroendocrine carcinoma. Immunohistochemical differentiation from simulators, including malignant involvement consistent with a melanoma ment. Bengoechea-Beeby et al showed melanoma. J Cutan Pathol 1991 Apr;18(2):120-7. in situ presentation. There was no deep invasion of the dermal capillaries in 6. Bengoechea-Beeby MP, Velasco-Oses A, Mourino Fernandez F, et al. Epidermotropic metastatic intravascular involvement. There are also all of their reported epidermotropic melanoma. Are the current histologic criteria adequate documented cases of epidermotropic metastatic skin lesions.6 Our case to differentiate primary from metastatic melanoma? metastatic malignant melanoma arising showed no intravascular involvement. Cancer. 1993; 72: 1909-13. 7. Requena L, Sanchez Yus E, Nunez C et al. directly from a diverse array of cutaneous Epidermotropically metastatic breast carcinomas. Rare pathologies including primary and The melanocytic lesions in this patient, histopathologic variants mimicking melanoma and as well as the others aforementioned and Paget's disease. Am J Dermatopathol 1996 junctional melanoma, benign, dysplastic, Aug;18(4):385-95. 8 9,12,13,14 discussed by their respective authors, are compound and congenital nevi. 8. Allen AC, Spitz S. Malignant melanoma A The biopsies in our patient revealed a instructive for outlining the plethora of clinicopathological analysis of the criteria for diagnosis clinical and histolpathological features and prognosis. Cancer 1953; 6:1-45. pattern of histology similar to that as 9. Kornberg R, Harris M, Ackerman AB: Epidermotropi- described by Kornberg and Ackerman. salient to EMMM. One may still question cally metastatic malignant melanoma. Arch Dermatol the usefulness differentiating between pri- 1978; 114:67. There were discrete nests of melanocytes 10.White WL, Hitchcock MG. Dying dogma: the overlying the epidermis with atypical mary melanomas and epidermotropic pathological diagnosis of epidermotropic metastatic melanocytic involvement in the dermis. metastatic lesions, arguing that the nature malignant melanoma. Semin Diagn Pathol. 1998; of published data is sparse and case 15: 176-88. There was no lateral extension in the 11. Abernethy JL, Soyer HP, Kerl H, et al. Epidermotropic epidermal component. reports are inconclusive. One may even metastatic malignant melanoma simulating melanoma argue the point that a patient who has in situ. A report of 10 examples from two patients. Am J Surg Pathol. 1994; 18: 1140-9. In attempting to distinguish between had primary malignant melanoma is at 12.Warner TF, Seo IS, Bennett JE. Minimal deviation epidermotropic metastatic malignant increased risk for having multiple primary melanoma with epidermotropic metastases arising in a 17 congenital nevus. Am J Surg Pathol. 1980; 4: 175-83. melanoma and melanocytic nevi, melanomas. We conclude that the 13.Conejo-Mir JS, Camacho F, Rios JJ, Gonzalez-Cam- histologic markers were helpful. We clinical history provides a compelling case pora R. Epidermotropic metastasis coexisting with multiple primary cutaneous malignant melanomas. utilized HMB-45 and Ki-67. They are that the subsequent lesions found in our Dermatology. 1993; 186: 149-52. proliferation markers and their role is well patient were indeed true metastases as 14.Warner TF, Gilbert EF, Ramirez G: Epidermotropism in established in the diagnosis of malignant opposed to multiple primary lesions or melanoma. J Cutan Pathol. 1980; 7: 50-4. 15.Ruhoy SM, Prieto VG, Eliason SL, et al. Malignant melanomas. They are strongly expressed benign nevi. The sheer number of melanoma with paradoxical maturation. Am J Surg in melanomas and metastases and show lesions, size, location, and time course Pathol. 2000; 24:1600-14. 16.McNutt NS, Urmacher C, Hakimian J, Hoss DM, Lugo insignificant superficial dermal staining in toward development make a strong case J. Nevoid malignant melanoma: morphologic patterns benign nevi.16 Although the extent of for metastases.11 It is of utmost and immunohistohemical reactivity. J Cutan Pathol. 1995; 22: 502-17. expression of Ki-67 and HMB-45 staining importance to accurately diagnose and 17.Bellet RE, Vaisman I, Mastrangelo MJ, et al. Multiple supported the diagnosis of melanoma, we differentiate between EMMM, melanocytic primary malignancies in patients with cutaneous also demonstrated a diminished expres- nevi, and primary malignant melanoma, melanoma. Cancer 1977 Oct;40(4 Suppl):1974-81. sion of the markers deeper in the dermis. the resultant therapeutic and prognostic

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