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

2009-2010 AOCD Officers President: Marc I. Epstein, D.O., FAOCD President-Elect: Leslie Kramer, D.O., FAOCD First Vice-President: Bradley P. Glick, D.O., FAOCD Second Vice-President: James B. Towry, D.O., FAOCD Third Vice-President: Karen E. Neubauer, D.O., FAOCD Secretary - Treasurer: Jere J. Mammino, D.O., FAOCD Immediate Past-President: Donald K. Tillman, Jr., D.O., FAOCD Trustees: David L. Grice, D.O., FAOCD Mark A. Kuriata, D.O., FAOCD Rick Lin, D.O., FAOCD Editors Suzanne Rozenberg, D.O., FAOCD Jay S. Gottlieb, DO Andrew Racette, D.O., FAOCD Jon Keeling, DO Celeste Angel, D.O., FAOCD Andrew Racette, DO Executive Director: Rebecca Mansfield

Editorial Review Board Kevin Belasco, DO Sponsors: Rich Bernert, M.D. Global Pathology Laboratory

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Matt Leavitt, DO, FAOCD AOCD • 1501 E. Illinois • Kirksville, MO 63501 Mark Lebwohl, MD 800-449-2623 • FAX: 660-627-2623 www.aocd.org Rick Lin, DO Megan Machuzak, D.O. COPYRIGHT AND PERMISSION: written permission must be obtained from the Journal of the American Osteopathic College of Dermatology Jere Mammino, DO, FAOCD for copying or reprinting text of more than half page, tables or figures. John Minni, DO Permissions are normally granted contingent upon similar permission from the author(s), inclusion of acknowledgement of the original source, Navid Nami, DO and a payment of $15 per page, table or figure of reproduced material. Permission fees are waived for authors wishing to reproduce their own Shaheen Oshtory, DO articles. Request for permission should be directed to JAOCD c/o AOCD John Perrotto, DO PO Box 7525 Kirksville, MO 63501 Copyright 2003 by the Journal of the American Osteopathic College of Stephen Purcell, DO, FAOCD Dermatology Michael Scott, DO, FAOCD Printed by: The Dimensional Group, Mason City, IA 50401 Kevin Spohr, DO Proofreading: Julia Layton, Freelance Proofreading and Editing Journal of the American Osteopathic College of Dermatology Vo l u m e 17, Nu m b e r 1 Ju l y 2010 Journal of the

Americaocdan Osteopathic College of Dermatology Co n t e n t s

Letter from the JAOCD Editors...... 4 Letter from the President...... 5 A Case of and a Brief Review of Shaft Disorders...... 6 Dan Marshall, D.O.,* Ben Nasman, OMS III** Familial ...... 8 Derrick Adams, DO,* Hassan Nasir, OMSIV,** Eric Seiger, DO, FAOCD,*** Michael Mahon, DO, FAOCD**** Treatment of Arising from Hypertrophic ...... 10 Rachel Epstein, D.O.,* Dunnett Durando, B.S.,** David Dorton, D.O., FAOCD,*** Richard Miller, D.O.,FAOCD**** Allergic Contact to Red Tattoo Dye...... 12 James Yousif, MSIV,* Peter Saitta, D.O.,** Steven K. Grekin, D.O.,*** Jenifer Lloyd, D.O.**** Sweet’s Syndrome: A Case Report and Discussion...... 16 Daquesha Chever, MSIV,* Jenifer R. Lloyd, D.O.** Cutaneous Endometriosis - A Case Report...... 18 Sadaf (Sabrina) Waqar, DO, MPH,* Les Rosen, MD,** Janet Allenby, DO*** Linear Lichen Planus: A Case Report...... 23 Shari Sperling, DO,* Marvin Watsky, DO** A Case Report: Complex...... 25 Brent Loftis, D.O.,* Monica Ata, OMS III,** Bill Way, D.O., FAOCD*** Diagnostic and Therapeutic Dilemmas in an NF-1 Patient...... 27 Reagan Anderson, DO, MPH, MCS,* Michael Baze, DO, RPh,** Raja Rabah, MD,*** Steven Grekin, DO**** Pediatric Case Series: Phototoxic and Photoaging Effects of Voriconazole...... 32 Andrew J. Racette, D.O.,* Angela M. McKinney, D.O.** to the ...... 37 Vienna Lowenbraun, DO,* Payal Patel, DO,** Kimball Silverton, DO*** The Use of Dermoscopy in Osteopathic Dermatology Training...... 40 Bradley Neuenschwander, DO,* Howard Lipkin, DO,** Annette LaCasse, DO*** Hailey-Hailey Disease: A Case Report and Review of Updates in Pathogenesis and Treatment...... 45 Carrie Watson, OMS III,* Brooke Walls, DO, Intern,** Melinda Greenfield, DO, FAOCD,*** Christopher Bass, PA,**** Kevin Boyd, PA***** A Case Report: Epidermolysis Bullosa Acquisita...... 48 Prethi Sundaram-Mohip, DO,* Asma Ahmed, OMS IV,** Bradley Glick DO, MPH, FAOCD*** Actinic Prurigo...... 50 Maryam Shahsavari, D.O., M.S.,* Michael Land, B.S.,** Ronald Horowitz, D.O.,*** David Horowitz, D.O., F.A.O.C.D.**** Mistaken as a Pyogenic : A Case Report and Review of the Literature...... 52 Jesse D. Jensen, MSIV,* Jenifer R. Lloyd, D.O.** Keratoacanthoma Occurrence in a Red Tattoo: A Case Presentation...... 55 Andrew J. Racette, D.O.,* Morgan J. McCarty, OMSIV** Hyperpigmented Plaques on the of a Young Man...... 59 Joshua Kentosh, DO, LT, MC, USN,* Donald Shenenberger, MD, FAAD, FAAFP, CDR, MC, USN** Confetti-like et atrophicus in the setting of chronic graft vs. host disease...... 60 Magalys Vitiello, MD,* Andleeb Usmani, DO,** Janet Allenby, DO, FAOCD,*** Paolo Romanelli, MD,**** Francisco A. Kerdel, BSc, MBBS***** Tuberous Sclerosis: Case Report ...... 63 Robert A. Norman, DO, MPH,* Mike Forgione** Wound Care and Management: A Literature Review...... 64 Michael Kassardjian, MSIV,* Patrick Keehan, D.O.,** Bill V. Way, D.O.*** A Case of Multiple Gargantuan Seborrheic Keratoses...... 69 Fawn J. Winkelman, OMS-IV,* Janee D. Steinberg, MD, FAAD, FAACS** Le t t e r Fr o m Th e Ed i t o r s

Ja y Go t t l i e b , DO, Jo n Ke e l i n g , DO, An d r e w Rac e t t e , DO, FAOCD Senior Editor FAOCD Editor FAOCD Editor Help the JAOCD to grow…

Please do not take the JAOCD for granted! We are one of the only specialty colleges within the American Osteopathic Association that has its own journal. This does not just happen. It requires the continued efforts of many members and residents of our college.

As the editors of the Journal of the American Osteopathic College of Dermatology, we get great pleasure in working with the residents of our college and producing a journal that gives them, and the rest of the members of the college, pride in being a member of the AOCD. We all must work together to create a better journal to represent our college.

We continuously solicit you to be a reviewer for the journal. The reality is, if we had 50 reviewers, we could promise that each reviewer would only need to review 2 to 3 manuscripts each year! That is a couple of hours a year to make our journal better.

In the next few months we will be soliciting you again to join the review board of the JAOCD. Please consider contributing a little time to help us improve the journal that represents all of us. You will get a great sense of satisfaction with very little effort.

Sincerely,

Jay S. Gottlieb, DO, FAOCD (Senior Editor)

Jon Keeling, DO, FAOCD (Editor)

Andrew Racette, DO, FAOCD (Editor)

4 Letter From the Editors Le t t e r f r o m t h e Pr e s i d e n t o f t h e AOCD

Ma r c (I. Ep s t e i n , DO)

Pr e s i d e n t

Hello again, my colleagues,

I’m at the halfway point in my presidency and can tell you that, as is usually the case in life, we just don’t know what’s coming around the corner. It was a pleasure seeing many of you at our Midyear Meeting in breathtaking Sedona, Arizona. I would like to extend congratulations on behalf of myself and the College to our Second Vice President James Towry, who, with the help of our executive staff and a little from the Board of Trustees, put on an outstanding meeting, well worth the time and investment of the attendees. Overall, the meeting was successful and informative; however, as President, it is my responsibility not only to recognize our College’s accomplishments, but also to identify and address opportunities for improvement. In this letter I would ask, and encourage, all of us to step outside our comfort zone as we recognize a critical problem. I realize what I am about to discuss may be unpleasant to some, but I feel it will ultimately benefit all of us so we can grow as a College.

I would first like to acknowledge those members of our College who, through their dedication and persistence, acted as pillars shoul- dering and supporting the College through its sometimes tremulous evolution and expansion. Our College is again at a crossroads: With 20-plus residency programs and the promise of graduating more than 30 board-certified dermatologists per year, the College has grown, and so have its needs. Since it is no longer small, it is the responsibility of the entire membership to embrace the legacy of our founders. The time is now to volunteer as chairs and members of our committees to foster new ideas, infuse new insights, and provide new perspectives. The College can only be as strong as our membership’s support.

An important part of that growth relies heavily on the strength of our residency programs and their directors. To our College’s credit, we have many outstanding program directors who invest countless hours, energy, and effort in nurturing their residents. Being a program director requires a tremendous commitment and responsibility. Resident presentations, in part, represent the culmination of their dedication to the advancement of dermatology. As such, they reflect on the residents, their directors, their programs, and ulti- mately our College. If, and when, the quality of resident presentations is lacking, is it not our responsibility to ask why? Is it the quality of our residents? Is it a lack of guidance and instruction? Is it a lack of material or appropriate topic selection? A primary focus of the College and its Board of Trustees is to ensure that our outstanding residents become the future leaders of our College and of derma- tology. Should we not be asking the following questions?

• Are we, as a College, giving the necessary support to our program directors? • Are the residents provided the opportunity to review their annual mock performance reports? • Can the College and the residency directors take more of an initiative in suggesting and cultivating presentation topics? • Are the residents receiving enough support as they prepare their presentations and papers? An added benefit of our membership being more involved in the College is the assurance that the ACOD maintains its high level of commitment and excellence. In achieving this goal, I believe, as other members do, that our College will achieve parity with our MD counterparts as well as in the eyes of the general public. Another way to accomplish this is by becoming more involved in vari- ous allopathic academic meetings. Those members who are gifted in writing papers or lecturing are encouraged to participate at the AAD national level. Consider presenting a lecture or heading a focus session, leading a discussion group or symposium at an upcoming academic meeting, or authoring a paper for publication in a peer-reviewed allopathic journal. I am the first to admit that the first several lectures or papers are difficult, but the more you do, the easier they become. Taking advantage of these opportuni- ties will not only elevate the status of our College, but also serve as an example to our residents. Being committed to achieving this goal is the missing piece of the puzzle that will solidify the high academic standards of the AOCD while fulfilling without question our Osteopathic fellow status in the AAD.

Sincerely yours,

Marc I. Epstein, D.O. President, AOCD 2009-2010

letter from the president 5 A Ca s e o f Mo n i l e t h r i x a n d a Br i e f Re v i e w o f Ha i r Sh af t Di s o r d e r s

Dan Marshall, D.O.,* Ben Nasman, OMS III** *Dermatologist, Alpine Dermatology Clinic PC, Rexburg, ID **OMS III, A.T. Still University at KCOM, Kirksville, MO

Abstract

Monilethrix is an inherited hair-shaft disorder resulting in easily broken hair due to periodic constrictions in hair-shaft diameter. We report a classic case of monilethrix and discuss its genetic basis, usual clinical presentation and diagnosis, along with other details of progression and treatment. We also give a brief overview of other hair-shaft disorders.

Clinical Case primarily in those of European origin, results showing no breakage and stimulated although there have been pedigrees from hair growth. After treatment had been dis- Arabic and Indian origin also showing continued for four months, the symptoms A 2-year-old Hispanic male presented the trait. Most genetic malformations are resumed. Menni et al. reports that the with his mother for evaluation of abnormal found on chromosome 12q13, where there keratin gene has high sulfur content. Two hair growth. The mother complained that is at least one type II basic keratin hair 11-year-old patients were administered the boy’s hair had been normal-growing cluster.5 The KRT86 and KRT81 genes have L-cysteine, and some clinical improvement until he was 6 months old, and then she been located as common sites for spontane- was observed. This is a safe treatment that began to notice patches of hair that would ous point mutations. Monilethrix appears can be continued for many months. Topi- not grow out. This became progressively to be a hair-cortex disease because these cal retinoic acid, glycolic acid, and minoxi- evident over the time prior to presenta- genes are associated with cortical tricho- dil have also been used with limited success tion. She denied any other skin issues for 4 cytes.2 One case reported a G to A transi- in the treatment of monilethrix. Most her son. Upon further questioning, she tion in base 1 of the codon, and another treatments have proven minor efficacy dur- reported that her mother and brother had from a G to T transition in base 3 on the ing the times they are administered, but the same condition. same codon.5 The acidic counterparts to monilethrix returns after treatments are On examination, most of the patient’s terminated. scalp was covered with short, course- this cluster may also contribute to moni- lethrix, but they have yet to be analyzed.5 There are essentially two classes of appearing hair that was somewhat lighter hair-shaft abnormalities: those associated than expected. On a pull test, were The lanugo hair in newborns appears to be normal in monilethrix patients, and with increased fragility and those that easily broken off for microscopic exam, aren’t associated with increased fragility. which showed hair shafts with regularly symptoms don’t appear until growth of terminal hair.3 Monilethrix presents with Hair shaft abnormalities associated with alternating normal hair sections and sec- increased fragility are trichorrhexis invagi- tions that were constricted in diameter, as alopecia predominately in the occipital region, but in more severe cases can involve nata (bamboo hair), monilethrix, , shown in Figure 1. Further examination , and trichothiodystro- failed to reveal any abnormalities, fol- any hair follicles throughout the body. The hair shafts have large nodes interconnected phy. Those that aren’t associated with licular hyperkeratosis, or dental defects. increased hair fragility are acquired pro- Since the mother had family mem- by narrow internodes. The large nodes are the same in diameter and structure as a gressive kinking of the hair, loose anagen bers with monilethrix, she was aware of hair, and pseudo pili annulati, the chronic nature of the condition. She normal hair follicle, whereas the internodes seem to lack a medulla, making them sus- pili bifurcati, pili multigemini, spun-glass was informed that although there are lim- hair (uncombable hair), and woolly hair. ited treatment options the condition may ceptible to breakage and thus alopecia. The improve at puberty. The patient was seen space between nodes usually measures .7 just one time and then lost to follow-up, as mm to 1 mm.3 Diagnosis of monilethrix Hair shaft abnormalities the parents were migrant workers. is made my scanning electron microscopy (SEM), but genetic testing is also suggested. associated with increased Discussion Symptoms have been shown to hair fragility improve during puberty and pregnancy. Monilethrix is an autosomal-domi- treatment has been attempted , commonly nant hair disorder that has been found in a number of cases without remarkable known as bamboo hair, is a disorder result- success, thus no single hormonal factor has ing from defective keratinization. This been identified.2 One female responded results in a softened cortex, causing intus- to treatment with hydroprogesterone, tri- susceptions of the distal hair shaft into amcinolone and topical .2 the proximal hair shaft. This fragility She showed improvement in hair growth often appears shortly after birth, and can and pigmentation. There are a number of improve in adulthood. On microscopy, other symptoms that can be associated with broken hair shafts resemble the ends of golf monilethrix including , per- tees. Trichorrhexis invaginata is seen with ifollicular hyperkeratosis, , den- linearis circumflexa in Nether- tal, and other nail defects. ton’s syndrome patients. Treatment for monilethrix has been Pili torti, or corkscrew hair, has a flat- Figure 1. Beaded hair pattern of monil- extremely limited in the past. Acitretin tened shaft with twisting of the hair fiber. ethrix on trichogram. was used with success to stimulate normal The hair twists on itself and can have a hair growth in a 7-year-old girl.3 Treat- spangled appearance. There are three con- ment was continued for 12 months, with genital forms and one acquired form of pili 6 A Case of Monilethrix and a Brief Review of Hair Shaft Disorders torti. Classic pili torti can appear at birth in the facial hair region and is character- or in the first two years of life. It is usually ized by multiple hairs protruding from one associated with other ectodermal abnor- papilla. Each hair has an inner root sheath malities, and all those with pili torti should but shares the outer root sheath. have their hearing tested. Menkes syndrome Spun-glass hair is commonly referred is also associated with pili torti. Menkes to as “uncombable” hair. It has triangular- syndrome is an X-linked, recessive, cop- shaped hair shafts on cross-section. The per-metabolism disorder with several other deformity is caused by abnormal keratiniza- symptoms including psychomotor retarda- tion giving the hair flattened surfaces that tion, growth failure, and seizures. There is reflect the light and appear like “spun glass.” currently no treatment for pili torti. Woolly hair has a frizzy and wiry Trichorrhexis nodosa is the most com- appearance. Microscopy shows elliptical mon hair shaft fracture abnormality. Under cross sections with axial twisting. Trichor- light microscope, there is a characteristic rhexis nodosa may also be seen.1 splaying out of the cortical cells which is often described as ends of brushes pushed together. Trichorrhexis nodosa can be con- genital or acquired, and is suggested to be REFERENCES: a defect in the intercellular cement of the 1. Bolognia JL. (2007). Dermatology (2nd ed.). New York: hair shaft. Proximal trichorrhexis nodosa Elsevier Health Sciences. 2. Gebhardt M, et al. “Monilethrix: Improvement by Hormonal is associated with years of hair straighten- Influences?” Pediatric Dermatology (1999): 297-300. ing, distal trichorrhexis nodosa is caused by 3. Karincaoglu Y, et al. “Monilethrix: Improvement with Acitre- cuticular damage, and circumscribed trich- tin.” American Journal of Clinical Dermatology (2005): 407- orrhexis nodosa is commonly seen in facial 410. hair and scalp hair. 4. Menni S, et al. “Ultrastructural and Clinical Improvement in Monilethrix Treated with L-cystine.” Journal of Dermatologi- Trichothiodystrophy is a sulfur defi- cal Treatment (1993): 149-151. ciency in the hair. It is an autosomal- 5. Van Steensel M.A.M, et al. “A Missense Mutation in the recessive disorder with a number of Type II hair Keratin hHb3 is Associated with Monilethrix.” neuroectodermal complications depending Journal of Medical Genetics (2004): 1-4 on the severity of the disease. Clinically it can present as just the hair abnormality or can include intellectual impairment, short stature, ichthyosis, photosensitivity, nail dys- trophy, dental caries, , decreased fertility, bony defects, and immunodefi- ciency. On microscopy the hair shaft has light and dark bands shown with polarized light. Half of patients also have photosen- sitivity complaints caused by impairment in the nucleotide excision repair pathway. Diagnosis should be based on low sulfur content, trichoschisis, light and dark bands on polarizing microscopy, and damaged hair cuticles seen on scanning electron micros- copy.1

Hair shaft abnormali- ties not associated with increased hair fragility

Loose anagen hair syndrome is seen mostly in females with short blond hair. They often present with patchy alopecia, with the hair painlessly pulled from the scalp. This disorder is caused by early kera- tinization of the inner root sheath resulting in weak anchoring of the hair. Pili annulati and pseudo pili annulati are associated with bright and dark bands on reflected light. It is also called ringed hair, and can be an autosomal-dominant or sporadic trait. Microscopy of the hair shafts shows variation of diameter. No treatment is necessary. Pili bifurcati is a bifurcation of the hair shaft at different, unequal intervals followed by re-fusion of the hair shaft. Pili multigemini is seen predominantly Marshall, Nasman 7 Fa m i l i a l Ps e u d o p e l a d e o f Br o c q

Derrick Adams, DO,* Hassan Nasir, OMSIV,** Eric Seiger, DO, FAOCD,*** Michael Mahon, DO, FAOCD**** *Botsford Hospital/Pontiac Osteopathic Hospital Consortium, Farmington Hills, MI **Michigan State University College of Osteopathic Medicine, East Lansing, MI ***Skin & Vein Center, Fenton, MI ****Program Director, Botsford Hospital/Pontiac Osteopathic Hospital Consortium, Farmington Hills, MI

Background: four of the siblings. All specimens demon- strated total absence or marked reduction in follicular units and sebaceous glands, Historically, the classification of pri- with a dense reticular dermal fibrosis. mary alopecias can be problematic. The Sparse perivascular lymphocytic infiltrate literature is abounding with a century of was noted in most samples. Fungal con- conflicting and nebulous terminology. This trol stain was negative on all biopsies. No greatly complicates the critical analysis and mucin, vacuolar, or lichenoid changes were standardization of the alopecia literature visible (Photo 3). Pseudopelade of Brocq across the decades. The evolution of termi- was diagnosed after careful consideration nology and improved diagnostic techniques of end-stage lichen planopilaris (LPP), have aided significantly in categorizing the end-stage discoid erythematous Photo 1 majority of cases. Pseudopelade of Brocq (DLE), central centrifugal cicatricial alope- is an entity that continues to defy both our cia (CCCA), and striae-distensae. understanding and classification scheme of The lesions proved to be unrespon- primary alopecias. sive to numerous topical high-potency ste- roids, intralesional , topical anti-fungals, topical , and oral History and Clinical Pre- doxycycline. Since all cases lacked a clinical sentation: inflammatory stage upon which to focus treatment, focal scalp reduction and close follow-up for evolving lesions was offered Ten healthy siblings of Iraqi descent to the family. presented over the course of two years with an insidious onset of patchy, scarring alo- Discussion: Photo 2 pecia. The patients denied any pruritis, pain or other symptoms with the exception The term “pseudopelade of Brocq” has of one male who described itching and ten- elicited controversy since first coined in derness. Six females and four males were 1888 by French dermatologist Louis-Anne- equally affected, with symptoms beginning Jean Brocq. Subsequently, many authors around five or six years of age in each. Most have called for abandoning its use. It is a lesions were discovered incidentally during diagnosis of exclusion, without histological grooming, and patients were unaware of or immunological findings, and represents their true duration or activity. a clinical pattern of end-stage alopecia.1,2,3 There was no family history of any Pseudopelade was initially described as diagnoses or cultural practices to “atrophic, oval to round, white to ivory account for the lesions. One female had a plaques classically lacking signs of inflam- Photo 3 history of lichen planus, , and iron- mation.”4 It has recently been reclassified deficient anemia. No history consistent by the North American Hair Research Soci- technique outside of classification into with lichen planopilaris or discoid lupus ety as “clinically discrete, smooth, flesh- lymphocytic, neutrophilic, mixed, or “non- could be elicited. toned areas of alopecia without follicular specific” processes. It is also difficult, if not Discrete, smooth, skin-toned patches hyperkeratosis or perifollicular inflamma- impossible, to distinguish between LPP, of ovoid and linear alopecia were pres- tion.” We believe both definitions can be DLE, and other scarring alopecias in the ent. No follicular hyperkeratosis or peri- applied to our patients, especially given late, “burned-out” stages. follicular were noted (Photos the mixed presence of atrophy both in our There have been two previous case 1&2). Many lesions were atrophic, with the patients and among the two varying defini- reports of familial pseudopelade in the lit- appearance of “footprints in the snow.” No tions. erature, with one author proposing the exis- scales, , or pustules were noted. Arriving at a specific diagnosis for the tence of an autosomal-dominant form.5 , 6 Remainder of hair-bearing areas, denti- patients proved challenging given the lack Some authors consider pseudopelade of tion, and nails were unremarkable. No of clinical inflammation and the non-spe- Brocq an autonomous disease. Proposed hair fragility or structural anomalies were cific, “burned-out” histological findings. etiologies include: acquired automimmu- seen. test media, potassium The working classifications of scarring alo- nity,7 Borrelia infection,8,9 and premature hydroxide stains, complete count, pecias have undergone several revisions senescence of the follicular stem-cell res- anti-nuclear antibody, rapid plasma reagin, in the past decades, making review of past ervoirs.10 A recent study of lesions previ- ferritin, thyroid stimulating hormone, and literature problematic at best. Distinct pri- ously classified as pseudopelade revealed anti-thyroid antibodies were all unremark- mary cicatricial alopecias cannot be dis- 67% to be most consistent with either LPP able. Histopathology was obtained on tinguished with current histopathologic 8 Familial Pseudopelade of Brocq or DLE.11 Thus, it is possible that pseu- dopelade of Brocq is a term that reflects our current limitations in understanding scarring alopecias and may become a relic of medical literature in the future. While no treatment is universally accepted for pseu- dopelade of Brocq, the University of British Columbia Hair Clinic approaches treatment in a fashion similar to lichen planopilaris, noting no single modality of exceptional benefit. Many authors consider the condi- tion intractable. A similarly curious report document- ing a scarring alopecia in Iraqi patients was reported in 2002.12 Idiopathic striae dis- tensae of the scalp was described in several non-consanguineous Baghdadi children. It is interesting that the clinical findings and patient demographics strongly resemble the findings in our case. Given the uncanny similarities between the two and the ever- evolving understanding of scarring alope- cias, revisiting this case in the future may be warranted. In review, we describe a report of the largest case to date of familial pseudopelade of Brocq and its inherent difficulties in both classification and treatment.

REFERENCES: 1. Sullivan JR, Kossard S. Acquired scalp alopecia. Part I: A review. Australas J Dermatol. 1998;39:207–219. 2. Nayar M, Schomberg K, Dawber RP, Millard PR. A clini- copathological study of scarring alopecia. Br J Dermatol. 1993;128:533–536. 3. Anderton RL, Cullen SI. Pseudopelade of Brocq secondary to lichen planus. Cutis. 1976;17:916–918. 4. Brocq L. Les folliculites et perifolliculites de calvantes. Bull Mem Soc Med Hop Paris. 1888;5:399–408. 5. Collier PM, James MP. Pseudopelade of Brocq occurring in two brothers in childhood. Clin Exp Dermatol. 1994;19:61– 64 6. Sahl WJ. Pseudopelade: an inherited alopecia. Int J Der- matol. 1996;35:715–71 7. Pincelli C, Girolomoni G, Benassi L. Pseudopelade of Brocq: an immunologically mediated disease? Dermato- logica. 1987;174:49–5. 8. Schwarzenbach R, Djawari D. Pseudopelade Brocq— mogliche folgeeiner borreliose stadium III? [English abstract] Hautarzt. 1998;49:835–837. 9. Kostler E, Hubl W, Seebacher C. PCR-nachweis von bor- relia-burgdorferi DNA in einergewebeprobebei pseudope- lade Brocq. Hautarzt. 1999;50:897. 10. Sullivan JR, Kossard S. Acquired scalp alopecia. Part I: A review. Australas J Dermatol. 1998;39:207–219. 11. Amato L, Mei S, Massi D, Gallerani I, Fabbri P. Cicatricial alopecia; a dermatopathologic and immunopathologic study of 33 patients (pseudopelade of Brocq is not a specific clinico-pathologic entity). International Journal of Dermatology. 41(1):8-15, January 2002. 12. Sharquie Khalifa E, Al-Waiz Makram M, Al-Nuaimy Adil A. Striae distensae-like lesions. A cause of scarring alo- pecia among children. Saudi Medical Journal 2002; Vol. 23 (12): 1489-1491.

Adams, Nasir. Seiger, Mahon 9 Tr e a t m e n t o f Ke r a t o aca n t h o m a Ar i s i n g f r o m Hy p e r t r o p h i c Li c h e n Pl a n u s : A Ca s e Re p o r t a n d Re v i e w o f t h e Li t e r a t u r e

Rachel Epstein, D.O.,* Dunnett Durando, B.S.,** David Dorton, D.O., FAOCD,*** Richard Miller, D.O.,FAOCD**** * 1st Year Dermatology Resident, Sun Coast Hospital/HCA/Largo Medical Center/NSU-COM, Largo, FL ** 4th Year Medical Student, Virginia College of Osteopathic Medicine, Blacksburg, VA *** Associate Faculty, Sun Coast Hospital/HCA/Largo Medical Center/NSU-COM, Largo, FL **** Program Director, Sun Coast Hospital/HCA/Largo Medical Center/NSU-COM, Largo, FL

Abstract

Hypertrophic lichen planus is a variant of lichen planus that has the potential to undergo malignant transformation. We report an 86-year-old Caucasian female who presented with multiple squamous-cell carcinomas of the keratoacanthoma type arising from hypertrophic lichen planus on the anterior shins. Due to the high number of lesions in this challenging anatomic location, a unique treatment approach was attempted. Four weeks after her initial treatment there was marked clinical improvement of the squamous-cell carcinomas in addition to the underlying hypertrophic lichen planus. An overall decline in new lesions was also observed. Our findings suggest that intralesional is a valuable treatment option for arising from hypertrophic lichen planus on the lower extremities.

Introduction calcineurin inhibitors, and oral or topical retinoids. Lichen planus (LP) is a papu- losquamous skin disorder of unknown eti- ology. This inflammatory condition can Case Report affect the skin, mucous membranes, geni- talia, nails, and scalp. Although the disease An 86-year-old Caucasian female pre- may occur at any age, it most commonly sented for evaluation of a tender, enlarg- affects middle-aged adults, with a slight ing on the left lower leg that had predominance in females. The course of been present for two months. Physical lichen planus can be chronic, with the ini- examination revealed a 1-cm, erythema- tial eruption clearing within one year in tous, indurated, dome-shaped nodule on Figure 2. The two marked lesions were 68% of patients, although 49% recur.1 The the left anterior lower leg. A shave biopsy biopsy-proven SCCs of the keratoacan- lesions of LP are usually described as pla- was performed, and histopathologic exami- thoma type. nar, polygonal, violaceous that can nation revealed a squamous cell carcinoma cause significant pruritus in some patients. of the keratoacanthoma type. Due to the Lesions can also ulcerate and erode and location of this malignancy, electrodessica- may heal with postinflammatory hyperpig- tion and curettage (ED&C) was performed. mentation. Lesions that persist for months Two weeks later, she presented with delayed can become thicker, hyperkeratotic, darker healing of the ED&C site along with stasis in color, more confluent, and are usually dermatitis of the bilateral lower extremi- referred to as hypertrophic lichen planus. ties. At this time, the was Hypertrophic lichen planus is just one treated with urea 40% (U-Kera®) of the several variants of LP. Other variants and cream (Topicort®). include actinic, annular, atrophic, erosive, Subsequent follow-up revealed improve- follicular, hypertrophic, linear, pigmented, ment of the stasis dermatitis; however, and vesicular/bullous forms. Hypertrophic several erythematous-to-violaceous, flat- Figure 3. Marked improvement and LP is a benign disorder that occurs most topped papules and 1-cm, erythematous, resolution of hypertrophic lichen planus commonly on the extensor aspects of the indurated, dome-shaped nodules were lesions after treatment with intralesional lower extremities, especially the pretibial now present on the left anterior lower leg. triamcinolone. Notice the residual post- areas and ankles. Hypertrophic LP usually Additional biopsies were performed (Fig- inflammatory . There has a more chronic course and can lead to ure 1). The patient’s past medical history were two new lesions present at this time. postinflammatory pigment alteration, scar- Previously treated ring and malignancy. Malignant transfor- LP (ED&C) SCC mation is most often seen in the oral form of lichen planus, although neoplastic trans- formation has also been documented in patients with chronic hypertrophic lichen planus. SCC A wide range of modalities has been used to treat hypertrophic LP. The first- line treatments are topical steroids, partic- ularly class I or II ointments. Second-line therapies include systemic immunosup- pressive agents such as oral or intramuscu- lar steroids, azathioprine and cyclosporine. Figure 1. Lichen planus lesions and two Figure 4. Three-month follow-up. Notice Other treatment options include narrow- lesions that were biopsy-proven SCC. resolution of the lesions. band or broadband UVB, PUVA, topical 10 Treatment of Keratoacanthoma Arising from Hypertrophic Lichen Planus was significant for hypertension. She denied Giesecke et al. This patient’s keratoacan- squamous cell carcinoma of the keratoa- any personal or family history of thoma was surgically excised, and the hyper- canthoma type, arising from chronic hyper- or any other dermatologic conditions. She trophic lichen planus lesions were treated trophic lichen planus. Our patient’s lesions denied and use of any medications. with topical dipropionate were treated with intralesional triamcino- was non-contributory. and intralesional triamcinolone. They dis- lone acetonide 5 mg/cc , 0.1 cc per lesion, Histology of the superior lesion on the cussed the importance of chronic inflamma- every four weeks. This patient experienced left anterior shin demonstrated a prolifera- tion and prolonged local trauma as possible marked improvement of the lesions even tion of well-differentiated squamous epithe- risk factors in the development of kera- after the initial injections. A reduction in lium infiltrating the . The epithelial toacanthomas and other types of SCC in the number of new keratoacanthomas aris- cells had abundant glassy, eosinophilic cyto- hypertrophic LP.3 ing from previous hypertrophic LP lesions plasm, and there was a central keratin-filled The treatment of lichen planus is dif- was also seen after successive treatments. crater. These findings were consistent with ficult and differs depending on the severity To our knowledge, there are no published squamous cell carcinoma, invasive, well- of the disease, location of the lesions, and studies involving the treatment of keratoa- differentiated, of the keratoacanthoma (KA) whether there is malignant transformation canthomas arising from hypertrophic LP type. Biopsy of the inferior lesion demon- of these lesions. Patients who have limited with intralesional triamcinolone injections. strated compact orthokeratosis, wedged- disease respond well to potent topical ste- We offer intralesional as a shaped hypergranulosis, squamatization of roids or intralesional steroid injections. This valuable treatment option to consider for the , and acanthosis. A lichenoid, is not the case for those patients with wide- keratoacanthomas arising from hypertro- chronic, inflammatory cell infiltrate was also spread disease, who may require systemic phic lichen planus. noted. The diagnosis of hypertrophic lichen therapy with corticosteroids, isotretinoin, planus was made. and immunosuppressant agents. REFERENCES: At follow-up, there were also several Topical steroids, either class I or II, 1. Irvine C, et al. Long-term follow-up of lichen planus. Acta other lesions clinically consistent with SCC. can be used initially for limited disease and Derm Venereol 1991; 71:242. Both the hypertrophic LP and suspicious help with the severe pruritus. It is recom- 2. Ardabili M, Gambichler T, Rotterdam S, Altmeyer P, Hoff- mann K, Stucher M. Metastatic cutaneous squamous cell SCC lesions were treated with 0.1 cc of tri- mended to use plastic occlusion overnight carcinoma arising from a previous area of chronic hyper- amcinolone acetonide 5 mg/cc. Four weeks to enhance the effectiveness of topical ste- trophic lichen planus. Dermatology Online Journal 2003; 9 1 (1):10. later, she returned for reevaluation with roids. Although topical corticosteroids are 3. Giesecke LM, Reid CM, James CL, Huilgol SC. Giant improvement of her left leg; however, addi- widely used as the initial therapy, published keratoacanthoma arising in hypertrophic lichen planus. Australian Journal of Dermatology 2003; 44: 267-269. tional keratotic, erythematous nodules sus- clinical trials demonstrating their efficacy 4. Joshi R, Durve U. Squamous cell carcinoma in hyper- picious for keratoacanthomas were evident are lacking. However, propionate trophic lichen planus. Indian J Dermatol Venereol Leprol 2007; 73:54-55. (Figure 2). These lesions were injected with applied frequently has been recommended 5. Sengupta S, Das JK, Gangopadhyay A. Malignant trans- 0.1 cc of triamcinolone acetonide 5 mg/cc by some authorities, as well as the use of formation of hypertrophic lichen planus. Indian J Dermatol Venereol Leprol 2006; 72:470. in an attempt to eradicate any underlying intralesional injections of triamcinolone 6. Cribier B, Frances Camille, Chosidow O. Treatment of inflammatory process that may have been acetonide 10 mg/ml for hypertrophic lichen Lichen Planus. Arch Dermatol 1998; 134. 9,10 7. Badell A, Marcoval J, Gallego I, Moreno A, Peyr J. Kera- contributing to the eruptive phenomenon. planus lesions. toacanthoma arising hypertrophic lichen planus. British Four weeks after prior treatment, the patient Grover et al. studied intralesional Journal of Dermatology 2000; 142:370-393. 8. Odom B, James D, Berger G. Lichen Planus. In: Andrew’s continued to notice improvement of the injections of triamcinolone acetonide to Diseases Of The Skin, Clinical Dermatology, Ninth ed. lesions (Figure 3). A decrease in the number the proximal nail fold in 30 patients with Philadelphia, PA. W.B Saunders Company, 2000. 9. Oliver GF, Winkelmann RK. Treatment of lichen planus. of new lesions was also seen after each treat- twenty-nail dystrophy. Of those, 14 patients Drugs. 193; 45:56-65. ment. At three-month follow-up, the lesions had nail lichen planus. They found that 10. Cribier B, Frances C, Chosidow O. Treatment of Lichen and post-inflammatory pigmentary changes out of the 28 patients who completed the Planus: An Evidence-Based Medicine Analysis of Efficacy. treatment protocol, 16 patients showed a Arch Dermatol Dec 1998; 12. 11. Grover C, Bansal S, Nanda S, Reddy BS. Efficacy of were completely resolved (Figure 4). 11 75-100% improvement. Other drugs stud- Triamcinolone Acetonide in Various Acquired Nail Dystro- ied for the treatment of cutaneous lichen phies. J Dermatol 2005; 32(12): 963-8. 12. Laurberg G, Geiger JM, Hjorth N, et al. Treatment of Discussion planus include acitretin and low-dose enox- lichen planus with acitretin: a double-blind, placebo-con- aparin (low-molecular-weight heparin). A trolled study in 65 patients. J Am Acad Dermatol 1991; 24: 434-437. double-blind vs. placebo trial using acit- 13. Hodak E, et al. Low-dose low-molecular-weight heparin Lichen planus is a common skin dis- retin in 65 patients suffering from cutane- (enoxaparin) is beneficial in lichen planus. J Am Acad Der- matol 1998, 38:564. order that affects the skin, hair, nail, and ous LP showed a significant improvement mucous membranes, especially the oral of the disease in 75% of the patients who mucosa. Hypertrophic lichen planus is a completed the trial.10,12 These patients were variant of LP, manifesting more commonly treated for eight weeks using 30 mg of acit- on the shins. The lesions of hypertrophic retin daily. Sixty-four percent of the treated LP are usually violaceous and thickened patients vs. 13% of the placebo-group and have a superficial scale; these charac- patients experienced significant improve- teristics, along with pruritus and symmetric ment or even remission. involvement of the shins, are a clue to the In a study including 10 patients, Hodak clinical diagnosis of the disease. Although et al. utilized low-dose enoxaparin to treat rare, malignant transformation of chronic widespread lichen planus associated with hypertrophic lichen planus lesions has been intense pruritus. The patients were treated reported. Oral LP has the highest incidence with 3 mg of enoxaparin subcutaneously of neoplastic change, occurring in 0.3 to once weekly for a total of four injections 3% of patients. Ardabili et al. reported a in three patients and six injections in the case of metastatic cutaneous squamous cell remainder of the patients. They found that carcinoma arising from hypertrophic LP in nine patients, the pruritus resolved within and indicated that long-standing hypertro- two weeks. Within four to 10 weeks, eight of phic lichen planus seems to predispose the nine patients experienced complete regres- 2 patient to malignant transformation. A sion of the inflammatory eruption.13 case of keratoacanthoma arising in chronic In conclusion, we presented a case of hypertrophic lichen planus was reported by Epstein, durando, dorton, miller 11 Al l e r g i c Co n t ac t De r m a t i t i s t o Re d Ta t t o o Dy e

James Yousif, MSIV,* Peter Saitta, D.O.,** Steven K. Grekin, D.O.,*** Jenifer Lloyd, D.O.**** *Michigan State College of Osteopathic Medicine, East Lansing, MI **Department of Dermatology, Oakwood Southshore Medical Center, Trenton, MI ***Department of Dermatology, Oakwood Southshore Medical Center, Trenton, MI ****Co-Director, Residency Program, University Hospitals Health System - Richmond Heights Hospital, Department of Dermatology, Case Western Reserve University School of Medicine, Cleveland, OH

Abstract

Pathologic consequences of tattooing are relatively rare, but allergic (ACD) to the components in tattoo dye has nevertheless been reported. The causative agents for allergic reactions are typically dependent upon the color dye used, with red dye reactions being most common. We present a case of ACD to red tattoo dye in a 36-year-old African American female and review the literature specifically surrounding red tattoo reactions. Notably, we compare the histopathology seen in classic ACD to red tattoo dye reaction and weigh the role of patch testing in diagnosis.

REPORT OF A CASE dye components, the classic culprit being cluded that the lightening agents such as mercuric sulfide (in cinnabar and vermil- titanium, aluminum, silicon, and calcium ion). However, several case reports and were added to the red dye. A 36-year-old African American studies implicate other allergenic compo- Table 1 depicts the various compo- female presented to our department with nents in red dye. For instance, mercury- nents uncovered in red tattoo dye, and an inflammatory reaction to a tattoo placed free innovations such as sienna/red ochre Table 2 depicts the most common compo- 18 months previously, situated on the dor- (ferric hydrate), cadmium red (cadmium sitions of tattoo pigments of other hues. It sum of the left . She complained of selenide), organic vegetable dyes (sandal- seems likely that our patient had more than an extreme pruritus and scaling, which she wood and brazilwood), and Devil’s Red one type of red-dye component within her had experienced for almost 12 months, in (azo compound) have caused inflamma- various tattoos, but clearly the most recent addition to skin texture and color changes. tory reactions.1,2 Moreover, Sowden et al. contained a novel allergen. Her symptoms were confined to the red examined the chemical composition of red A number of reports have character- areas of the tattoo. The patient did have a pigments by X-ray microanalysis in indi- ized the clinical presentation of individu- number of other tattoos, performed at var- viduals with cutaneous reactions to red als with ACD to red tattoo dye. Briefly, it ious parlors, which remained unchanged tattoo dye and implicated iron, sulfur, tita- should be noted that all tattoo placement and symptom-free, even where red color- nium, phosphorus, aluminum, silicon, and is initially accompanied by some degree ing had been used. Her past medical his- calcium as potential allergens.3 They con- of , inflammation, exudation, or tory, social history, and family history were insignificant. There were no known drug Table 1: allergies. A review of systems was negative for preceding illness, recent weight loss, or Metallic Composition of Red Ink Tattoos constitutional symptoms. The patient did not report any photoaggravation of the Author/Yr/Type of Manuscript Metallic Component inflammatory reaction. Goldstein/1967/Case Series5 Cadmium, Mercuric sulfide Physical examination revealed a well- Sulfur, Silicon, Aluminum, Chlorine, Taaffe/1978/Case Series6 appearing patient with several coalesc- Mercury ing, granulomatous, purple, scaly nodules Slater/1983/X-ray Microanalysis Aluminum, Chlorine, Mercury, Chro- sharply limited to the red portions of the Investigation24 mium, Titanium tattoo. The word “angel” was written in Iron, Sulfur, Titanium, Calcium, Mer- Sowden/1991/X-ray Microanalysis black, and was flanked by red angel wings. cury, Phosphorus, Aluminum, Cad- and Patch Test Investigation3 No lymphadenopathy was noted. The mium, Silicon patient was offered a punch biopsy, but Yazdian/2001/Case Report1 Cadmium declined due to cost. Thus, we made the presumptive diagnosis of ACD to red tattoo dye and injected the nodules with 0.3ml of intralesional triamcinolone 5mg/ml. We Table 2: 2 prescribed clobetasol 0.05% ointment to Classic Composition of Tattoo Ink Pigments be applied twice daily under occlusion and Color Pigment Composition instructed the patient to return to clinic in Red See Table 1 four weeks. Black Carbon (India ink), Iron oxide, Logwood Brown Ferric oxide DISCUSSION Blue Cobalt aluminate ACD to tattoo dyes is well docu- Green Chromic oxide, Lead chromate, Phthalocyanine dyes mented, with the most common reactions Yellow Cadmium sulfide occurring at red tattoo sites. These reac- Purple Manganese, Aluminum tions can be attributed to a number of red White Titanium oxide, Zinc oxide 12 Allergic Contact Dermatitis to Red Tattoo Dye crust formation, lasting approximately three rhea, , and malaise.15 It is note- cation of a tattoo is made when brown, weeks.4 Persistent signs of inflammation, worthy that patch-testing does not appear black, blue, yellow, or red pigment is visual- pruritus, or pain, are seen in ACD.1,3,4-16 In to induce systemic ACD in patients cutane- ized in the dermis, usually confined to the these instances, patients usually present ously challenged with patches. loose fibrous tissue surrounding blood ves- with prominent scaling or crusts, with some Granulomatous red dye skin reactions sels in the superficial and mid-dermis.23 The evidence of induration, tenderness, and/ may be a presenting manifestation of under- deposits may be present within macrophages or pruritus.1,3-6,8,10,12-17 This was the case in lying sarcoidosis. Four cases reported as sar- or found in the extracellular environment our patient, who presented with scaly, pru- coidosis beginning with presumed ACD to between bundles. These pigments ritic nodules. It is apparent that there is no red tattoo dye have been documented.13,19-21 are refractile, but not doubly refractile. In definitive timetable as to the onset of ACD Skin biopsies in all cases demonstrated a addition to the pigment deposits, there are to red tattoo dye, as reactions have occurred granulomatous pattern. However, as will also slight histopathologic changes percep- immediately following placement and as be later discussed, a granulomatous pattern tible in tattooed skin. These changes are late as 45 years thereafter.1,3,4-17 Though it does not definitively indicate an underlying listed in Table 4. has been presumed that these reactions are sarcoidosis, as many cases of ACD to red When the inflammatory response is related to a delayed cell-mediated hypersen- tattoo dye present with this histopathology. pronounced enough to result in a so-called sitivity process,18 the variability in the time While there may be a question as to whether ACD, distinct histological patterns emerge. of onset speaks against this notion. or not the skin lesions in these clinical cases Photosensitivity and the presence of are a byproduct of the disease process itself A lichenoid pattern is the most common systemic dermatitis can aide greatly in iden- or merely an unrelated phenomenon, it change, which some theorize is likely indica- tifying the responsible allergen in cases of may be vital for the dermatologist to initi- tive of a graft versus host response.3,6-8,11-12,14,24 ACD to red tattoo dye. Several reports have ate a workup for sarcoidosis in instances in Other forms may display nodular infiltrates documented photosensitivity in those red which skin biopsies suggest a sarcoid-like of inflammatory cells with a well-demar- 20 dyes containing cadmium; some document pattern. Iannuzzi et al. describe a com- cated Grenz zone, or be granulomatous in a degree of photoaggravation of pre-existing prehensive workup for patients presenting origin.3,7,23-24 The latter may be character- 22 symptoms; and others attribute the initial in this manner. Table 3 outlines the ini- ized by either a sarcoid-like infiltrate with 1,3,5,17 tattoo reaction to sunlight exposure. tial steps of this workup. Even though our aggregates of epithelioid histiocytes con- Commonly, cadmium sulfide is used in yel- patient had a granulomatous appearance taining small quantities of pigment and few low tattoo coloring and distinctively causes to her skin lesions, we could not pursue a giant cells or a foreign-body-type reaction 5 photoallergic responses. Interestingly, a biopsy because the patient could not afford with an abundance of pigment-contain- minute amount of cadmium sulfide is used the procedure. Our patient did not portray ing giant cells.3-4,8,13,23,19-21 Finally, a pseudo- to render a brighter color in red dye. Gold- other signs of sarcoidosis. lymphomatous pattern where the infiltrate stein reported 15 subjects who had pho- Various histological patterns exist appears quite dense and difficult to distin- toallergic red tattoo reactions, all of which defining the inflammatory response to tat- guish from lymphoma has been reported.17 contained trace amounts of cadmium. A too dye. Classically, the histological identifi- Knowledge of the existence of a pseudolym- sunscreen was the only topical preparation that relieved symptoms in the majority of the 15 patients, and one patient had com- Table 3: plete resolution with purely topical treat- Initial Clinical Evaluation of Sarcoidosis22 ment.5 Yazdian et al. presented a similar case Initial Assessment with partial resolution of symptomology History and physical Exam (attention to family history and environmental/occupa- when the tattoo area was protected from tional exposure) 1 sunlight. Biopsy of affected organ In addition to the above, systemic con- tact dermatitis can be seen in patients with Posteroanterior and lateral chest radiographs red tattoo dye containing mercury sulfide Pulmonary-function tests - spirometry with bronchodilator, total lung capacity, and when these individuals are challenged with diffusion capacity mercury-containing products. For instance, Complete ophthalmologic evaluation (slit-lamp, tonometric, and funduscopic Tsuruta and colleagues reported a case of exams) systemic ACD in a patient orally challenged Complete blood count with platelet count and measurement of serum calcium, with 250 grams of raw swordfish and alfon- creatine, alkaline phosphatase, alanine aminotransferase, and aspartate amino- sino. The patient developed a generalized transferase levels pruritic eruption and lichenified macules at Measurement of angiotensin-converting enzyme (if elevated, may help monitor the red tattoo site. The authors concluded patient compliance) that the patient experienced a systemic ACD Other tests for involved organs: caused by initial sensitization to mercury in the red tattoo pigment, aggravated later - Holter monitor, echocardiography, cardiac PET, MRI, and electrophysi- by consumption of mercury-contaminated ological studies for inducible arrhythmias fish. Shark, swordfish, king mackerel, alfon- sino, and tilefish are known to contain high Lung - right-heart catheterization for levels of mercury.1,2 Similar cases have been documented upon exposure to broken ther- Central nervous system - MRI with gadolinium and cerebrospinal fluid analysis mometers, inhalation of mercury vapor, antiseptics, mercury-containing creams, Table 4: vaccines, gamma globulin preparations, Histopathologic Changes Seen in Tattooed Skin antitoxins, amalgam dental fillings, and con- Histological Finding tact lens solution.15 Though it has not been specifically documented in relation to red Superficial perivascular infiltration composed of small tattoo dye, other signs of systemic ACD may numbers of lymphocytes and pigment-containing macro- phages closely arrayed around dilated vessels include nausea, vomiting, arthralgia, diar- Mild fibrosis of the papillary dermis Yousif, Saitta, Grekin, Lloyd 13 phomatous histological pattern may prevent into three types: aggregates of fine, round, applied for two months duration.7 In con- misdiagnosis of lymphoma. granular material of moderate electron den- trast, Mortimer et al. successfully utilized Comparing the histopathology seen in sity which in places were membrane bound; 0.05% cream under tattoo reactions with the histology classi- large and highly electron-dense particles occlusion, but the patient needed treatment cally seen in ACD is one point of discussion with an angular appearance; and particles for a total of four months. The use of highly that is currently lacking in the literature. with an intermediate size compared with potent topical steroids in combination with Conventionally, ACD is characterized by the first two classes.24 One setback of this intralesional corticosteroids were found to epidermal spongiosis, mild to moderate protocol was the inability to identify carbon be ineffective in relieving symptoms in one infiltration of lymphocytes, macrophages, or organic dyes because atomic numbers patient.8 We chose to use this combination and Langerhans cells in the upper dermis less than 11 could not be detected.24 Similar in our patient, but are unaware of the out- surrounding the superficial plexus, and exo- methods have been utilized.6 come because we lost the patient in follow- cytosis of lymphocytes. Chronic lesions may Studies scrutinizing the efficacy of up. While surgical excision and skin grafting show little spongiosis but prominent epider- patch testing have suggested that it is not a may be viable options, patients may want mal hyperplasia. In contrast, the histologic useful diagnostic tool in cases of ACD to red to keep their tattoo or may not find these process in ACD to red tattoo dye is confined tattoo dye. In one study, for instance, seven choices aesthetically pleasing. As in any sur- more neatly to the dermis, lacking, in most patients were patch tested for elements in gery, there are associated risks such as infec- cases, epidermal spongiosis or even epider- their red tattoos, but only one produced a tion and permanent scarring. mal involvement all together. Furthermore, positive result that correlated with patch Advancements in laser technology may the lichenoid pattern in red tattoo dye reac- testing.3 In another investigation, Taafee et provide a desirable alternative. Two lasers tions is the most common finding, and this al. found mercury hypersensitivity through have been used in anecdotal instances – the histological pattern is uncommon in clas- patch testing in one of four patients, but the Nd:YAG and CO2 lasers – both of which are sic ACD. Granulomatous ACD, however, red pigment did not contain mercury when known to target red pigmentation. In one refers to the presence of in the examined by scanning electron microscopy case, a 63-year-old male patient was treated dermis and is similar to the granulomatous and X-ray microanalysis. Of interest, how- every three months for a total of four treat- infiltrates of ACD to red tattoo dye. The ever, was the observation that hypersensitiv- ments with an Nd:YAG laser (532nm; power discrepancies between the histopathological ity was provoked by intracutaneous injection of 2.8 J/cm^2; 3mm spot). The treatments processes suggest that ACD to red tattoo dye in those with negative patch results.6 This relieved pruritus and flaking of the skin.10 In may represent a distinct pathological entity, finding raises the possibility that intrader- another instance, participants had six treat- at least in terms of the microscopic inflam- mal testing may be of assistance in elucidat- ments at weekly intervals with the Nd:Yag matory response. This idea may be further ing the allergenic components in red tattoo at the above settings, and were instructed supported by the varied clinical onset seen dye. Finally, Table 5 outlines the cases of to use topical 0.05% clobetasol propionate in ACD to red tattoo dye. ACD to red tattoo dye documented in the ointment between visits. Substantial flatten- Despite these discrepancies, reactions to literature, the majority of which demon- ing, improved skin coloration, and decreased red tattoo dye are currently presumed to be strate little success with patch testing. pruritus were noted. No major recurrences a form of ACD. Diagnosis of classic ACD is Treatment for tattoo reactions can be were seen at six-month follow-up.7 Similar usually based on clinical findings, but given difficult because patients seek a therapy resolution of symptoms was noted in two the possibility of underlying internal disease that decreases skin inflammation but pre- patients with utilization of CO2 laser treat- the literature suggests that a histological serves the tattoo. Attempts involving the ment, as well.9 examination is warranted in instances of use of topical steroids have shown mixed This is not to say that laser therapy is ACD to red tattoo dye. We unfortunately results.7-8,10 Antony et al. showed that topi- completely without side effects. The most did not have the opportunity to biopsy our cal 0.05% clobetasol propionate ointment common side effect is localized skin inflam- patient, even though she presented with under occlusion was ineffective, even when mation, but widespread anaphylactoid reac- granulomatous nodules. In addition to biopsy, some have pursued further analysis Table 5: using special imaging to identify the aller- Cases Utilizing Patch Testing genic components of the red dye. Others have utilized patch testing. These additional Number of Patients Author/Yr Pertinent Results steps do not appear to be useful in terms of Receiving Patch Tests making a diagnosis, but are discussed below Weidman/196621 1 for academic purposes. Patch tests with Hg, Cr, Ni, Co; all Two studies have employed methods negative except for the site of the to determine the composition of tattoo pig- test with Co (was studded with tiny purpuric papules) ments. These studies entail the use of X-ray Goldstein/19675 13 microanalysis in combination with elec- 2 patients with verrucous responses tron microscopy and/or light microscopy. in red tattoo sites had strongest The largest investigation was conducted by response to patch testing; 2 subjects Slater and Durrant, who combined light and trace reactions to bichloride of mer- electron microscopy with X-ray microanaly- cury, 1 patient trace reaction to mer- sis. In this study, tattoo specimens from thiolate; remaining negative 12 17 patients were analyzed. The use of light Clarke/1979 2 1 patient with mercury sensitivity on microscopy divided histological appear- patch testing but negative to dye ances into three types: no cellular reaction, powder; 1 patient not sensitive to a lichenoid cellular reaction, and a nodular patch testing for Hg but possible sen- cellular reaction with a dense perivascular sitivity to injected Hg 14 lymphohistiocytic infiltrate extending from Hindson/1995 1 Negative patch testing with ICDRG the deep reticular to the papillary dermis. European battery and ammoniated The use of electron microscopy with X-ray Hg at 2 and 4 days microanalysis helped to divide the appear- ance of the pigment within the cytoplasm KEY: Hg = Mercury, Cr = Chromium, Ni = Nickel, Co = Cobalt

14 Allergic Contact Dermatitis to Red Tattoo Dye tions have been reported, as well.18 Lasers 10. Dave R, Mahaffey PJ. Successful treatment of an allergic reaction in a red tattoo with the Nd-YAG laser. Br J Plast target the intracellular tattoo pigment by Surg. 2002 Jul; 55(5):456. causing rapid thermal expansion of cells and subsequent fragmentation. It has been 11. Winkelmann RK, Harris RB. Lichenoid delayed hypersensi- tivity reactions in tattoos. J Cutan Pathol. 1979 Feb; 6(1):59- postulated that the expelled tattoo pigment 65. is likely identified as a foreign substance 12. Clarke J, Black MM. Lichenoid tattoo reactions. Br J Derma- by the immune system, thus inducing tol. 1979 Apr; 100(4):451-4. anaphlaxis.18 13. Sowden JM, Cartwright PH, Smith AG, Hiley C, Slater DN. Sarcoidosis presenting with a granulomatous reac- tion confined to red tattoos. Clin Exp Dermatol. 1992 Nov; CONCLUSION 17(6):446-8.

In 1991, a 5,300-year-old man, “Oetzi 14. Hindson C, Foulds I, Cotterill J. Laser therapy of lichenoid the ice man,” made the headlines of news- red tattoo reaction. Br J Dermatol. 1995 Oct; 133(4):665-6. papers worldwide when his frozen body was 15. Tsuruta D, Sowa J, Higashi N, Kobayashi H, Ishii M. A red discovered on a mountain between Austria tattoo and a swordfish supper. Lancet.2004 Aug 21-27; and Italy. Perhaps the best preserved corpse 364(9435):730. of the time, “Oetzi the ice man” bore 57 16. Lubeck G, Epstein E. Complications of tattooing. Calif Med. tattoos: a cross on the inside of his left 1952 Feb; 76(2):83-5. knee, six straight lines 15 centimeters long 17. Blumental G, Okun MR, Ponitch JA. Pseudolymphomatous above the kidneys, several parallel lines on reaction to tattoos. Report of three cases. J Am Acad Der- the ankles, as well as numerous others. It mattol. 1982 Apr; 6(4 Pt 1):485-8. was hypothesized that these markings were 18. Ashinoff R, Levine VJ, Soter NA. Allergic reactions to tat- likely of medical significance. Today, tat- too pigment after laser treatment. Dermatol Surg. 1995 Apr; tooing remains a common practice in vari- 21(4):291-4. ous countries and cultures. 19. Iveson JMI. Cotterill JA. Wright V. Sarcoidosis presenting Whether used for body art, cultural with multiple tattoo granulomata. Postgrad Med J 1975; 51: practice, or medical intervention, the place- 670-2. ment of tattoo ink can result in unwanted 20. Dickinson JA. Sarcoidal reactions in tattoos. Archives of side effects, including ACD. This review Dermatology 1969; 315-319. stressed that: 1) multiple allergenic cul- 21. Weidman AI, Andrade R, Franks AG. Sarcoidosis: Report of prits are at large in ACD to red tattoo dye a case of sarcoid lesions in a tattoo and subsequent deliv- in addition to mercuric sulfide; 2) at very ery of pulmonary sarcoid. Archives of Dermatology 1966; 94 (3): 320-325. least, a biopsy should be performed; 3) analysis for metallic components with the 22. Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl aforementioned technologies and patch J Med. 2007 Nov 22; 357(21):2153-65. Review. testing is unnecessary; 4) intradermal test- 23. Goldstein AP.VII. Histologic reactions in tattoos. J Dermatol ing may be of value; 5) the pathogenesis in Surg Oncol. 1979 Nov; 5(11):896-900. terms of the inflammatory reaction may be 24. Slater DN, Durrant TE. Tattoos: light and transmission elec- better characterized by some other entity, tron microscopy studies with X-ray microanalysis. Clin Exp not ACD, as there is varied time of onset, Dermatol. 1984 Mar; 9(2):167-73. little correlation with patch testing, and, most important, differing histological pat- terns.

REFERENCES:

1. Yazdian-Tehrani H. Reaction in a red tattoo in the absence of mercury. Br J Plast Surg. 2001 Sep; 54(6):555-6.

2. Ngan, V. Tattoo-associated skin reactions. DermNet NZ. Created 2005. Last Updated 03 Sep 2007. http://www. dermnetnz.org/reactions/tattoo-reaction.html.

3. Sowden JM, Byrne JP, Smith AG, Hiley C, Suarez V, Wagner B, Slater DN. Red tattoo reactions: X-ray micro- analysis and patch-test studies. Br J Dermatol. 1991 Jun; 124(6):576-80.

4. Madden JF. Reactions in tattoos. Arch Dermatol 1939; 40:256-62.

5. Goldstein N. Mercury-cadmium sensitivity in tattoos. A photoallergic reaction in red pigment. Ann Intern Med. 1967 Nov; 67(5):984-9.

6. Taaffe A, Knight AG, Marks R. Lichenoid tattoo hypersen- sitivity. Br Med J. 1978 Mar 11; 1(6113):616-8.

7. Antony FC, Harland CC. Red ink tattoo reactions: suc- cessful treatment with the Q-switched 532 nm Nd:YAG laser. Br J Dermatol. 2003 Jul; 149(1):94-8.

8. Mortimer NJ, Chave TA, Johnston GA. Red tattoo reac- tions. Clin Exp Dermatol. 2003 Sep; 28(5):508-10.

9. Kyanko ME, Pontasch MJ, Brodell RT. Red tattoo reac- tions: treatment with the carbon dioxide laser. J Dermatol Surg Oncol. 1989 Jun; 15(6):652-6. Yousif, Saitta, Grekin, Lloyd 15 Sw e e t ’s Sy n d r o m e : A Ca s e Re p o r t a n d Di s c u s s i o n

Daquesha Chever, MSIV,* Jenifer R. Lloyd, D.O.** * Ohio University College of Osteopathic Medicine, Athens, Ohio ** Co-Director, Residency Program, University Hospitals Health System – Richmond Heights Hospital, Department of Dermatology, Case Western Reserve University School of Medicine, Cleveland, Ohio

Abstract

Sweet’s syndrome, also known as acute febrile neutrophilic dermatosis, is one of the five neutrophilic dermatoses. It was first described by Dr. Robert Douglas Sweet in 1964 as a disease with distinct clinical as well as histopathological features.1 Throughout the years, there have been reports describing different vari- ants of Sweet’s syndrome, as well as associations between Sweet’s syndrome and other disease entities. This case report focuses on classic Sweet’s syndrome.

Case Presentation signs of , confirming the diagnosis of Sweet’s syndrome. On the follow-up visit, the skin lesions were all clear with A 52-year-old Caucasian female pre- only some residual skin discoloration. No sented to the office complaining of a dif- scarring was noted. The patient remained fuse over her trunk and extremities. on oral for an additional six Prior to the outbreak of the rash, she had weeks, after which a slow taper was started. complained of , , myalgia, To date, the patient has not suffered from a and lethargy. She stated her flu-like illness began approximately one week prior to the reoccurrence. development of the rash. Also, the symp- toms had been progressively getting worse, Discussion despite having received a course of antibi- Figure 1: Erythematous, maculo-pap- ular rash appearing on extremities. otics from her family physician. The neutrophilic dermatoses comprise Physical exam revealed a diffuse, a group of cutaneous disorders that are dilection for the upper body and . The erythematous, maculo-papular and tender characterized histologically by infiltration lesions typically have a bullous or - rash on her trunk, but worse on her upper of the dermis with mature neutrophils with ated appearance that could be mistaken for extremities (Figure 1). In some areas the or without vessel wall destruction.2 There pyoderma gangrenosum. It is important papules coalesced to form plaques, while in are many different types of neutrophilic to note that MASS can occur before the other areas they were distinct circumferen- dermatoses that have been described since diagnosis of cancer is made. It could also tial lesions with central clearing, which gave Dr. Sweet’s discovery. The most commonly be the first warning sign of a recurrence of them a “bull’s eye” or target-like appear- reported examples have been pyoderma a cancer.5 ance. No adenopathy, oral lesions or hepa- gangrenosum, rheumatoid neutrophilic Drug-induced Sweet’s syndrome tosplenomegaly was noted. dermatitis (RND), and bowel bypass (DISS) has been related to many medi- The differential diagnosis syndrome. The remaining types of neu- cations, including but not limited to included Sweet’s syndrome, erythema mul- trophilic dermatoses include subcorneal trimethoprim-sulfamethoxazole, minocy- tiforme, erysipelas or , and ery- pustular dermatosis, erythema elevatum thema elevatum diutinum. Because the cline, carbamazepine, clozapine, celecoxib, diutinum, palisaded neutrophilic and gran- furosemide, nitrofurantoin, and propyl- patient was febrile and ill-appearing, an ulomatous dermatitis, and neutrophilic extensive laboratory work-up was ordered thiouracil. However, the most commonly eccrine . Neutrophilic der- associated drug is granulocyte colony stim- to help further narrow down the differ- matoses have been reported in association ulating factor. ential. A CBC, ANA, ESR, ASO titer, uric with autoimmune disease, hematological Sweet’s syndrome has been reported acid level, rheumatoid factor and lyme titer and solid malignancy, as well as infectious worldwide without racial predilection were ordered. A 4mm punch biopsy from processes. the left upper arm was also taken to aid in or age predominance, with the youngest Classical or idiopathic Sweet’s syn- 8 the diagnosis. In the meantime, taking into drome usually occurs in women between patient being a seven-week-old infant. consideration the nature of the patient’s the ages of 30 and 50 years. It most often The majority of patients presenting with skin lesions and the severity of her consti- occurs after suffering from a non-specific Sweet’s syndrome appear very ill. The typ- tutional symptoms, a working diagnosis respiratory or gastrointestinal tract infec- ical cutaneous findings are tender, ery- was that of Sweet’s syndrome. The patient tion.3 However, it can also occur during the thematous papules and plaques which may was given a prescription for oral predni- first or second trimester of pregnancy, in be present on the arms, legs, face, , sone and told to follow up in the office in association with inflammatory bowel dis- and trunk. Many of the lesions may have a 10 days. She was contacted the next day ease, malignancy or autoimmune disease, transparent, vesicle-like appearance due to and reported that she had been afebrile and or it can be drug induced.4,5 An underlying edema in the upper dermis. However, when had not experienced any further headache. malignancy occurs in approximately 21% the lesions are palpated they are found to She also reported that the rash appeared to of patients with documented Sweet’s syn- be solid. The lesions can vary from patient be getting better. The patient was contacted drome. Malignancy associated Sweet’s syn- to patient, but typically progress in size and once again three days later with her lab drome (MASS) has been documented in number throughout the course of the ill- results, which were all negative. Once again both solid and hematological malignancy, ness. It has also been demonstrated that the she reported to the office that she had been with the majority of people suffering from lesions of Sweet’s syndrome show cutane- afebrile, and her rash was completely gone. a hematological disorder such as acute ous pathergy, with new lesions developing The histopathology findings showed a dif- myelogenous leukemia.5,6,7 The cutaneous at sites of trauma. When the lesions are fuse neutrophilic dermal infiltrate without findings associated with MASS have a pre- localized to the , it is called “neutro- 16 Sweet’s Syndrome: A Case Report and Discussion philic dermatosis of the dorsal hands” or medical intervention.8 The gold standard of 778. 5,9 1 “pustular vasculitis of the dorsal hands.” treatment is oral systemic corticosteroids. 9. Burrall B. Sweet’s syndrome. J Dermatology online 5(1):8 In this variant, the lesions can appear either The starting dose is between 30 mg and 60 10. Robbins C, Mason S, Hughey L. Sweet Syndrome With as erythematous-based pustules or as tiny mg, which is then tapered to 10 mg after Pulmonary Involvement in A Healthy Young Woman. Arch pustules on top of red papules. Other 4-6 weeks. Symptoms quickly resolve after Dermatol 2009;145(3): 344-346. organ systems can be affected as well, with initiation of treatment, with the majority 11. Noda K, Okuma Y, Fukae J, et al. Sweet’s syndrome Asso- reports of , CNS, ocular, renal, cardio- of patients having resolution of their con- ciated with Encephalitis. J Neurol Sci. 2001;188(1-2): 95-7 vascular, gastrointestinal, and pulmonary stitutional symptoms within 48-72 hours 12. Kemmett D, Hunter JA. Sweet’s syndrome: a clinicopatho- involvement. Approximately 33-62% of after starting prednisone. However, the skin logic review of twenty- nine cases. J Am Acad Dermatol patients will have arthralgia/arthritis.9 The lesions may take up to 3 weeks to resolve. 1990; 23: 503-507. underlying culprit of the extracutaneous Two additional first-line agents are potas- involvement appears to be related to the sium iodide and colchicine.8 predominance of neutrophils and their asso- Despite excellent response to therapy, ciated inflammatory activity. In the major- disease recurrence is common. Kemmett et ity of cases, treatment with corticosteroids al. reported that 21% of their patients had proves to be efficacious.10,11 more than one episode of Sweet’s syndrome, The etiology of Sweet’s syndrome is not and another 10% had chronic relapsing dis- well understood. Because many patients ease for at least 3 years duration.12 present with a febrile upper respiratory tract infection or tonsillitis prior to the skin lesions, a bacterial cause has under- Conclusion gone review. The role of cytokines and other immune mediators, either directly or indi- Sweet’s syndrome, also known as acute rectly, has also been reported as playing a neutrophilic dermatosis, is considered one part in the pathogenesis. In particular, gran- of the neutrophilic dermatoses. It can be ulocyte colony stimulating factor, granulo- idiopathic, as in the case of classical Sweet’s cyte macrophage colony stimulating factor, syndrome, and can occur after an upper interferon-gamma, interleukin-1, interleu- respiratory or gastrointestinal-tract illness. kin-3, interleukin-6, and interleukin-8 are 3,5 It can also be associated with pregnancy, potential cytokine candidates. medications, and many other disease enti- Sweet’s syndrome is complex and may ties including autoimmune and paraneo- often be mistaken for another cutaneous plastic processes. There has been widespread disease process. The differential diagnosis documentation of extracutaneous manifes- encompasses non-infectious, infectious, and tations involving most organ systems due neoplastic causes (Table 1). The diagnos- to the infiltration of neutrophils and the tic criteria for classical Sweet’s syndrome associated inflammatory response. Sweet’s includes: (1) the abrupt onset of painful, syndrome is characterized by a constellation erythematous plaques or nodules, (2) histo- of clinical symptoms, physical features, and pathologic evidence of a dense neutrophilic pathologic findings including fever, neu- infiltrate without evidence of leukocyto- trophilia, tender erythematous skin lesions o clastic vasculitis, (3) pyrexia >38 C, (4) (papules, pustules, and plaques) and a dif- association with an underlying hematologic fuse infiltrate of mature neutrophils in the or visceral malignancy, inflammatory dis- upper dermis. There is typically a good ease, or pregnancy, or preceded by an upper response to systemic corticosteroids, which respiratory or gastrointestinal infection or is the standard of treatment, although recur- vaccination, (5) excellent response to treat- rence is possible. ment with systemic corticosteroids or potas- sium iodide, (6) abnormal laboratory values REFERENCES: at presentation (three or four): erythro- 1. Sweet RD. An acute febrile neutrophilic dermatosis. Br J cyte sedimentation rate >20mm/hr; positive Dermatol 1964; 74: 349-356. C-reactive protein; >8,000 leukocytes; >70% 2. Owen C, Malone J, Callen J. Sweet-like Dermatosis in 2 neutrophils. The presence of both major Patients with Clinical Features of and criteria (1 and 2) and two of the four minor Underlying Autoimmune Disease. Arch Dermatol 2008; 144 (11): 1486-1490. criteria (3, 4, 5, and 6) is required in order to establish the diagnosis of classical Sweet’s 3. von den Driesch P. Sweet’s syndrome (acute febrile neu- 7 trophilic dermatosis). J Am Acad Dermatol 1994; syndrome. 31: 535-556. Skin biopsy is very important in the 4. Camarillo D, Mc Calmont T, Frieden I, et al. Two Pediatric diagnosis of Sweet’s syndrome due to the Cases of Nonbullous Histiocytoid Neutrophilic Dermatitis distinct histopathological features of the dis- Presenting as a Cutaneous Manifestation of Lupus Erythe- ease. However, these features are not specific matosus. Arch Dermatol 2008; 144: 1495-1498. and can also occur with an infectious etiol- 5. Cohen PR. Sweet’s syndrome - a comprehensive review of an acute febrile neutrophilic dermatosis. Orphanet J ogy, when the mounting of an appropriate Rare Dis 2007; 2: 34. immune response is warranted. Therefore, 6. Buck T, Gonzalez L, Lambert C, et al. Sweet’s syndrome a tissue culture should also be considered to with hematologic disorders: a review and reappraisal. Int J check for bacterial, viral, fungal, and myco- Dermatol 2008; 47: 775-782. bacterial etiologies when Sweet’s syndrome 7. Habif T. Clinical Dermatology, Fourth Edition: A Color is suspected.5 Guide to Diagnosis and Therapy. Philadelphia: Mosby: In classical Sweet’s syndrome, the dis- 2003. pp 650-651. ease can be self limiting and resolve without 8. Cohen PR, Kurzrock R. Sweet’s syndrome revisited: a review of disease concepts. Int J Dermatol 2003; 42: 761-

chever, lloyd 17 Cu t a n e o u s Endometriosis - A Ca s e Re p o r t

Sadaf (Sabrina) Waqar, DO, MPH,* Les Rosen, MD,** Janet Allenby, DO*** *2nd Year Dermatology Resident, Palm Beach Center for Graduate Medical Education (PBCGME)-Columbia Hospital program, West Palm Beach, FL **Dermatopathologist, Dermpath Diagnostics, Pompano Beach, FL ***Program Director, Palm Beach Center for Graduate Medical Education (PBCGME)-Columbia Hospital Dermatology residency, West Palm Beach, FL

Case Report: ical endometriosis occurs with an esti- [implantable] tissue.” Therefore, umbilical mated incidence of 0.5–1.0% in all patients endometriosis may arise by direct lym- A 29-year-old, nulliparous, black with endometriosis [4, 5], and may arise phatic or hematogenous dissemination, or woman presented for evaluation and man- spontaneously or in association with a pre- by metaplasia, or possibly by a combina- agement of a persistent umbilical nodule, vious scar. In fact, a majority of cutaneous tion of the two [7]. which she described as a “new growth in endometrial lesions develop in surgical Literature also describes pregnancy- belly button.” She first noticed the nodule scars related to previous episiotomy, cesar- induced spontaneous onset, or prolifer- while on a cruise, several weeks prior, and ean section, hysterectomy, or other pel- ation of underlying dormant cutaneous assumed it was an insect bite. Initially, the vic or abdominal laparoscopic procedures. endometriosis, especially of the umbilical nodule was smaller and somewhat “pink.” According to some estimates, approxi- region and particularly in the first trimes- Later, size increased a little but stabilized, mately 0.03-0.4% of all cesarean section ter. Of note, the level of estrogen is con- and color evolved to her natural skin color. sites will develop an endometrial nodule siderably higher during the first trimester, She denied pruritus, tenderness, erythema, [4]. The nodule typically occurs within six which theoretically provides an optimum or induration. The nodule remained per- months to three years post surgery/pro- hormonal environment for endometrial sistent for weeks. Her medical history was cedure [1]. Classically, the nodule pres- tissue to grow. Later in pregnancy, as the completely unremarkable. Her current ents with a pattern of pain (corresponding level rises and estrogen level medication regimen included Yaz (oral with menstrual cycle), hemorrhage, swell- drops, stromal decidualization with sclero- contraception, which she recently initiated) ing, and enlargement of the lesion, with or sis of endometrial lesions can occur [8]. and Zyrtec. Her surgical history was unre- without pelvic pain. Most cases of endome- markable. triosis respond favorably to estrogen and Clinical Presentation: On physical examination, she was a progesterone, with control of proliferation, well-developed, well-nourished woman in differentiation and bleeding [1,4,5]. no acute distress. Her abdominal exami- An even rarer phenomenon, “malignant Endometriosis is typically described nation revealed a 7mm, firm, brown pap- degeneration” of surgical-scar endome- in women of childbearing age. Dysmen- ule in the umbilicus without erythema or triosis has been described in the litera- orrhea, menorrhagia, and infertility are induration. An initial clinical assessment ture as a possibly fatal complication of common and well-established symptoms was made of a possible recurrent or longstanding endometriosis of endometriosis. Cyclical pain, tenderness, versus . A punch biopsy was performed, [2,6], unresponsive to surgical and medical and swelling of the ectopic tissue are also and histology revealed a proliferation of management. Malignant degeneration is commonly reported. glands surrounded by 2-3 layers of epithe- reported as occurring in 0.3–1.0% of cuta- Cutaneous endometrial lesions are lial cells, in a cellular stroma with fibrosis neous endometriosis. Of the few reported typically single, but can be multiple. Mor- and hemosiderin deposition. A diagnosis of cases, associated with malig- phology can range from being cystic to cutaneous endometriosis was established. nant degeneration of ectopic endometrial a hard nodule, typically with a dark col- tumors include: oration -- blue/red to blue/brown; how- • Endometrioid carcinoma (most ever, it can be a bright red in color, as well Background: common) [4,5]. A dark brownish discharge can be an • , between (2nd most com- associated finding, especially during the Endometriosis is defined as the growth mon) menstrual cycle. In addition, cutaneous of endometrial glands and stroma outside • Clear-cell carcinoma endometriosis can share clinical features the uterus [1]. It is an estrogen-depen- • Mucinous or serous carcinoma with malignant [4]. dent disease that occurs in approximately These tumors frequently present a low Particular attention needs to be 10% of women, and nearly exclusively in grade of malignancy and are rarely meta- directed toward previous surgical and menstruating women of reproductive age. static. obstetrical history, including any compli- Extra-pelvic endometriosis may occur in cated deliveries or abortions. The expected up to 12% of women with endometriosis Pathophysiology: cyclical or intermittent pattern of symp- [2]. toms must be specifically explored during Common locations for primary endo- the patient interview. metriosis are the pelvic cavity, specifically There is a fairly wide agreement in ovaries, fallopian tubes, uterine ligaments, medical literature that the etiology of cuta- recto-vaginal septum and pelvic perito- neous endometriosis is multifactorial. The Diagnostic Studies: neum. However, unusual locations outside metaplasia theory asserts that embryonic the pelvis have been reported and include coelomic mesothelium under certain stim- Standard laboratory evaluation cutaneous tissue, submucosal tissue of uli is capable of differentiating into endo- (CBC, coagulation profile, hepatic func- genitourinary tract, gastrointestinal tract, metrial tissue [7]. Steck and Helwig [8] tion, plasma electrolytes, and inflammatory pulmonary tract, renal system, and central suggested a combination of theories, claim- markers) should be completed. nervous system [3]. ing that “endometrial cells undergo imi- In general, most commonly utilized In cutaneous endometriosis, the most tative metaplasia and cellular replication diagnostic studies are: abdominal/pelvic common location is peri-umbilical. Umbil- when they are transported to a susceptive ultrasonography, serum tumor markers 18 Cutaneous Endometriosis - A Case Report of CA 125, CA19-9, and CA 15.3, CEA, [4,5]. Condyloma lata, bowenoid papulosis, Continuous GnRH agonists provide and pelvic laparoscopy. In the presence of , , dermoid another therapeutic option. Their adminis- a suspected cutaneous lesion, biopsy and cyst, and must be excluded [3]. tration reduces the hormone receptors on histologic correlation are warranted. A the anterior pituitary gland, thereby reduc- biopsy yields significantly more sensitive ing the release of FSH and LH. The latter is and specific value in diagnosis of cutane- Histology: followed by reduction of ovarian estrogen ous endometriosis compared with any other production and ultimately the cessation of modality available [9]. Interestingly, there is Histology reveals ectopic endometrial ovulation and menstruation. Side effects a consensus in the literature that dissemina- glands with surrounding cellular stroma, include irreversible reduction in bone min- tion of malignant endometrial cells along occasionally associated with extravasation of eral density. GnRH agonists are not recom- the biopsy tract is a possible phenomenon. erythrocytes in the stroma and some acute mended to be used alone for more than Therefore, some authors recommend an inflammatory infiltrates around the glands. six months; they must be accompanied by excisional biopsy (removing the nodule in Tidman and Albrecht [9] have described the low-dose estrogen/progestin hormone- toto, with a clinically clear margin) versus a features of cutaneous endometriosis as fol- replacement therapy if used for more than punch. lowing: irregularly shaped glandular struc- six months. Radiographic studies and serum mark- tures surrounded by cellular and vascular Short-term preoperative hormonal ers, on the other , are highly unreliable. stroma. There are features consistent with therapy followed by complete surgical However, they could help in narrowing the uterine endometrium at each of the main resection of the cutaneous lesion is the differential diagnosis of a pigmented, hem- menstrual phases, which can be differenti- recommended approach in the literature. orrhagic, cutaneous nodule. Serum levels of ated. In the proliferative phase, a uniform Short-term use of GnRH agonists (around CA 125 (a significant yet indirect and non- stromal cell population and pronounced three months) after surgical resection is specific marker of pelvic endometriosis) epithelial mitotic activity are seen. In the also acceptable and correlated with com- may be useful for both diagnosis and fol- secretory phase, decapitation secretion plete resolution of cutaneous endometriosis low-up of patients with pelvic endometrio- within the glandular cells and two stromal [3,5,7,8]. sis [10]. CD10, on the other hand, can serve cell types, a large cell and a small, clear cell, Medical therapy alone is unsatisfactory as a more reliable and sensitive immunohis- are evident. Disintegration of epithelium and not recommended. Again, laparoscopic tochemical marker of endometrial stroma and dissociation from stroma resembles exploration is recommended to exclude the and confirms histologic diagnosis with an menstruation. presence of other lesions. Some studies have estimated sensitivity of 88% [9]. shown that serum CA 125 levels may be In addition to a definitive diagnosis via helpful if positive, primarily to establish a biopsy and histologic studies, a laparoscopic Management: baseline and then follow regression after exploration of the abdominal cavity is highly medical and surgical intervention [8,15]. recommended to exclude the presence of Primary surgical excision is the main- In the case of recurrent cutaneous other lesions. However, clinicopathologic stay of management. Chene et al. [4] rec- endometriosis or malignant transforma- correlation and risks versus benefits of lapa- ommend a 3-5mm free margin to ensure tion of the lesion, radiotherapy and chemo- roscopy must be carefully evaluated. clearance and avoid recurrence. Recurrence therapy can be used. According to Chene et Dermoscopy provides an additional can occur frequently (in up to 15% of cases), al. [4], in management of malignant trans- diagnostic tool. In “Cutaneous endome- most commonly within the first year after formation of ectopic endometrial lesions, triosis: non-invasive analysis by epilumi- resection [2]. Preoperative hormonal ther- surgery, followed by complementary radio- nescence microscopy,” De Giorgi et al. [11] apy can help improve the symptoms and therapy and complementary progestin ther- describe typical features of cutaneous endo- reduce the size of lesions, including cutane- apy, gives a five-year survival rate of 77% metriosis using pattern analysis according ous lesions. Therefore, hormonal therapy [2]. consists of platinum- to the Rome Consensus Conference 2000. A is recommended prior to a planned surgi- based drugs and is indicated for malignant typical lesion would show positive findings cal excision. Currently, two major classes transformation of endometriosis only. of homogeneous reddish pigmentation, reg- of hormonal therapy are approved by the ularly distributed, gradually fading toward FDA: Danazol and gonadotropin-releasing the periphery. Within this typical pigmenta- hormone (GnRH) agonists. Additional hor- Summary: tion are small, red, globular structures, more monal therapy options include progestins defined and of a deeper hue, the “red atolls.” and oral contraceptive medications. Cutaneous endometriosis should be con- The negative findings include absence of Danazol is a synthetic derivative of 17- sidered in the differential diagnosis of any pigment network and other dermoscopic alpha-ethinyl testosterone, which acts on cutaneous, mucosal, or scar-related lesion parameters of melanocytic proliferations the hypothalamic-pituitary axis. Danazol that is located near the perineum, umbili- (i.e. brown globules, radial streaming and reduces the release of FSH and LH, thereby cus, or inguinal regions. Pain and tender- pseudopods). reducing the production of ovarian estro- ness (especially worsened with menstrual If clinical course is complicated with gen. Danazol also displaces serum androgens cycles), pruritus, ulceration, and hemor- recurrent cutaneous lesions, a malignant from androgen-binding proteins, thereby rhage are all signs that can alert one to con- degeneration of cutaneous endometriosis increasing free testosterone. Clinical data has sider ectopic endometriosis. There is often must be considered. In such cases, an MRI consistently shown that Danazol-induced a history of pelvic surgery or complicated or PET scan may be necessary. hormonal regulation results in atrophy of delivery. If suspected, an excisional biopsy ectopic endometrial tissue, including cuta- must be undertaken. Punch biopsy is not neous lesions. recommended given a risk of iatrogenic Differential Diagnosis: Standard dose of Danazol is 400mg spread into the biopsy tract. CA 125 can BID, ideally started on the first day of men- be requested to establish a baseline and, An ulcerative, hemorrhagic, and per- ses. Side effects can include , , if positive, to follow treatment response. haps apparently pigmented cutaneous weight gain, and fluid retention. More importantly, ovarian cancer must be nodule with discharge is a sign of several and deepening of voice can be permanent, excluded if CA 125 is indeed elevated. Pub- pathologic conditions, including nodular even after cessation of therapy. Therefore, lished literature suggests that if histology melanoma and primary or metastatic carci- long-term use of this medication is fre- is consistent with cutaneous endometri- of the ovary or gastrointestinal tract quently limited by its side effects. osis, exploratory laparoscopy is manda-

Waqar, Rosen, Allenby 19 tory. However, clinical correlation is always necessary before undertaking any invasive procedure. Mainstay of therapy is a combi- nation of medical (hormonal) therapy and surgical resection. Pre-operative hormonal therapy to reduce the size of lesion, followed by complete surgical excision with at least a 3-5mm free clinical margin, is recom- mended to reduce recurrence. In fact, this explains the benign clinical course of our patient: the fact that she coincidentally initi- ated oral contraception served to suppress further proliferation and discomfort of the endometrial nodule. The nodule was excised fully during biopsy, and the patient is doing well without further recurrence. Fig 1. Low-power view shows deep, dermal glandular REFERENCES: proliferation in a dense, cellular, and fibrotic stroma. 1. Aydin O. Scar endometriosis - a gynaecologic pathology often presented to the general surgeon rather than the gynaecologist: report of two cases. Langenbecks Archives of Surgery. 392(1):105-9, 2007 Jan.

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4. De Giorgi V, Massi D, Mannone F, Stante M, Carli P. Cuta- neous endometriosis: non-invasive analysis by epilumines- cence microscopy. Clinical & Experimental Dermatology. 28(3):315-7, 2003 May.

5. Elm MK, Twede JV, Turiansky GW. Primary cutaneous endometriosis of the umbilicus: a case report. Cutis. 81(2):124-6, 2008 Feb.

6. Friedman PM, Rico MJ. Cutaneous endometriosis. Derma- tology Online Journal. 6(1):8, 2000 Sep.

7. Kazakov DV, Ondic O, Zamecnik M, Shelekhova KV, Mukensnabl P, Hes O, Dvorak V, Michal M. Morphological Fig 2. The decapitation secretion of the endometrial glan- variations of scar-related and spontaneous endometriosis dular tissue is evident. Note the extravasation of erythro- of the skin and superficial : a study of 71 cases with emphasis on atypical features and types of Mullerian cytes and formation of a thrombus in the lumen. differentiations. Journal of the American Academy of Der- matology. 57(1):134-46, 2007 Jul.

8. Kim MK, Lee JR, Jee BC, Ku SY, Suh CS, Kim SH. A Table 1: Characteristic Clinical Features of Cutaneous Endometriosis suprapubic dermoid cyst confused with cutaneous endo- metriosis: a case report. Fertility & Sterility. 89(3):724.e5-7, 2008 Mar. • Symptoms correlating with menstruation: localized, lesional pain, tenderness, and pruritus 9. Lee A, Tran HT, Walters RF, Yee H, Rosenman K, Sanchez MR. Cutaneous umbilical endometriosis. Dermatology • Menstrual bleeding Online Journal. 14(10):23, 2008. • Childbearing age

10. Luisi S, Gabbanini M, Sollazzi S, Calonaci F, Razzi S, • History of pelvic or abdominal surgery/instrumentation, complicated delivery, or Petraglia F. Surgical scar endometriosis after Cesarean pregnancy termination, justifying endometrial-cell implantation section: a case report. Gynecological Endocrinology. 22(5):284-5, 2006 May.

11. Scholefield HJ, Sajjad Y, Morgan PR. Cutaneous endo- metriosis and its association with caesarean section and Table 2: Management of Cutaneous Endometriosist gynaecological procedures. Journal of Obstetrics & Gynae- cology. 22(5):553-4, 2002 Sep. • Primary surgical excision with clinical margins (mainstay of therapy) 12. Tidman MJ, MacDonald DM. Cutaneous endometriosis: a • Preoperative hormone therapy (may reduce size of initial lesion): histopathologic study. Journal of the American Academy of Dermatology. 18(2 Pt 1):373-7, 1988 Feb. o Danazol and gonadotropin-releasing hormone (GnRH) agonists o Progestins and oral contraceptive medications 13. Von Stemm AM, Meigel WN, Scheidel P, Gocht A. Umbi- • Medical therapy alone can be unsatisfactory; therefore, based on individual lical endometriosis. Journal of the European Academy of Dermatology & Venereology. 12(1):30-2, 1999 Jan. clinical presentation, consider: o Laparoscopic exploration to exclude presence of other lesions. o CA-125 (a non-specific marker) may be helpful if positive (to estab- lish baseline and follow regression after medical and surgical inter- vention). • In case of recurrent cutaneous endometriosis or, rarely, malignant transfor- mation of lesion, radiotherapy and chemotherapy can be used. o Surgery, followed by complementary radiotherapy and complemen- tary progestin therapy, gives a five-year survival rate of 77% [2]. o Chemotherapy consists of platinum-based drugs and is indicated for malignant transformation of endometriosis only.

20 Cutaneous Endometriosis - A Case Report B:9.25” T:8.5” S:7”

In the management of , the direction is clear . . . Powerful Change for the Journey Ahead B:12.25” S:10” T:11”

Early efficacy1,2 with safety for the long term3

• Reduction in inflammatory lesion count seen as early as week 1,24 • Similar efficacy to doxycycline 100 mg in reducing inflammatory lesions1 • No evidence of bacterial resistance4 and no increase in side effects over the long term (9 months)3 • Patients pay no more than $25* for each Oracea® prescription

* For a 30-day/30-capsule prescription of Oracea® (excludes Medicaid, Medicare, or federal or state programs).

Important Safety Information Oracea® is indicated for the treatment of only inflammatory lesions (papules and pustules) of rosacea in adult patients. In clinical trials, the most common adverse events reported were gastrointestinal upsets, nasopharyngitis/pain, and nasal congestion/sinusitis. Oracea® should not be used to treat microbial , and should be used only as indicated. This drug is contraindicated in people who have shown hypersensitivity to any of the tetracyclines, and, like other tetracycline drugs, may cause fetal harm when administered to a pregnant woman. Oracea® should not be used during pregnancy, by nursing mothers, or during development (up to the age of 8 years). Although photosensitivity was not observed in clinical trials, Oracea® patients should minimize or avoid exposure to natural or artificial sunlight. All contraindications, warnings, and precautions associated with tetracyclines must be considered before prescribing Oracea®. The safety of Oracea® treatment beyond 9 months has not been established. Please see brief summary of Prescribing Information on next page. References: 1. Del Rosso JQ, Schlessinger J, Werschler P. Comparison of anti-inflammatory dose doxycycline versus doxycycline 100 mg in the treatment of rosacea. J Drugs Dermatol. 2008;7(6):573-576. 2. Fowler JF Jr. Combined effect of anti-inflammatory dose doxycycline (40-mg doxycycline, USP monohydrate controlled-release capsules) and metronidazole topical gel 1% in the treatment of rosacea. J Drugs Dermatol. 2007;6(6):641-645. 3. Preshaw PM, Novak MJ, * Mellonig J, et al. Modified-release subantimicrobial dose doxycycline enhances scaling and root planing in subjects with .J Periodontol. 2008;79(3):440-452. 4. Del Rosso JQ, Webster GF, Jackson M, et al. Two randomized phase III clinical trials evaluating anti-inflammatory dose doxycycline (40-mg doxycycline, USP capsules) administered once daily for treatment of rosacea. J Am Acad Dermatol. 2007;56(5):791-802.

*

Oracea and Galderma are registered trademarks of Galderma Laboratories, L.P. ©2010 Galderma Laboratories, L.P. Galderma Laboratories, L.P. 14501 N. Freeway Fort Worth, TX 76177 ORA-365F Printed in USA 01/10 www.oracea.com/HCP B:9.25” T:8.5” S:7”

Rx Only Keep out of reach of children. MICROBIOLOGY

The plasma concentrations of doxycycline achieved with ORACEA during administration (see DOSAGE AND B/W Prints: Trim: PI_m11 #:Summary Job Brief ORA-0039 ADMINISTRATION) are less than the concentration required to treat bacterial diseases. In vivo microbiological studies utilizing a similar drug exposure for up to 18 months demonstrated no detectable long-term effects on

bacterial fl ora of the oral cavity, skin, intestinal tract, and . 11"h x 8.5"w Carcinogenesis, Mutagenesis, Impairment of Fertility: Doxycycline was assessed for potential to induce carcinogenesis in a study in which the compound was administered to Sprague-Dawley rats by gavage at Brief Summary of Full Prescribing Information dosages of 20, 75, and 200 mg/kg/day for two years. An increased incidence of uterine polyps was observed INDICATIONS AND USAGE in female rats that received 200 mg/kg/day, a dosage that resulted in a systemic exposure to doxycycline ORACEA is indicated for the treatment of only infl ammatory lesions (papules and pustules) of rosacea in approximately 12.2 times that observed in female humans who use ORACEA (exposure comparison based upon adult patients. area under the curve (AUC) values). No impact upon tumor incidence was observed in male rats at 200 mg/kg/ Live Area:Live The dosage of ORACEA differs from that of doxycycline used to treat infections. To reduce the development day, or in either gender at the other dosages studied. Evidence of oncogenic activity was obtained in studies with of resistant as well as to maintain the effectiveness of other antibacterial drugs, ORACEA should be related compounds, i.e., oxytetracycline (adrenal and pituitary tumors) and minocycline (thyroid tumors). used only as indicated. Doxycycline demonstrated no potential to cause genetic toxicity in an in vitro point mutation study with CLINICAL PHARMACOLOGY mammalian cells (CHO/HGPRT forward mutation assay) or in an in vivo micronucleus assay conducted in CD-1 mice. However, data from an in vitro assay with CHO cells for potential to cause chromosomal aberrations Pharmacokinetics suggest that doxycycline is a weak clastogen. 9.875"h x 7"w ORACEA capsules are not bioequivalent to other doxycycline products. Oral administration of doxycycline to male and female Sprague-Dawley rats adversely affected fertility and CONTRAINDICATIONS reproductive performance, as evidenced by increased time for mating to occur, reduced sperm motility, velocity, This drug is contraindicated in persons who have shown hypersensitivity to doxycycline or any of the other and concentration, abnormal sperm morphology, and increased pre-and post-implantation losses. Doxycycline tetracyclines. induced reproductive toxicity at all dosages that were examined in this study, as even the lowest dosage WARNINGS tested (50 mg/kg/day) induced a statistically signifi cant reduction in sperm velocity. Note that 50 mg/kg/day is approximately 3.6 times the amount of doxycycline contained in the recommended daily dose of ORACEA for a Teratogenic effects: 1) Doxycycline, like other tetracycline-class antibiotics, can cause fetal harm 60-kg human when compared on the basis of AUC estimates. Although doxycycline impairs the fertility of rats when administered to a pregnant woman. If any tetracycline is used during pregnancy or if the when administered at suffi cient dosage, the effect of ORACEA on human fertility is unknown. patient becomes pregnant while taking these drugs, the patient should be informed of the potential hazard to the fetus and treatment stopped immediately. Pregnancy: Teratogenic Effects: Pregnancy Category D. (see WARNINGS section). Results from animal ORACEA should not be used during pregnancy (see PRECAUTIONS: Pregnancy). studies indicate that doxycycline crosses the placenta and is found in fetal tissues. 2) The use of drugs of the tetracycline class during tooth development (last half of pregnancy, Nonteratogenic effects: (see WARNINGS section). infancy, and childhood up to the age of 8 years) may cause permanent discoloration of the teeth Labor and Delivery: The effect of tetracyclines on labor and delivery is unknown. (yellow-gray-brown). This adverse reaction is more common during long-term use of the drug but has been Nursing Mothers: Tetracyclines are excreted in human milk. Because of the potential for serious adverse reactions observed following repeated short-term courses. has also been reported. Tetracycline drugs, therefore, should not be used during tooth development unless other drugs are not likely to in infants from doxycycline, ORACEA should not be used in mothers who breastfeed. (see WARNINGS section). be effective or are contraindicated. Pediatric Use: ORACEA should not be used in infants and children less than 8 years of age (see WARNINGS 3) All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fi bula growth rate section). ORACEA has not been studied in children of any age with regard to safety or effi cacy, therefore use has been observed in premature human infants given oral tetracycline in doses of 25 mg/kg every 6 hours. in children is not recommended. This reaction was shown to be reversible when the drug was discontinued. ADVERSE REACTIONS Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can Adverse Reactions in Clinical Trials of ORACEA: In controlled clinical trials of adult patients with mild to cause retardation of skeletal development on the developing fetus. Evidence of embryotoxicity has been noted moderate rosacea, 537 patients received ORACEA or placebo over a 16-week period. The most frequent in animals treated early in pregnancy (see PRECAUTIONS: Pregnancy section). adverse reactions occurring in these studies are listed in the table below. Gastrointestinal effects: Pseudomembranous colitis has been reported with nearly all antibacterial agents and may range from mild to life-threatening. Therefore, it is important to consider this diagnosis Incidence (%) of Selected Adverse Reactions in Clinical Trials of ORACEA (n=269) vs. Placebo (n=268) in patients who present with diarrhea subsequent to the administration of antibacterial agents. ORACEA Placebo Treatment with antibacterial agents alters the normal fl ora of the colon and may permit overgrowth of clostridia. Nasopharyngitis 13 (4.8) 9 (3.4) Studies indicate that a toxin produced by Clostridium diffi cile is a primary cause of “antibiotic-associated colitis”. Pharyngolaryngeal Pain 3 (1.1) 2 (0.7) If a diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild Sinusitis 7 (2.6) 2 (0.7) cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe

Nasal Congestion 4 (1.5) 2 (0.7) B:12.25”

cases, consideration should be given to management with fl uids and electrolytes, protein supplementation, and S:10” T:11” treatment with an antibacterial drug clinically effective against Clostridium diffi cile colitis. Fungal Infection 5 (1.9) 1 (0.4) Metabolic effects: The anti-anabolic action of the tetracyclines may cause an increase in BUN. While this Infl uenza 5 (1.9) 3 (1.1) is not a problem in those with normal renal function, in patients with signifi cantly impaired function, higher Diarrhea 12 (4.5) 7 (2.6) serum levels of tetracycline-class antibiotics may lead to azotemia, hyperphosphatemia, and acidosis. If renal impairment exists, even usual oral or parenteral doses may lead to excessive systemic accumulations of the Abdominal Pain Upper 5 (1.9) 1 (0.4) drug and possible liver toxicity. Under such conditions, lower than usual total doses are indicated, and if therapy Abdominal Distention 3 (1.1) 1 (0.4) is prolonged, serum level determinations of the drug may be advisable. Abdominal Pain 3 (1.1) 1 (0.4) Photosensitivity: Photosensitivity manifested by an exaggerated reaction has been observed in Stomach Discomfort 3 (1.1) 2 (0.7) some individuals taking tetracyclines. Although this was not observed during the duration of the clinical studies with ORACEA, patients should minimize or avoid exposure to natural or artifi cial sunlight (tanning beds or Note: Percentages based on total number of study participants in each treatment group. UVA/B treatment) while using ORACEA. If patients need to be outdoors while using ORACEA, they should Adverse Reactions for Tetracyclines: The following adverse reactions have been observed in patients wear loose-fi tting clothes that protect skin from sun exposure and discuss other sun protection measures receiving tetracyclines at higher, antimicrobial doses: with their physician. Gastrointestinal: anorexia, nausea, vomiting, diarrhea, , dysphagia, enterocolitis, and infl ammatory PRECAUTIONS lesions (with vaginal ) in the anogenital region. Hepatotoxicity has been reported rarely. Rare instances General: Safety of ORACEA beyond 9 months has not been established. of esophagitis and esophageal ulcerations have been reported in patients receiving the capsule forms of the As with other antibiotic preparations, use of ORACEA may result in overgrowth of non-susceptible micro- drugs in the tetracycline class. Most of the patients experiencing esophagitis and/or esophageal ulceration took organisms, including fungi. If superinfection occurs, ORACEA should be discontinued and appropriate therapy their medication immediately before lying down. (see DOSAGE AND ADMINISTRATION section). instituted. Although not observed in clinical trials with ORACEA, the use of tetracyclines may increase the Skin: maculopapular and erythematous . Exfoliative dermatitis has been reported but is uncommon. incidence of vaginal candidiasis. Photosensitivity is discussed above. (see WARNINGS section). ORACEA should be used with caution in patients with a history of or predisposition to candidiasis overgrowth. Renal toxicity: Rise in BUN has been reported and is apparently dose-related.(see WARNINGS section). Bacterial resistance to tetracyclines may develop in patients using ORACEA. Because of the potential for drug- Hypersensitivity reactions: urticaria, angioneurotic edema, , anaphylactoid purpura, serum sickness, resistant bacteria to develop during the use of ORACEA, it should be used only as indicated. pericarditis, and exacerbation of systemic . Autoimmune Syndromes: Tetracyclines have been associated with the development of autoimmune Blood: Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have been reported. syndromes. Symptoms may be manifested by fever, rash, arthralgia, and malaise. In symptomatic patients, liver function tests, ANA, CBC, and other appropriate tests should be performed to evaluate the patients. Use OVERDOSAGE of all tetracycline-class drugs should be discontinued immediately. In case of overdosage, discontinue medication, treat symptomatically, and institute supportive measures. Dialysis does not alter serum half-life and thus would not be of benefi t in treating cases of overdose. Tissue Hyperpigmentation: Tetracycline class antibiotics are known to cause hyperpigmentation. Tetracycline therapy may induce hyperpigmentation in many organs, including nails, bone, skin, eyes, thyroid, visceral DOSAGE AND ADMINISTRATION tissue, oral cavity (teeth, mucosa, alveolar bone), sclerae and heart valves. Skin and has THE DOSAGE OF ORACEA DIFFERS FROM THAT OF DOXYCYCLINE USED TO TREAT INFECTIONS. been reported to occur independently of time or amount of drug administration, whereas other pigmentation EXCEEDING THE RECOMMENDED DOSAGE MAY RESULT IN AN INCREASED INCIDENCE OF SIDE has been reported to occur upon prolonged administration. Skin pigmentation includes diffuse pigmentation EFFECTS INCLUDING THE DEVELOPMENT OF RESISTANT MICROORGANISMS. as well as over sites of scars or injury. One ORACEA Capsule (40 mg) should be taken once daily in the morning on an empty stomach, preferably at Pseudotumor cerebri: Bulging fontanels in infants and benign intracranial hypertension in adults have least one hour prior to or two hours after meals. been reported in individuals receiving tetracyclines. These conditions disappeared when the drug was Effi cacy beyond 16 weeks and safety beyond 9 months have not been established. discontinued. Administration of adequate amounts of fl uid along with the capsules is recommended to wash down the Laboratory Tests: Periodic laboratory evaluations of organ systems, including hematopoietic, renal and hepatic capsule to reduce the risk of esophageal irritation and ulceration. (see ADVERSE REACTIONS section). studies should be performed. Appropriate tests for autoimmune syndromes should be performed as indicated. Drug Interactions: 1. Because tetracyclines have been shown to depress plasma prothrombin activity, HOW SUPPLIED patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. ORACEA (beige opaque capsule printed with CGPI 40) containing doxycycline, USP in an amount equivalent to 2. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid 40 mg of anhydrous doxycycline. Bottle of 30 (NDC 64682-009-01). giving tetracycline-class drugs in conjunction with penicillin. 3. The concurrent use of tetracycline and Storage: All products are to be stored at controlled room temperatures of 15°C-30°C (59°F-86°F) and methoxyfl urane has been reported to result in fatal renal toxicity. 4. Absorption of tetracyclines is impaired by dispensed in tight, light-resistant containers (USP). Keep out of reach of children. bismuth subsalicylate, proton pump inhibitors, antacids containing aluminum, calcium or magnesium and iron- Patent Information: U.S. Patents 5,789,395; 5,919,775; 7,232,572; 7,211,267 and patents pending. containing preparations. 5. Doxycycline may interfere with the effectiveness of low dose oral contraceptives. To ORACEA is a registered trademark of CollaGenex Pharmaceuticals, Inc. avoid contraceptive failure, females are advised to use a second form of contraceptive during treatment with doxycycline. 6. There have been reports of pseudotumor cerebri (benign intracranial hypertension) associated Manufactured by: Marketed by: with the concomitant use of isotretinoin and tetracyclines. Since both oral retinoids, including isotretinoin CardinalHealth Galderma Laboratories, L.P. and acitretin, and the tetracyclines, primarily minocycline, can cause increased intracranial pressure, the Winchester, KY 40391 Fort Worth, TX 76177 concurrent use of an oral retinoid and a tetracycline should be avoided. 7961-01 BPI 06/08

43355ETL_0039_PI_v1 1 12/16/08 7:33:23 PM B:9.25” T:8.5” S:7”

Rx Only Keep out of reach of children. MICROBIOLOGY

The plasma concentrations of doxycycline achieved with ORACEA during administration (see DOSAGE AND B/W Prints: Trim: PI_m11 #:Summary Job Brief ORA-0039 ADMINISTRATION) are less than the concentration required to treat bacterial diseases. In vivo microbiological Li n e a r Li c h e n Pl a n u s : A Ca s e Re p o r t studies utilizing a similar drug exposure for up to 18 months demonstrated no detectable long-term effects on bacterial fl ora of the oral cavity, skin, intestinal tract, and vagina. 11"h x 8.5"w Carcinogenesis, Mutagenesis, Impairment of Fertility: Doxycycline was assessed for potential to induce Brief Summary of Full Prescribing Information carcinogenesis in a study in which the compound was administered to Sprague-Dawley rats by gavage at Shari Sperling, DO,* Marvin Watsky, DO** dosages of 20, 75, and 200 mg/kg/day for two years. An increased incidence of uterine polyps was observed *Dermatology Resident, PGY1, St. John’s Episcopal Hospital, Far Rockaway, NY INDICATIONS AND USAGE in female rats that received 200 mg/kg/day, a dosage that resulted in a systemic exposure to doxycycline *Program Director, St. John’s Episcopal Hospital, Far Rockaway, NY ORACEA is indicated for the treatment of only infl ammatory lesions (papules and pustules) of rosacea in approximately 12.2 times that observed in female humans who use ORACEA (exposure comparison based upon adult patients. area under the curve (AUC) values). No impact upon tumor incidence was observed in male rats at 200 mg/kg/ Live Area:Live The dosage of ORACEA differs from that of doxycycline used to treat infections. To reduce the development day, or in either gender at the other dosages studied. Evidence of oncogenic activity was obtained in studies with Abstract of resistant bacteria as well as to maintain the effectiveness of other antibacterial drugs, ORACEA should be related compounds, i.e., oxytetracycline (adrenal and pituitary tumors) and minocycline (thyroid tumors). used only as indicated. Doxycycline demonstrated no potential to cause genetic toxicity in an in vitro point mutation study with Linear lichen planus is a rare variant of lichen planus. It is characterized by a pruritic or non-pruritic eruption of lichenoid, violaceous papules in a linear dis- CLINICAL PHARMACOLOGY mammalian cells (CHO/HGPRT forward mutation assay) or in an in vivo micronucleus assay conducted in CD-1 mice. However, data from an in vitro assay with CHO cells for potential to cause chromosomal aberrations tribution that follow the lines of Blaschko. A 44-year-old woman presented to the clinic with a pruritic rash for one month that affected the right side of her Pharmacokinetics suggest that doxycycline is a weak clastogen. 9.875"h x 7"w ORACEA capsules are not bioequivalent to other doxycycline products. body. Based on her clinical and histological findings, she was treated with a diagnosis of linear lichen planus. Oral administration of doxycycline to male and female Sprague-Dawley rats adversely affected fertility and CONTRAINDICATIONS reproductive performance, as evidenced by increased time for mating to occur, reduced sperm motility, velocity, This drug is contraindicated in persons who have shown hypersensitivity to doxycycline or any of the other and concentration, abnormal sperm morphology, and increased pre-and post-implantation losses. Doxycycline tetracyclines. induced reproductive toxicity at all dosages that were examined in this study, as even the lowest dosage Case Report WARNINGS tested (50 mg/kg/day) induced a statistically signifi cant reduction in sperm velocity. Note that 50 mg/kg/day is approximately 3.6 times the amount of doxycycline contained in the recommended daily dose of ORACEA for a Teratogenic effects: 1) Doxycycline, like other tetracycline-class antibiotics, can cause fetal harm 60-kg human when compared on the basis of AUC estimates. Although doxycycline impairs the fertility of rats when administered to a pregnant woman. If any tetracycline is used during pregnancy or if the when administered at suffi cient dosage, the effect of ORACEA on human fertility is unknown. A 44-year-old Hispanic female pre- patient becomes pregnant while taking these drugs, the patient should be informed of the potential hazard to the fetus and treatment stopped immediately. Pregnancy: Teratogenic Effects: Pregnancy Category D. (see WARNINGS section). Results from animal sented to the dermatology clinic complain- ORACEA should not be used during pregnancy (see PRECAUTIONS: Pregnancy). studies indicate that doxycycline crosses the placenta and is found in fetal tissues. ing of a rash on her body for four weeks. 2) The use of drugs of the tetracycline class during tooth development (last half of pregnancy, Nonteratogenic effects: (see WARNINGS section). The rash began on her right neck and shoul- infancy, and childhood up to the age of 8 years) may cause permanent discoloration of the teeth Labor and Delivery: The effect of tetracyclines on labor and delivery is unknown. (yellow-gray-brown). This adverse reaction is more common during long-term use of the drug but has been der and over a few days progressed to spread Nursing Mothers: Tetracyclines are excreted in human milk. Because of the potential for serious adverse reactions observed following repeated short-term courses. Enamel hypoplasia has also been reported. Tetracycline to her right chest, abdomen, and lower drugs, therefore, should not be used during tooth development unless other drugs are not likely to in infants from doxycycline, ORACEA should not be used in mothers who breastfeed. (see WARNINGS section). be effective or are contraindicated. Pediatric Use: ORACEA should not be used in infants and children less than 8 years of age (see WARNINGS extremity. She did complain of mild pruri- 3) All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fi bula growth rate section). ORACEA has not been studied in children of any age with regard to safety or effi cacy, therefore use tus that preceded the rash by a few days, but in children is not recommended. has been observed in premature human infants given oral tetracycline in doses of 25 mg/kg every 6 hours. denied systemic symptoms of fever, nausea, This reaction was shown to be reversible when the drug was discontinued. ADVERSE REACTIONS Figure 5 Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can Adverse Reactions in Clinical Trials of ORACEA: In controlled clinical trials of adult patients with mild to vomiting, or diarrhea. Patient was other- cause retardation of skeletal development on the developing fetus. Evidence of embryotoxicity has been noted moderate rosacea, 537 patients received ORACEA or placebo over a 16-week period. The most frequent wise healthy and had no past medical his- Figure 1 in animals treated early in pregnancy (see PRECAUTIONS: Pregnancy section). adverse reactions occurring in these studies are listed in the table below. Gastrointestinal effects: Pseudomembranous colitis has been reported with nearly all antibacterial tory, no surgical history, denied use of any agents and may range from mild to life-threatening. Therefore, it is important to consider this diagnosis Incidence (%) of Selected Adverse Reactions in Clinical Trials of ORACEA (n=269) vs. Placebo (n=268) medications, and had no known allergies to in patients who present with diarrhea subsequent to the administration of antibacterial agents. ORACEA Placebo medication. Treatment with antibacterial agents alters the normal fl ora of the colon and may permit overgrowth of clostridia. Nasopharyngitis 13 (4.8) 9 (3.4) Studies indicate that a toxin produced by Clostridium diffi cile is a primary cause of “antibiotic-associated colitis”. Pharyngolaryngeal Pain 3 (1.1) 2 (0.7) On physical exam, the patient had vio- If a diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild Sinusitis 7 (2.6) 2 (0.7) laceous and pink macules and papules with cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe

Nasal Congestion 4 (1.5) 2 (0.7) lichenifiedB:12.25” plaques in a linear distribution,

cases, consideration should be given to management with fl uids and electrolytes, protein supplementation, and S:10” T:11” treatment with an antibacterial drug clinically effective against Clostridium diffi cile colitis. Fungal Infection 5 (1.9) 1 (0.4) respecting the midline on the right side of Metabolic effects: The anti-anabolic action of the tetracyclines may cause an increase in BUN. While this Infl uenza 5 (1.9) 3 (1.1) the body including the right neck, right is not a problem in those with normal renal function, in patients with signifi cantly impaired function, higher Diarrhea 12 (4.5) 7 (2.6) serum levels of tetracycline-class antibiotics may lead to azotemia, hyperphosphatemia, and acidosis. If renal , right chest, right abdomen, and Abdominal Pain Upper 5 (1.9) 1 (0.4) impairment exists, even usual oral or parenteral doses may lead to excessive systemic accumulations of the right lower extremity. There was sparing drug and possible liver toxicity. Under such conditions, lower than usual total doses are indicated, and if therapy Abdominal Distention 3 (1.1) 1 (0.4) Figure 6 is prolonged, serum level determinations of the drug may be advisable. Abdominal Pain 3 (1.1) 1 (0.4) of the face, upper extremities, and mucous Photosensitivity: Photosensitivity manifested by an exaggerated sunburn reaction has been observed in Stomach Discomfort 3 (1.1) 2 (0.7) membranes (Figures 1-3). The differential some individuals taking tetracyclines. Although this was not observed during the duration of the clinical studies with ORACEA, patients should minimize or avoid exposure to natural or artifi cial sunlight (tanning beds or Note: Percentages based on total number of study participants in each treatment group. diagnosis was deep fungal infection, lichen UVA/B treatment) while using ORACEA. If patients need to be outdoors while using ORACEA, they should Adverse Reactions for Tetracyclines: The following adverse reactions have been observed in patients planus, lichen striatus, inflammatory linear Figure 2 wear loose-fi tting clothes that protect skin from sun exposure and discuss other sun protection measures receiving tetracyclines at higher, antimicrobial doses: with their physician. Gastrointestinal: anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, and infl ammatory verrucous epidermal , linear , PRECAUTIONS lesions (with vaginal candidiasis) in the anogenital region. Hepatotoxicity has been reported rarely. Rare instances and atypical mycobacterial infection. General: Safety of ORACEA beyond 9 months has not been established. of esophagitis and esophageal ulcerations have been reported in patients receiving the capsule forms of the Two 3-millimeter punch biopsies were As with other antibiotic preparations, use of ORACEA may result in overgrowth of non-susceptible micro- drugs in the tetracycline class. Most of the patients experiencing esophagitis and/or esophageal ulceration took organisms, including fungi. If superinfection occurs, ORACEA should be discontinued and appropriate therapy their medication immediately before lying down. (see DOSAGE AND ADMINISTRATION section). performed on her right dorsal and right instituted. Although not observed in clinical trials with ORACEA, the use of tetracyclines may increase the Skin: maculopapular and erythematous rashes. Exfoliative dermatitis has been reported but is uncommon. lateral leg. Skin biopsy, tissue culture and incidence of vaginal candidiasis. Photosensitivity is discussed above. (see WARNINGS section). culture for acid-fast bacilli were sent for ORACEA should be used with caution in patients with a history of or predisposition to candidiasis overgrowth. Renal toxicity: Rise in BUN has been reported and is apparently dose-related.(see WARNINGS section). Bacterial resistance to tetracyclines may develop in patients using ORACEA. Because of the potential for drug- Hypersensitivity reactions: urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness, pathology. Pathology revealed a superfi- resistant bacteria to develop during the use of ORACEA, it should be used only as indicated. pericarditis, and exacerbation of systemic lupus erythematosus. cial perivascular and lichenoid dermatitis Autoimmune Syndromes: Tetracyclines have been associated with the development of autoimmune Blood: Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have been reported. Figure 7 syndromes. Symptoms may be manifested by fever, rash, arthralgia, and malaise. In symptomatic patients, composed of lymphocytes with scattered liver function tests, ANA, CBC, and other appropriate tests should be performed to evaluate the patients. Use OVERDOSAGE eosinophils and histiocytes. There was mild of all tetracycline-class drugs should be discontinued immediately. In case of overdosage, discontinue medication, treat symptomatically, and institute supportive measures. Dialysis does not alter serum half-life and thus would not be of benefi t in treating cases of overdose. epidermal hyperplasia with hypergranu- Discussion Tissue Hyperpigmentation: Tetracycline class antibiotics are known to cause hyperpigmentation. Tetracycline therapy may induce hyperpigmentation in many organs, including nails, bone, skin, eyes, thyroid, visceral DOSAGE AND ADMINISTRATION losis with scattered necrotic keratinocytes tissue, oral cavity (teeth, mucosa, alveolar bone), sclerae and heart valves. Skin and oral pigmentation has THE DOSAGE OF ORACEA DIFFERS FROM THAT OF DOXYCYCLINE USED TO TREAT INFECTIONS. and melanophages (Figures 4-7). No been reported to occur independently of time or amount of drug administration, whereas other pigmentation EXCEEDING THE RECOMMENDED DOSAGE MAY RESULT IN AN INCREASED INCIDENCE OF SIDE Lichen planus (LP) is an idiopathic has been reported to occur upon prolonged administration. Skin pigmentation includes diffuse pigmentation EFFECTS INCLUDING THE DEVELOPMENT OF RESISTANT MICROORGANISMS. microorganisms were seen on H+E, AFB Figure 3 inflammatory disease of the skin and as well as over sites of scars or injury. One ORACEA Capsule (40 mg) should be taken once daily in the morning on an empty stomach, preferably at or PAS stained sections and tissue culture. mucous membranes characterized by pru- Pseudotumor cerebri: Bulging fontanels in infants and benign intracranial hypertension in adults have least one hour prior to or two hours after meals. The diagnosis proved linear lichen planus. been reported in individuals receiving tetracyclines. These conditions disappeared when the drug was Effi cacy beyond 16 weeks and safety beyond 9 months have not been established. ritic, violaceous, polygon-shaped, flat- discontinued. Administration of adequate amounts of fl uid along with the capsules is recommended to wash down the Blood results showed a complete blood topped papules. Lesions typically favor the Laboratory Tests: Periodic laboratory evaluations of organ systems, including hematopoietic, renal and hepatic capsule to reduce the risk of esophageal irritation and ulceration. (see ADVERSE REACTIONS section). count within normal limits, negative hepati- studies should be performed. Appropriate tests for autoimmune syndromes should be performed as indicated. flexor surfaces of the wrists and , Drug Interactions: 1. Because tetracyclines have been shown to depress plasma prothrombin activity, HOW SUPPLIED tis panel, and non-reactive RPR. dorsal hands, and lower extremities. Lichen patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. ORACEA (beige opaque capsule printed with CGPI 40) containing doxycycline, USP in an amount equivalent to The patient was treated with the diag- 2. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid 40 mg of anhydrous doxycycline. Bottle of 30 (NDC 64682-009-01). planus is the prototype of lichenoid derma- giving tetracycline-class drugs in conjunction with penicillin. 3. The concurrent use of tetracycline and Storage: All products are to be stored at controlled room temperatures of 15°C-30°C (59°F-86°F) and nosis of linear lichen planus with Temo- toses with histology showing a band-like, methoxyfl urane has been reported to result in fatal renal toxicity. 4. Absorption of tetracyclines is impaired by dispensed in tight, light-resistant containers (USP). Keep out of reach of children. vate cream and a prednisone taper. The lymphocytic infiltrate at the dermal-epi- bismuth subsalicylate, proton pump inhibitors, antacids containing aluminum, calcium or magnesium and iron- Patent Information: U.S. Patents 5,789,395; 5,919,775; 7,232,572; 7,211,267 and patents pending. lesions did not progress, and the patient did containing preparations. 5. Doxycycline may interfere with the effectiveness of low dose oral contraceptives. To ORACEA is a registered trademark of CollaGenex Pharmaceuticals, Inc. dermal junction. Other features include avoid contraceptive failure, females are advised to use a second form of contraceptive during treatment with not complain of pruritus any longer. The doxycycline. 6. There have been reports of pseudotumor cerebri (benign intracranial hypertension) associated Manufactured by: Marketed by: hyperkeratosis without parakeratosis, hyper- with the concomitant use of isotretinoin and tetracyclines. Since both oral retinoids, including isotretinoin CardinalHealth Galderma Laboratories, L.P. patient will continue to follow up in our granulosis, irregular acanthosis and lique- and acitretin, and the tetracyclines, primarily minocycline, can cause increased intracranial pressure, the Winchester, KY 40391 Fort Worth, TX 76177 concurrent use of an oral retinoid and a tetracycline should be avoided. 7961-01 BPI 06/08 dermatology clinic. factive degeneration at the basal-cell layer. Figure 4 There are many variants of lichen planus, sperling, Watsky 23

43355ETL_0039_PI_v1 1 12/16/08 7:33:23 PM including actinic, acute, annular, atrophic, Planus in the Lines of Blaschko. Pediatric Dermatology 2002; 19 (6): 541-545. bullous, hypertrophic, inverse, LP pigmen- 6. Rahman S, Bari A, Mumtaz N. Unilateral Blaschkoid tosus, lichen planopilaris, linear, oral, LP- Lichen Planus Involving the Entire Half of the Body, A Unique Presentation. Dermatology Online Journal 13(3): lupus erythematosus overlap syndrome, nail, 36. ulcerative, vulvovaginal and drug-induced 7. Batra P, Wang N, Kamino H, Possick P. Linear Lichen Pla- nus. Dermatology Online Journal 2008; 14 (10): 16. (1). 8. James W, Berger T, Elston D. Andrews’ Diseases of the Linear lichen planus is a rare variant of Skin, Tenth Edition 2006. Pg 218- 219. 9. Rapini R. Eczematous and Papulosquamous Diseases. lichen planus, occurring in approximately Practical Dermatopathology. Philadelphia: Elsevier, 2005: 0.24% to 0.64% of patients with lichen pla- 53-56.v nus (2). It is more common in Japan, occur- ring in eight out of 77 cases (2). Eruptions are generally sudden in onset, spontaneous and occur in otherwise healthy adults (3). It is usually seen in patients in their late 20s or early 30s, but the initial presentation can be seen at any time in the first to eighth decades (1). The cause and pathogenesis is unknown, but it may be a multifactorial process (4). Lesions may be associated with the use of ibuprofen or with dental metal , may be found in areas of prior her- pes zoster infection, or may be related to hepatitis C infection (4). Linear lichen planus is typically reserved for lesions that appear within the lines of Blaschko spontaneously. Blaschko described a pattern of skin disease in unusual lines in 1901 (2). Blaschko’s lines follow a charac- teristic S-shape on the abdomen, a V-shape near the posterior midline, a linear pattern on the lower extremity, and whorls on the face and scalp (2). The areas of Blaschko do not correspond to any known nervous, vascular or lymphatic structures (5). They never cross the anterior truncal midline, but instead run along it (6). Some authors consider linear lichen planus an intermedi- ate entity between lichen planus and lichen striatus (1). Theories have been presented explaining the lines of Blaschko, including fetal stretching of the skin, embryonic muta- tion, and environmental triggering (3). Linear lesions occur in classic lichen planus caused by Koebner’s phenomenon, but true linear lichen planus is more exten- sive and follows the lines of Blaschko (7). Linear lichen planus presents as papules with varying degrees of overlying hyperker- atosis or simple hyperpigmentation. There can be areas of normal skin between the individual lesions (8). The pathology of lichen planus typically shows a compact hyperkeratosis with hypergranulosis, acan- thosis, liquefaction degeneration of basal layer, and lichenoid lymphocytes in the pap- illary dermis (9). Linear lichen planus is histopathologically identical to lichen planus (7). Based on these criteria, our patient was treated with a working diagnosis of linear lichen planus.

REFERENCES: 1. Bolognia J, Jorizzo J, Rapini R. Dermatology. Second Edition, Mosby 2008, pgs 159- 170. 2. Long C, Finlay A. Multiple Linear Lichen Planus in the lines of Blaschko. British Journal of Dermatology 1996; 135 (2): 275-276. 3. Sciallis G, Loprinzi C. Progressive Linear Lichen Planus and Metastatic Carcinoma. British Journal of Dermatology 2005; 152: 368- 403. 4. Kokcam I, Ozercan I. A Case of Linear Lichen Planus. The Journal of Dermatology 2005; 32 (9): 756- 758. 5. Kabbash C, Laude T, Weinberg J, Silverberg N. Lichen 24 Linear Lichen Planus: A Case Report A Ca s e Re p o r t : Tu b e r o u s Sc l e r o s i s Co m p l e x

Brent Loftis, D.O.,* Monica Ata, OMS III,** Bill Way, D.O., FAOCD*** * 1st year Resident, Dermatology Institute, Texas Division of A.T. Still University, Kirksville College of Osteopathic Medicine, Duncanville, TX **OMS III, WV School of Osteopathic Medicine, Lewisburg, WV ***Dermatology Residency Program Director, Dermatology Institute, Texas Division of A.T. Still University, Kirksville College of Osteopathic Medicine, Duncanville, TX

Abstract

Tuberous sclerosis complex (TSC) is an autosomal-dominant disorder characterized by multiple hamartomas affecting the skin, brain, heart, kidney, retina, and lungs. Although it is an autosomal-dominant disorder, more than two-thirds occur from spontaneous mutations. Incidence is approximately 1/10,000 births. We present a case of a pregnant, 18-year-old, Hispanic/Caucasian female with tuberous sclerosis complex. Awareness of this condition is important for primary care physicians (PCP) in order to accurately diagnose and manage patients, including referral of patients to a genetic counselor so that patients are able to make educated choices and understand the risks of passing the disorder to future children.1 Case Presentation: a fibrous (cutaneous ) (Fig. 4). Patient is positive for three major fea- In February 2009, an 18-year-old His- tures and one minor feature of tuberous panic/Caucasian female with an 11-week, sclerosis complex: facial , viable intrauterine pregnancy and recent periungual , shagreen patch and history of seizures was referred by her PCP confetti macules, respectively. Patient was for possible TSC and treatment of multiple given information regarding her disorder, small papules on her nose and cheeks bilat- but treatment was delayed due to her cur- erally. Lesions first appeared during puberty rent pregnancy. Patient since has been at age 12. The patient denied pruritus, ten- closely observed and was advised to return if derness to touch, or pus formation. Patient any skin changes develop. was seen by her PCP for recent history of seizures occurring mostly at night during Figure 4: Shave biopsy of angiofibroma: sleep. A CT of her head showed findings proliferation of thin-walled vessels embed- concerning for tuberous sclerosis complex. ded in dense collagenous stroma with Patient denied heart, kidney, GI problems, stellate fibrocytes and focal chronic and a family history of TSC. Patient was inflammation. referred to a neurologist by her PCP and is also under the care of a maternal-fetal medi- cine specialist for her high-risk pregnancy. Discussion: Physical examination of the skin revealed multiple, 1-3 mm, small, flesh-to- Tuberous sclerosis complex is an pink colored papules on the nose, nasolabial Figure 1: Angiofibromas on nose, nasola- autosomal-dominant disorder character- folds, and bilateral cheeks consistent with bial folds and bilateral cheeks. ized by multiple hamartomas affecting the angiofibromas skin, brain, heart, kidney, retina, and lungs. (Fig. 1). A flesh-colored, 5 mm in Although autosomal-dominant, more than diameter papule was found on the left lum- two-thirds occur from spontaneous muta- bar area, and there was a thickened, 10 x 3 tions.2 TSC birth incidence is approximately mm, orange-peel-textured plaque on the 1/10,000 births.3 The Vogt Triad of epilepsy, mid epigastric area, both characteristic of a mental retardation, and angiofibromas is shagreen patch (Fig. 2). On further exami- seen in 25% of patients. nation, two flesh-colored, nodular, protrud- There are two gene mutations associ- ing lesions were found at the proximal nail ated with TSC: TSC1on chromosome 9q34 folds of the right 5th toe and left 3rd toe, con- and TSC2 on chromosome 16p13, which sistent with periungual fibromas (Koenen code for the tumor suppressor proteins tumors) (Fig. 3). A small, light-brown, cafe- Figure 2: Shagreen patch on the epigas- hamartin and tuberin, respectively.4 Hamar- au-lait macule was present below the left tric area and cafe-au-lait macule of the left tin and tuberin work as a heterodimer that inframammary area, and Wood’s lamp con- inframammary area. functions as a tumor suppressor by inhibit- firmed a hypomelanotic macule (ash leaf ing the mammalian target of rapamycin macule) and multiple 2-5 mm hypomela- (mTOR), which plays an important role in notic macules (confetti macules) on the the regulation of cell proliferation.5 . Enamel pitting was not extensive The following are cutaneous lesions of but was present. TSC, listed in order decreasing prevalence: A shave biopsy of a 2 mm papule was hypomelanotic taken from the left nasal ala during the ini- ash-leaf macule, known as Fitzpatrick tial visit. Pathology report showed super- patch; facial angiofibromas commonly dis- ficial proliferation of thin-walled vessels tributed over the nose, bilateral cheeks and embedded in dense collagenous stroma with nasolabial folds; connective-tissue nevus the presence of stellate fibrocytes and focal known as shagreen patch (most common chronic inflammation. It was diagnosed as Figure 3: Koenen tumor on 3rd proximal in the lumbosacral region); molluscum nail fold. Loftis, Ata, Way 25 sperling, Watsky 25 pendulum; fibrous plaques of the ; the prevention of tuberous sclerosis.9 periungual fibromas (Koenen tumors); and Tuberous sclerosis is a multiorgan confetti-like macules. The Fitzpatrick patch disorder that requires a multidisciplinary is usually present at birth, with a prevalence approach. Most often the initial clinical of 97.2%.5 TSC should be high on the dif- presentations are the cutaneous lesions, and ferential when a baby presents with seizures therefore dermatologists are often called and hypomelanotic ash-leaf macules.6 upon to help in the diagnosis of the disease. Systemic manifestations include the brain lesions cortical tubers, subependy- REFERENCES: mal nodules, and giant-cell astrocytomas, 1. Monaghan HP, Krafchik BR, MacGregor DL, Fitz CR. which are responsible for seizures in 90% “Tuberous Sclerosis Complex in Children.” American Jour- of patients.7 In the kidneys, up to 80% nal of Diseases of Children. 135 (10) 1981:912-917. of patients develop . 2. Kwiatkowski DJ, Short PM. “Tuberous Sclerosis.” Archives Although lung involvement is rare, lymph- of Dermatology. 130 (1994): 348-354. angiomyomatosis is the most common lung 3. Bolognia JL, Jorizzo JL, Rapini RP. Dermatology E-Dition. finding. is a tumor found E ed. Vol. 1: 858-865. St. Louis: Mosby, 2003. in the heart as early as infancy that regresses 4. Caldemeyer KS, Mirowski GW. “Tuberous sclerosis. Part I. Clinical and central nervous system findings.” Journal of over time and is therefore an early diagnos- the American Academy of Dermatology. 45 (2001): 448- tic finding. Retinal hamartomas, and more 449. 8 often enamel pitting, can develop. 5. Schwartz RA, Geover F, Kotulska K, Jozwiak S. “ Tuberous The Tuberous Sclerosis Alliance devel- sclerosis complex: Advances in diagnosis, genetics, and management.” Journal of the American Academy of Der- oped a diagnostic criteria based on major matology. 57 (2007): 189-202. 5,7 and minor features: 6. Jozwiak S, Goodman M, Lamm SH. “Poor Mental Devel- opment in Patients With Tuberous Sclerosis Complex.” Major Features Archives of Neurology. 55 (1998):379-384. 1. Facial angiofibromas or forehead plaque 7. Habif TP. Clinical Dermatology: A Color Guide to Diagnosis th 2. Nontraumatic ungual or periungual and Therapy. 4 ed. St. Louis: Mosby, 2003; 909-912. 8. Eagle RC, et al. “Hamartomas of the Iris and Ciliary Epithe- lium in Tuberous Sclerosis Complex.” Archives of Ophthal- 3. Hypomelanotic macule (three or more) mology. 118 (2000):711-715. 4. Shagreen patch (connective-tissue nevus) 9. Paghdal KV, Schwartz RA. “Sirolimus (rapamycin): From 5. Multiple retinal nodular hamartomas the soil of Easter Island to a bright future.” Journal of the 6. Cortical tubers American Academy of Dermatology. 57 (2007): 1046-1050. 7. Subependymal nodule 8. Subependymal giant-cell astrocytoma 9. Cardiac rhabdomyoma, single or multiple 10. Lymphangiomyomatosis 11. Renal Minor Features: 1. Multiple, randomly distributed pits in dental enamel 2. Hamartomatous rectal polyps 3. Bone 4. Cerebral white-matter radial migration lines 5. Gingival fibromas 6. Nonrenal hamartomas 7. Retinal achromic patch 8. ‘‘Confetti’’ skin lesions 9. Multiple renal cysts

Definite TSC: Either two major features, or one major feature plus two minor features Probable TSC: One major plus one minor feature Possible TSC: Either one major feature or two or more minor features

Currently the management of TSC is treatment of symptoms. Sirolimus, also known as rapamycin, is an antiproliferative and an immunosuppressant that inhibits mTOR and subsequently inhibits protein translation, producing cell-cycle arrest and possibly reducing hamartoma formation or regression. Studies have also shown that sirolimus inhibits vascular endothelial growth factor, which may have benefits in

26 A Case Report: Tuberous Sclerosis Complex Di ag n o s t i c a n d Th e r ap e u t i c Di l e m m a s i n a n NF-1 Pa t i e n t

Reagan Anderson, DO, MPH, MCS,* Michael Baze, DO, RPh,** Raja Rabah, MD,*** Steven Grekin, DO**** *PGY4 – Dermatology, Oakwood Southshore Medical Center, Trenton, MI **PGY1 – Montgomery Regional Hospital, Blacksburg, VA ***Dermatopathologist, University of Michigan, Ann Arbor, MI ****Program Director, Oakwood Southshore Medical Center Dermatology Residency, Trenton, MI

Abstract

Neurofibromatosis type 1 (NF-1) is a progressive disorder most often affecting the cutaneous, nervous and skeletal systems. The dermatologist plays a vital role in the diagnosis, patient education and treatment of the cutaneous manifestations. Diagnosis is by history and clinical examination. When indicated, genetic testing is available to confirm the diagnosis. The pathomechanisms of NF-1 are complex and varied, primarily involving various signal transducers. Patient management should include a team of clinicians from multiple disciplines who are familiar with NF-1. Current treatment is aimed at controlling symptoms and complications. Many clinical trials are currently underway for therapies aimed at the specific manifestations of NF-1 (e.g., , café-au-lait macules, cognitive deficits, skeletal dysplasia). History and Clinical buccal mucosa. Asymmetry of the left side of her tongue was noted due to a soft-tissue Presentation mass. The right hand hypothenar eminence has a soft-tissue mass which does not seem A 6-year-old white female presents to the adherent to underlying tendinous structures. clinic with masses on the left jaw, right hand The left ankle has a similar soft-tissue mass and left ankle, which have been progressively which encompasses most of the heel. No and symmetrically enlarging for the last bruits or are associated with four years. The patient was initially seen the lesions. Further examination reveals by multiple providers for “excess skin” on multiple café au lait macules (CALMs) on her right hand and left foot. Consultation her legs, back, and arm. Some are larger than at three years of age with Genetic and 5 mm. No other abnormalities are noted on Metabolic Disorders at the Detroit Medical physical examination. Center Children’s Hospital of Michigan by orthopedics was not conclusive, but a diagnosis of neurofibromatosis type 1 (NF- Radiographic and 1) was entertained. MRI of the left foot Laboratory Studies was performed at three years of age and was read as a “likely venous or lymphatic structure.” Follow-up with ultrasound Normal Findings: Ophthalmology exam (US) was recommended by radiology and skeletal X-rays were normal at three but not performed. The patient was sent years of age. Spinal X-ray at three years of to ophthalmology and had a normal age showed levoconvex curvature, which was examination. likely positional in nature. The patient presents to our clinic, now Abnormal Findings: Left foot MRI at at six years of age, with concerns that the three years of age revealed a likely venous or masses of tissue on the left jaw, right hand, lymphatic structure. MRI of hand at six years and left ankle have been proportionately of age revealed a likely venous or lymphatic growing with child. She is asymptomatic, structure. US performed at six years of age and the lesions do not interfere with her indicate that the affected left submandibular daily life except for having to buy different region and right hand are likely lymphatic sized shoes. So far, cheek and tongue lesions malformations. Embolization was suggested do not interfere with eating or swallowing as possible treatment. The patient’s left and do not increase in size when illnesses are foot has a more “diffuse-type of lymphatic present. malformation.” Biopsy of right hand and left The patient was born full-term to ankle showed plexiform (see a then 33-year-old G2P1 who reports a below). normal pregnancy with no complications A full-body MRI is scheduled to and no known exposures to teratogens, determine if other lesions are present as well illegal drugs, or radiation. The patient has as to ascertain the depth of each lesion. Yearly attained all developmental milestones and ophthalmology consults are recommended. is developmentally age-appropriate. Her parents report no behavioral problems. The Dermatopathology patient is otherwise in good health with no known illnesses or conditions other than the soft-tissue masses. Family history is Two elliptical biopsies were submitted, non-contributory except for a maternal first Physical Exam one from the mass on the right hand and one cousin once removed from the patient who from the left ankle. These showed “skin with hyperkeratosis with diffuse proliferation has been diagnosed with NF-1. The patient’s left face has a prominent tumorous mass which extends into the of elongated cells in a myxoid background

Anderson, Baze, Rabah, Grekin 27 Table 1: Manifestations of NF-1 are more likely than neurofibromas to be present in younger patients and may help to System Manifestations make the diagnosis in this population.19 In patients with NF-1, LNs are found in 15% Cutaneous CALMs,* intertriginous freckling (), neurofibromas to 20% of children by six years of age and Ophthalmic Lisch nodules in 95% of adults.15 Optic pathway gliomas Kyphoscoliosis, pseudarthrosis, sphenoid dysplasia, bowing of (OPGs) are slow-growing tumors of the Skeletal long optic nerve, which are found in 15% to 20% Neurofibromas, brain tumors, optic nerve gliomas, cognitive of children with NF-1.3,15,20 Among NF-1 Neurologic dysfunction patients, OPGs are the most common CNS tumor and produce symptoms such as eye Endocrine Growth hormone deficiency, proptosis and decreased visual acuity in 2% to 5% of patients.3,10,20 *Café-au-lait macules separated by fibrous septae. Plexiform NF-1 patients within the first year of life.3,9,10 Skeletal manifestations arrangement is noted in the deep portion. Classically, CALMs are well demarcated, No atypical changes are seen. Both lesions appear homogenous and can vary from tan Skeletal involvement in NF-1 is reach the margins of excision. No lymphatic to dark brown in color. CALMs may be seen varied and includes bowing of long bones, malformation is identified.” Diagnosis is of in persons unaffected by NF-1. However, the pseudarthrosis, sphenoid dysplasia, scoliosis diffuse and plexiform neurofibromas. frequency of five or more CALMs in normal and kyphosis. Abnormal skeletal development persons is rare, and greater than this number occurs in 10–20% of NF-1 patients.21 provides a significant diagnostic feature for Osteoblasts, osteoclasts, chondrocytes, NF-1 Introduction 4,11 NF-1. Patients continue to accrue CALMs , and vascular endothelial cells during childhood, but these often fade during also express neurofibromin, and therefore NF-1 is the most common form of adulthood. may be functionally compromised when neurofibromatoses, a heterogenous class Another cardinal feature of NF-1 levels are decreased or absent.22 Evidence of neurocutaneous disorders. Worldwide, is intertriginous freckling (Crowe sign). suggests that there is also a deficiency in NF-1 occurs in approximately 1 of 3,000 Intertriginous freckling is usually the second osteoblasts and increased osteoclast survival live births, regardless of race, sex, or ethnic clinical manifestation noted in NF-1 patients, in NF-1 patients.22 Fractures and bone background.1,2 Neurofibromatosis became develops in early childhood and is present 3,9,12- deformities are present in 5–10% of young first recognized in the late 1800s when in 80% to 90% of affected individuals. 23 14 patients, especially boys. Orthopedic the German pathologist Friedrich von Diffuse freckling is not an uncommon surgery to correct these defects often fails Recklinghausen described a series of patients finding in the general population. However, due to pseudarthrosis or nonunion of bone with a combination of cutaneous lesions and clustering hyperpigmentation on the axilla due to compromised healing.21 The tibia tumors of the nervous system.3 NF-l is an and inguinal area is very unusual, except in 4 is the most frequent site associated with autosomal-dominant, progressive disorder NF-1. bowing and pseudoarthrosis.15 Multiple 1,3-5 with diverse clinical manifestations. The In addition to the pigmentary patterns, forms of scoliosis occur in at least 10% of cardinal features of NF-1 are café-au-lait patients with NF-1 may also have cutaneous NF-1 patients, usually manifesting by 10 macules (CALMs), intertriginous freckling and subcutaneous neurofibromas. These years of age.4,15 Chronic constant pressure of (Crowe sign), neurofibromas, and iris benign growths are derived from a nerve neurofibromas on the ribs can result in areas hamartomas. A number of complications sheath and comprised of Schwann cells, of erosion, predisposing the patient to rib such as an increased predisposition to skeletal fibroblasts, perineural cells, mast cells, fractures.12-14,25 abnormalities, malignancies and learning axons and blood vessels.15 Cutaneous disabilities are also associated with NF-1.6-8 neurofibromas often present as soft, fleshy, tan-to-brown colored, dome-shaped tumors Nervous-system with a broad base or pedunculated papules manifestations Clinical Presentation or nodules.15,16 Subcutaneous neurofibromas are palpable, firm nodules that arise along NF-1 can involve almost any organ sys- the course of a nerve and may be visible Various abnormalities of the CNS may tem. Thus, the presenting signs and symp- just beneath the skin.3 Both cutaneous and occur in NF-1 patients, including neoplasms toms may vary widely. The morbidity and subcutaneous neurofibromas vary in number and cognitive deficiencies. NF-1 patients mortality caused by NF-1 are dictated by and size and usually appear in late childhood have a predisposition to develop tumors of the type and occurrence of complications. or early adolescence, after the appearance of the central nervous system, in particular, 24 Because of the additional risk for malignant CALMs and freckling.9 They can be tender, astrocytomas of the brain and OPGs. 5 disease, patients with NF-1 have a higher but more often cause significant pruritus. Rasmussen et al. report that brain tumors are mortality rate than the general population.5 These lesions have no malignant potential more than five times as common in patients Table 1 lists possible NF-1 manifestations on but may be a source of psychological burden with NF-1 as in the general population. multiple organ systems. due to cosmetic disfigurement.12-14,17 Brain tumors associated with NF-1 are less common in adults than in children.8 Most brain tumors in children with NF-1 are low- Dermatologic Ophthalmic manifestations grade, glial-cell types.4,8 Astrocytomas affect patients with NF-1 at a mean age of 4.5 years manifestations 26 Lisch nodules (LNs) are pigmented from diagnosis. hamartomas of the iris that increase in Learning disability and attention deficit Examination of a patient with NF-1 number with age in patients with NF-1. occurs in as many as 60% of NF-1 patients, may reveal unusual pigmentary patterns 4 LNs are benign growths that do not impact while 5-10% may have mental retardation. such as CALMs and Crowe sign. CALMs 27 vision but have diagnostic utility.14 LNs can A 2006 review by Levine et al. found that are most often the first clinical manifestation be visualized and differentiated from iris NF-1 patients have academic deficiencies, of NF-1 and are present in essentially all freckling by slit-lamp examination.18 LNs slightly lower intelligence quotient and 28 Diagnostic and Therapeutic Dilemmas in an NF-1 Patient a higher incidence of attention deficit function.30 PNs are further subdivided into manifestations hyperactivity disorder. This is important to two groups: nodular and diffuse. Nodular note, as unrecognized learning disabilities plexiform neurofibromas arise in nerves Endocrinologic problems associated and attention deficit can lead to poor within organs or tissues and often cluster 3 with NF-1 are common. Growth-hormone performance at school and poor academic around proximal nerve roots. They vary deficiency and short stature are more achievement. in size and can grow along the length of the common in these patients than in the general Psychiatric disorders reportedly occur in nerve. The clinical significance depends on population. However, scoliosis, medications 33% of NF-1 patients, with dysthymia being tumor location and size. For example, when 28 and intracranial pathology can also the most common. Depressive, anxiety nodular PNs arise from the proximal nerve contribute to the short stature that may be and personality disorders also have a high root they may extend through foramina and seen in NF-1 patients. Pheochromocytoma is prevalence. Perhaps, largely contributing cause cord compression, vertebral erosion a rare complication, affecting between 0.1% to the development of these disorders is and scoliosis. The skin overlying a diffuse to 5.7% of NF-1 patients, producing sequelae the impaired quality of life. In a survey of plexiform neurofibroma may be thickened, that include hypertension, headaches and 176 American patients with NF-1, Page et hyperpigmented, have coarse hairs arising anxiety.33 al.29 reported that the emotional aspects of from the area and be confused for a congenital 15 Patients with NF-1 are at increased risk the cutaneous manifestations significantly . Because of their of cardiovascular abnormalities, including impacted the quality of life. infiltrative nature, complete surgical excision vasculopathy, hypertension, and congenital Neurofibromas are benign tumor of PNs may be difficult or impossible. In 8% heart defects.3 Hypertension in adult masses of the peripheral nervous system. to 10% of NF-1 patients, preexisting PNs patients with NF-1 is more commonly Neurofibromas may be discrete, diffuse, can undergo transformation to malignant associated with essential hypertension, while well circumscribed, or infiltrative. There peripheral nerve-sheath tumors (MPNSTs), 3,31,32 in children, renal-artery stenosis is the likely are three types of neurofibromas: cutaneous, which can be very aggressive and fatal. 3 32 cause. Cerebrovascular abnormalities are subcutaneous and plexiform, all classified In a study by Evans et al. , the median age also seen, particularly stenosis or occlusion according to localization and histology of at diagnosis of MPNSTs in NF-1 patients was of the internal carotid arteries.3 the tumor(s). Neurofibromas may arise 26 years. In another study by Friedrich et sporadically at any point along a peripheral al.,31 NF-1 children with MPNSTs who died nerve or in association with NF-1. Although showed a median survival time of 20 months Diagnosis uncommon, neurofibromas can also develop after diagnosis. Evans et al.32 concluded that in the gastrointestinal tract, most often the lifetime risk of MPNSTs in NF-1 patients presenting after early childhood.10 These can warrants careful surveillance and a low Diagnosis of NF-1 is usually made on a cause bleeding and obstruction. threshold for investigation. Should a patient clinical basis, but may require other specialty Plexiform neurofibromas (PNs) are complain of persistent pain or rapid growth examinations or diagnostic tests. Diagnostic the least common subtype, often appearing of a previously stable PN, MPNSTs must be criteria for NF-1 were established at the in the first decade of life.30 They can be investigated. National Institutes of Health Consensus found in all organ systems, infiltrate and Development Conference in 1987. Criteria are met if two or more of the features listed encase major nerves, blood vessels, and Endocrine and vascular other vital structures causing impaired in Table 2 are present. These diagnostic Table 2: NF-1 Diagnostic Criteria34 criteria have been shown to be both highly specific and sensitive for adults with NF-1,13 Criteria but are not as sensitive in children, as they may not manifest until later in life.15 1. Six or more CALMs* larger than 5 mm in greatest diameter in prepubertal Genetic testing is available for NF-1. persons, and larger than 15 mm in greatest diameter in postpubertal persons Previous testing for NF-1 had a sensitivity 2. Two or more neurofibromas of any type or one plexiform neurofibroma of about 70%.15 Now, a tiered set of tests, 3. Freckling in the axillary or inguinal regions which includes protein truncation, direct 4. Optic glioma sequencing, PCR with Southern blot analysis, 5. Two or more Lisch nodules fluorescent in situ hybridization and/or cytogenetic analysis, yields an improved 6. A distinctive osseous lesion, such as sphenoid dysplasia or thinning of long sensitivity of over 95%.15,35 Genetic testing bone cortex, with or without pseudarthrosis is not indicated in routine care for NF-1 7. A first-degree relative with NF-1 according to the above criteria patients. Rather, the indication extends to those suspected of having NF-1 or when prenatal genetic diagnosis is desired. *Café-au-lait macules The differential diagnosis for NF-1 includes Proteus syndrome, blue rubber bleb Neurofibromin nevus syndrome, Maffucci’s syndrome and isolated venous malformations. G T P-R as G DP-R as (Active) (Inactive) Pathogenesis

Pathogenesis of many NF-1 disease manifestations is believed to involve loss of NF-1 gene function. The NF-1 gene is located on the long arm of chromosome 17 at band q11.2 and encodes for neurofibromin, Signal Cell Proliferation a protein with tumor-suppressing action.10,36 Although many cases of NF-1 are inherited, Transduction and Neoplasia an estimated 50% occur de novo from Molecules spontaneous mutations.15 This gene has Anderson, Baze, Rabah, Grekin 29 one of the highest rates of spontaneous ing of the pathogenesis of NF-1, there is still or symptoms suggest lesions or complications. mutation in the entire human genome.37 no definitive treatment to prevent or reverse For example, MRI of the brain and the spine can The types of mutations that cause the NF-1 the complications. Given the variable nature help localize lesions and elucidate the extent of phenotype vary and include gene deletions, and severity of the disease, defining the correct involvement. CT and plain radiographs can be insertions, rearrangements and postzygotic level of care is difficult. However, common to used to assess the extent of skeletal involvement (i.e., mosaicism).15 NF-1 is essentially fully all NF-1 patients is the need to be managed ef- (e.g., scoliosis, enlarged neural foramina, rib penetrant by age 20, with considerable fectively and be followed by a multi-disciplin- notching). variation in the phenotypic expression of the ary medical team familiar with the disease. The Research discovering therapies that are disease even within the same family.4,8,15 dermatologist plays a vital role on this team. more specific for the treatment of NF-1 is The best-understood biochemical After the diagnosis is made, the dermatologist ongoing and encouraging. Proteins involving function of neurofibromin is its activity can educate the patient regarding his or her the Ras signal-transduction pathway have as a negative regulator of the Ras proto- condition, manage the cutaneous manifesta- been identified as potential therapeutic targets. oncogene. Under normal cellular conditions, tions and make appropriate referrals. During Other genes and regulators that play a role neurofibromin acts to accelerate the conversion follow-up visits, the dermatologist can evaluate in the pathogenesis of NF-1 have also been of active, GTP-bound Ras to inactive, GDP- the patient for any changes or disease progres- identified and may be treatable by agents that bound Ras38,39 (Figure 1). In its active sion. block or reverse the abnormally activated form, the Ras gene encodes cellular signal Two models of NF-1 management in signaling pathways.4 The following studies transduction molecules, which are involved adults have been proposed and studied.48 The show promise but warrant further research to in cell proliferation and differentiation.8 first model employs an investigation protocol elucidate their potential in the treatment of Mutations in the NF-1 gene result in loss aimed at detecting various NF-1 complications NF-1 in humans. of or diminished neurofibromin function, (e.g., extensive imaging, 24-hour urinary cat- Several drugs for the treatment of affording increased Ras activity. This leads to echolamine levels, etc.). The second model is progressive plexiform neurofibromas in increased cell proliferation and a syndrome clinical follow-up with no further investigation NF-1 patients are in clinical trial. Imatinib that predisposes patients to the development unless symptoms occur. For example, an NF-1 mesylate, an agent with c-kit tyrosine kinase of neoplastic disease.6,40 In fact, compared to patient presenting with hypertension may have blocking properties, has shown potential in the general population, NF-1 patients are at underlying pheochromocytoma or renal-artery the treatment of plexiform neurofibromas. a four-fold increase for malignant disease.41 stenosis. In one study by Drappier et al.,48 the Imatinib inhibits stem-cell factor’s growth- Excessive Ras activity may also play a causal two models were compared, and the number of potentiating effects.50 Yang et al.50 reported role in the learning deficits seen in NF-1 treated complications was similar. The authors on a three-year-old girl with a plexiform patients.42 Neurofibromin is expressed in concluded that routine screening investigations neurofibroma causing life-threatening airway many cells, primarily in neurons, glial cells, were not justified, but that clinical follow-up is compression. After three months of treatment Schwann cells, and early in melanocyte important because of the unpredictable nature with imatinib mesylate, a 70% reduction in development.43,44 Studies have also shown of NF-1. It is important to note that this study tumor volume was noted. Current research is that neurofibromin affects not only Ras but included adults and cannot be extrapolated also looking at sirolimus and pirfenidone for also other cellular pathways such as protein to children. The clinical follow-up model is the treatment of plexiform neurofibromas.15,51 kinase C and adenylate cyclase, which also now recommended in most guidelines, such Sirolimus is an immunosuppressant that influence processes that promote cellular as the National Institutes of Health consensus inhibits mTOR, which is a regulator of cell proliferation.4 In NF-1 patients, Schwann panel.48 growth in the nervous system.52 Pirfenidone cells and melanocytes, both descendents of Children with NF-1 should have regular is a broad-spectrum oral antifibrotic drug that the neural crest and with mutations in both general clinic evaluations with the frequency modulates the action of cytokines.51 NF-1 alleles, are considered the primary of visits increasing as needed to address dis- Lovastatin, a specific inhibitor of 3- tumor cell in neurofibromas and CALMs, ease complications. Children under five years hydroxy-3-methylglutaryl coenzyme A respectively.15 Increased growth factors of age should have biannual follow-ups with reductase, reversed cognitive impairments and growth-factor receptors, leading to a pediatrician familiar with NF-1, and an- associated with NF-1 in the mouse model.53 increased growth-stimulating activity in nual examinations thereafter.10 Preschool and However, in the human model, these results neurofibromas, have also been reported as elementary-school age children should have could not be replicated after three months contributors to NF-1 pathology.45 annual neurologic and ophthalmic examina- of treatment with simvastatin.54 Studies are In describing the pathogenesis as it tions.14 Children need to be checked regularly underway to investigate skeletal dysplasia as relates to neurofibromin, the literature also for changes in neurofibromas, blood pressure, another target of lovastatin therapy for patients suggests a link with cellular cytoskeleton neurodevelopmental progress and skeletal de- with NF-1.55 organization. For example, Koivunen et velopment, with anticipatory guidance given to Costa et al.42 reported of improved cognition al.7 propose that defective formation of the caregiver.10 When complications develop, in the mouse model with a farnesyltransferase cell-cell and cell-matrix contacts due to appropriate referrals should be made. inhibitor (FTI). Farnesyltransferase is an altered neurofibromin-assisted assembly of Surgery may be needed when the tumors enzyme involved with posttranslational intermediate filaments may be a key element compress organs, or chemotherapy used for modification called farnesylation, which is in the pathogenesis of NF-1. A study cancerous growths. The patient must be fol- essential for Ras functioning.56 FTIs have also with cells cultured from neurofibromas lowed closely to detect malignant degeneration been shown to rescue other NF-1 phenotypes, demonstrated haphazard organization of of neurofibromas. When neurofibromas en- such as Schwann-cell proliferation in human intermediate filaments and actin.4 It has also large or become tender, an excision or biopsy cells.57 In an in vitro study that employed been proposed that when neurofibromin should be performed to rule out malignant a combination of an FTI with lovastatin, binds to certain cytoskeletal structures (e.g., transformation.49 This carries the risk of nerve Wojtkowiak et al.58 reported a decrease in cell microtubules), this association is important injury, bleeding and tumor recurrence. Che- proliferation and an induction of apoptosis in for regulating the growth-promoting activity motherapy has been shown to be effective and the treatment of MPNSTs. of Ras.6,46,47 is commonly used in symptomatic patients un- Patients with CALMs should wear der the age of 5 years.3 Radiation is more often sunscreen and be advised of this. CALMs will used in older children who have had a partial darken with sunlight exposure and fade with Management resection or progression after surgery and/or time. Treatment options for CALMs include chemotherapy.3 Q-switched ruby, Q-switched Nd:YAG laser, Despite great progress in the understand- Imaging in NF-1 may be useful when signs and pigmented lesion dye lasers.59 A study

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Anderson, Baze, Rabah, Grekin 31 Pe d i at r i c Ca s e Se r i e s : Ph o t o t o x i c a n d Ph o t o a g i n g Eff e c t s o f Vo r i c o n a z o l e

Andrew J. Racette, D.O.,* Angela M. McKinney, D.O.** *Omni Dermatology, Phoenix, Arizona **Oakwood Southshore Medical Center, Trenton, Michigan

INTRO ally on her cheeks and other skin darken- she was seen by GI and told to follow up ing noted for one year. She stated the skin with dermatology due to increased freck- changes began to occur after she started Voriconazole is a second-generation ling. trimethoprim-sulfate for pulmonary infec- triazole used to treat resistant fungal in- tion prophylaxis. Trimethoprim-sulfate Patient 2 fections, including aspergillosis. In thera- was stopped due to side effects; however, peutic trials, side effects included visual Patient two is a 13-year-old female the spots continued to increase. At the referred on November 12, 2007, regarding disturbances, elevated liver enzymes and same time, she was also on her second dermatological reactions ranging from a skin rash. She has a history of pulmonary course of voriconazole therapy in the per- and disseminated coccidiomycosis. She mild erythema to skin cancer (1,2,3). We vious 1.5 years to treat pseudallescheria are reporting follow-up information of a was being treated with various antifungals boydii. In addition, she was using tretinoin and fluconazole systemically. She started 15-year-old female who developed lentigi- cream for comedones on her nose. nes and characteristic aging of the skin af- voriconazole three months prior to her On exam, increased freckling on the visit, and she and her father noticed a red ter a year-long treatment of voriconazole malar area, cheeks, nose and were for a sinus infection (4). Moreover, we re- skin rash shortly after starting this medica- noted. There was wrinkling on the dorsum tion. On exam, she had striking erythema port three additional cases of children with of her hands and grayish wrinkling of the serious fungal infections who developed on her scalp, face, anterior and posterior skin on her anterior forearms and anterior neck, anterior chest and upper back (Fig- photoaging and phototoxic reactions dur- right lower leg. A hyperkeratotic area on ing treatment with voriconazole, similar to her right lower leg developed as well. The the initial report. skin was dry and flaking on her lips. A punch biopsy was taken from the Case Report skin of her right lower extremity to rule out solar elastosis and . The histologic results were unremarkable, with Patient 1 only mild ectasia of papillary dermal ves- Patient one is a 9-year-old female liv- sels. There was no evidence of solar elasto- ing in Phoenix, Arizona, with cystic fibro- sis or actinic keratosis. sis who was placed on voriconazole several Her antifungal treatment course was times over an 18-month period to treat as follows: On 6/20/06 she started vori- chronic pulmonary infections. She had conazole for a fungal sinus infection. Four approximately 10 months of voriconazole months later she discontinued the vori- treatment over the 18-month time span. conazole and trimethoprim-sulfate ther- The last course was for six straight months, apy. At this visit she had increased fatigue at which time she started to develop len- for two weeks and noted skin redness on tigines on her cheeks. She then devel- exam. On 12/05/06 for a routine visit, she oped redness of her dorsal hands and fine grew pseudallescheria boydii on sputum wrinkling. She was referred to Phoenix culture and restarted voriconazole 50 mg Children’s Hospital (PCH) department of daily. On March 5, 2007, when seen by her dermatology and seen on June 6, 2007, due pulmonologist her voriconazole dose was to increasing numbers of bilater- increased to 100 mg daily. On June 5, 2007, Figure 1a Table 1: Voriconazole: Comparison of treatment length, reaction and sequelae On Other Immuno- Dose Duration Resolution with suppressant Patient Sex Age Diagnosis (mg/day) (Months) Reaction Type Discontinuation Sequelae Agents? CF/Fungal Lentigines, Solar Pulmonary elastosis, Dry, None to Patient 1 F 9 Infection 100 10 (total) Erythema Yes date No Pulmonary & Dissemi- Lentigines, Solar nated Coc- elastosis, Dry, None to Patient 2 F 13 cidiomycosis 100 3 Erythema Yes date No Coccidiomy- Lentigines, Solar cosis Infec- elastosis, Ery- Lentigines None to Patient 3 F 8 tion 100 12 thema remain date No Sinus Lentigines, Solar Curvularia elastosis, Ery- Lentigines Mela- Patient 4 F 15 Lunata 400 11 thema remain noma No

32 Pediatric Case Series: Phototoxic and Photoaging Effects of Voriconazole ure 1a). Her forehead showed several faint, prominent today. sented to the office again for another laser 2-3 mm, light brown macules. The dor- treatment. Three years later, she still has sum of her hands bilaterally appeared red Patient 4 most of her lentigines, which darken when and erythematous, with the overlying skin Patient four is a 15-year-old female who she is out in the sun and lighten after laser appearing wrinkly with subtle changes of we previously reported in 2005, after she treatments. solar elastosis (Figure 1b). Her skin overall developed erythema, dryness, psuedo-por- appeared very dry. She had erythema with phyria cutanea tarda-like , lentigines, DISCUSSION scaling on her chest, back and abdomen and and solar elastosis while on voriconazole mild scaling and hyperkeratosis on her feet (Figures 3a,3b). One month after the case These four cases demonstrate an bilaterally. Her voriconazole was stopped, report was submitted, the changing mole on adverse cutaneous reaction involving len- and she was treated with hydrocortisone her right lower calf (Figure 4) was biopsied tigines, nevi and skin laxity after exposure 2.5% cream daily on her face and neck, and and proved to be an invasive melanoma (0.4 to voriconazole treatment. In addition, triamcinolone 0.1% cream on her trunk and mm). She underwent surgical removal along patients two and four experienced erythema extremities. Her reaction resolved after vori- with sentinel lymph node dissection, which and dryness, which is similar to retinoid- was negative. The solar elastosis of the dor- like reactions in previously reported cases sal hands resolved after discontinuation of (5,6,7). her voriconazole; however, her lentigines Voriconazole is metabolized by the remained on her face and dorsal hands. She CYP450 enzymes CYP2C19, CYP2C9 and chose to have the lentigines treated with the CYP3A4 (4,8,9). Weiss and colleagues Q-switched ruby laser, with excellent results. recently demonstrated that the number of However, approximately one year later the variant CYP2C19 alleles explains a sub- lesions had slowly darkened, and she pre- stantial part of the wide variability of vori- conazole pharmacokinetics, whereas the presence of functional CYP3A5 and the CYP2C9 genotype has no significant impact on voriconazole exposure(10). This genetic variability may account for why only a select Figure 1b population of patients receiving voricon- conazole was withdrawn. azole develops adverse reactions as seen in our patients. The other interesting obser- Patient 3 vation is that all of our patients have been Patient three is an 8-year-old female females, and we are without a plausible seen on October 15, 2007, regarding new explanation for this observation. Voricon- development of freckles on her cheeks azole is oxidatively metabolized mainly by N-Oxidation. UK-121,265 accounts for and redness of both hands (Figure 2). The Figure 3a patient had a one-year history of voricon- 72% of its metabolite breakdown. Other azole use for suppression of coccidioidomy- major metabolites are glucuronide conju- cosis infection. On exam, there was a diffuse gates. Thus far, no studies have investigated eruption of 3-7 mm, light brown macules whether or not these metabolites are benign across the cheeks. Additionally, erythema or possess phototoxic capabilities. was noted across the dorsum of her hands The development of solar lentigines was and arms bilaterally. There was also a a universal finding in all four of our patients, glazed, wrinkled appearance of the dorsum which does not seem to be a drug side effect of the arms suggesting solar elastosis. The commonly reported in the literature. We chest and back were clear of any cutaneous believe these to be lentigines are not ephi- changes. A punch biopsy was offered but lides because they are persistent, however was declined by the family. She did, how- without a biopsy we cannot be 100% sure. ever, remain on voriconazole treatment after All patients were offered a biopsy but only an in-depth discussion weighing the risks one let us perform a punch biopsy and this was on an area of her leg which appeared to versus benefits. Her lentigines are still very Figure 3b be solar elastosis without any hyperpigmen- tation. Although solar lentigines can occur at any age, they are usually identified as the hallmark of advanced age with 90% of Cau- casians over age 60 being affected(11,12). More often ephelides are found in children, correlated with sun exposure, darken in summer and fade in winter, and are pre- dominantly seen in skin types I and II. Len- tigines tend to appear on severely damaged skin and serve as a marker for high intensity UV radiation or cumulative radiation over time(13). The former being more applicable to intense UV reaction inflicted upon vori- conazole-induced photosensitive skin. Solar lentigines can be induced by phototherapy (psoralen plus ultraviolet A treatments) as Figure 2 well as tanning bed use (UVA). Figure 4 The development of eruptive, pig- Racette, McKinney 33 mented lesions has been related to local skin have a variety of cutaneous adverse reactions. 6. Rubenstein M, Levy ML, Metry D. Voriconazole-Induced Retinoid-Like Photosensitivity in Children. Pediatric Der- inflammation, with diminished immune Erythema and may be explained by matology 2004; 21(6): 675-678. surveillance allowing melanocyte growth increased levels of systemic retinols; however, 7. Denning DW, Griffiths CE. Muco-Cutaneous retinoid-effects and facial erythema related to the novel triazole antifungal factors to promote development of pig- photoaging and pigmentation sequelae require agent voriconazole. Clin Exp Dermato 2001; 26:648-53. mented lesions in genetically predisposed further clarification. Additional research of 8. Baildon R, Pfizer flobal research and development. Avail- able from: http://www.fda.gov/ohrms/dockets/ac/01/slides/ individuals(14). Richert et al. suggested drug metabolite and potential for phototoxic 3792s2_01_1-Pfizer-main.ppt. Accessed October 13, such eruptions could be drug-induced reactions is a reasonable course for investiga- 2003. 9. Hyland R, Jones BC, Smith DA. Identification of the cyto- (15). This may be explained by the effect of tion. The hallmark feature of extrinsic aging chrome P450 enzymes involved in the N-oxidation of vori- β- growth factor (β-FGF) on mel- is solar elastosis and irregular pigmentation conazole. Drug Metab and Dispos 2003; 31:540-547. 10. Weiss J, Ten Hoevel M, Burhenne J, et al. Genotype Is a anocytes. During normal cutaneous wound such as freckling and lentigines, which nor- Major Factor Contributing to the Highly Variable Pharmaco- healing, β-FGF is produced by basal kera- mally results from lifelong exposure to ultra- kinetics of Voriconazole. Journal of Clinical Pharmacology. 2008. tinocytes and fibroblasts. β-FGF has been violet radiation. We present four patients 11. Ortonee J-P. Pigmentary changes of the ageing skin. Br J shown to be a mitogen for melanocytes and who exhibit clinical findings consistent with Dermatol 1990; 122(suppl35):21-28 12. Wolff K, Goldsmith L, Katz S, Gilchrest B, Paller A, Leffell is enhanced by proinflammatory mediators. photoaging after voriconazole use, including D. Fitzpatrick’s Dermatology in General Medicine 7e. 2007; In turn, it up-regulates cAMP in melano- pigmentation sequelae. Patients should be Chapter 108,122. 13. Dereure O. Drug-Induced Skin Pigmentation Epidemiology, cytes. The β-FGF produced during wound warned of this permanent side effect before Diagnosis and Treatment. Am J Clin Derm 2001; 2(4): 253- healing and inflammation may then stimu- being placed on voriconazole, especially in 262. 14. Bovenschen HJ, Tjioe M, Vermaat H, et al. Induction late local growth and differentiation of mel- cases where significant sun exposure is likely. of eruptive benign melanocytic naevi by immune sup- anocytes into pigmented lesions, especially In addition, they should take means to pre- pressive agents, including biologicals. Br J Dermatol. 2006;154(5):880-884. during times of inflammation (Figure 5). vent this side effect through sun avoidance, 15. Bloom RS, Seraly F. Widespread eruptive dermal and atyp- It is plausible then that the inflammatory protective clothing, and sun block on exposed ical melanocytic nevi in association with chronic myelocytic leukemia. J Am Acad Derm 1996. effect from the photosensitivity seen with skin. The mechanism behind the findings in 16. Sauvaigo S, Bonnet-Duquennoy M, Odin F, et al. DNA voriconazole is capable of inducing pig- our patients is not well established, and uncer- repair capacities of cutaneous fibroblasts: Effect of sun exposure, age and smoking on response to an acute oxi- mented lesions such as lentigines through tainty of photocarcinogenic drug effect war- dative . British Journal of Dermatology 2007; 157:26- this pathway. Although only a short time rants regular skin exams for anyone with this 32. 17. Pillai S, Oresajo C, Hayward J. Ultraviolet radiation and period has elapsed in three of the patients, reaction. The means behind reversing elasto- skin aging: roles of reactive oxygen species, inflammation pigmentation seems to be permanent even sis is yet to be determined and remains at the and protease activation, and strategies for prevention of inflammation-induced matrix degradation – a review. Int J after discontinuation (as seen in patient forefront of photoaging treatment. of Cos Sci 2005; 27:17-34. four, who is three years post treatment), and 18. Takahashi Y, Moriwaki S, Sugiyamin Y, et al. Decreased gene expression responsible for post ultraviolet DNA repair the photocarcinogenic effects are yet to be REFERENCES: synthesis in aging: A possible mechanism of age-related determined. 1. Vanacher A, Fabre G, Van Dorpe J, Peetermans WE, Maes reduction in DNA repair capacity. J of Inv Derm 2005; To the contrary, solar elastosis B. Aggressive Cutaneous Squamous Cell Carcinoma Asso- 124:435-442. ciated with Prolonged Voriconazole Therapy in a Renal 19. Goukasian D, Gad F, Yaar M, Eller M, Nehal US, Gilchrest did resolve shortly after stopping voricon- Transplant Patient. American Journal of Transplantation BA. Mechanism and implications of the age-associated azole use. The phenotype of aging does 2008; 8: 877-880. decrease in DNA repair capacity. The FASEB Journal 2. McCarthy DL, Playford EG, Looke DF, Whitby M. Severe 2000; 14:1325-1334. appear to be genetically and environmen- photosensitivity causing multifactoral squamous cell carci- 20. Lucas CR, Ke MS, Matsul MS, et al. Immune protective tally determined; however, manifestations nomas secondary to prolonged voriconazole therapy. Clin effect of moisturizer with DNA repair ingredients. J Cos Infect Dis 2007; 44: e55-e56. Derm 2008; 7:132-135. are unusual in children. The fact that it did 3. U. S. Food and Drug Administration. VFEND IV VFEND 21. Gothard P, Rogers TR. Voriconazole for serious fungal occur and later resolved is of interest. Skin Tablets VFEND for Oral Suspension. Available from: http:// infections. Int J Clin Pract 2004; 58:74-80. www.fda.gov/cder/foi/label/2006 21266s18,021267s19,021 22. Mrass P, Rendl M, Mildner M, et al. Retinoic Acid Increases damaged by reactive oxygen species nor- 630s10lbl.pdf 05-22-2006. the Expression of p53 and Proapoptotic Caspases and mally responds by initiating different cytok- 4. Racette AJ, Roenigk H, Hansen R, et al. Photoaging and Sensitizes Keratinocytes to Apoptosis. Canc Res 2004; phototoxicity from long term Voriconazole treatment in a 15 64:6542-6548. ines, inflammatory mediators and repair year old girl. J Am Acad Dermatol 2005; 52:81-85. systems (10,16-20). There is a degradation 5. Sharp MT, Horn TD. Pseudoporphyria induced by voricon- and disorganization of collagen fibrils that azole. J Am Acad Dermtol 2005; 23. are responsible for the strength and resil- ience of skin. It is well known that young VORICONAZOLE SUN E XPOS URE skin is equipped with thicker and more THERAPY abundant elastin to begin with. Perhaps, skin aging is reversible in children because Local Skin Inflammation & their DNA repair capacity is not violated. Decreased Immune Takahashi and Moriwaki et al. revealed a Surveillance marked reduction in the mRNA expression of DNA repair-synthesis related genes in the cells of elderly persons compared to young adults (18). Furthermore, a recent study demonstrated that repair of DNA strand breaks was slower in sun-exposed cells and that aging was associated with decreased FORMA TION OF INCREASED β−FGF DNA repair capacities for single-strand PIGMENTED LESIONS breaks in both sun-exposed and sun-pro- tected skin (16). This notion of post-UV By basal keratinocytes and DNA repair defect is supported by diseases fibroblasts such as xeroderma pigmentosum, where DNA damage is cumulative and irreversible. CONCLUSION Stimulation of local growth factors and cAMP Voriconazole is a second-generation tri- in ME LANOCYTES azole designed to treat serious and resistant fungal infections which has been shown to Figure 5 34 Pediatric Case Series: Phototoxic and Photoaging Effects of Voriconazole The Future of Dermatology

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Vienna Lowenbraun, DO,* Payal Patel, DO,** Kimball Silverton, DO*** *Intern, Largo Medical Center-Suncoast, Indian Rocks Campus, Largo, FL **Dermatology Resident, Year Three, Genesys Regional Medical Center, Grand Blanc, MI ***Program Director, Genesys Regional Medical Center, Grand Blanc, MI

CASE REPORT staining for pankeratin and CK7 (Figures 2 manifestations such as infections, vascular and 3). Staining for CK20, ER/PR, HMB-45, abnormalities, , connective- S-100, and TTF-1 were all negative. tissue disease, bullous disease and cutaneous A 90-year-old female presented to her The final diagnosis was poorly differ- metastasis.1 This paper will concentrate primary care office complaining of a “rash entiated of the with specifically on the presentation of cutaneous on her chest” of several months duration skin metastasis consistent with a carcinoma metastasis and how the physician should (Figure 1). The patient had a past medi- maintain a high degree of suspicion in order cal history significant for hypothyroidism, en cuirasse morphological pattern. to diagnose these rare cases. glaucoma, osteopenia, total abdominal hys- Metastasis to the skin can occur via terectomy and recent hospitalization for DISCUSSION different mechanisms and depends on sev- pneumonia. Her medications included eral factors. Proximity to the skin is perti- furosemide, levothyroxine, cetirizine, dor- Internal malignancies are capable of nent for direct metastasis, and proximity to zolamide/timolol ophthalmic, travoprost presenting as a wide array of cutaneous lymph channels and blood vessels in rela- ophthalmic and acetaminophen/propoxy- tion to the tumor is important for regional phene napsylate. The patient denied signifi- cant tobacco or use. Physical examination revealed a large, firm, pink-purple, leathery plaque extend- ing over her right axilla, shoulder, breast and chest. There were no skin changes involving the areola. In addition, there was edema of the right arm and right breast. The skin over her left breast was unremarkable. Pal- pation of the area revealed severe indura- tion, which made it difficult to confirm right axillary adenopathy. Palpation of the left axilla was negative for adenopathy or FIGURE 1: Large firm, pink-purple, leath- masses. There were no palpable masses of ery plaque extending over the right axilla, her bilaterally. Lung sounds were shoulder, chest and extending to, but not Position Available diminished bilaterally on pulmonary exam. involving, the areola. Computed tomography scan of the chest was performed, which showed right axil- lary adenopathy with supraclavicular and posterior cervical adenopathy, a mass along the right second rib involving the scalenus muscle, and thickening and subcutaneous soft-tissue stranding in the right breast and hemithorax concerning for malignancy. A right-sided pleural effusion was also seen on chest X-ray, and a diagnostic thoracentesis of this effusion was performed, which was negative for malignant cells. Basic labs were

as follows: Na 141, K 4.2, Cl 109, CO2 27, Glu 111, BUN 16, Cr 1.1, Alk Phos 57, T.Bili 0.6, Ca 8.4, Alb 2.9. A punch biopsy of the right breast was performed and showed desmoplasia of the reticular dermis with infiltration by cohesive nests and aggregates of pleomorphic epi- thelioid-appearing neoplastic cells. There were marked nuclear pleomorphism and nuclear hyperchromasia. There was a vari- able amount of cytoplasm with occasional FIGURE 3: Punch Biopsy (H&E), right vacuolization. Some of the neoplastic cells chest. Neoplastic cells arranged in primi- were arranged in primitive cord- and duct- tive cords and ducts. Many of the cells like structures. Immunoperoxidase stains FIGURE 2: Punch biopsy of right chest. are arranged in a “single file” configura- were performed for further classification of Positive CK7 (left) and pankeratin (right) tion and are seen between fibrotic colla- the malignant process and showed positive immunohistochemistry staining. gen bundles Lowenbraun, patel, Silverton 37 or distant metastasis. As was the case for this sparing of the epidermis. Other character- confirming 50 percent of the cases observed. patient, if breast metastasize to the istics include necrosis, inflammation, and This study confirmed metastatic melanoma skin, they tend to do so directly because of lymphovascular invasion.16 using positive HMB-45, and all cases showed the proximity to the skin. Regardless of the Compared with other metastases, cuta- lymphovascular invasion and were also CK7 metastatic route, certain known and com- neous metastases are rare, with occurrences negative (-), CK20-, and S100 positive (+). plicated steps occur to achieve this spread. ranging from 0.7 percent to 10 percent and Metastatic lung cancers all showed focal It may start with just a few cells that detach an average of 2.3 percent.9,18 Two large ret- glandular features and intracytoplasmic from the primary tumor, invade a vessel, rospective studies in the early 1990s reported mucin positive for anti-TTF, CK7+, CK20-, circulate, exit from the vessel, invade into that 5 and ten percent of internal malignan- and S100-. GI-tract tumor metastases were new tissue and finally proliferate.2,3 The cies, respectively, metastasized to the skin.9,10 all and histologically simi- mechanism of spread to the skin is hypoth- In a 2007 study of 1,287 patients, 1.2 percent lar to the primary tumor, with goblet cells esized by the nature of the skin lesions. of all internal malignancies metastasized to and intraglandular neutrophils. GI-tract More widespread and distant lesions usu- the skin.8 Although rare, cutaneous spread metastasis histochemical profile was CK7-, ally occur from vascular spread. Lymphatic may be the first sign of malignancy. Saeed CK20+, and S100-. Bladder cancers showed spread is common in breast carcinoma and et al. found that of their 70 cases of skin abundant clear cytoplasm and central bland squamous-cell carcinoma of the breast, and metastasis reviewed, 23.3 percent of the skin nuclei with vascular stroma and were CK7+, the metastases appear later and oftentimes metastases were the primary presentations CK20+, and S100-. Breast cancers dem- over the skin of the primary site.4 Whether of the internal malignancies.13 Brownstein onstrated gland formation and the spread is thought to be via hematoge- et al. found that lung, kidney and ovarian necrosis with ductal carcinoma cases and nous or lymphatic route, the tumor cells can cancers were the most common types of lobular carcinoma cases, showing single row pass between both and may actually occur cancers to have skin metastases as the initial filing which was similar to our case study. simultaneously.3,5 sign of disease. The most predictive features Immunohistochemical staining for estrogen Different internal malignancies have in locating the primary site of the cancer and progesterone were helpful in confirm- also shown predilections to metastasize to was sex of the patient and site of the skin ing cases of adenocarcinomas of the breast specific cutaneous sites. This can usually tumor.8 expressing CK7+, CK20- and S100-. Head be accounted for by looking at the route Early detection of cutaneous metastasis and neck metastases were all poorly differ- of metastatic spread. For example, breast is imperative in diagnosis of a possible pri- entiated squamous-cell carcinomas without and lung cancers frequently metastasize to mary tumor,8,9 and of recurrent or dissemi- epidermal involvement. Non-epidermal the anterior chest wall by direct or local nated disease.7,9,10,17,20,21 One study reported involvement helped to differentiate the head metastasis.6 Cancers of the bowel, ovary, that distant metastases occurred in 39 per- and neck metastases from primary cutane- and bladder are more likely to metastasize cent of patients with cutaneous spread, with ous squamous-cell carcinomas, which all to the abdomen.6 Breast cancer in women the most frequent primary tumors being have epidermal involvement.13 and lung cancer in males were most com- melanoma, lung and breast cancers.9 Most Carcinoma en cuirasse is a specific monly seen to have skin metastases.6 The cutaneous metastases develop months or presentation of cutaneous metastasis most second most common cancers to have cuta- years after a primary malignancy is diag- commonly seen with recurrent breast can- neous metastases were colon and melanoma nosed, and 40 percent of patients found to cers. However, as with the above case pre- in males, and lung and ovary cancers in have skin metastases were also discovered to sentation, rarely will this presentation occur females.7,8,9 The scalp has a high rate of skin have internal metastases.6,11 as the primary presentation of breast can- metastases at five percent of all skin metas- Unfortunately, skin metastasis usually cer.20,24,25 Other names for this condition tases.10,11,8,12 The face encompasses 12 per- represents a poor prognosis and may be the include scirrhous carcinoma, pachydermia, cent of all skin metastases, with oral cancers first sign of secondary involvement, so early and Acarcine eburnee.20,24,25 Although car- being a primary source likely due to its close recognition may help to prevent widespread cinoma en cuirasse is the most common proximity. Renal and lung carcinomas also disease.22 In a 2007 case, Chen et al. reported association with breast malignancy, it is also commonly metastasize to the face because that one year post treatment of a 72-year- associated with adenocarcinomas of the of their tendency for vascular spread.4,13 old female with stage IIB squamous-cell lung, GI tract and kidney.19 Carcinoma en Although extremities are rarely involved in carcinoma of the cervix, the patient pre- cuirasse usually initially presents as firm, cutaneous metastasis, one should search for sented with erythematous lesions on the erythematous papules or nodules that even- a melanoma in this instance as extremities, trunk and scalp. A biopsy was tually coalesce to form the -like are the most common to present in this performed and showed metastatic squa- and sclerodermoid plaque changes.19,26 His- body site.14 mous-cell carcinoma. MRI of the pelvis and tologically, carcinoma en cuirasse shows an Cutaneous metastases commonly CT of the chest and bones revealed wide- “Indian file” pattern in which the tumor present as nodules that are firm and rub- spread disease to the lung and bone.23 As cells form lines between collagen bundles.27 bery, with histological features similar to shown in this particular case, early recogni- Their nuclei are larger, angulated and more their primary tumor.10,11 Oftentimes, skin tion of metastases is helpful in tailoring the basophilic than the surrounding unaffected metastases are inaccurately diagnosed as treatment of the primary tumor.9,10,19 cells.28 Because of this, tumor cells can often cysts, benign fibrous tumors or vascular Certain features of a biopsy and immu- be overlooked due to their fibroblast-like tumors.10 Eighty-six percent of cutaneous nohistochemical stains are helpful in deter- appearance.28 metastases were found to be nodular in one mining the nature of metastasis.13 A 2004 Other cutaneous metastatic findings study.6 Interestingly, clinical appearance study by Saeed et al. used histology, clinical in breast cancers include carcinoma erysi- of cutaneous metastasis can mimic other correlation and immunohistochemistry to pelatoides and carcinoma telangiectaticum, skin disorders such as pyogenic granulo- help determine the link between the skin which are variants of inflammatory breast mas, acute , erysipelas, or herpes lesions and primary tumor where appli- cancer.29 Carcinoma telangiectaticum pres- zoster.15,16,7,17 This can make an inaccurate cable. Immunohistochemistry using cyto- ents as small, pink to purplish papules, pseu- or delayed diagnosis until much later in the keratin-7 (CK-7), cytokeratin-20 (CK-20), dovesicles, and . Carcinoma progression of the cancer. Histologically, HMB-45 (a monoclonal antibody), S-100 (a erysipelatoides presents with erythema, metastatic skin tumors have a general “pyra- calcium-binding protein), prostate-specific edema, warmth and a well-demarcated edge midal” appearance, with the apex pointing antigen (PSA), antithyroid transcription that is very similar to the appearance of ery- superficially. The majority of the lesion is factor antibody (anti-TTF), estrogen and sipelas. Histologically, there are neoplastic commonly confined to the dermis, with progesterone was found to be helpful in cells and dilated dermal vessels.14

38 CANCER METASTASIS TO THE SKIN Alopecia neoplastica, which is also seen is important to evaluate all skin abnormali- ease of the breast: a 33-year experience. J Am Coll Surg 1998;187:171-177. with metastatic breast cancers as well as ties, as cutaneous metastases often mimic 31. Heymann WR. Extramammary Paget’s disease. Clin Der- cancers of the kidneys and lungs, presents other skin disease such as pyogenic granu- matol 1993;11:83-87. 32. Ratnam K, Khor C, Su W. Leukemia cutis. Dermatol Clin most commonly on the scalp. It features an lomas or infections. Further evaluation is 1994;12:419-431. area of induration associated with alopecia necessary if the patient is not responding to 33. Cohen PR. Metastatic tumors to the nail unit: subungual metastases. Dermatol Surg 2001;27:280-293. and is histologically confirmed by seeing standard treatment or the cutaneous symp- 34. James W, Berger T, Elston D (Eds.) Andrews’ Diseases of loss of hair follicles and deposits of visceral toms are waxing and waning. Confirmation the Skin, Clinical Dermatology, 10th edition 2006. Philadel- malignancy.29 of diagnosis of cutaneous metastases can be phia, Elsevier Inc. 849. Paget’s disease is an erythematous, scal- made using microscopy and immunohisto- ing eruption that usually involves the nipple chemistry and may aide in the diagnosis of or anogenital region. When on the breast, the primary tumor. it is usually unilateral and slow-growing. It can also be pruritic, exudative and/or ulcer- REFERENCES: ative. Paget’s disease is often mistaken for 1. Kilic A, Gul U, Soylu S. Skin findings in internal malig- eczema because of these features, but can nant diseases. International Journal of Dermatology 2007;46:1055-1060. be differentiated by its unilateral appear- 2. Poste G, Fidler IJ. The pathogenesis of cancer metastasis. ance. Unlike carcinoma en cuirasse, Paget’s Nature1980;283:139-146. 3. Del Regato JA. Pathways of metastatic spread of malig- disease does not start as nodules and indu- nant tumors. Semin Oncol 1977;4:33-38. ration, and thickening occurs much later 4. Brenner S, Tamir E, Maharshak N, et al. Cutaneous mani- festations of internal malignancies. Clinical Dermatology in its progress. In the later stages of Paget’s 2001;19:290-297. disease, a subcutaneous nodule may be pal- 5. Liotta LA, Kohn E. Cancer invasion and metastases. JAMA 1990;263:1123-1126. pated, and usually a diagnosis of underly- 6. Gul U, Kilic A, Gonul M, Kulcu S, Erinckan C. Spec- ing intraductal breast carcinoma is found.30 trum of cutaneous metastases in 1287 cases of internal malignancies: a study from Turkey. Acta Derm Venereol When an extramammary manifestation is 2007;87:160-162. present, it may be the representation of an 7. Cohen PR. Skin clues to primary and metastatic malig- nancy. Am Fam Physician 1995;51:1199-1204. underlying malignancy, however it is more 8. Brownstein MH, Helwig EB. Patterns of cutaneous metas- commonly an intraepithelial adenocarci- tases. Arch Dermatol 1972;105:862-868. 9. Lookingbill DP, Spangler N, Sexton FM. Skin involvement noma derived from the basal layer of the as the presenting sign of internal carcinoma: a retrospec- skin.31 tive study of 7316 cancer patients. J Am Acad Dermatol 1990;22:19-26. Like breast cancer metastasis to the 10. Lookingbill DP, Spangler N, Helm KF, Cutaneous metasta- skin, other cancers have specific skin presen- ses in patients with metastatic carcinoma: a retrospective study of 4020 patients. J Am Acad Dermatol 1993;29:228- tations. Leukemia cutis infiltrates the skin 236. as non-tender plaques, nodules, erythema or 11. Weedon D. Cutaneous metastases. In: Weddon D, edi- tor. Skin pathology. Edinburgh: Churchill Livingstone, ulcerations. Although it can occur with all 1997:855-864. types of leukemia, CLL and AML have the 12. Faust HB, Treadwell PA. Metastatic adenocarcinoma 32 of the scalp mimicking a kerion. J Am Acad Dermatol highest occurrence rate. The most com- 1993;29:654. mon location for leukemia cutis is the face 13. Saeed S, Keehn C, Morgan M. Cutaneous metastasis: a clinical, pathological, and immunohistochemical appraisal. and may present as leonine facies if the brow J Cutan Pathol 2004;31419-430. and cheeks are involved.32 14. James W, Berger T, Elston D (Eds.) Andrews’ Diseases of the Skin, Clinical Dermatology, 10th edition 2006. Philadel- Subungual metastases have also been phia, Elsevier Inc. 629-630. reported and are most commonly associ- 15. Hagar CM, Choen PR. Cutaneous lesions of visceral malignancy mimicking pyogenic . Cancer Invest ated with lung cancers. Unfortunately, these 1999;17:385-390. often resemble other nail diseases and are 16. Cohen PR, Buzdar AU. Metastatic breast carcinoma mim- 33 icking an acute paronychia of the great tow: case report often misdiagnosed at initial presentation. and review of subungual metastases. Am J Clin Oncol Sister Mary Joseph nodule is a conflu- 1993;16:86-91. 17. Manteaux A, Cohen PR, Rapini RP. Zosteriform and epi- ence of metastatic tumors to the umbilicus. dermotropic metastasis: report of two cases. J Dermatol The primary site most commonly dissemi- Surg Oncol 1992;18:97-100. 18. Spencer PS, Helm TN. Skin metastases in cancer patients. nates from the stomach, followed by the Cutis 1987;39:119-121. large bowel, ovary and pancreas.4 Rare pre- 19. Schwartz RA. Cutaneous metastatic disease. J Am Acad Dermatol 1995;33:161-182. sentations of stomach carcinoma metastases 20. Mullinax K, Cohen J. Carcinoma en cuirasse presenting include zosteriform, linear or chancroidal as of the chest. Dermatol Surg 2004;30:226-228. 21. Cohen PR. Cutaneous manifestations of internal malig- ulcerations of the genitals or verrucous nod- nancy. In: Callen JP, Bone RC, eds. Current prac- ules of the legs.14 tice of medicine, vol 2. Philadelphia: Current Medicine, 1996:19.1-19.13. Lymphangiosarcoma, or Stewart-Treves 22. Gmitter TI, Dhawan SS, Phillips MG, et al. Cutaneous syndrome, develops from chronic lymph- metastases of colonic adenocarcinoma. Cutis 1990;46:66- 68. edema. This often occurs with breast car- 23. Chen C, Chao K, Wang P. Advanced cervical squamous cinomas in patients who have had axillary cell carcinoma with skin metastasis. Taiwan J Obstet 14 Gynecol 2007;46:264-266. lymph node resection. The metastatic 24. Pathophysiology and rotational subtotal skin electron beam lesions are bluish or reddish nodules that therapy (SSEBT), a new technique. Radat Med 1989;7:95- 104. usually arise on the arm. The lesions are 25. Siddiqui MA, Azman MN. Primary carcinoma en cuirasse. usually multiple, with frequent and further J am Geriatr Soc 1996;44:221-222. 34 26. Whitaker-Worth DL, Carlone V, Susser WS, Phelan N, metastases, and are often fatal. Grant-Kels JM. Dermatologic diseases of the breast and nipple. J Am Acad Dermatol 2000;43:733-51. 27. Schwartz RA. Histopathologic aspects of cutaneous meta- static disease. J Am Acad Dermatol 1995;33:649-657. CONCLUSION 28. Johnson W. Metastatic Carcinoma of the Skin: Incidence and dissemination. In: elder D, Elenitsas R, Jaworsky C, Johnson B, eds. Skin, 8th ed. Philadelphia: Lippincott- Although rare, cutaneous metastasis of raven, 1997:1011-1018. internal malignancies can be a sign of recur- 29. Giandoni MB, Fitzpatrick JE. Metastatic tumours. In: Fitz- patrick JE, Aeling JL (Eds). Dermatology secrets in colour, rent disease, spreading of primary disease or 2nd edition 2001. New Delhi, Jaypee Brothers. 344-347. the first manifestation of visceral disease. It 30. Kollmorgen DR, Varanasi JS, Edge SB, et al. Paget’s dis- Lowenbraun, patel, Silverton 39 Th e Us e o f De r m o s c o p y i n Os t e o pa t h i c De r m a t o l o g y Tr a i n i n g

Bradley Neuenschwander, DO,* Howard Lipkin, DO,** Annette LaCasse, DO*** *Dermatology Resident, PGY IV, Pontiac Osteopathic Hospital, Michigan State University, East Lansing, Michigan **Brighton Dermatology & Cosmetic Surgery Center, Brighton, Michigan ***Program Chair, Commerce Institute of Skin, Commerce, Michigan

Abstract

Background: Dermoscopy is a noninvasive method used to evaluate the morphological structures of pigmented and non-pigmented cutaneous lesions. Visu- alization of the lesions is achieved by a hand-held light source using either polarized or non-polarized light. Objective: The purpose of our study was to assess the training and use of dermoscopy by osteopathic dermatology residents and identify methods to improve their dermoscopy skills. Methods: We conducted an on-line survey from September to October 2008 of all current dermatology residents during the 2008-2009 academic year. The survey was also distributed to the residents at the annual academy meeting in October 2008. Results: Of the 98 current dermatology residents, 52 responded to the survey (response rate of 53%). Results from the survey demonstrate that residents learn dermoscopy through a variety of methods, but respondents believe the two most effective methods are learning directly from an attending physician or participating in a lecture or conference. Among respondents, 56% felt they are not proficient at using dermoscopy. Only 31% of the residents are somewhat satisfied or very satisfied with the dermoscopy training they receive. However, 92% of residents believe that dermoscopy is a valuable clinical skill when evalu- ating pigmented lesions. Conclusions: To improve the skill level and training satisfaction regarding dermoscopy, we recommend exposing residents to dermoscopy early in their train- ing, encouraging attending physicians to take an active role in teaching residents dermoscopy, and providing lectures on dermoscopy at the annual college meeting.

Introduction moscopy by residents, and 4) determine Results methods to improve dermoscopy training. Dermoscopy is a noninvasive method Of the 98 current residents, 52 of evaluating the morphological structures Methods responded (response rate 53%). Among of pigmented and non-pigmented cutane- those responding, 20 (38%) were PGY2, ous lesions. Visualization of the lesions All current osteopathic dermatology 18 (35%) were PGY3, and 14 (27%) were can be performed with either polarized or residents in training during the 2008-2009 PGY4. Thirty-eight (72%) of the respon- non-polarized light sources. The use of a academic year were invited to participate dents own a dermoscopy unit. A signifi- polarized light source allows for the visu- in the study. The survey was posted on an cant majority obtained a dermoscopy unit alization of structures in the upper der- Internet site hosted by Zoomerang. Par- during their first year of training (42 out mis. Polarizing lenses reduce the amount ticipation was requested via email with a of 52 respondents, 82%). Of the remain- of light seen, which is reflected from the link to the Zoomerang website. A repeat ing respondents, 6 (12%) obtained a der- matoscope during their second year of stratum corneum. Non-polarized light email was sent after two weeks. The survey training, while 3 (6%) obtained one dur- dermoscopy uses a liquid interface between was also distributed to the residents at the ing their third year. The length of time the dermatoscope and the cutaneous sur- October 2008 annual academy meeting using dermoscopy by respondents ranged face. This liquid interface eliminates the held in Las Vegas, Nevada. air interface, thereby reducing the amount from 48% (n=25) using less than one year, of reflected light visualized. This technique 31% (n=16) using between one and two is better suited for visualizing structures of years, and 21% (n=11) using longer than the superficial layers of the skin.1,2 The first reported use of dermos- copy to evaluate pigmented lesions was by Goldman in the 1950s.3 Many names have been used to describe the technique: sur- face microscopy, epiluminescence micros- copy, dermatoscopy and amplified surface microscopy.2,3,4 In 1991, Friedman and colleagues introduced the term “dermos- copy,” which is now the most commonly used term.2 Dermoscopy has since been demonstrated to increase the diagnostic accuracy of benign-versus-malignant pig- mented lesions.4,5 However, in 2002, a sur- vey of dermatologists in the United States found that less than 25% of the respon- dents used dermoscopy.4 The goal of our study was multifac- eted. We wanted to 1) assess how residents are taught dermoscopy, 2) assess resident satisfaction with the dermoscopy training received, 3) assess the current use of der- 40 The Use of Dermoscopy in Osteopathic Dermatology Training two years. When asked how they learned dermoscopy, respondents noted a variety of methods for obtaining a foundation in der- moscopy. See Table 1. In answer to which method they pre- ferred to learn dermoscopy, 33% believed attending a conference or lecture to be effec- tive, and 31% believed that learning directly from their attending physician was the best method. See table 2. The use of pattern analysis was the method most preferred by residents to eval- uate melanocytic lesions. The results for which methods residents prefer to analyze pigmented lesions is seen in Table 3. Frequency of using dermoscopy to evaluate pigmented lesions by residents var- ied: 36% of the residents reported using dermoscopy less than 40% of the time to evaluate pigmented lesions, while 57% of the respondents reported using dermoscopy over 60% of the time when evaluating mela- nocytic lesions. Forty-nine percent of respondents reported using their dermatoscopes fewer than 10 times per day. Residents were asked to rate themselves on proficiency using dermoscopy to evaluate pigmented lesions. These results are shown in Table 4. Most residents felt they were not pro- ficient (n=15, 29%) or only somewhat pro- ficient (n=14, 27%) using dermoscopy, and only a small portion (n=8, 16%) felt they were proficient with dermoscopy. None reported feeling very proficient. The majority of residents believed that dermoscopy is a valuable tool to evaluate pigmented lesions. Ninety percent (n=47) believed that dermoscopy is somewhat or very useful. Only one respondent (2%) felt that dermoscopy was rarely useful in evalu- ating pigmented lesions. Resident satisfaction with dermoscopy training was 31% (n=16) feeling somewhat or very satisfied, 31% (n=16) being neutral, and 37% (n=19) being either somewhat or very unsatisfied with the current level of training. Discussion

The use of dermoscopy can increase diagnostic accuracy of pigmented lesions by 5-35% compared to examination with the naked eye, with a sensitivity of 89% and a specificity of 79%.3,4,5 A study by Benelli et al. demonstrated the utility of dermoscopy. Based on clinical exam alone, the correct diagnosis of malignant melanoma was made only 67% of the time. Using only dermos- copy to evaluate the same lesions provided a correct diagnosis of melanoma in 80% Carli et al. found that clinicians trained in malignant lesions between 12:1 and 14:1.4 of the cases. However, combining the two dermoscopy reduced the ratio of benign to Several algorithms have been estab- methods of clinical exam and dermoscopy malignant lesions being excised from 18:1 to lished to aid the clinician when evaluating increased the accuracy to 93%.2 Findings 4:1, whereas clinicians evaluating pigmented pigmented lesions with dermoscopy. The by Bono and colleagues in a separate study lesions without the aid of dermoscopy four most common algorithms are pattern found similar results.2 Further demon- maintained a biopsy ratio of benign versus analysis, the ABCD (Asymmetry, Border, strating the clinical utility of dermoscopy, Neuenschwander, Lipkin, LaCasse 41 Color, Differential structures) rule of der- awarded 1 point. Architectural disorder is college meetings. Lectures at college meet- moscopy, Menzies’ method and the seven- classified as none/mild, moderate and severe ings will also aid attendings in being more point checklist. All four methods have been and given either 0, 1 or 2 points respec- comfortable instructing residents in der- shown to improve the diagnostic accuracy tively. Symmetry is based on the shape of moscopy. of pigmented lesions, but none of the algo- the lesion as well as dermoscopic structures. rithms will diagnose all melanomas.2,3,5,6 No points are awarded for biaxial symme- REFERENCES: Pattern analysis, which was the first try, 1 point for monaxial symmetry and 2 1. Pan Y, et al. Polarized and nonpolarized dermoscopy. Arch established dermoscopy algorithm, makes points for biaxial asymmetry. Homogene- Dermatol 2008;144:828-29. 2. Argenziano G, Soyer P. Dermoscopy of pigmented skin use of the numerous morphologic structures ity is defined as the number of morpho- lesions – a valuable tool for early diagnosis of melanoma. seen with dermoscopy to determine the logic structures found within the lesion, Lancet Oncol 2001;2:443-49. 3. Braun P, et al. Dermoscopy of pigmented skin lesions. J benign or malignant nature of a pigmented and 1 point is awarded for each. A score of Am Acad Dermatol 2005;52:109-121. lesion. Pattern analysis is the most reliable 8 or more classifies the lesion as suspect for 4. Menzies, S. Why perform dermoscopy? Arch Dermatol 8 2006;142:1211-12. method in diagnosing pigmented lesions. melanoma. 5. Stolz W, et al. Principles of dermatoscopy of pigmented However, significant experience with the Our study demonstrated that residents skin lesions. Semin Cutan Med Surg 2003;22:9-20. 6. Annessi G, et al. Sensitivity, specificity, and diagnostic method is needed to become proficient and believe dermoscopy to be valuable when accuracy of three dermoscopic algorithmic methods in the achieve results similar to those that have evaluating pigmented lesions. Ninety per- diagnosis of doubtful melanocytic lesions. J Am Acad Der- matol 2007;56:759-67. been published. A study by Annessi et al. cent stated they felt dermoscopy to be either 7. Carli P, et al. Pattern analysis, not simplified algorithms, found that the pattern analysis method cor- somewhat useful or very useful to evaluate is the most reliable method for teaching dermoscopy for melanoma diagnosis to residents in dermatology. Br J Der- rectly diagnosed 82.3%of pigmented lesions lesions. Eagerness to learn dermoscopy is matol 2003;148:981-984. with a sensitivity of 79.4%, specificity of seen by the number of residents obtaining 8. Henning S, et al. The CASH (color, architecture, symmetry, 6 and homogeneity) algorithm for dermoscopy. J Am Acad 79.6% and a diagnostic accuracy of 70.8%. dermatoscopes during their first year of res- Dermatol 2007;56:45-52. Carli et al.7 also found that pattern analysis idency, 82%. However, 36% of the respon- had the best diagnostic accuracy when com- dents stated they use dermoscopy less than pared to the ABCD rule and the seven-point 40% of the time when evaluating pigmented checklist. lesions, and 49% of respondents use their The ABCD rule of dermoscopy was dermatoscopes fewer than 10 times a day. proposed by Stolz et al. in 1993.3 This algo- Only 17% of the residents felt they were rithm uses a complicated scoring system proficient in their use of dermoscopy. This based on the asymmetry, border, color and increased to 44% when including residents different dermoscopic structures within the who described themselves as somewhat lesion. The total score will range between proficient, leaving 56% of residents who 1 and 8.9. Lesions scoring greater than 5.45 felt they are not proficient in dermoscopic are considered to be melanoma. Lesions techniques. This lack of proficiency can be scoring less than 4.75 are considered benign. explained by several factors. First, 38% of Lesions with intermediate scores (between the respondents were first-year dermatology 4.75 and 5.45) are viewed as suspicious and residents; second, 48% of respondents had should be removed or monitored closely. been using dermoscopy less than one year; The study by Annessi et al. noted the ABCD and third, the residents used their dermato- rule correctly diagnosing 79.3% of melano- scopes relatively infrequently. Another pos- cytic lesions, demonstrating a sensitivity of sible reason for residents’ perceived lack of 84.4%, specificity of 74.5% and diagnostic proficiency is that dermoscopy is not widely accuracy of 67.8%.6 used among attending physicians. Thirty- Menzies’ method employs two negative six percent (n=19) of respondents stated features and nine positive features to diag- that of the physicians they regularly train nose melanoma. If both negative features with, only one or two use dermoscopy. It are present, the lesion is considered benign. is less likely that residents will become pro- If one of the negative features is absent, ficient in dermoscopy if they don’t receive evaluation for the presence of any of the instruction and guidance from experienced positive features is undertaken. The pres- attendings. ence of one positive feature makes the lesion Dermoscopy is a useful adjunct when highly suspect for melanoma.3 combined with the clinical exam and history The seven-point checklist established of the lesion. As studies have demonstrated, by Argenziano et al. uses three major cri- dermoscopy increases both sensitivity and teria and four minor criteria to evaluate specificity for the diagnosis of melanoma pigmented lesions. Major criteria met are and therefore should be a key examination given a score of 2, and each minor criteria technique for the diagnosis of pigmented present is given a score of 1. A score totaling lesions. 3 or more is necessary to diagnose mela- Survey respondents suggested that noma. Annessi et al. found the seven-point increased teaching from their attending checklist correctly diagnosing 71.2% of pig- physicians, lectures, and a structured cur- mented lesions, with a sensitivity of 78.1%, riculum would improve their dermoscopy specificity of 64.7% and diagnostic accuracy proficiency. We recommend residents be of 57.7%.6 exposed to dermoscopy early in their train- In 2007, Henning and colleagues intro- ing through teaching from attendings. This duced the CASH algorithm.8 The acronym will best be accomplished through having stands for color, architecture, symmetry and dermoscopy units available, providing texts, homogeneity. As with other algorithms, atlases and web-based tutorials to under- a scoring system is used to stratify mela- stand dermoscopic technique, and schedul- nocytic lesions. Each color in the lesion is ing lectures on dermoscopy during annual

42 The Use of Dermoscopy in Osteopathic Dermatology Training

Ha i l e y -Ha i l e y Di s e a s e : A Ca s e Re p o r t a n d Re v i e w o f Up d a t e s i n Pa t h o g e n e s i s a n d Tr e a t m e n t

Carrie Watson, OMS III,* Brooke Walls, DO, Intern,** Melinda Greenfield, DO, FAOCD,*** Christopher Bass, PA,**** Kevin Bush, PA***** * Georgia Campus-Philadelphia College of Osteopathic Medicine, Suwanee, GA ** Largo Medical Center, Largo, FL ***Board-certified dermatologist, Albany Dermatology Clinic, Albany, GA **** Practicing physician’s assistant of dermatology, Albany Dermatology Clinic, Albany, GA ***** Practicing physician’s assistant of dermatology, Albany Dermatology Clinic, Albany, GA

Abstract

Hailey- Hailey disease (HHD), or familial benign chronic , is a rare genodermatosis characterized by fissured plaques and acantholysis of the epi- dermis with a predilection for the intertriginous areas. HHD often goes misdiagnosed for years, and the lesions can be painful, purulent, and malodorous, causing severe social debility. There is no cure for Hailey-Hailey disease, and most patients have a chronic, relapsing course. Treatment options to help control the disease range from an array of topical or oral antibiotics and steroids. We present a case of a 65-year-old African American gentleman with an approximate 20-year history of axillary lesions and a positive family history of similar symptoms, who was referred to the dermatology clinic for these persistent and irritating lesions. A literature review revealed recent updates in the pathogenesis of this disease and therapeutic approaches for difficult cases.

Introduction a “dilapidated brick wall” appearance, and macerated and erythematous plaques with PAS stain for fungi was negative. Based upon fissuring and crusting found on the neck, history, physical exam, clinical presentation, axillae, and/or groin, often coupled with First described by the Hailey brothers and histology, a diagnosis of familial benign complaints of sensations of burning or - in 1939, Hailey-Hailey disease (HHD) is chronic pemphigus, or Hailey-Hailey dis- ing.1 These lesions are often associated with a genodermatosis characterized by small ease, was made. The patient was initiated on secondary bacterial or fungal infections vesicular lesions forming fissured plaques topical therapy including econazole, Lidex resulting in further inflammation, discom- that occur in flexures of the body, most cream, and clindamycin lotion. The patient fort, malodor, and enlargement of the lymph commonly in the axillae and groin regions.1 returned for follow-up in July 2009. The nodes near the affected area.1 Presentation This autosomal-dominant disease demon- lesions were found to be reduced in size ranges from localized areas to widespread strates incomplete penetrance and typically and localized to his axillae at that time (Fig- inflammation and vesicles in various regions presents in the late teens or early twenties, ure 1). There were no new areas of inflam- of the body. Uncommon presentations of but can show up as late as the mid-forties. mation or signs of concurrent infection at the disease include lesions on the trunk and To date, there is no definitive data describing the follow-up visit. He stated the lesions in the antecubital and popliteal fossae.2 In the incidence of Hailey-Hailey disease. The were less troublesome for him and were most cases, a trigger exists that sets off the associated genetic defect involves a mutation effectively being managed on the current initial flare. This trigger may be friction, in a calcium ATPase, known as ATP2C1, on regimen. No changes were made to his treat- chemicals, an infection, and very commonly chromosome 3q21. Dysfunction of this gene heat. Sun exposure is a known trigger for the results in abnormal calcium release from the ment at that time. development or the worsening of affected Golgi apparatus and endoplasmic reticulum areas; therefore, summertime typically exac- in the epidermis, causing faulty keratinocyte erbates the condition for patients.2 Biopsy is adhesion, resembling the defect associated 1 necessary for definitive diagnosis of HHD. with Darier disease. Histopathology of affected skin reveals fea- tures similar to both Darier disease and Gro- Case Study ver’s disease, demonstrating full-thickness acantholysis with an intact basal layer that A 65-year-old African American male is often described as having a “dilapidated presented to Albany Dermatology Clinic in brick wall” appearance.1 April 2009 complaining of a persistent rash in his axillae and groin. He indicated the lesions had been present for many years; Pathogenesis however, recently they had become quite painful, sometimes with a burning sensation The pathogenesis of HHD is quite that was exacerbated by heat. The pain and Figure 2: Right axilla of African American interesting, and the intricacies of causality malodor prompted him to present to the patient with Hailey-Hailey disease have not yet been entirely explained. The clinic. His past medical history was signifi- gene linked to HHD is the ATP2C1 gene, cant for hypertension and . Family which encodes a secretory pathway Ca²+/ history was positive for a similar rash in a Discussion Mn²+ -ATPase (SPCA1) ion pump on the number of his relatives extending back to trans face of the golgi apparatus in cells.4,5 his great-grandmother. On physical exam, Diagnosis of Hailey-Hailey disease is This ion channel transports a single cal- it was noted the patient was significantly based initially on clinical findings. Delay cium ion per each ATP hydrolyzed. The obese. His axillae and under his abdomi- of confirmed diagnosis may occur as this formation and stability of desmosomes, and nal pannus manifested well-demarcated, disease can mimic and fungal thus cell adhesion, is closely regulated by white, moist, fissured plaques with overly- infections. In two-thirds of cases, patients calcium-dependent interactions between ing scale and mild malodor. Punch biopsy will indicate other family members have cells. Calcium homeostasis is important for was performed from his right axilla. The similar lesions.1 Some clues to look for when cell adhesion and proper desmosomal func- histology showed acantholysis along with evaluating a patient for possible HHD are tioning. Interestingly, this gene is ubiqui- Watson, Walls, Greenfield, Bass, BUsh 45 tously expressed on all eukaryotic cells, but D, has been shown to effectively treat pso- J/cm2. At her three-year follow-up, the acantholysis only occurs in suprabasalar riasis, which created interest as to how this patient was pleased but requested additional keratinocytes of affected individuals. Haplo- medicine would affect the skin plaques and treatments to minimal recurrent lesions insufficiency is hypothesized to be responsi- bullae associated with Hailey-Hailey dis- bilaterally. She was treated with two passes at ble for the phenotypes in HHD; one correct ease.10 In a study performed to look at this 15 J/cm2 bilaterally. At her 3.5-year follow- copy of the gene in keratinocytes is insuf- new treatment option, a 65-year-old man up, the patient had complete resolution in ficient to encode adequate levels of the pro- with a 13-year history of HHD had signifi- her right axilla, but some residual lesions in ton pump for normal function.4 Therefore cant improvement once starting the topical her left axilla.12 The use of short pulsed and the inability of keratinocytes to compensate tacalcitol. The patient had been treated pre- short dwell-time CO2 lasers needs larger for the abnormal ion pump may possibly viously with various types of patient population study; however, this case explain why the disease manifestations only ointment, as well as full-thickness skin graft- report confirms that it can be efficacious in occur in the skin. The pathogenesis of HHD ing of his left inguinal region, which proved the treatment of HH disease, with less scar- is still quite an enigma, but exciting research to be unsuccessful when an HHD lesion ing than surgical options. is being conducted to elucidate the underly- developed in the graft one year later. This There are a variety of surgical ing mechanism. man first started using Tacalcitol ointment approaches used to treat lesions of HHD. For 2mg/g applied twice daily to the left inguinal example, wide excision with skin graft- region, and continued using topical corti- ing has been used, often with recurrence Treatment costeroid ointment twice daily to the right of HHD and significant scarring. Derm- inguinal area for comparison. After two is a promising option with fewer There is no cure for Hailey-Hailey months, no differences were observed, but side effects than excision. One study from Disease. Improvement can be attained in the patient reported he had not been apply- Germany found 10 patients with severe some cases with systemic antibiotics, topical ing the ointments twice daily as they were HHD had significant improvement with clindamycin, or antifungal agents. Tetracy- prescribed. One month later, after proper dermabrasion.13 In the study, 46 different clines are the mainstay of antibiotic therapy. application of the medicine, resolution of regions of the body were treated with derm- Topical and/or systemic corticosteroids have pustules, erosions, crusts, and thickened abrasion in these 10 patients. Samples were had some success as well, but use is lim- skin in the left inguinal area was observed. taken before and after surgery, revealing ited due to side effects such as atrophy of Punch biopsies were taken after treatment the plane of abrasion effectively removed the skin.3 Anecdotal evidence has indicated with the tacalcitol, and in areas of remission, the entire epidermis. On average, reepithe- dapsone, systemic corticosteroids, meth- no acantholysis was observed. The efficacy lialization was complete in seven to 10 days otrexate, retinoids, and etretinate to have of 1α, 24-Dihydroxyvitamin D in HHD is in the treated areas. Upon reexamination, some success in refractory cases.1 To help attributable to its effect on keratinocytes and occurring on average 42 months after the prevent relapses caused by friction, it is rec- the inhibition of acantholysis. Specifically, it dermabrasion treatments, all treated areas ommended that patients maintain a healthy has been reported that vitamin D transacti- remained completely disease free except diet and an appropriate weight. Clothing vates the β-integrin gene. This transcription for four sites with major recurrences and that rubs the affected areas and restrictive of integrins is involved in intercellular adhe- four sites with minor occurrences. Four of fabrics are also to be avoided. There have sion and may have the ability to normalize the areas with recurrences were re-treated been many case reports of disease remission cellular adhesion. This study showed that with dermabrasion without subsequent and control with many different modalities tacalcitol, an analogue of active vitamin D₃, relapse. Researchers in this study propose that may prove to be beneficial, especially in is an effective option for treating a patient the efficacy of treatment to be attributed patients with recalcitrant HHD. Alternative with HHD.10 to the fact that the intrinsic defect of cell therapies reported in the literature include Another treatment modality proved to adhesion in HHD seems to be limited to topical Tacrolimus 0.1%, topical tacalcitol, be effective for HHD includes the Erbium: epidermal keratinocytes and spares adnexal Er:YAG laser ablation, CO2 laser vaporiza- YAG laser. The Erbium:YAG laser was structures from which rapid re-epitheli- tion, dermabrasion, and botulinum toxin used in a study performed on two patients alization occurs.13 In conclusion, this study injections.1 While many of these are small with HHD and two patients with Darier found that dermabrasion offers excellent case reports, their outcomes prove to be disease.11 It effectively removed lesions and functional and cosmetic long-term results. quite promising. We will offer a quick sum- had excellent long-term results. One of the Botulinum toxin Type A, while most mary of some of the more promising cases HHD patients showed only partial remission noted for its use for rhytides, has had excel- reported in the literature. after treatment, but the three other patients lent outcomes for use in other diseases, Tacrolimus, a topical calcineurin inhib- had complete remission of disease, con- including , and has been used itor that has been approved for the use of firmed by biopsy results. The benefit of the successfully in patients with HHD. The basis moderate to severe , is ben- YAG laser is the ability to control the depth for looking at the use of botulinum toxin in eficial for cutaneous therapy in Hailey-Hai- of thermal injury, resulting in no scaring as HHD is related to its inhibition of choliner- ley disease due in part to its tissue-sparing opposed to the continuous CO2 laser.11 gic transmission resulting in decreased sweat effect; it also proves to be a potent immu- The use of CO2 lasers in the treatment production. Sweat is recognized as a trigger nomodulator. Topical tacrolimus is effec- of HHD was conducted in a case report of a that can irritate and worsen the lesions of tive in suppressing HHD when combined 26-year-old female with severe disease affect- HHD. A case report describing a 54-year-old with intermittent use of a topical steroid, ing her axillae. This patient’s lesions had man with moist, malodorous plaques and resulting in diminished side effects includ- been found to be refractory to therapy with excessive sweating with disease exacerba- ing atrophy and striae. When compared to topical and oral steroids, topical and oral tions in the summer was treated with 25 other immunomodulators such as topical antibiotics, and oral isotretinoin.12 Her dis- units of Botox at 20 injection sites in his left cyclosporine, Tacrolimus use was superior, ease presentation was equal bilaterally. First, axilla.14 At three weeks there was 50% reduc- possibly because of its lower molecular to confirm efficacy, the left axilla was treated tion in the size of the lesion in the left axilla weight and therefore increased absorption with two passes of a short dwell-time CO2 compared to the right. Six months later, he into the epidermis. Specifically, Tacrolimus laser at 25 J/cm2, and her right axilla was was injected with 50 units of Botox to each 0.1% ointment applied twice daily combined used as the control. Due to the success seen axilla. At three-week follow-up, this patient with intermittent topical steroid therapy had with laser treatment of the left axilla, at the showed complete remission of disease. Of a positive outcome in case reports. patient’s four-month follow-up, the right note, other untreated affected sites showed Tacalcitol, 1α, 24-Dihydroxyvitamin axilla was treated with three passes at 28 no improvement or worsening during this

46 Hailey-Hailey Disease: A Case Report and Review of Updates in Pathogenesis and Treatment time.14 One obvious disadvantage of botuli- don, Kenneth B., MD; Cook, Brian, MD, MBA; Montalvo, Augusto, MD, MPH. Botulinum Toxin Type A for the Treat- num toxin is the need for continuous injec- ment of Axillary Hailey-Hailey Disease. Dermatol Surg. tions approximately every six months for life 2000; 26:371-374. 13. Aoki, T., Hashimoto, H., Koseki, S., Hozumi, Y., Kondo, S. to maintain remission. Also of importance, 1α,24-Dihydroxyvitamin D₃ (tacalcitol) is effective against botulinum toxin injections may be of use Hailey-Hailey disease both in vivo and in vitro. British Jour- nal of Dermatology. 1998; 139:897-901. prior to wide excision surgery of diseased 14. Hamm, H., Metze, D., Brocker, EB. Hailey-Hailey dis- lesions to decrease the size of lesions and ease. Eradication by dermabrasion. Arch Dermatol. 1994; decrease the post-operative risk of infection. 130(9): 1187-1189.

Conclusion

Hailey-Hailey disease is a challenging medical condition. Diagnosis is often made difficult by its ability to mimic other cutane- ous diseases. There is no definitive standard of care, and few treatments are available that are known to be successful for every patient. Even with proper response to first-line med- ications, patients should expect to experi- ence recurrent relapses and remissions. New options for management of this disease are promising and may offer relief to patients with severe or refractory lesions. Our patient may be an excellent candidate for botuli- num toxin injections if his lesions continue to persist, as they seem to be most exacer- bated by excess sweating in the summer. As the science behind the pathogenesis of this disease is better understood, new therapeu- tic options may become available as well. Increased awareness of Hailey-Hailey dis- ease will aid in earlier identification, proper treatment, and an improved quality of life for those affected.

REFERENCES: 1. Helm Thomas N, Lee Thomas C. Familial Benign Pemphi- gus (Hailey-Hailey Disease). http://emedicine.medscape. com/article/1063224-overview Updated: Aug 13, 2008, retrieved July 26, 2009. 2. James, William D, et al. Familial Benign Chronic Pemphi- gus (Hailey-Hailey Disease). Andrews’ Diseases of the Skin: Clinical Dermatology. 10th Ed 2006, 559-560. 3. Graham-Brown Robin AC, Burge Susan M. Hailey-Hailey Disease. Treatment of Skin Disease, Comprehensive therapeutic strategies. 2006, 262. 4. Dhitavat, J, R.J. Fairclough, A. Hovnanian and S.M. Burge. Calcium Pumps and Keratinocytes: lessons from Darier disease and Hailey-Hailey disease. The British Journal of Dermatology. 2004;150:821-828. 5. Ramos-Castaneda, Jose, Young-nam Park, Ming Liu, Karin Hauser, hans Rudolph, Gary E. Shull, Marcel F. Jonkman, Kazutoshi Mori, Shigaku Ikeda, Hideoki Ogawa, and Peter Arvan. Deficiency of ATP2C1, a Golgi Ion Pump, Induces Secrety Pathway Defects in Endoplasmic Reticulum (ER)- associated Degradation and Sensitivity to ER Stress. The Journal of Biological Chemistry. 2005. Vol. 280, No. 10:9467-9473. 6. Hakuno, Megumi, Masashi Akiyama, Hiroshi Shimizu, Margaret J. Wheelock and Takeji Nishikawa. Upregulation of P-cadherin expression in the lesional skin of pemphigus, Hailey-Hailey and Darier Disease. Journal of Cutaneous Pathology. 2001;28:277-281. 7. Behne, Martin J. Chia-Ling Tu, Ida Aronchik, Ervin Epstein, Graham Bench, Daniel D. Bikle, Tullio Pozzan, and Theo- dora M. Mauro. Human Keratinocyte ATP2C1 Localizes to the Golgi and Controls Golgi Ca Stores. The Society for Investigative Dermatology, Inc. 2003. 121;4:688-694. 8. Van-Khue Ton and Rajini Rao. Expression of Hailey-Hailey Disease Mutations in Yeast. The Journal of Investigative Dermatology. 2004;1192-1194. 9. Umar, Saleem A., Pradip Bhattacharjee, Robert T Brodell. Treatment of Hailey-Hailey disease with tacrolimus oint- ment and clobetasol propionate foam. Journal of Drugs in Dermatology. Mar-Apr 2004. 10. Beier, Christian, MD; Roland Kaufmann, MD. Efficacy of Erbium:YAG Laser Ablation in Darier Disease and Hailey- Hailey Disease. Arch Dermatology. Vol. 135, Apr 1999. 11. Christian, Mary M., MD; Ronald L. Moy, MD. Dermatol Surg. Treatment of Hailey-Hailey Disease (or Benign Familial Pemphigus) Using Short Pulsed and Short Dwell Time Carbon Dioxide Lasers. Dermatol Surg. 1999; 25:661-663. 12. Lapiere, Jean-Christophe, MD; Hirsh, Alex, MD; Gor-

Watson, Walls, Greenfield, Bass, Boyd 47 A Ca s e Re p o r t : Ep idermolysis Bu l l o s a Ac q u i s i ta

Prethi Sundaram-Mohip, DO,* Asma Ahmed, OMS IV,** Bradley Glick DO, MPH, FAOCD*** *2nd-year dermatology resident, Wellington Regional Medical Center/LECOM, West Palm Beach, FL **4th-year medical student, Chicago College of Osteopathic Medicine, Downers Grove, IL ***Program director, Wellington Regional Medical Center/LECOM, West Palm Beach, FL

Case Presentation: knees.2,5 Mucosal involvement is seen in Salt-split-skin indirect immunofluores- about 10 percent of patients.2 Proposed cence demonstrates circulating IgG autoan- A 49-year-old male presented to the diagnostic criteria include the following: tibodies against the basement membrane emergency room with a four-month history bullous disorder arising in adulthood or, that target the dermal floor, the noncollag- of recurrent “” on his abdomen, groin, less commonly, childhood; no family his- enous domain NC1 and NC2 of collagen axillae and mouth. He complained of asso- tory of bullous diseases; spontaneous or VII of anchoring fibrils.3,4 This characteris- ciated symptoms of pain, pruritus, fever, post-traumatic bullae resembling heredi- tic helps to differentiate EBA from bullous and chills, with moderate odynophagia. tary dystrophic epidermolysis bullosa; (BP), where antibodies are Patient stated the most recent flare exclusion of other bullous diseases; subepi- found on the epidermal roof of the subepi- started two weeks prior, and this time it dermal on histology; deposition of dermal blister.4,9 Also, C3 deposition along IgG at DEJ; and IgG deposits localized to was accompanied by a yellow discharge with the linear IgG is more commonly seen the lower lamina densa or sublamina densa from his eyes. Lesions were intermittently in BP, whereas IgG without C3 is more of the DEJ.5 responsive to antibiotics. His past medical 10 EBA may be categorized into four common in EBA. Indirect immunofluo- history is significant for ulcerative colitis rescence can be used to test for serum anti- and a total proctocolectomy two years ago. different clinical presentations: clas- sic mechanobullous, bullous pemphig- basement membrane IgG; however, this is a Patient also admitted to and mari- positive result in almost all cutaneous sub- juana use. oid-like, cicatricial pemphigoid-like, and 4 epidermal autoimmune blistering disorders On physical exam the patient had mul- IgA bullous dermatosis-like. The classic mechanobullous presentation is the most and thus is a nonspecific finding.11 Gold tiple papules and pustules on an erythema- standard for diagnosis is immunoelectron tous base, and blisters and areas of erosion common type. It is characterized by skin fragility, noninflammatory, tense blisters, with purulent discharge on his palms, soles, erosions, and scars typically on areas of Figure 1 axillae and groin. Exam was also positive minor repetitive trauma, such as extensor for (Fig. 1 & 2). He surfaces.7 Classic EBA may be confused had eroded ulcers on his labial and buccal clinically with or mucosa with white . Differential hereditary epidermolysis bullosa.4 On the diagnosis included Behcet’s disease, epi- other hand, the -like dermolysis bullosa acquisita, bullous pem- EBA is a generalized inflammatory process phigoid, pemphigus foliaceous and bullous characterized by tense bullae on the trunk, lupus erythematosus. Biopsies showed skin folds, or extremities. Cicatricial pem- subepidermal blister with many neutrophils phigoid-like presentation predominantly and eosinophils on H&E (Fig.3). Direct affects the mucous membranes, leading to immunofluorescence revealed thick, ser- erosions and scarring of oropharynx, con- Figure 2 rated linear IgG along the basement mem- junctiva, anus, or vagina.7 The IgA bullous brane zone (Fig. 4) and on salt-split skin, dermatosis-like EBA presents as vesicles in IgG was on the dermal side (Fig. 5). The an annular arrangement on extremities and working diagnosis of epidermolysis bullosa mucous membranes. acquisita was made based on histopathol- When patients present with the condi- ogy and clinical history. tion in adulthood, they may also have other underlying comorbidities such as Crohn’s Discussion: disease, systemic lupus erythematous, amy- loidosis, and multiple myeloma. Usually, EBA is a chronic, subepidermal blis- childhood-onset EBA is not accompanied tering disease that classically occurs dur- by these comorbidities, although workup 2 ing the fourth or fifth decade of life, with should still be performed. Childhood- no gender or race predisposition.1, 2, 3 The onset EBA tends to be characterized by disease is associated with autoimmunity more frequent mucosal involvement, but to the 145-kDa noncollagenous amino- less severe than in adult-onset.7 Figure 3 terminal domain (NC-1 and NC-2) of EBA shares common clinical and labo- type VII collagen, a large component of ratory exam features with other mucocu- anchoring fibrils in the basement mem- taneous bullous diseases and thus must be brane.4,5 Patients present with tense ves- examined in a systematic format to arrive icles and bullae that lead to scarring and at a proper diagnosis. Standard hematoxy- milia.6 Any mucocutaneous surface may lin and eosin staining of skin biopsy will be affected, but it typically occurs on areas show separation between epidermis and prone to trauma, such as extensor surfaces dermis.8 Linear IgG can be demonstrated 5 like knuckles, hands, elbows, ankles, and by direct immunofluorescence at the DEJ. 48 A Case Report: Epidermolysis Bullosa Acquisita strictures.13,14 Anti-collagen VII antibody Figure 4 titers may be useful for therapy manage- ment since they may reflect EBA activity and treatment response.15

REFERENCES 1. McCuin JB, et al. Autoimmune bullous diseases: diagno- sis and management. Dermatology Nursing. 2006; 18.1: 20-25. 2. Gagnon L. “Diagnosing EBA is multi-step process.” Derma- tology Times. Feb 2007: 64-65. 3. Chaudhari P, et al. What’s new in blistering disorders? Cur- rent Allergy and Asthma Reports. 2007, 7: 255-263. 4. Wolff K, Johnson RA. Fitzpatrick’s Color Atlas and Syn- opsis of Clinical Dermatology, 6th Edition. New York: McGraw-Hill, 2009. 5. Lehman J, et al. Epidermolysis bullosa acquisita: concise review and practical considerations. International Journal of Dermatology. 2009; 48: 227–236. 6. Woodley DT, et al. Autoimmunity to Type VII Collagen: Epi- dermolysis Bullosa Acquisita. Clinic Rev Allerg Immunol. 2007; 33:78–84. 7. Woodley DT, Ram R, Doostan A, et al. Induction of epi- dermolysis bullosa acquisita in mice by passive transfer of autoantibodies from patients. J Invest Dermatol 2006; 126:1324–1330. 8. Woodley DT, Gammon WR, Briggaman RA. Epidermolysis bullosa acquisita. In: Freedberg IM, Eisen AZ, Wolff K, et al., eds. Fitzpatrick’s Dermatology in General Medicine, 4th edition. New York: McGraw-Hill, 1999; 702–709. Figure 5 9. Tucker ME. Salt-split test narrows bullous disorder diagno- sis. Skin & Allergy News. March 2007. 10. Smoller BR, Woodley DT. Differences in direct immu- nofluorescence staining patterns in epidermolysis bullosa acquisita and bullous pemphigoid. J Am Acad Dermatol- ogy. 1992; 27 (5 Part 1): 674-678. 11. Kushniruk W. The immunopathology of epidermolysis bullosa acquisita. Can Med Assoc J. 1973; 108: 1143. 12. Borradori L, Bernard P, Bolognia J, et al. Dermatology. London: Mosby, 2003: 463. 13. Dantas PE, et al. Bilateral corneal involvement in epider- molysis bullosa acquisita. Cornea. 2001 Aug; 20 (6): 664-7. 14. Hester JE, et al. Laryngeal manifestations of epidermolysis bullosa acquisita. Arch Otolaryngol Head Neck Surg. 1995 Sep, 121 (9): 1042-4. 15. Niedermeir A, et al. Clinical response of severe mecha- nobullous epidermolysis bullosa acquisita to combined treatment with immunoadsorption and rituximab (anti-CD20 monoclonal antibodies). Arch Dermatol. 2007 Feb; 143 (2): 192-8.

microscopy to demonstrate autoantibodies binding to the anchoring fibrils.12 Western blot and ELISA test are also available to trace type VII antibodies in EBA sera.4 There is no gold standard in treat- ment, and therapeutic response is variable. EBA patients may be resistant to treatment, and clinical course of the disease may be chronic.5 Treatments that are used include immunosuppressants such as corticoster- oids, azathioprine, and mycophenolate mofetil. Other anecdotal treatments used include intravenous immunoglobulin, dap- sone, rituximab, and extracorporeal plasma photopheresis.2 Colchicine is further being explored as a first-line treatment because of its low risk profile compared to other treatment options for EBA. However, the side effect of diarrhea makes it less ideal for patients with inflammatory bowel disease, the most common comorbidity of EBA.7 Supportive therapy such as wound care and trauma avoidance is recommended for all EBA patients.3 Complications without effec- tive therapy include scarring, which may lead to corneal perforation and esophageal Sundaram-mohip, ahmed, glick 49 Ac t i n i c Pr u r i g o

Maryam Shahsavari, D.O., M.S.,* Michael Land, B.S.,** Ronald Liskanich, D.O.,*** David Horowitz, D.O., F.A.O.C.D.**** *2nd-year Dermatology Resident, Western University of Health Sciences/Pacific Hospital of Long Beach, Long Beach, CA **4th-year Medical Student, Touro University College of Osteopathic Medicine, Vallejo, CA ***Dermatology Residency Co-Program Director, Western University of Health Sciences/Pacific Hospital of Long Beach, Long Beach, CA ****Dermatology Residency Program Director, Western University of Health Sciences/Pacific Hospital of Long Beach, Long Beach, CA

Abstract

February 2009, the Western University/Pacific Hospital dermatology residency program joined DOCare on a medical mission based out of Antigua, Guatemala. Each day we traveled to rural areas, administered care, and educated the patients on their conditions. Of the patients evaluated by the dermatology team, a strikingly high proportion of patients had photodermatitis, and the majority was clinically diagnosed as actinic prurigo. We will now review actinic prurigo and share clinical photographs.

Introduction Pathogenesis Figure 2 Actinic prurigo (AP) is a familial pho- Studies have shown AP affects ethnic todermatitis most commonly found in groups that express specific alleles of major Mestizo populations (mixed Indian and histocompatability complex classes I and European ancestry) of Central and South II.1,2 Grabczynska et al., in a 1999 study America and Indians of North America.1,2 containing 57 AP patients, found HLA typ- AP was initially described by ing confirmed the strong association (90%) Hutchinson in 1879, and again in 1918 by between AP and the DR4 allele. In par- Haxthausen, as a variant of PMLE.3 The ticular, the rare subtype DRB1*0407, which term actinic prurigo was then coined by was present in 60% of their patients.11 Lopez-Gonzalez in 1961.4 These results suggest patients with AP AP can present at any age, but most have a genetic predisposition to develop a commonly first appears at ages 6 to 8 years response to certain stimuli. UV radiation old, and females predominate over males has been shown to produce characteristic 5,6 (2:1). It almost exclusively affects Mestizo lesions in non-exposed skin.12 Phototesting populations with Fitzpatrick skin types IV however has yielded inconsistent results, Figure 3 and V who live at altitudes of greater than with up to two-thirds of patients having 1,000 meters in warm, dry climates. In tem- abnormal phototesting results, one-third perate climates, the eruption is intermittent reacting to UVB, one-third reacting to UVB and worst in the summer. In patients living and UVA, and the last third having normal in Central America and Mexico, the erup- 5,6 3,7 results. tion occurs perennially. T lymphocytes have also been demon- strated in lesional skin in massive numbers Clinical Features in the dermis, with focal migration into the epidermis. The cytokine interleukin-2 is Lesions of AP include macules, pap- hypothesized in AP to stimulate the prolif- ules, plaques, crusts, hyperpigmentation, eration of lymphocytes and production of and lichenification on sun-exposed sites other cytokines that trigger pruritus.13 (face, V of neck, dorsal forearms). Cheili- UVB light stimulates the produc- tis of the lower is quite common and tion of TNF-α by suprabasal keratino- occasionally the only finding of AP, and cytes, which when present in substantial Figure 4 involves scaling, swelling, crusting, and amounts induces necrosis.14 It has been ulceration in severe cases. In up to 45% demonstrated that in certain inflammatory of Mexican patients, the conjunctiva are processes TNF-α, in association with inter- affected, with early forms involving tearing and hyperemia and later forms resulting in Figure 1 hyperpigmentation and pseudopterygium that could interfere with vision.8,9 Lane et al., in a case series of 93 Amer- indian patients, found age of onset was the most important feature for diagno- sis and prognosis of AP. Younger age of onset (up to 20 years of age) was associated more often with cheilitis, acute eruptions, and improvement after approximately five feron gamma, induces expression of inter- years. Patients with a later age of onset (21 years of age and above) tended to have a cellular adhesion by keratinocytes. This milder, more chronic form of AP.10 may play a role in the epidermotropism of lymphocytes exhibited by AP lesional 50 Actinic Prurigo skin.14 The above is supported by the effi- efficacy.21,22 While not first-line choices, anti- cacy of thalidomide for treatment of AP,6 malarials such as hydroxychloroquine and as thalidomide has been shown to inhibit chloroquine phosphate are also treatment TNF-α.15 options, known for their anti-inflammatory effects.23 Histopathology Patients with ocular manifestations such as limbitis or conjunctivitis may be Histologic criteria for AP include the treated with topical 2% cyclosporine for 24 presence of epidermal hyperplasia with or symptomatic relief. without parakeratosis, spongiosis, vacuo- Due to the unavailability of dermato- lar alteration of basal cells, thickening of logic therapies listed above, the occurrence the basement membrane, dense lymphoid of advanced presentation of disease is much infiltrate in the dermis with formation of more prevalent in Third World countries, lymphoid follicles particularly on the lips, such as Guatemala. dilated blood vessels, and dermal edema.1,2 Arrese et al. evaluated 20 biopsy speci- REFERENCES: mens from Mexican patients with AP and 1. McCuin JB, et al. Autoimmune bullous diseases: diagno- sis and management. Dermatology Nursing. 2006; 18.1: found the dense inflammatory infiltrate was 20-25. composed predominantly of helper T type 1 2. Gagnon L. “Diagnosing EBA is multi-step process.” Derma- tology Times. Feb 2007: 64-65. lymphocytes admixed with scattered B-cell 3. Chaudhari P, et al. What’s new in blistering disorders? Cur- lymphoid follicles and numerous dermal rent Allergy and Asthma Reports. 2007, 7: 255-263. 4. Wolff K, Johnson RA. Fitzpatrick’s Color Atlas and Synop- dendrocytes. Keratinocytes contained abun- sis of Clinical Dermatology, 6th Edition. New York: McGraw- dant TNF-α and calprotectin. Hill, 2009. 5. Lehman J, et al. Epidermolysis bullosa acquisita: concise They concluded that in subjects geneti- review and practical considerations. International Journal cally predisposed to AP, ultraviolet light may of Dermatology. 2009; 48: 227–236. 6. Woodley DT, et al. Autoimmunity to Type VII Collagen: Epi- trigger excessive TNF-α production by kera- dermolysis Bullosa Acquisita. Clinic Rev Allerg Immunol. tinocytes whose sustained release in turn 2007; 33:78–84. 7. Woodley DT, Ram R, Doostan A, et al. Induction of epi- exerts its proinflammatory activity and del- dermolysis bullosa acquisita in mice by passive transfer eterious epidermal effects. Such a cascade of of autoantibodies from patients. J Invest Dermatol 2006; 126:1324–1330. events is in line with the therapeutic benefit 8. Woodley DT, Gammon WR, Briggaman RA. Epidermolysis already reported when thalidomide is used bullosa acquisita. In: Freedberg IM, Eisen AZ, Wolff K, et 16 al., eds. Fitzpatrick’s Dermatology in General Medicine, 4th to treat AP. edition. New York: McGraw-Hill, 1999; 702–709. 9. Tucker ME. Salt-split test narrows bullous disorder diagno- sis. Skin & Allergy News. March 2007. Treatment 10. Smoller BR, Woodley DT. Differences in direct immu- nofluorescence staining patterns in epidermolysis bullosa acquisita and bullous pemphigoid. J Am Acad Dermatol- ogy. 1992; 27 (5 Part 1): 674-678. 11. Kushniruk W. The immunopathology of epidermolysis A 1989 study by Farr and Diffey sup- bullosa acquisita. Can Med Assoc J. 1973; 108: 1143. ports that although PUVA is an effective 12. Borradori L, Bernard P, Bolognia J, et al. Dermatology. London: Mosby, 2003: 463. treatment for AP, the underlying mecha- 13. Dantas PE, et al. Bilateral corneal involvement in epider- nism of photosensitivity is unaltered. The molysis bullosa acquisita. Cornea. 2001 Aug; 20 (6): 664-7. 14. Hester JE, et al. Laryngeal manifestations of epidermolysis protective effect it has appears to be local bullosa acquisita. Arch Otolaryngol Head Neck Surg. 1995 and secondary to an increase in melanin Sep, 121 (9): 1042-4. 15. Niedermeir A, et al. Clinical response of severe mecha- pigmentation and epidermal thickness.17 nobullous epidermolysis bullosa acquisita to combined A small study performed by Lane et al. treatment with immunoadsorption and rituximab (anti-CD20 monoclonal antibodies). Arch Dermatol. 2007 Feb; 143 (2): used Clobetasol 17-propionate 0.05% oint- 192-8. ment for an interval of three to 14 days and achieved clearing of lesions in seven out of eight patients who had previously not cleared with lower potency topical steroids.18 A preliminary, uncontrolled study by Torres-Alvarez et al. in 2004 measured the clinical efficacy of pentoxifylline (PTX, a TNF-α inhibitor) in 10 patients with severe AP. Patients were given PTX over six months with clinical improvement of lesions and pruritus evident in all participants. Five of the patients were followed for two years, with two obtaining complete remission and three having a significant reduction in the use of corticosteroids.19 Sun protection, emollients and topi- cal steroids are the mainstay of treatment for AP. Intralesional steroid, systemic ste- roid, psoralen plus ultraviolet A (PUVA), azathioprine, and thalidomide have been used in patients with variable results.20 The ingestion of trisoralen, 4-5-8 trimethlylp- soralen, has historically been used to treat AP, but there have been variable results in Shahsavari, Land, Liskanich, Horowitz 51 Py o d e r m a Ga n g r e n o s u m Mi s t ak e n a s a Py o g e n i c In f e c t i o n : A Ca s e Re p o r t a n d Re v i e w o f t h e Li t e r a t u r e

Jesse D. Jensen, MSIV,* Jenifer R. Lloyd, D.O.** *Arizona College of Osteopathic Medicine, Glendale, Arizona **Co-Director, Residency Program, University Hospitals Health System - Richmond Heights Hospital, Department of Dermatology, Case Western Reserve University School of Medicine, Cleveland, Ohio

Abstract

Pyoderma gangrenosum is a rare, neutrophilic dermatosis with multiple clinical variants, the ulcerative form being most common and usually located on the lower extremity. Its morphology is commonly mistaken for an infection, but it is a clinical diagnosis. We present a case of an 83-year-old female with ulcers on her legs and abdomen that were treated as an infection with antibiotics but continued to demonstrate rapid expansion. Blood and wound cultures were all sterile. She had a history of adenocarcinoma of the colon and was otherwise healthy. Once the proper diagnosis was made, the patient was treated with systemic prednisone with noticeable regression by the third day.

Introduction only mild discomfort and some fatigue. prior. Adenocarcinoma of the colon and She denied any nausea, fever, chills, night other solid tumors have occurred in con- sweats, or headaches. junction with PG and have been reported Pyoderma gangrenosum (PG) is a rare, Her past surgeries were exclusive in a few publications.5,6,7,8 About 7% of chronic, and recurrent noninfectious neu- to a right hemicolectomy as a result of a PG’s occurrence is associated with some trophilic dermatosis that manifests itself colonic/appendageal adenocarcinoma that type of cancer,9 most commonly a hema- as a rapidly enlarging, necrotic ulcer that was resected eight months prior to this visit tologic malignancy. In this patient, closer demonstrates pathergy, or the ability to be in March 2009. The patient had no known proximity between the PG outbreak and induced by minor cutaneous trauma, in drug allergies. the colonic adenocarcinoma, and then up to 30% of cases. It has clinical overlap On clinical examination, there were observing the resolution of PG with cancer with fulminating infections like necrotizing resection, would be a more picture-perfect 1 2 two flat-topped, suppurative nodules with fasciitis, post-operative infections, and central necrosis on the left medial lower scenario to make a cause-effect association spider bites; hence, it’s often misdiagnosed leg, each measuring approximately 3 centi- between the two diagnoses. Other authors and mismanaged. The diagnosis of PG has meters in diameter (Figures 1 and 2). Her have reported cases of PG in association been found to be a misdiagnosis of another with inactive terminal ileitis as well as the 3 abdomen had a deep ulceration with a mild disease process in 10% of its cases. The exudate, extending into the subcutaneous lack of effective resolution of lesions after correct diagnosis is often made after a graft fat. Overlying granulation tissue was pres- bowel resection due to ulcerative colitis,10 has failed on a leg ulcer, or when debride- ent. The lesion measured approximately providing evidence that the lesions don’t ment, which commonly works well for leg 6 x 4 centimeters, surrounded by an ery- necessarily go away with removal of the ulcers, worsens the condition. Systemic thematous rolled border in an arcuate pat- offending cause. This leads one to ask the diseases, with inflammatory bowel disease tern along the superior edge accompanied question of whether or not the lesions being the most common, are commonly by some undermining of the inferior edge may appear after or as a sequelae of the 4 associated with its presentation. Due to at 6 o’clock (Figure 4). The punch biopsy colonic carcinoma, perhaps showing up PG’s diagnostic and therapeutic challenges, taken prior to her dermatologic office visit later. There is one case in the literature, we present this case to demonstrate its clin- was noticeably located on the inferior edge to our knowledge, of PG manifesting itself ical morphology and behavior. of the lesion. A new lesion had begun to eight years after colonic carcinoma resec- appear one day prior to the visit on her left tion. No relapses have been observed in Presentation of a Case buttock (Figure 3). She denied any pain that particular patient, so it may have been or discomfort originating from the lesions a coincidence.11 A follow-up colonoscopy and also denied fever, chills, or nausea at has been scheduled. An 83-year-old Caucasian female this time. The lesions typically produce a strong presented to the dermatology clinic after A biopsy and culture was performed sensation of pain,12,13,14 but our patient being discharged from a one-night stay on the lesion in Figure 3. The patient’s stated that she had very little discomfort. in the hospital, stating she had sores on lesions were treated by injection with In the largest of the lesions (Figure 4), her abdomen and left lower leg that were intralesional triamcinolone 5mg/ml, and on the patient’s abdomen, the prior punch treated with antibiotics and were still wors- 80 mg oral prednisone. The pathology of biopsy site is seen on the inferior edge. ening. The lesions had appeared one week the biopsy taken from the left buttock is This ulcer was the same size as the others prior, and she had gone to her primary care shown in Figures 5 and 6. on the legs, indicating a pathergic response physician (PCP) to be seen for burning to the punch biopsy. This clue, along with upon urination in conjunction with her the sterile cultures from the biopsy, helped sores. Her PCP had given her a prescrip- Discussion support the clinical diagnosis. Pyoderma tion for Bactrim and told her to follow up gangrenosum is a clinical diagnosis, and in one week. On follow-up, the lesions had Inflammatory bowel disease is the the pathology report for this condition is enlarged, and she was sent to the emer- most common association with PG. Recent more of a descriptive diagnosis. Histopa- gency room by her PCP. She was given a data has shown that approximately one- thology serves as a source to rule out other dose of I.V. Bactrix, was admitted to the third of ulcerative PG patients have IBD, causes of ulceration. The classical picture hospital, and was subsequently discharged and both ulcerative colitis and Crohn’s is that of a central suppurative necrotizing the following morning so she could make disease occur with equal frequency. The inflammation with a rim of perivascular a visit to the dermatology clinic. The sores patient had a history of adenocarcinoma and intravascular lymphocytes. did not bother her. She stated she had of the colon that occurred nine months The treatment of choice is predni- 52 Pyoderma Gangrenosum Mistaken as a Pyogenic Infection: A Case Report and Review of the Literature sone 60-120 mg started at high doses. The scale studies have been done to determine Figures steroids are slowly tapered as ulcers heal. this, but only 180 cases of PG were diag- Intralesional injections can be used when nosed at the Mayo Clinic over a period of oral steroids are contraindicated. Systemic 53 years. The literature contains only case steroids were given once primary pathology reports, with a few of them involving more reports were reviewed. The steroids worked than 19 patients.23,24,25,26,27 It can occur in well for this patient to achieve a noticeable children, though it is rare, comprising only regression by the third day of treatment. 3% to 4% of the diagnoses of PG.28 It has Oral sulfasalazine has been reported as an been reported in healthy individuals, and effective treatment in people with and with- the lack of disease association is noted in out IBD.14 Dapsone, usually at a dose of 100 22% to 50% of patients.24 to 150 mg, can be effective with or without The pathogenesis of PG is still poorly steroids. understood. Its prevalence in conjunction Local wound care is important to pre- with autoimmune diseases presents a cur- vent secondary infection. Benzoyl perox- rent hypothesis of immunologic abnormal- ide washes, saline lavages, and wet-to-dry ity. Immunosuppressive therapy, infection, dressings, along with topical sulfone, may or immune-lowering diseases such as HIV help.15 The underlying disease should also or humoral defects have occurred in patients be treated since its resolution is associ- with PG. Defects in both humoral and Figure 1: Violaceous plaques with a ated with a favorable prognosis.8 Combi- cell-mediated immunity have been dem- rolled border and central necrosis on nations of corticosteroids with cytotoxic onstrated.4 Many reports in the literature the left ankle. Note the surrounding, drugs such as azathioprine, cyclophosph- demonstrate its pathergy as a result of var- erythematous halo. amide, or chlorambucil are used in patients ious causes of cutaneous trauma, which with disease that is resistant to corticoster- aggravates the condition in about 20% to oids. Early diagnosis and proper treatment 30% of PG patients. This may represent a is paramount. Trauma must be avoided. localized, misdirected, host-mediated effec- There are reports of surgeries performed tor-cell response to cutaneous tissue anti- to debride these ulcers that have resulted genically changed by trauma in a patient in unnecessary amputations of the digits as with altered immune reactivity.4 About half PG worsens after surgical treatment.16 In a of the patients who develop PG have inflam- case series of seven patients by Huish et al., matory bowel disease, and those that have 13 misdiagnoses resulted in 16 unnecessary either Crohn’s disease or ulcerative colitis surgeries and four amputations. Surgery will develop PG in approximately 0.75% should only be used as an adjunct to immu- to 5.9% of cases.29,30 Other associated, less nosuppression in patients with stable disease common underlying diseases include arthri- or partial remission.17 tis and myeloproliferative disorders, with as Figure 2: Violaceous plaques with a many as 37% of PG patients having arthri- rolled border and central necrosis on tis-associated PG.31 the left calf. Note the surrounding, Review of the Literature The most common location for PG to erythematous halo. appear is on the lower extremity.21 It typi- Pyoderma gangrenosum has been a rec- cally starts as a papulopustule surrounded ognizable dermatologic entity since the early by an erythematous halo that rapidly 20th century. PG was originally attributed to enlarges, typically at the rate of 1 to 2 centi- being first described by Brocq in 1916 when meters in diameter in a centrifugal pattern,32 he called it phagedenisme geometrique.18 while the center undergoes necrosis and a More recently, a dermatologic atlas with deep ulcer develops. There are four different descriptions and sketches by Marie Nico- presenting morphologies for PG, including las Devergie, dating back to 1826 in Paris, bullous, pustular, superficial granuloma- was reported in the literature in 2000 as tous/vegetative, and ulcerative, which is the being very consistent with the morphology most common form. A newer entity follow- of PG, reflecting a possibility that this entity ing abdominal surgery has emerged. Many was recognized a century earlier than once cases of peristomal PG following abdominal thought.19 The term pyoderma gangreno- surgery for Crohn’s disease and ulcerative sum actually wasn’t designated until 1930, colitis are now reported in the literature. when Brunsting, Goeckerman, and O’Leary Atypical pyoderma gangrenosum, which described the entity as having an infectious is a variant of PG that is more superficially etiology, hypothesizing that streptococcal located in the dermis, more commonly pres- Figure 3: This lesion was located on species were responsible for the gangrene. ents on the upper extremity with hemor- the left buttock and biopsied (Figures 5 & 6). This is an early lesion of pyo- Histologic studies that were performed by rhagic bullae. It has been reported to resolve 20 derma gangrenosum. Percival disproved this theory, but the faster than typical ulcerative PG.24 name retains the original etiologic theory. Its designation is, of course, a misnomer, as it is neither pyogenic nor gangrenous. Male and female patients are affected equally, with the median age range between 25 and 54 years of age.21 Its overall inci- dence is difficult to assess, as it will vary according to the referral patterns of the institution that report the cases.22 No large-

Jensen, Lloyd 53 and adrenocortical carcinoma. Cutis 1989;44(3):205-208. 9. Hensley CD, Caughman SW. Neutrophilic dermatoses associated with hematologic disorders. Clin Dermatol 2000;18(3):355-367.

Figure 4: Violaceous, rolled border and ulceration extending into the sub- cutaneous fat as seen at 6 o’clock.

Figure 5: (10x) Pseudoepithelioma- tous/pseudocarcinomatous hyper- plasia, which can appear similar to carcinoma; the nuclei do not show atypical features. Diffuse dermal fibrosis; note in the left lower field the necrosis and foci of ulceration.

Figure 6: (40x) Dermal lesion with dermolysis and a collection of mixed inflammatory cells.

REFERENCES: 1. Barr KL, Chhatwal HK, Wesson SK, et al. Pyoderma gangrenosum masquerading as necrotizing fasciitis. Am J Otolaryngol. 2009;30(4):273-276. 2. Hornez E, Monchal T, Ottomani S, et al. Pyoderma gan- grenosum mimicking abdominal sepsis after colorectal surgery. J Chir (Paris). 2009 Dec;146(6):576-578. Epub 2009 Nov 17. 3. Weenig RH, Davis MDP, Dahl PR, Daniel Su WP. Skin ulcers misdiagnosed as pyoderma gangrenosum. N Engl J Med 2002;347:1412–1418. 4. Powell FC, Su WP, Perry HO. Pyoderma gangrenosum: classification and management. J Am Acad Dermatol. 1996;34(3):395-409. 5. Gallo R, Parodi A, Rebora A. Pyoderma gangreno- sum in a patient with gastric carcinoma. Int J Dermatol 1995;34(10):713-714. 6. Cailhol J, Viard JP, Dupont B, Aaron L. Cutaneous and extracutaneous pyoderma gangrenosum associated with sigmoid adenocarcinoma. Gastroenterol Clin Biol 2003;27(10):955-957. 7. Bunte C, Popp-Habeler J, Mischer P, et al. Concomitant manifestation of pyoderma gangrenosum and colorectal carcinoma. Scand J Gastroenterol 2008;43(6):756-758. 8. Cole HG, Nelson RL, Peters MS. Pyoderma gangrenosum

54 Pyoderma Gangrenosum Mistaken as a Pyogenic Infection: A Case Report and Review of the Literature Ke r a t o aca n t h o m a Occ u r r e n c e i n a Re d Ta t t o o : A Ca s e Pr e s e n t a t i o n

Andrew J. Racette, D.O.,* Morgan J. McCarty, OMSIV** *Omni Dermatology, Phoenix, AZ **Midwestern University, Glendale, AZ

Abstract

Keratoacanthoma (KA) is generally considered a benign lesion, with some exceptions; therefore, biopsy is necessary to differentiate from invasive squamous- cell carcinoma (SCC). Much debate exists as to whether KA is a type of SCC, however several unique clinical clues distinguish the lesion from SCC. KA gener- ally develop over several months, rather than the lengthy evolution of SCC; they are not associated with an initial actinic keratosis; they usually occur in hair follicle areas; and they occasionally resolve without treatment. Multiple KA lesions may occur with excessive sun, carcinogen exposure such as tar, trauma, or as part of such KA syndromes as: Muir-Torre syndrome, Grzybowski eruptive KA, multiple familial KA of Witten and Zak, and Ferguson-Smith familial KA. 1,2 This case reports KA associated with red tattoo ink.

Background tattoo three months prior to presentation. She noticed rapid growth of the nodules one month after receiving her tattoo. The Multiple KA are a part of the Muir- nodules were non-pruritic but extremely Torre syndrome, an autosomal-dominant painful with any level of pressure. The disorder associated with sebaceous-gland patient applied topical fungal cream without tumors and visceral carcinoma of the gastro- improvement in appearance or symptom- intestinal and genitourinary tract.1 Another ology. The patient denied any weight loss, syndrome, Grzybowski eruptive KA, is asso- weight gain, fever, or chills. Family history ciated with sudden onset of numerous KA in was only significant for non-melanoma skin a variety of locations. Patients have multiple cancer. Initially, the patient refused biopsy areas of involvement including vocal cords and opted for a kenalog injection. The and eyelid retraction. The lesions are highly patient returned in three weeks with mild pruritic and will persist without treatment.3 improvement in appearance of the nodules The autosomal-dominant Ferguson-Smith Figure 2: Well circumscribed keratin but with continued intense pain with pres- familial KA exhibits large, nodular KA that filled central crater sure. The patient consented to punch biopsy. periodically cycle from evolution to involu- Dermatopathology revealed SCC KA-type in tion and resolve.4 While several syndromes both nodules. Excision was advised, and the exist which involve KA, the histology dis- patient consented. One month post-exci- cerns the reactive versus neoplastic charac- sion, the patient had complete resolution of ter. symptoms and no recurrence. The histology of KA has a constella- tion of presentations. KA exhibit prom- inent patterns of keritinization but with Discussion several variations, from compact, anucleate and eosinophilic to lamellated anucleate Reactive KA following trauma or within basophilic hyperkeratosis. With regression, surgical margins have been reported.5 Reac- hyperkeratotic characteristics become lamel- tive KA is theorized to be associated with the lated and basophilic. An important distinc- Koebner phenomenon, which is a reaction tion in KA associated with red tattoo ink to external forces unique to each individ- Fugure 3: Illustrates macophages with versus SCC is the transepidermal elimina- ual and generally more common in certain red ink cytoplasm tion and adnexal hyperplasia to wall off the dermatologic conditions such as psoriasis. 6 red ink. These multiple variations dem- However, KA is rarely reported in associ- onstrate the importance of reporting the ation with tattoos.5,10 The first red tattoo dermopathology precisely for patient conti- associated KA was reported by Mcquarrie in nuity of care. Complete excision is the treat- 1966.7 A literature review reveals a total of ment of choice. 22 reported patients with squamous lesions, Case Report

A 41-year-old female presented with two hyperkeratotic nodules, one 4 mm diameter and one 6 mm diameter, on her right lateral ankle within a red-pigmented, heart-shaped tattoo. Several other 1-2 mm round papules were confined to the red- Fugure 4: Transepidermal elimination pigmented region of the tattoo. No lesions red tattoo ink demonstrated crossed to the lighter pink pigment of the eight of which were KA, within tattoos.6 tattoo, nor to the normal skin surrounding There is no conclusion on the exact role red the tattoo (Fig. 1). The patient obtained the Figure 1: Patient Lesion pigment plays in the development of KA.

Racette, McCarty 55 Many other case reports of red tattoo lesions 4. Kato N, Ito K, et al. Ferguson smith type multiple keratoacan- thomas and a keratoacanthoma centrifugum marginatum were stated to be pruritic and became evi- in a woman from Japan. Journal of the American Academy dent to patients with sun exposure.7,10,11 Pru- of Dermatology 2003; 49(4):741-746. 5. Hadley J, Tristani-Firouzi P, et al. Case Series of Multiple ritus and sun exposure were not experienced Recurrent Reactive Keratoacanthomas Developing at sur- by this patient although she resides in Ari- gical margins. Dermatol Surg 2009; 35:2019-2024. 6. Fraga G, Prossick T. Tattoo-associated keratoacanthomas: zona. Reaction times also vary, from a few a series of 8 patients with 11 keratoacanthomas. J. Cutan. weeks after a tattoo to many years later. Path online 2009. 7. McQarrie DG. An unusual breast cancer: squamous-cell car- Historically, cinnabar, which contains cinoma arising in a tattoo. Minn Med 1966;49:799. mercury, has been known to cause red tat- 8. Goldenberg G, Patel S, et al. Eruptive squamous cell carci- nomas, keratoacanthoma type, arising in a multicolor tat- too reactions. However, mercury use in tat- too. J Cutan Pathol 2008;35:62–64. too ink was banned in 1976. Analysis of red 9. Mortimer NJ,Chave TA, Johnston GA. Red tattoo reactions. Clinical and Experimental Dermatology 2003;28:508–510. tattoo inks today reveals aluminum, iron, 10. Yus S, Simon E, et al. Solitary keratoacanthoma: a self- calcium, silicon, titanium, and cadmium. healing proliferation that frequently becomes malignant. American Journal of Dermatopathology 2000;22(4):305- Manufacturers are not required to list their 11. Kluger N, Minier-Thoumin C, Plantier F. Keratoacanthoma ingredients, and no FDA regulation exists occurring within the red dye of a tattoo. J Cutan Pathol 8,9 2008;35:504-507. as to the formulation of red tattoo inks, 12. “Ancient Ink.” The History Channel. A&E Television Net- so tattoo establishments can obtain ink in works. 14 July 2008. 13. “Ultraviolet tattoos.” Tattoohealth.org 4 Nov 2008. Available the global marketplace. Previous studies at http://www.tattoohealth.org/content/uv.asp. conducted with patch skin testing of these various metallic elements in the ink have not unveiled a specific source for these reactions. What is apparent from Fragan and Prossick’s examination of the histology is a transepi- dermal elimination and adnexal hyperplasia to wall off the red ink, which was also dem- onstrated in this case report (Fig. 4). Though considered benign, about 1% of KA transition to invasive SCC. This tran- sition is noted to be more frequent in the elderly.8,9 The histology is derived from epi- thelial keratinocytes, and a wide range of histological features occur in KA, making the distinction between SCC and benign growth difficult. Fragan and Prossick sug- gest reporting the lesions as KA rather than pseudoepitheliomatous hyperplasia, well-differentiated SCC, or squamous-cell carcinoma-keratoacanthoma type.6 Derma- tologists must be aware of the association of KA with tattoo reactivity, Muir-Torre syndrome, differentiation into invasive SCC, recurrences of KA years later, and the importance of correct dermatopatholgy reporting to health insurance agencies. Pre- cise reporting of KA histology can prevent financial burden on patients seeking private insurance coverage. This case report joins that of only a few reported KA appearing in association with red tattoo ink but serves to demonstrate the myriad of medical and social consider- ations necessary to contemplate in order to best serve the patient. Dermatologists must stay abreast of changing trends in tattoo culture. New techniques are emerging, such as intra-conjunctiva tattoos and black-light- reactive tattoo ink.12,13 Many dermatological ramifications will emerge in the future from these new trends, and practitioners must be conscientious.

REFERENCES: 1. Bolognia J, Jorizzo J, Rapini R. Dermatology Second Edition: Elsevier, 2008. 2. Agarwal M, Chander R, Karmakar S, Walia R. Multiple Famil- ial Keratoacanthoma of Witten and Zak – A Report of Three Siblings. Dermatology 1999;198:396-399. 3.“Grzybowski eruptive keratoacanthoma.” DermNet NZ 26 Dec 2006. Available at http://dermnetnz.org/lesions/grzybowski. html.

56 Keratoacanthoma Occurrence in a Red Tattoo: A Case Presentation

Hy p e r p i g m e n t e d Pl a q u e s o n t h e Ab d o m e n o f a Yo u n g Ma n

Joshua Kentosh, DO, LT, MC, USN,* Donald Shenenberger, MD, FAAD, FAAFP, CDR, MC, USN** *Diving/Undersea Medical Officer, Naval Submarine Support Center Undersea Medicine, Bangor, WA **Staff Dermatologist, Department of Dermatology, Naval Medical Center, Portsmouth, VA Abstract Confluent and reticulated papillomatosis (CRP) is a rash that is characterized by red macules and papules that reticulate and widen into a papillomatous sur- face. CRP usually begins in the intermammary or mid-scapular region and becomes generalized over the trunk. Young people, otherwise asymptomatic, tend to present in the second or third decade of life with CRP. The etiology remains unclear, however it tends to respond very well to minocycline therapy with complete resolution in 70-80% of cases.

Case Report ity, abnormal host reaction to Pityrosporum treat cases of CRP appropriately, as resolu- orbiculare colonization, and abnormal kera- tion can be simple and cost effective with A 24-year-old male presented to the tinization have all been proposed as possible minocycline therapy. dermatology clinic with a 5-year history of etiologies but have remained unproven.1,3,5 The views expressed in this article are a rash on his upper abdomen. He had been CRP is characterized histologically by those of the authors and do not necessarily treated by his primary care physician with orthohyperkeratosis and thinning of the reflect the official policy or position of the multiple topical agents including anti-fun- stratum granulosum observed with acan- Department of the Navy, Department of gals and steroids, all without improvement. thosis and papillomatosis and often accom- Defense, or the United States Government. The patient denied any pruritus, bleeding, panied by dermal edema and a perivascular Address correspondence to Dr. Kentosh pain or other symptoms associated with the infiltrate.3 The findings are not entirely spe- at [email protected]. Reprints are eruption, and his family history was nega- cific for CRP, as acanthosis nigricans, pig- not available from the authors. tive for endocrine abnormalities. A CBC, mented , and Darier’s CMP and thyroid panel were drawn and disease can all produce a similar appearance REFERENCES: were all negative. under magnification. Laboratory evalu- 1. Davis MD, Weenig RH. Confluent and reticulate papil- ation of CRP should include a complete lomatosis (Gougerot-Château syndrome): a minocycline- On physical examination, a hyperkera- responsive dermatosis without evidence for yeast in totic, brown and somewhat velvety plaque, blood count, biochemical profile, urinalysis pathogenesis. A study of 39 patients and a proposal of and a complete endocrine study and will be diagnostic criteria. British Journal of Dermatology 2006, several centimeters at its widest diameter, 154: 287-293 was noted over the patient’s mid-epigastrum negative for any significant findings. The 2. Mutasim DF. Confluent and reticulated papillomatosis diagnosis is primarily clinical, with augmen- without papillomatosis. Journal of the American Academy (see figures). The remainder of the exami- of Dermatology 2003, 49: number 6 nation was negative for notable findings. A tation by the pathologic findings.1,2,3 3. Odom RB, James WD, Berger TG. Andrew’s Diseases of the Skin, 9th Edition, W.B. Saunders Company 2000, USA, 4-millimeter punch biopsy was performed. 367-370, 633-635, 716-718, 804-806 4. Nordby CA, Mitchell AJ. Confluent and reticulated papil- Treatment: lomatosis responsive to selenium sulfide. International Diagnosis: Journal of Dermatology 1986 Apr; 25(3):194-9 Numerous agents have been used to 5. Scheinfeld N. Confluent and reticulated Papillomatosis: A review of the Literature. American Journal of Clinical Der- The patient was diagnosed with conflu- treat CRP, with most providing poor results. matology 2006: 7 (5): 305-313 ent and reticulated papillomatosis (CRP). Patients treated with corticosteroids, keto- 6. Lee MP, Stiller MJ, McClain SA, Shupack JL, Cohen DE. Confluent and reticulated papillomatosis: Response to CRP typically begins in the intermammary conazole, and 20% sodium thiosulfate typ- high-dose oral isotretinoin therapy and reassessment of or midscapular area as punctuate, verrucous, ically fail to respond.1,2 Topical selenium epidemiologic data. Journal of the American Academy of Dermatology 1994; 31: 327-31 pigmented papules that become generalized sulfide and retinoids have been useful in over the trunk. An isolated eruption can some patients, however the best response also occur in these regions, but spread to has been observed with minocycline ther- the neck, axillae, and back is relatively com- apy.6 Minocycline, 100mg twice daily given mon.1,2,3 The lesions are often asymptom- for 1 to 3 months, carries the most support atic and rarely affect the lower extremities. in the literature and is the current treatment In time they develop into pale red mac- of choice. Davis et al. reported in a retro- ules and papules, reticulate, and widen into spective study of 39 patients with CRP that confluent, brownish, papillomatous sur- 14 of 22 patients treated with minocycline .4 These changes are greatest between had complete clearing of the skin, and four the breasts and around the umbilicus. CRP more had partial clearing.1 Minocycline is affects young people preferentially, with the effective in 70% to 80% of cases, it is com- onset of the disease usually occurring within mon and cheap, and it causes relatively few the second or third decades.1 significant side-effects. It should always be considered the drug of choice unless con- Etiology: traindicated.1,2,3,4 The cause of CRP is unclear and yet Follow-up: to be defined. It was originally thought that it was an atypical response to fungal Minocycline therapy was initiated, and infection; however, potassium-hydroxide at three-month follow-up there was com- preparation and Wood’s light examination plete resolution of symptoms. CRP is a are almost always negative, as is the fungal relatively benign condition; however, it often stain and culture of the skin biopsy.5 Vari- presents significant cosmetic concerns for ous endocrine abnormalities, photosensitiv- patients. It is important to recognize and

Kentosh, shenenberger 59 Co n f e t t i -l i k e l i c h e n s c l e r o s u s e t a t r o p h i c u s i n t h e s e t t i n g o f c h r o n i c g r af t v s . h o s t d i s e a s e

Magalys Vitiello, MD,* Andleeb Usmani, DO,** Janet Allenby, DO, FAOCD,*** Paolo Romanelli, MD,**** Francisco A. Kerdel, BSc, MBBS***** *Clinical Dermatology Research Fellow, University of Miami Hospital/Florida Academic Dermatology Centers, Miami, FL **Columbia Hospital, West Palm Beach, FL ***Osteopathic Dermatology Program Director, Columbia Hospital, West Palm Beach, FL ****Associate Professor of Dermatology, Miller School of Medicine, University of Miami Jackson Memorial Hospital, Miami, FL *****Director of Dermatology Inpatient Service, University of Miami Hospital/Florida Academic Dermatology Centers, Miami, FL

Introduction temic lupus erythematous, discoid lupus sis and follicular plugging, thin epidermis erythematosus, , dermatomyo- with homogenization of the upper dermal sitis, Sjogren’s syndrome, lichen planus, collagen and foci of vacuolar alteration Chronic graft-versus-host dis- lichen sclerosus et atrophicus (LS&A) and of the dermo-epidermal junction and a ease (GVHD) occurs in approximately morphea. Our patients were distinct in that few lymphocytes (Fig. 2). There was pres- 25-80% of long-term survivors of alloge- their LS&A lesions were confetti-like over ence of interface dermatitis around adnexal neic hematopoietic cell transplant.[1] This most of their bodies, a morphological vari- structures in the reticular dermis and of immunologic complication is a major cause ant not previously recognized. sclerotic changes with patchy, chronic der- of morbidity and mortality, accounting for mal infiltrate in the lower dermis (Fig. 3). about one-quarter of deaths in long-term The histopathological diagnosis was lichen survivors of transplants performed for leu- Case Reports sclerosus et atrophicus. He was started on kemia and two-thirds of deaths in long- photopheresis every two weeks, and after term survivors of allografts undertaken for [9] the third course the oral lesions improved severe aplastic anemia. The incidence of Case 1 considerably and the pain and pruritus dis- chronic GVHD is likely to rise due to the A 63-year-old male presented with a appeared. The LS&A lesions, on the other increasing availability and use of unrelated history of diffuse large B-cell non-Hodg- hand, remained unchanged. donors as well as the inclusion of older kin’s lymphoma diagnosed 10 years prior, recipients of non-myeloablative reduced treated initially with cyclophosphamide, conditioning regimens. However, GVHD , vincristine and prednisone Case 2 has been reported after syngeneic and (CHOP) chemotherapy with an incom- A 50-year-old male presented with a even autologous marrow transplant, which plete response. He subsequently had an history of chronic lymphocytic leukemia confirms that this condition may occur autologous stem-cell transplant as well as (CLL) diagnosed and treated with che- without histocompatibility antigen (HLA) another course of chemotherapy with car- motherapy nine years prior and an autol- disparity and suggests that environmental boplatin, BCNU (carmustine) and etopo- ogous stem-cell transplant three years antigens such as peritransplant viral infec- side. The patient went into remission for prior, developing cutaneous GVHD one tions may play a role in the development of approximately seven years, then relapsed year after the transplant. At that time he the disease.[1,2] and was placed on and Ritux- was treated with mycophenolate mofetil, Chronic GVHD, as initially defined, imab with an incomplete response. After but his condition progressively worsened. resembles an autoimmune disorder occur- this he enrolled in a clinical trial where he He had recently completed a one-month ring 100 days after allogeneic transplanta- was given pentostatin, busulfan and ritux- course of imatinib mesylate (Gleevec) after tion and may occur as a continuation of imab. At this point the patient also had an a relapse of the CLL. He presented to our the acute form, after its resolution or start allogenic stem-cell transplant for which the service with signs of rapidly deteriorating “de novo” without any previous history donor was a 10/10 HLA haplotype match. cutaneous disease: sclerotic, indurated and of acute GVHD. On the other hand, the Ten months after the transplant, the patient tender, confetti-like, reticulated, brown and most important risk factor for developing began to notice mouth hypersensitivity, white patches over the skin of the trunk, chronic GVHD is prior history of acute dryness and painful oral ulcers associated back, neck and extremities were noted on GVHD, and strategies that prevent acute with generalized xerosis evolving into ery- physical exam (Fig. 4), with tenderness on GVHD decrease the risk of chronic GVHD. thema and with pruritus and movement of the arms and asso- Other important risk factors are the use of pain. He further developed hypopigmented ciated with limitation of motion. He was a non-T cell-depleted graft, older age of changes of the skin. The patient was diag- also complaining of difficulty breathing donor and recipient, and male recipients of nosed with GVHD and was placed on oral due to the restriction caused by the severely alloimmune female donors. prednisone with moderate response after tight and indurated skin of his chest. Other Clinically, both acute and chronic four months of treatment. He was then causes of shortness of breath were ruled GVHD may present with cutaneous mani- referred to our service for photopheresis. out. A skin biopsy confirmed the lichen festations, with the skin often the earliest On physical exam, the skin showed sclerosus et atrophicus diagnosis. organ affected, ranging from a maculopap- mottled poikilodermatous, hypopig- The patient is being treated with tac- ular exanthema that can progress to exfo- mented, confetti-like, atrophic macules and rolimus and methylprednisone, which, liation in the acute form, to sclerodermoid patches, with tissue paper-like consistency, after the patient developed steroid-induced and lichenoid lesions in the chronic form. most extensive on his trunk and back but diabetes, has been tapered down to eventu- ally be discontinued. At this point, extra- Other papulosquamous GVHD subtypes extending to his upper extremities and face corporeal photopheresis was added to the have been reported including psoriasiform, (Fig. 1). The lower extremities were rela- treatment until a total of 28 cycles are com- keratosis pilaris–like, and asteatotic forms. tively spared, and a white, tender plaque pleted. [10] Chronic GHVD can also share or mimic with ulceration was noted on the side of clinical and histopathological features of his tongue. He also reported some weight multiple autoimmune diseases, such as sys- loss. A skin biopsy showed hyperkerato- 60 Confetti-like lichen sclerosus et atrophicus in the setting of chronic graft vs. host disease Discussion

The pathogenic mechanisms of acute and chronic forms of GVHD are differ- ent, are still not well understood, and are difficult to treat. This is in part due to the comorbidities associated with the transplant itself, the chronic inflammation and the pro- longed use of immunosuppressive therapy that may lead to infection and development of new malignancies in these patients. Our patients presented with “de novo” chronic GVHD; that is, without any previous clini- Figure 3 - H&E, 4x magification: orthok- cal manifestations or histopathological evi- eratotic, atrophic epidermis with efface- dence of an acute phase of the disease. They ment of the rete ridges and homogenized, also represented a management challenge pale papillary dermis with dispersed mel- since many different therapeutic regimens anophages. had been previously administered without Figure 1 - Mottled poikilodermatous, complete response. hypopigmented, confetti-like, atrophic Clinical manifestations of chronic macules, and patches over the back of GVHD are similar to autoimmune collagen the patient. vascular diseases, and include oral ulcer- ations (lichen planus), keratoconjunctivitis sicca, xerostomia, polyserositis, esophagitis with stricture, vaginal ulceration with stric- ture, intrahepatic obstructive liver disease, obstructive pulmonary disease, scleroderma, morphea, eosinophilic fasciitis and dermat- omyositis. Patients with extensive disease will invariably require systemic immunosup- Figure 4 - Confetti-like, reticulated brown pressive therapy, while most patients with and white patches over the neck and limited disease do not. back. The diversity of organ involvement, the chronic nature of the illness, and the hema- part through direct induction of lymphocyte tologic and immunologic dysfunction asso- apoptosis and by increasing donor regula- ciated with the syndrome contribute to the tory T cells, and by indirectly reducing the difficulties in successfully treating chronic number of donor effector lymphocytes that GVHD. Patients with progressive chronic had never been exposed to psoralen and GVHD are more likely to receive corticos- ultraviolet A radiation.[12] In a series of 21 teroids and tacrolimus or cyclosporine at Figure 2 - H&E, 10x magnification: loss cases reported by Knobler and the Vienna onset, but are less likely to respond to these of adnexal structures, follicular plugging GVHD-ECP team, patients with both acute and other immunosuppressive therapies.[4,8] and sclerotic dermis. and chronic GVHD with extensive skin and By contrast, patients who develop chronic high response rates, even for patients with systemic involvement who failed conven- GVHD after an interval of response to treat- lung involvement. tional therapy were treated with ECP. After ment for acute GVHD (quiescent form) or Other agents that have been studied a median of 14 cycles, 67% of the acute patients who have never had acute GVHD in the past decade are etritrenate, thalido- GVHD patients showed complete response, (de novo form) are more likely to respond to mide, hydroxychloroquine, extracorporeal and 80% of the patients with chronic GVHD therapy. In these latter situations, institution photopheresis, UVB, and PUVA. Cutane- showed complete resolution of the cutane- of tacrolimus or cyclosporine in combina- ous involvement most frequently responds, ous manifestations. Oral mucosal involve- tion with is often effective. while pulmonary disease rarely responds to ment resolved in all of the patients. ECP was Patients with GVHD and bronchiolitis any of these treatments. tolerated without significant side effects or obliterans have an extremely poor prognosis severe infections after treatment discontinu- Recent studies in murine models dem- [13] independent of other clinical manifestations onstrated that transfection of the hepatocyte ation. of chronic GVHD. They respond poorly to growth factor gene (HGF) in vivo prevented Our patients tolerated the photophere- corticosteroids and other immunosuppres- the development of chronic GVHD. Intra- sis without any complications, and a rapid sive therapy and progress over months to venous injection of HGF in mice enhanced response was observed following three cycles years to become oxygen dependent, culmi- kidney and liver regeneration, and high in the Case 1 patient. Whether that response nating in respiratory failure. levels of HGF were found in acute GVHD will be long-lasting is impossible to deter- The recent recognition of tumor necro- patients, suggesting that its production is mine. Furthermore, at this point we do not sis factor (TNF) as an effector molecule in related to tissue-damage repair counterac- know if the cutaneous changes will respond GVHD has drawn attention to the use of tion.[3] These findings may point to future to the photopheresis. These cases illustrate monoclonal antibodies and receptor antago- interventions in this condition. a unique morphological variant of lichen nists for the treatment of GVHD. Both a One of our patients responded favor- sclerosus et atrophicus that has not been humanized (adalimumab) and a chime- ably to extracorporeal photopheresis (ECP), recognized within the GVHD spectrum. It ric (infliximab) antibody against TNF, as a technique that exposes isolated white also shows an encouraging early response to well as a (etanercept), blood cells to photoactivatable 8-methoxyp- photopheresis. have been studied in patients with chronic soralen and ultraviolet A radiation. Photo- GVHD.[3,11] Preliminary reports have shown pheresis is thought to control this disease in vitiello, usmani, allenby, romanelli, kerdel 61 REFERENCES 1. Appleton AL, Sviland L. Current thoughts on the patho- genesis of graft versus host disease. J Clin Pathol 1993;46:785-789. 2. Iwasaki T. Recent advances in the treatment of graft- ver- sus- host disease. Clinical Medicine and Research 2004; 2(4):243-252. 3. Lee SJ. New approaches for preventing and treat- ing chronic graft-versus-host disease. Blood 2005;105(11):4200-4206. 4. Breuckmann F, Gambichler T, Altmeyer P, et al. UVA /UVA I phototherapy and PUVA photochemotherapy in diseases and related disorders: a research based review. BMC Dermatology 2004;4(11):1-14. 5. Janin-Mercier A, Devergie A, Van Cauwenberge D, et al. Immunohistologic and ultrastructural study of the sclerotic skin in chronic graft-versus-host disease in man. Am J Pathology 1984;115:296-306. 6. Chu Y, Gress RE. Murine models of chronic graft-versus- host disease: insights and unresolved issues. Biol Blood Marrow Transplant 2008;14(4):365-378. 7. Shulman HM, Sale GE, Lerner KG, et al. Chronic cutane- ous graft-versus-host disease in man. Am J Pathol 1978; 92:545-570. 8. Arora M. Therapy of chronic graft-versus-host disease. Best Pract Res Clin Haematol.2008; 21(2):271-279. 9. Socie G, Stone JV, Wingard JR, et al. Long-term survival and late deaths after allogeneic bone marrow transplanta- tion. Late Effects Working Committee of the International Bone Marrow Transplant Registry. New Engl J Med 1999; 341: 14_21. 10. Hymes SR, Turner ML, Champlin RE, Couriel DR. Cutane- ous manifestations of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2006; 12(11):1101-1113. 11. Cooke KR, Krenger W, Hill G, et al. Host reactive donor T cells are associated with lung injury after experimental allogeneic bone marrow transplantation. Blood 1998; 92: 2571-2580. 12. Gatza E, Rogers CE, Clouthier SG, et al. Extracorporeal photopheresis reverses experimental graft-versus-host dis- ease through regulatory T cells. Blood. 2008; 112(4):932-3. 13. Knobler RM, et al. Successful Use of Extracorporeal Photochemotherapy in the Treatment of Severe Acute and Chronic Graft-Versus-Host Disease. Blood 1998; 92(9):3098-3104.

62 Confetti-like lichen sclerosus et atrophicus in the setting of chronic graft vs. host disease Tu b e r o u s Sc l e r o s i s : Ca s e Re p o r t

Robert A. Norman, DO, MPH,* Mike Forgione** *Board Certified Dermatologist, Dermatology Healthcare, LLC, Tampa, FL **Student Researcher, University of South Florida, Tampa, FL

Abstract

Tuberous sclerosis is a genetically processed disorder that affects cellular demarcation and propagation, which consequently produces a hamartoma formation in a variety of organs such as the skin, brain, eye, kidney, and even heart. The term “tuberous sclerosis complex” (TSC) is currently used to emphasize the diver- sified nature of its materializations. In this case, a 42-year-old man with a lifelong history of seizures exhibits the signs of tuberous sclerosis.

Background of two papules were taken on 2/10/09 for further review and analysis. The differen- tial diagnosis for tuberous sclerosis is acne Tuberous sclerosis is an autosomal- vulgaris, connective tissue nevus, nevus ane- dominant affliction with a birth incidence micus, and vitiligo. The facial angiofibromas of 1/10,000. Its mutation rate can reach and (colloquially known as adenoma sebaceum) exceed 75%, with mutations identified in consist of a capricious development of two genes: TSC1 (chromosome 9Q34) and TSC2 (chromosome 16p13), with their pro- fibrous tissues and associated blood vessels. tein products being hamartin and tuberin.

Essential cutaneous facets include: hypopig- mented macules, facial angiofibromas, col- lagenomas, and periungual fibromas. Also, its native oral findings are gingival fibromas and dental enamel pits. The most commonly associated disturbances are cited as being seizures, mental deficits, and neuropsychi- atric disorder. Some individuals are severely affected, while others have very few features. Most of the patients treated are diagnosed between two and six years old. Cardiac and cortical tubers typically develop at infancy, while skin lesions are evidenced in over Figure 1. Tuberous sclerosis. Multiple 90% of patients regardless of age. Approxi- papules on right side of nose of a 42-year- mately a quarter of intensely affected infants old man. usually die before they reach 10 years old, The treatment for tuberous sclero- while 75% die before they reach 25 years sis for established patients is neurode- old; despite this, the lifetime projection for a velopmental testing, ophthalmologic patient diagnosed later on in life with fewer examination, EEG to monitor seizures, cutaneous lesions depends mostly on the echocardiography for cardiac symptoms, related internal tumors. renal ultrasonography every one to three years, cranial CT or MRI every one to three years, and a chest CT if pulmo- Case Report nary symptoms develop. For potentially affected family members, cranial CT, This is the case of a 42-year-old man renal ultrasonography, and genetic testing affected by numerous dull, dome-shaped should be considered. papules on the apex and lateral sides of the nose, specifically the right and left nares, throughout his entire life (since nine months of age). He has also experienced sei- zures for as long as he has suffered from said papules—his last seizure was recorded on 1/13/09. He recently had surgery on every periungual region of his toes, with some nails being completely excised. The patient claimed that some of the horns and papules were very sensitive and would occasionally bleed either from rubbing or other irrita- tions. He also claimed that the condition of his nose has worsened over time and that the only way the papules were reduced was through a surgical procedure. The patient’s current medications are: Tegretol, Lipitor, Carbatrol, HCTZ, and lisinopril. Biopsies

Norman, Forgione 63 Wo u n d Ca r e a n d Ma n a g e m e n t : A Li t e r a t u r e Re v i e w

Michael Kassardjian, MSIV,* Patrick Keehan, D.O.,** Bill V. Way, D.O.*** *Touro University College of Osteopathic Medicine, Vallejo, CA **Dermatology Resident, Third Year, Northeast Regional Medical Center Department of Dermatology, Kirksville College of Osteopathic Medicine – Texas Division, Duncanville, TX ***Dermatology Program Director, Northeast Regional Medical Center Department of Dermatology, Kirksville College of Osteopathic Medicine – Texas Division, Duncanville, TX

Introduction ing growth factor alpha (TGFa).9,10 An the inflammatory response and the pro- increased demand for oxygen ensues due to liferation of fibroblasts and collagen syn- 19 Chronic wounds and cutaneous ulcers the high metabolic activity at the site of the thesis. Inadequacy of tissue oxygenation are common medical problems that fre- wound, leading to angiogenesis stimulated and perfusion also affects wound healing, quently present a challenge in manage- by vascular endothelial cell growth fac- often resulting in local vasoconstriction 11 ment. Wound healing normally involves an tor (VEGF). The fibroblasts restore the due to sympathetic overactivity. Fibro- orderly process consisting of specific bio- structure and function of the injured tissue blast production, as well as collagen forma- logical and molecular events of cell migra- by producing collagen within the wound tion through the hydroxylation of proline 12 20 tion, cell proliferation and extracellular site. The formation of the extracellular and lysine, requires oxygen. Additionally, matrix deposition. However, in pathologic matrix (ECM) provides the initial support excessive tension leads to tissue ischemia and is degraded by serine proteases and and necrosis, which may be a result of tight conditions, this well-orchestrated process is 21 disrupted. An estimated 2.5 million pres- MMPs, followed by types 3 and 1 colla- or improperly placed sutures. sure ulcers are reported annually in United gen deposition, and finally remodeling by collagen cross-linking and scar matura- States acute-care facilities alone.1 It has Treatment tion.6 If the skin was previously unin- been reported that these ulcers add over jured, contraction of the wound continues $1 billion in costs annually and an addi- The evaluation of the wound is neces- until a maximum tensile strength of 60% is sary in determining the most appropriate tional 2.2 million Medicare hospital days 13 2 reached. Although this structured process management. An important initial con- on the healthcare system. Approximately is characteristic of normal wound heal- 0.2% of the general population and 2% of sideration is whether there are any signs of ing, pathologic responses may disrupt any infection. The stratum corneum typically people over the age of 80 are affected with sequence of this process, resulting in cuta- such lesions.3 does not support pathogenic microbial neous ulcers and chronic wounds. This growth, so cutaneous pathogenic infections disruption usually occurs due to a local rarely occur unless the skin is broken or the Pathogenesis or systemic compromise in health, such tissue is necrotic, serving as a medium for as diabetes, infection, or trauma. Nutri- bacterial proliferation. Common cutane- The wound healing process consists tional deficiencies also impede this process, ous bacterial infections include Streptococ- of three phases: the inflammatory phase, such as a lack of vitamin C for use in the cus, Staphylococcus aureus (gram-positive proliferative phase, and remodeling phase. hydroxylation of proline and lysine in col- bacteria) and Pseudomonas aeruginosa During the initial inflammatory phase, lagen polymerization and cross-linking. (gram-negative bacteria).22 The wound platelets come into contact with collagen In its absence, collagen formation is poor, should be cultured to identify the causative exposed during wound formation, and fol- leading to the susceptibility of proteolysis microorganism, and then should be treated lowing aggregation, platelets release essen- of the unhydroxylated protein.14,15 Vita- with debridement and application of an tial growth factors and cytokines, such as min C deficiency also affects the ability to appropriate topical agent and dressing. platelet-derived growth factor (PDGF) and resist infection, as free-radical production Debridement removes any dead, devi- transforming growth factor beta (TGF- is impaired. Neutrophil function is inhib- talized or contaminated tissue, as well as β). PDGF initiates the chemotaxis of neu- ited in the absence of vitamin C, which is any foreign substances from the wound. trophils and macrophages, which aid in necessary in reducing oxygen to a superox- This process assists in eliminating any con- wound debridement.4 Neutrophils func- ide. Additionally, in vitamin A deficiency, taminants or additional substances that tion to remove foreign material, bacteria macrophage recruitment into the wounds may impede proper healing.23 Foreign and damaged components of the matrix is impeded, leading to effective phagocy- bodies also potentiate infection. There are at the wound site.5 Monocytes evolve into tosis and cellular immunity.16 Similarly, it five different methods of debridement: sur- macrophages, and along with fibroblasts has been demonstrated that zinc-deficiency gical, autolytic, enzymatic, mechanical and and endothelial cells form early granulation significantly delays healing and exhibits a biosurgical.24 tissue at the site of injury. This begins the decrease in tensile strength.17 Therefore, Surgical debridement is advantageous process of contraction.6 These specialized adequate nutrition must be maintained to as it is fast and selective. However, it neces- wound macrophages are the main inflam- aid in proper wound healing.Medications sitates topically applied local anesthetics, matory cells involved in the normal healing may also adversely affect wound healing such as a combination of lidocaine and process.7 Delayed healing response is due and should be reviewed. Antimetabolites prilocaine cream for at least 30 minutes to the inhibition of macrophage function.8 such as methotrexate and 5-fluorouracil prior to this procedure.25 Bleeding is likely During the proliferative phase, the function by inhibiting purine and pyrimi- to occur in surgical debridement. This process of epithelization is stimulated by dine synthesis. This disrupts DNA replica- changes the wound from a chronic to acute activated wound macrophages, platelets tion and RNA transcription and therefore state and induces the recruitment of cytok- and keratinocytes that produce epider- impedes the healing process.18 Corticoster- ines and growth factors to promote heal- mal growth factor (EGF) and transform- oids also disrupt this process by inhibiting ing. 64 Wound Care and Management: A Literature Review Autolytic debridement is a natural and for proper placement. A study by Hien et al. Silver sulfadiazine (Silvadene) is a topi- selective process consisting of the wound demonstrated that transparent film dress- cal sulfonamide compound effective against bed utilizing phagocytic cells and proteolytic ings, when combined with dry gauze and a variety of flora, including gram-negative endogenous enzymes, such as elastase, colla- antibiotic ointment, exhibited an expedited bacteria such as E. coli, Enterobacter, and genase, and myeloperoxidase.26 Although rate of wound contraction and reepitheli- Pseudomonas, as well as gram-positive bac- this form of debridement is slow, the use of alization. This led to shorter healing times teria and Candida albicans.56,57 With sil- occlusive dressings maintains a moist wound and better cosmetic results.36 In a study, ver sulfadiazine, healing is thought to be bed and promotes this natural process. This Rubio et al. used transparent film dressings promoted through its bactericidal effects. leads to the formation of granulation tis- on 3,637 surgical incisions. It was reported However, silver sulfadiazine may inhibit the sue while managing any excessive exudate, that no symptoms of wound infections were effect of PMNs in killing microorganisms.58 allowing for a relatively painless procedure found. In addition to more rapid wound Resistance and superinfection to silver sul- for the patient.27,28 healing, this dressing provides the ability fadiazine is rare.56 Aquacel Ag provides Hydrocolloids and hydrogels are con- to visualize and assess healing. Less scar- broad-spectrum antimicrobial properties ducive to autolytic debridement as they ring, decreased pain, increased mobility, and through increased silver-ion availability, promote moisturization of dead tissue and improved hygiene were all reported.37 which is effective against methicillin-resis- rehydrate the wound bed, and are more Enzymatic debridement is a selective tant Staphylococcus aureus (MRSA) and appropriate for lightly exudative wounds. method of wound debridement, utilizing vancomycin-resistant Enterococci (VRE).59 Hydrogels donate water molecules to dehy- various manufactured proteolytic enzymes. Additional therapies have been studied drated tissues, enabling water vapor and One form is the collagenase-based debride- in response to chronic cutaneous ulcers. It oxygen to reach the wound surface. This ment, which is derived from Clostridium has been reported that activated protein promotes the phagocytic activity of leuko- histolyticum. It has the ability to specifi- C, a serine protease, may stimulate wound cytes and the enzymatic activity of damaged cally digest only triple helical collagen and healing by increasing matrix metallopro- cells, resulting in the removal of devitalized remove dead tissue, and is painless with teinase 2 activity. This promotes angiogen- tissue and autolysis.29 Hydrocolloids consist minimal blood loss.38,39 Papain is a nonspe- esis and reepithelialization, while it inhibits of gel-forming agents, such as gelatin, that cific proteolytic enzyme that breaks down inflammation.3 An alternative therapy used absorb wound exudate and provide a moist fibrinous substances in necrotic tissue but is Hyalofill, an esterified , healing environment to promote wound does not digest collagen.40 However, since which has been shown to enhance angio- healing. It is only recommended for the papain produces an inflammatory response, genesis and the phagocytic response of mac- management of light to moderate exudate. significant pain is often experienced with rophages.60,61 Hyaluronic acid supports the They may adhere to uneven surfaces and can the use of this substance.41 influx of fibroblasts and endothelial cells in be molded, providing an effective bacterial Mechanical debridement removes the wound site and subsequent granulation- barrier, but are generally opaque, making it necrotic tissue and debris in a nonselec- tissue formation.62 One study demonstrated difficult to assess the wound.30 tive method, such as wet-to-dry dressings. an average 63% decrease in wound area after Alginates, cellulose dressings and It may damage healthy granulation tissue, eight weeks of treatment with compression foams should be used when it is necessary causing discomfort to the patient. It also bandaging.63 Provant stimulates the pro- to absorb exudate. This limits damage to involves substantial medical attention and duction of endogenous growth factors and the surrounding normal skin, but it may cost.42 Additional mechanical debridement the proliferation of fibroblasts and epithelial cause the wound bed to dehydrate.31 Alg- methods to remove bacteria, foreign sub- cells through low-level radio-frequency sig- inate dressings are natural polysaccharides stances and necrotic tissue include pres- naling on growth factors. A study by Ritz et composed of calcium alginate and found in surized irrigation, ultrasound treatment, al. demonstrated accelerated closure of pres- the brown algae Phaeophyceae. It has the and vacuum-assisted closure (VAC). VAC sure wounds with utilization of Provant.64 ability to absorb between 15 to 20 times increases blood flow and granulation forma- Becaplermin gel (Regranex) is a genetically its own weight in fluid. However, these tion while decreasing edema and enhancing engineered, platelet-derived growth factor dressings may be too drying if there is not epithelialization.43,44,45 Finally, the biosur- (PDGF) used for the treatment of lower enough exudate, resulting in maceration of gery technique of debridement utilizes ster- extremity ulcers and chronic wounds.65 surrounding tissues. A secondary dressing is ile maggots, which are inexpensive, promote Similar to native human PDGF, becaplermin often required.32 Cellulose dressings are bio- healing, and are selective towards necrotic induces the proliferation of fibroblasts and synthetic microfibrillar substances produced tissue.46 serves as a chemotactic agent for inflamma- from Acetobacter xylinum, and have the Antiseptics are applied to intact skin, tory cells.66,67 ability to absorb water and provide mechan- in contrast to topical agents that are directly ical strength. This is particularly useful in placed on the wound. They function to Conclusion partial-thickness burns and chronic or acute inhibit microorganism growth and reduce wounds. These dressings also promote faster bacterial contamination.47 However, anti- healing time, improve granulation and sur- septics have been shown to be toxic to fibro- Chronic wounds and cutaneous ulcers face epithelialization, and reduce infection blasts, thus impairing epithelialization.48,49 present a great challenge in medicine. These rates.33 In response to increased antibiotic- Acetic acid is a bactericidal antiseptic agent wounds may lead to different complications, resistant pathogens, the use of natural honey against gram-positive and gram-nega- and treatment requires constant care and for wound management has been utilized, tive organisms, specifically Pseudomonas follow-up, contributing to the high costs. which, in addition to antibacterial action, aeruginosa.50 Hydrogen peroxide is a com- Various forms of management are available, promotes autolytic debridement and anti- monly used antiseptic; however, it has been and new, innovative methods and technolo- inflammatory response.34,35 reported as having limited bactericidal effec- gies are continuously developing (see Table Transparent film dressings are water- tiveness.51,52 Hydrogen peroxide, through 1). Proper treatment requires complete proof and impermeable to bacteria but effervescent action, does provide mild deb- assessment of the lesion and knowledge of permit moisture vapor to cross the barrier. ridement of the wound.53 However, it has the different potential therapies prior to They have the advantage of allowing wound been shown that hydrogen peroxide delays selecting the most appropriate form of man- observation, and there is no need for sec- wound healing.54 Sodium hypochlorite is agement specific to the patient’s wound. ondary dressings. However, this method effective against Staphylococcus aureus and is not recommended for heavily exudative Streptococcus infections, and in controlling lesions. It requires the border of intact skin odor.55

Kassardjian, Keehan, Way 65 Table 1 acid in the treatment of superficial wounds infected by Debridement Hypergel, Santyl, Accuzyme Various methods of debridement: Debriding agents useful for devitalized, Pseudomonas aeruginosa. Lancet. 1968; 1:11-3. 51 Lau WY, Wong SH. Randomised, prospective trial of topi- surgical, autolytic, enzymatic, necrotic, or contaminated wounds, or if cal hydrogen peroxide in appendectomy wound infection. mechanical, and biosurgical. any foreign substances are present. Am J Surg. 1981; 142:393-7. Hydrogel Aquasorb, DuoDerm, Intrasite Water-based dressing that donates Used in lightly exudative wounds or dry 52 Leyden JJ, Bartelt NM. Comparison of topical antibiotic Gel, Nu-Gel, KY Jelly water molecules to dehydrated necrotic wounds, providing rehydration ointments, a wound protectant and antiseptics in the treat- tissues, promoting autolysis and for the wound bed. ment of human blister wounds contaminated with Staphy- removal of devitalized tissue. lococcus aureus. J Fam Pract. 1987; 24(6):601-4. Hydrocolloid CombiDERM, Comfeel, Consists of gel-forming agents, such Used in lightly exudative wounds or dry 53 Rodeheaver GT. Wound cleansing, wound irrigation, wound disinfection. In: Krasner D, Kane D. Chronic Wound DuoDerm CGF Extra Thin, as gelatin, promoting a moist healing necrotic wounds, providing rehydration Care: A Clinical Source Book for Healthcare Professionals, Tegasorb environment, and has the ability to for the wound bed. Second Edition. Wayne, PA: Health Management Publica- adhere to uneven surfaces. It tions, Inc., 1997:97-108. provides an effective bacterial 54 Thomas GW, Rael LT, Bar-Or R, et al. Mechanisms of barrier. delayed wound healing by commonly used antiseptics. J Alginate AlgiSite, Comfeel, Curasorb, Natural polysaccharides consisting Used in heavily exudative wounds. Trauma. 2009; 66(1):82-91. Kaltogel, Sorbsan, Tegagel of calcium alginate. Provides strong Secured with secondary dressing. 55 Heggers JP, Sazy JA, Stenberg BD, et al. Bactericidal and wound-healing properties of sodium hypochlorite solutions. tensile strength and absorptive J Burn Care Rehabil. 1999; 12:420-424. capacity. 56 Monafo WW, West MA. Current treatment recommenda- Transparent Film OpSite, Skintact, Tegaderm, Adhesive films that are waterproof, Used in lightly exudative wounds or tions for topical burn therapy. Drugs. 1990; 40:364-73. Bioclusive but permeable to vapor, and require clean, dry necrotic wounds 57 Monafo WW, Ayvazian VH. Topical therapy. Surg Clin North the borders of intact skin. Film is Am. 1978; 58:1157-1171. impermeable to bacteria and allows 58 Hansbrough JF, Zapata-Sirvent RL, Cooper ML. Effects of wound visualization, as well as topical antimicrobial agents on the human neutrophil respi- ratory burst. Arch Surg. 1991; 126:603-608. increased comfort and mobility for 59 Jones SA, Bowler PG, Walker M, Parsons D. Controlling the patient. wound bioburden with a novel silver-containing Hydrofi- Hydrofiber Aquacel, Aquacel-Ag, Versiva Produces hydrophilic gel with Used in exudative wounds. Secured ber® dressing. Wound Repear Regen. 2004; 12(3):288- wound exudate. Aquacel-Ag has with secondary dressing. 294. increased silver-ion availability, 60 West DC, Hampson LN, Arnold F, et al. Angiogenesis leading to strong antimicrobial induced by degradation products of hyaluronic acid. Sci- effects against MRSA and VRE. ence. 1985; 228:1324. 61 Ahlgren T, Jarstrand C. Hyaluronic acid enhanced phago- cytosis of human monocytes in vitro. 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The role of neutrophil apoptosis in influencing tis- factor-BB) in patients with nonhealing, lower-extremity, dia- 32 Jones V. Alginate dressings and diabetic foot lesions. Diab sue repair. J Wound Care. 2003. 12(1)13-6. betic ulcers: A combined analysis of four randomized stud- Foot. 1999; 2:8-14. 6 Falanga V. Wound healing and its impairment in the dia- ies. Wound Repair Regen. 1999; 7:335-46. 33 Portal O, Clark W, Levinson D. Microbial cellulose wound betic foot. Lancet. 2005; 366:1736-43. 66 Ross R, Raines EW, Bowen-Pope DF. The biology of dressing in the treatment of nonhealing lower extremity 7 Diegelmann RF, Cohen IK, Kaplan AM. The role of mac- platelet-derived growth factor. Cell. 1986; 46(2):155-69. ulcers. Wounds. 2009; 1. rophages in wound repair: a review. Plast Reconstr Surg. 67 Rees RS, Robson MC, Smiell JM, Perry BH. Becaplermin 34 Molan PC. Potential of honey in the treatment of wounds 1981; 68:107-113. gel in the treatment of pressure ulcers: A phase II, random- and burns. Am J Clin Dermatol. 2001; 2(1):13-9. 8 Leibovich SJ, Ross R. The role of the macrophage in ized, double-blind, placebo-controlled study. Wound Repair 35 Molan PC. Re-introducing honey in the management of wound repair. A study with hydrocortisone and antimac- Regen. 1999; 7(3):141-7. wounds and ulcers – theory and practice. Ost Wound rophage serum. Am J Pathol. 1975; 78:71-100. Manag. 2002; 48(11):28-40. 9 Yates RA, Nanney LB, Gates RE, King LE. Epidermal 36 Hien NT, Prawer SE, Katz HI. Facilitated wound healing growth factor and related growth factors. Int J Dermatol. using transparent film dressing following Mohs micro- 1991. 30:687-694. graphic surgery. Arch Dermatol. 1988; 124(6):903-6. 10 Schultz G, Rotatori DS, Clark W. EGF and TNF-alpha in 37 Rubio PA. Use of semiocclusive, transparent film dressings wound healing and repair. J Cell Biochem. 1991. 45:346- for surgical wound protection: experience in 3637 cases. 52. Int Surg. 1991; 76(4):253-4. 11 LaVan FB, Hunt TK. Oxygen and wound healing. Clin Plast 38 Alteres WV. Debriding enzymes. J Enterostam Ther. 1984; Surg. 1990. 17:463-72. 11:122-3 12 Clark RA. Fibrin and wound healing. Ann NY Acad Sci. 39 Krane SM. Collagenases and collagen degradation. J 2001. 936: 355 – 367. Invest Dermatol. 1982; 79(Suppl 1):83S-86S. 13 Ramasastry SS. Acute wounds. Clin Plast Surg. 2005; 40 Shapira E, Giladi A, Neuman Z. Use of water insoluble 32:195-208. papain (WIP) for debridement of burn eschar and necrotic 14 Ondrey FG, Hom DB. Effects of nutrition on wound healing. tissue. Plast Reconstr Surg. 1973; 52:279-81. Otolaryngol Head Neck Surg. 1994; 110(6):557-9. 41 Curtis R, Blache C, Johnston K, et al. Accuzyme papain 15 Lowther DA. Chemical aspects of collagen fibrillogenesis. urea ointment versus collagenase Santyl ointment in the Int Rev Connect Tissue Res. 1963; 1:63-125. treatment of partial thickness burn wounds. Proceedings: 16 Pollack SV. Wound healing: a review. J Dermatol Surg Am Burn Assoc Meeting, 1999. Oncol. 1982; 8:667-72. 42 Mosher BA, Cuddigan J, Thomas DR, Boudreau DM. 17 Rahmat A, Norman JN, Smith G. The effect of zinc defi- Outcomes of 4 methods of debridement using a decision ciency on wound healing. Brit J Surg. 2005; 61(4):271- analysis methodology. Adv Wound Care. 1999; 12(2):81-8. 273. 43 Dow G, Browne A, Sibbald RG. Infection in chronic 18 Payne W, Naidu D, Wheeler C, et al. Wound healing in wounds: controversies in diagnosis and treatment. Ost patients with cancer. Eplasty. 2008; 8:e9. Wound Manag. 1999; 45:23-40 19 Ehrlich HP, Hunt TK. The effects of and vitamin A 44 Kloth LC, McCulloch JM. Promotion of wound healing with on wound healing. Ann Surg. 1968; 167(3):324-8. electrical stimulation. Adv Wound Care. 1996; 9(5):42-5. 20 Whitney JD, Heitkemper MM. Modifying perfusion, nutri- 45 DeFranzo AJ, Argenta LC, Marks MW, et al. The use of tion, and stress to promote wound healing in patients with vacuum-assisted closure therapy for the treatment of acute wounds. Heart Lung. 1999; 28:123-133. lower-extremity wounds with exposed bone. Plast Reconstr 21 Shetty V, Schwartz H. Wound healing and perioperative Surg. 2001; 108(5):1184-91. care. Oral Maxillofac Clin North Am. 2006; 18(1):107-113. 46 Thomas S. Sterile maggots and the preparation of the 22 Harkess N. Bacteriology. In: Kloth LC, McCulloch JM, Fee- wound bed. In: Cherry GW, Harding KG, Ryan TJ (eds). dar JA, eds. Wound Healing: Alternatives in management. Wound bed preparation. Proceedings of a symposium Philadelphia, Pa: FA Davis Co; 1990: 60-61. sponsored by the European Tissue Repair Society; 2000; 23 Fowler E, van Rijswijk L. Using wound debridement to help Oxford UK. International Congress and Symposium Series achieve the goals of care. Ost Wound Manag. 1995; 41(7A 250. Royal Society of Medicine Press Limited, 2001: Suppl): 23S-35S. 59-66. 24 Sibbald RG, Williamson D, Orsted HL, et al. Preparing the 47 Brown CD, Zitelli JA. A review of topical agents for wounds wound bed – debridement, bacterial balance, and moisture and methods of wounding. J Dermatol Surg Oncol. 1993; balance. Ost Wound Manag. 2000a; 46:14-35. 19:732-737. 25 Vanscheidt W, Sadjadi Z, Lillieborg S. EMLA anaesthetic 48 Viljanto J. Disinfection of surgical wounds without inhibition cream for sharp leg ulcer debridement: A review of the of normal healing. Arch Surg. 1980; 115:253-256. clinical evidence for analgesic efficacy and tolerability. Eur 49 Shelanski HA, Shelanski MV. PVP-iodine: History, toxicity J Dermatol. 2001; 11(2):90-6. and therapeutic uses. J Int Coll Surg. 1956; 25:727-734. 26 Sinclair RD, Ryan TJ. Types of chronic wounds: Indications 50 Phillips I, Lobo AZ, Fernadez R, Gundara NS. Acetic for enzymatic debridement. In: Westerhof W, Vanscheidt W 66 Wound Care and Management: A Literature Review SOLODYN INNOVATION Introducing 2 New Dosing Options

SOLODYN is indicated to treat only infl ammatory lesions of non-nodular moderate to severe acne vulgaris in patients 12 years of age and older. SOLODYN did not demonstrate any effect on non-infl ammatory lesions. Safety of SOLODYN has not been established beyond 12 weeks of use. This formulation of minocycline has not been evaluated in the treatment of infections. To reduce the development of drug-resistant bacteria as well as to maintain the effectiveness of other antibacterial drugs, SOLODYN should be used only as indicated. SOLODYN Tablets Important Safety Information diarrhea subsequent to the administration of • The most commonly reported side effects were antibacterial agents. headache, fatigue, dizziness, and pruritus. • Central nervous system side effects, including • Minocycline, like other tetracyclines, can cause fetal light-headedness, dizziness, or vertigo, have harm when administered to a pregnant woman. been reported with minocycline therapy. • Tetracycline drugs should not be used during tooth • In rare cases, photosensitivity has been reported. development (last half of pregnancy and up to 8 • Should not be used during pregnancy nor by years of age) as they may cause permanent individuals of either gender who are attempting discoloration of teeth. to conceive a child; concurrent use of • Pseudomembranous colitis has been reported with tetracyclines with oral contraceptives may render nearly all antibacterial agents and may range from oral contraceptives less effective. mild to life-threatening; therefore, it is important to • This drug is contraindicated in persons who have consider this diagnosis in patients who present with shown hypersensitivity to any of the tetracyclines.

See reverse side for brief summary of Full Prescribing Information.

SOLODYN and Benefi ts built in are trademarks of Medicis Pharmaceutical Corporation. © 2009 Medicis, The Dermatology Company SOL 08-045 01/30/10

Medicis Creative Services Job number: Trim Size: 8.5" x 11" Colors: 4CP Contact: SOL 08-045 01-30-10 Bleed Size: 8.75" x 11.25" Spot(s): NONE Lisa Cherry SOLODYN New Strengths Journal Ad Live Area: 7.5" x 10" 480-291-5820 [email protected]

Additional Info: JAOCD BRIEF SUMMARY usual total doses are indicated, and if therapy measures with their physician. Treatment 100 and 300 mg/kg/day) increased numbers Adverse reactions not observed in the clinical (see package insert for Full Prescribing is prolonged, serum level determinations of the should be discontinued at the first evidence of of morphologically abnormal sperm cells. trials, but that have been reported with Information) drug may be advisable. skin erythema. Morphological abnormalities observed in sperm minocycline hydrochloride use in a variety of samples included absent heads, misshapen indications include: ® Central nervous system effects 2. Patients who experience central nervous SOLODYN heads, and abnormal flagella. 1. Central nervous system side effects including system symptoms (see WARNINGS) should Skin and hypersensitivity reactions: fixed drug (MINOCYCLINE HCl, USP) EXTENDED RELEASE be cautioned about driving vehicles or using Limited human studies suggest that eruptions, balanitis, , TABLETS light-headedness, dizziness or vertigo have been reported with minocycline therapy. Patients who hazardous machinery while on minocycline minocycline may have a deleterious effect on Stevens-Johnson syndrome, anaphylactoid Rx Only experience these symptoms should be cautioned therapy. Patients should also be cautioned spermatogenesis. purpura, photosensitivity, pigmentation of skin KEEP OUT OF REACH OF CHILDREN about driving vehicles or using hazardous about seeking medical help for headaches or SOLODYN® should not be used by individuals of and mucous membranes, hypersensitivity blurred vision. reactions, angioneurotic edema, anaphylaxis. INDICATIONS AND USAGE machinery while on minocycline therapy.These either gender who are attempting to conceive symptoms may disappear during therapy and ® 3. Concurrent use of tetracycline may render a child. Autoimmune conditions: polyarthralgia, SOLODYN is indicated to treat only usually rapidly disappear when the drug is oral contraceptives less effective (See Drug pericarditis, exacerbation of systemic lupus, inflammatory lesions of non-nodular moderate Pregnancy—Teratogenic Effects: Pregnancy discontinued. Interactions). category D (See WARNINGS) pulmonary infiltrates with eosinophilia, transient to severe acne vulgaris in patients 12 years of lupus-like syndrome. age and older. SOLODYN® did not demonstrate 2. Pseudotumor cerebri (benign intracranial 4. Autoimmune syndromes, including drug- All pregnancies have a background risk of hypertension) in adults and adolescents has induced lupus-like syndrome, autoimmune Central nervous system: pseudotumor cerebri, any effect on non-inflammatory lesions.Safety birth defects, loss, or other adverse outcome of SOLODYN® has not been established beyond been associated with the use of tetracyclines. hepatitis, vasculitis and serum sickness regardless of drug exposure. There are no bulging fontanels in infants, decreased hearing. Minocycline has been reported to cause or have been observed with tetracycline-class adequate and well-controlled studies on the use thyroid discoloration, abnormal 12 weeks of use. Endocrine: precipitate pseudotumor cerebri, the hallmark antibiotics, including minocycline.Symptoms of minocycline in pregnant women. Minocycline, thyroid function. This formulation of minocycline has not been of which is papilledema.Clinical manifestations may be manifested by arthralgia, fever, rash like other tetracycline-class antibiotics, crosses evaluated in the treatment of infections. include headache and blurred vision. Bulging and malaise. Patients who experience such : papillary thyroid cancer. the placenta and may cause fetal harm when To reduce the development of drug-resistant fontanels have been associated with the use symptoms should be cautioned to stop the Oral: glossitis, dysphagia, . administered to a pregnant woman.Rare bacteria as well as to maintain the effectiveness of tetracyclines in infants.Although signs and drug immediately and seek medical help. Gastrointestinal: enterocolitis, pancreatitis, ® spontaneous reports of congenital anomalies of other antibacterial drugs, SOLODYN should symptoms of pseudotumor cerebri resolve after 5. Patients should be counseled about including limb reduction have been reported with hepatitis, liver failure. be used only as indicated. discontinuation of treatment, the possibility for discoloration of skin, scars, teeth or that minocycline use in pregnancy in post-marketing Renal: reversible acute renal failure. permanent sequelae such as visual loss that can arise from minocycline therapy. experience. Only limited information is available CONTRAINDICATIONS may be permanent or severe exists. Patients Hematology: hemolytic anemia, This drug is contraindicated in persons who 6. Take SOLODYN® exactly as directed. Skipping regarding these reports; therefore, no conclusion thrombocytopenia, eosinophilia. should be questioned for visual disturbances on causal association can be established. have shown hypersensitivity to any of the prior to initiation of treatment with tetracyclines doses or not completing the full course of Preliminary studies suggest that use of tetracyclines. and should be routinely checked for papilledema therapy may decrease the effectiveness of Minocycline induced skeletal malformations minocycline may have deleterious effects on the current treatment course and increase the (bent limb bones) in fetuses when administered WARNINGS while on treatment. human spermatogenesis (see Carcinogenesis, likelihood that bacteria will develop resistance to pregnant rats and rabbits in doses of 30 Mutagenesis, Impairment of Fertility Concomitant use of isotretinoin and minocycline and will not be treatable by other antibacterial mg/kg/day and 100 mg/kg/day, respectively, Teratogenic effects should be avoided because isotretinoin, a section). 1) MINOCYCLINE, LIKE OTHER TETRACYCLINE- drugs in the future. (resulting in approximately 3 times and 2 systemic retinoid, is also known to cause CLASS ANTIBIOTICS, CAN CAUSE FETAL ® times, respectively, the systemic exposure to OVERDOSAGE pseudotumor cerebri. 7. SOLODYN should not be used by pregnant HARM WHEN ADMINISTERED TO A PREGNANT women or women attempting to conceive a minocycline observed in patients as a result In case of overdosage, discontinue medication, ® WOMAN. IF ANY TETRACYCLINE IS USED Photosensitivity child (See Pregnancy, Carcinogenesis and of use of SOLODYN ).Reduced mean fetal treat symptomatically and institute supportive DURING PREGNANCY OR IF THE PATIENT Photosensitivity manifested by an exaggerated Mutagenesis sections). body weight was observed in studies in which measures. Minocycline is not removed in minocycline was administered to pregnant rats BECOMES PREGNANT WHILE TAKING THESE sunburn reaction has been observed in some 8. It is recommended that SOLODYN® not be significant quantities by hemodialysis or at a dose of 10 mg/kg/day (which resulted DRUGS, THE PATIENT SHOULD BE APPRISED OF individuals taking tetracyclines.This has been used by men who are attempting to father a peritoneal dialysis. THE POTENTIAL HAZARD TO THE FETUS. reported rarely with minocycline. Patients should in approximately the same level of systemic child (See Impairment of Fertility section). HOW SUPPLIED ® minimize or avoid exposure to natural or artificial exposure to minocycline as that observed in SOLODYN should not be used during ® ® pregnancy nor by individuals of either gender sunlight (tanning beds or UVA/B treatment) Laboratory Tests patients who use SOLODYN ). SOLODYN (MINOCYCLINE HCl, USP) Extended

who are attempting to conceive a child (see while using minocycline.If patients need to be Periodic laboratory evaluations of organ systems, SOLODYN® should not be used during Release Tablets are supplied as aqueous outdoors while using minocycline, they should including hematopoietic, renal and hepatic pregnancy. If the patient becomes pregnant while film coated tablets containing minocycline PRECAUTIONS: Impairment of Fertility & Pregnancy). wear loose-fitting clothes that protect skin from studies should be performed.Appropriate tests taking this drug, the patient should be apprised hydrochloride equivalent to 45 mg, 65 mg, 90 sun exposure and discuss other sun protection for autoimmune syndromes should be performed of the potential hazard to the fetus and stop mg, 115 mg or 135 mg minocycline. 2) THE USE OF DRUGS OF THE TETRACYCLINE measures with their physician. as indicated. CLASS DURING TOOTH DEVELOPMENT treatment immediately. The 45 mg extended release tablets are gray, unscored, coated, and debossed with “DYN-045” (LAST HALF OF PREGNANCY, INFANCY, AND PRECAUTIONS Drug Interactions Nursing Mothers on one side. Each tablet contains minocycline CHILDHOOD UP TO THE AGE OF 8 YEARS) MAY 1. Because tetracyclines have been shown to Tetracycline-class antibiotics are excreted in General hydrochloride equivalent to 45 mg minocycline, CAUSE PERMANENT DISCOLORATION OF THE ® depress plasma prothrombin activity, patients human milk. Because of the potential for serious Safety of SOLODYN beyond 12 weeks of use supplied as follows: TEETH (YELLOW-GRAY-BROWN). has not been established. who are on anticoagulant therapy may require adverse effects on bone and tooth development This adverse reaction is more common during downward adjustment of their anticoagulant in nursing infants from the tetracycline-class NDC 99207-460-30 Bottle of 30 As with other antibiotic preparations, use dosage. NDC 99207-460-10 Bottle of 100 long-term use of the drug but has been of SOLODYN® may result in overgrowth of antibiotics, a decision should be made whether observed following repeated short-term courses. nonsusceptible organisms, including fungi. If 2. Since bacteriostatic drugs may interfere with to discontinue nursing or discontinue the drug, The 65 mg extended release tablets are blue, Enamel hypoplasia has also been reported. superinfection occurs, the antibiotic should be the bactericidal action of penicillin, it is advisable taking into account the importance of the drug unscored, coated, and debossed with “DYN-065”

TETRACYCLINE DRUGS, THEREFORE, SHOULD discontinued and appropriate therapy instituted. to avoid giving tetracycline-class drugs in to the mother (see WARNINGS). on one side.Each tablet contains minocycline conjunction with penicillin. hydrochloride equivalent to 65 mg minocycline, NOT BE USED DURING TOOTH DEVELOPMENT. Bacterial resistance to the tetracyclines may Pediatric Use 3. The concurrent use of tetracycline and ® supplied as follows: 3) All tetracyclines form a stable calcium develop in patients using SOLODYN,® therefore SOLODYN is indicated to treat only methoxyflurane has been reported to result in NDC 99207-463-30 Bottle of 30 complex in any bone-forming tissue.A decrease the susceptibility of bacteria associated with inflammatory lesions of non-nodular fatal renal toxicity. in fibula growth rate has been observed in infection should be considered in selecting moderate to severe acne vulgaris in The 90 mg extended release tablets are yellow, premature human infants given oral tetracycline 4. Absorption of tetracyclines is impaired by patients 12 years and older. Safety and unscored, coated, and debossed with “DYN-090” antimicrobial therapy.Because of the potential in doses of 25 mg/kg every 6 hours.This for drug-resistant bacteria to develop during antacids containing aluminum, calcium or effectiveness in pediatric patients below on one side. Each tablet contains minocycline reaction was shown to be reversible when the ® magnesium and iron-containing preparations. the age of 12 has not been established. hydrochloride equivalent to 90 mg minocycline, drug was discontinued. the use of SOLODYN, it should be used only as indicated. 5. In a multi-center study to evaluate the effect Use of tetracycline-class antibiotics below supplied as follows: Results of animal studies indicate that of SOLODYN® on low dose oral contraceptives, the age of 8 is not recommended due to NDC 99207-461-30 Bottle of 30 tetracyclines cross the placenta, are found Autoimmune Syndromes hormone levels over one menstrual cycle with the potential for tooth discoloration (see NDC 99207-461-10 Bottle of 100 in fetal tissues, and can cause retardation of Tetracyclines have been associated with the ® WARNINGS). and without SOLODYN 1 mg/kg once-daily The 115 mg extended release tablets are green, skeletal development on the developing fetus. development of autoimmune syndromes.The were measured. Geriatric Use unscored, coated, and debossed with “DYN-115” Evidence of embryotoxicity has been noted long-term use of minocycline in the treatment Based on the results of this trial, minocycline- Clinical studies of SOLODYN® did not include on one side. Each tablet contains minocycline in animals treated early in pregnancy (see of acne has been associated with drug-induced related changes in estradiol, progestinic sufficient numbers of subjects aged 65 and over hydrochloride equivalent to 115 mg minocycline, PRECAUTIONS: Pregnancy section). lupus-like syndrome, autoimmune hepatitis and vasculitis. Sporadic cases of serum sickness hormone, FSH and LH plasma levels, of to determine whether they respond differently supplied as follows: Gastro-intestinal effects breakthrough bleeding, or of contraceptive from younger subjects. Other reported clinical NDC 99207-464-30 Bottle of 30 have presented shortly after minocycline 1. Pseudomembranous colitis has been failure, can not be ruled out.To avoid experience has not identified differences in use.Symptoms may be manifested by fever, The 135 mg extended release tablets are pink reported with nearly all antibacterial contraceptive failure, female patients are advised responses between the elderly and younger rash, arthralgia, and malaise.In symptomatic (orange-brown), unscored, coated, and debossed agents and may range from mild to life- to use a second form of contraceptive during patients. In general, dose selection for an elderly patients, liver function tests, ANA, CBC, and with “DYN-135” on one side. Each tablet threatening. Therefore, it is important to treatment with minocycline. patient should be cautious, usually starting at other appropriate tests should be performed to contains minocycline hydrochloride equivalent to consider this diagnosis in patients who the low end of the dosing range, reflecting the evaluate the patients.Use of all tetracycline-class Drug/Laboratory Test Interactions 135 mg minocycline, supplied as follows: present with diarrhea subsequent to the drugs should be discontinued immediately. False elevations of urinary catecholamine greater frequency of decreased hepatic, renal, administration of antibacterial agents. or cardiac function, and concomitant disease or NDC 99207-462-30 Bottle of 30 Serious Skin/Hypersensitivity Reaction levels may occur due to interference with the Treatment with antibacterial agents alters other drug therapy. NDC 99207-462-10 Bottle of 100 Post-marketing cases of anaphylaxis and fluorescence test. the normal flora of the colon and may permit Store at 25ºC (77ºF); excursions are permitted to serious skin reactions such as Stevens Johnson ADVERSE REACTIONS overgrowth of clostridia. Studies indicate that Carcinogenesis, Mutagenesis & 15º-30ºC (59º-86ºF) [See USP Controlled Room syndrome and erythema multiforme have been Because clinical trials are conducted under a toxin produced by Clostridium difficile is a Impairment of Fertility Temperature]. reported with minocycline use in treatment prescribed conditions, adverse reaction rates primary cause of “antibiotic-associated colitis”. Carcinogenesis—Long-term animal studies Protect from light, moisture, and excessive heat. of acne. have not been performed to evaluate the observed in the clinical trial may not reflect the After the diagnosis of pseudomembranous rates observed in practice. However, adverse Dispense in tight, light-resistant container with Tissue Hyperpigmentation carcinogenic potential of minocycline.A colitis has been established, therapeutic reaction information from clinical trials provides child-resistant closure. Tetracycline class antibiotics are known to structurally related compound, oxytetracycline, measures should be initiated.Mild cases of a basis for identifying the adverse events that cause hyperpigmentation. Tetracycline therapy was found to produce adrenal and pituitary U.S. Patent 5,908,838* and Patents Pending pseudomembranous colitis usually respond to tumors in rats. appear to be related to drug use. *90 mg is also covered by U.S. Patents discontinuation of the drug alone. In moderate may induce hyperpigmentation in many organs, Adverse events reported in clinical trials for 7,541,347 and 7,544,373 to severe cases, consideration should be given including nails, bone, skin, eyes, thyroid, Mutagenesis—Minocycline was not mutagenic SOLODYN® are described below in Table 2. to management with fluids and electrolytes, visceral tissue, oral cavity (teeth, mucosa, in vitro in a bacterial reverse mutation assay Manufactured for:

protein supplementation, and treatment with alveolar bone), sclerae and heart valves.Skin (Ames test) or CHO/HGPRT mammalian cell Table 2 – Selected Treatment-Emergent Medicis, The Dermatology Company an antibacterial drug clinically effective against and oral pigmentation has been reported to assay in the presence or absence of metabolic Adverse Events in at least 1% of Clinical Scottsdale, AZ 85256

Clostridium difficile colitis. occur independently of time or amount of activation.Minocycline was not clastogenic in Trial Subjects July 2009 drug administration, whereas other tissue vitro using human peripheral blood lymphocytes ® 17110103 2. Hepatotoxicity – Post-marketing cases pigmentation has been reported to occur upon or in vivo in a mouse micronucleus test. Adverse Event SOLODYN PLACEBO of serious liver injury, including irreversible prolonged administration. Skin pigmentation (1 mg/kg) N=364 drug-induced hepatitis and fulminant hepatic Impairment of Fertility—Male and female N=674 (%) (%) includes diffuse pigmentation as well as over reproductive performance in rats was unaffected failure (sometimes fatal) have been reported with sites of scars or injury. At least one treatment- 379 (56) 197 (54) minocycline use in the treatment of acne. by oral doses of minocycline of up to 300 mg/ emergent event Information for Patients kg/day (which resulted in up to approximately Headache 152 (23) 83 (23) Metabolic effects (See Patient Package Insert for additional 40 times the level of systemic exposure to Fatigue 62 (9) 24 (7) The anti-anabolic action of the tetracyclines minocycline observed in patients as a result of Dizziness 59 (9) 17 (5) information to give patients) may cause an increase in BUN.While this 1. Photosensitivity manifested by an exaggerated use of SOLODYN®). However, oral administration Pruritus 31 (5) 16 (4) is not a problem in those with normal sunburn reaction has been observed in some of 100 or 300 mg/kg/day of minocycline to male Malaise 26 (4) 9 (3) renal function, in patients with significantly individuals taking tetracyclines, including rats (resulting in approximately 15 to 40 times Mood alteration 17 (3) 9 (3) impaired function, higher serum levels of minocycline. Patients should minimize or the level of systemic exposure to minocycline Somnolence 13 (2) 3 (1) tetracycline-class antibiotics may lead to observed in patients as a result of use of Urticaria 10 (2) 1 (0) avoid exposure to natural or artificial sunlight azotemia, hyperphosphatemia, and acidosis. (tanning beds or UVA/B treatment) while using SOLODYN®) adversely affected spermatogenesis. Tinnitus 10 (2) 5 (1) If renal impairment exists, even usual oral or minocycline. If patients need to be outdoors Effects observed at 300 mg/kg/day included Arthralgia 9 (1) 2 (0) parenteral doses may lead to excessive systemic while using minocycline, they should wear a reduced number of sperm cells per gram Vertigo 8 (1) 3 (1) accumulations of the drug and possible liver of epididymis, an apparent reduction in the Dry mouth 7 (1) 5 (1) loose-fitting clothes that protect skin from sun toxicity.Under such conditions, lower than exposure and discuss other sun protection percentage of sperm that were motile, and (at Myalgia 7 (1) 4 (1)

Medicis Creative Services Job number: Trim Size: 8.5" x 11" Colors: 4CP Contact: SOL 08-045 01-30-10 Bleed Size: 8.75" x 11.25" Spot(s): NONE Lisa Cherry SOLODYN New Strengths Journal Ad Live Area: 7.5" x 10" 480-291-5820 [email protected]

Additional Info: JAOCD A Ca s e o f Mu l t i p l e Ga r g a n t u a n Se b o r r h e i c Ke r a t o s e s

Fawn J. Winkelman, OMS-IV,* Janee D. Steinberg, MD, FAAD, FAACS** * Osteopathic Medical Student, Forth-year, Nova Southeastern University, Ft. Lauderdale, Florida ** Dermatologist and Medical Director of Advanced Cosmetic Laser Center, Tamarac and Boca Raton, Florida

Case Report disproven, as most people who develop SKs leukemia as opposed to adenocarcinoma.2 had their initial one prior to age 30. There According to Lynch et al., although the asso- is no predilection to race or sex, but there ciation of Leser-Trélat with adenocarcinoma A 94-year-old Caucasian female pre- seems to be an inherited pattern.6 Even of the breast is unclear, there was one case sented with multiple disfiguring lesions on though the lesions are completely benign, report of a 41-year-old black female and her her back, flanks, abdomen, and groin. The with no malignant potential, they are often 74-year-old mother who both developed patient was very depressed about her appear- confused with malignancies. This may be adenocarcinoma of the breast. Both mother ance and presented to the dermatologist to because there are multiple variants of the and daughter in the study had clinically seek removal. The lesions were described as lesions. Lesions may arise at any site on the demonstrated evidence for the Sign of Leser- multiple, brown to black, elevated, large oval body except the palms and soles. The typi- Trélat.7 The Sign of Leser-Trélat has been and round verrucous growths. There were cal SK has either a smooth, flat surface or a debated for many years. Some studies have numerous lesions, some extremely wide, rough surface with pearls of keratin (Figure proven an association of sudden numerous ranging from 2 mm to 4 cm in diameter, 1). Some SKs appear dry or cracked, while SKs with internal malignancy, while other and some that were individual and con- others appear flat and smooth. The lesions studies have shown no association. One fluent, especially on the back. The lesions usually have a sharply demarcated border such author, Fanti et al., reported a case of caused itching and were unsightly to the and range in size from 0.2 cm to greater a patient with Leser-Trélat sign seen with patient. She stated that the lesions came on than 3 cm in diameter.1 The lesions are cutaneous melanoma, while other authors gradually over many years, but that she had superficial and only extend within the epi- report no proven internal malignancy after noticed an increase in number and locations dermis. The lesions tend to have the classic extensive testing including appropriate lab over the previous two years. “stuck on” or waxy appearance, and the work, thoracic and abdominal CT scans, and The patient had a past medical history surface tends to break apart when picked.6 liver sonography.3,4 The tests that should be of hypertension, coronary artery disease, The color can vary, but most lesions are tan, performed if Leser-Trélat is suspected are hyperlipidemia, carpal tunnel syndrome, brown, or black. The lesions are highly vari- complete history and physical examination, and sciatica. Her blood pressure and choles- able and can include multiple colors and an routine blood and chemistry studies, chest terol were well-controlled with medication. irregular border, which can appear similar to X-ray, mammograms, cervical cytologic In addition, she took a daily baby aspirin. malignant melanoma. Therefore, a biopsy examination in women, prostate-specific She reported allergies to codeine and peni- of any suspicious lesion is always warranted, antigen in men, and complete endoscopic, cillin. She also denied any personal history along with an accurate clinical diagnosis. In colonoscopic, and radiologic examination of cancer, but stated that her mother, mater- a prospective study performed over a seven- of the gastrointestinal tract.2 We report nal aunt, and sister all had breast cancer and month period to examine diagnostic accu- a case of a 94-year-old Caucasian female are no longer living. She denied ever hav- racy in recognizing SKs, 103 patients were with numerous gargantuan SKs on multiple ing had BRACAnalysis® (Be Ready Against offered a biopsy of their lesions. The diag- areas of her body including her chest, arms, Cancer). She also denied any family history nostic accuracy was assessed using dermato- flanks, back, and groin. The majority of the of seborrheic keratoses. The patient had pathologic analysis. The results were that lesions are present on her back in a “Christ- no known history of skin cancer, including 101 of 103 patients had the correct diagno- mas tree” pattern, shown in Figure 2, one basal cell carcinoma, squamous cell carci- sis of SK, or greater than 99% accuracy. The of the most common locations for SK in noma, and malignant melanoma. other two patients had a final diagnosis of Leser-Trélat. One such lesion that is 4 cm In the patient’s most recent visit to her squamous cell carcinoma in situ, and one in diameter on her left flank is magnified in primary care physician, lab work was per- lesion consisted only of keratin.5 Figure 3. The patient demonstrates some formed, including CBC, CMP, liver panel, The Sign of Leser-Trélat refers to the characteristics of Leser-Trélat sign by hav- lipid panel, and urine analysis. All results sudden appearance or sudden increase in ing numerous individual and confluent SKs were within normal limits, and her choles- number and size of SKs with association in multiple areas of the body. Although the terol was well-controlled. She also had an of internal malignancy. The average age first lesions were noted more than 30 years electrocardiogram performed, which was of onset of Leser-Trélat is 61.1 This sign ago, they had increased in number and size within normal limits. In the previous 10 has been credited separately to Edmund gradually over the past 10 years. However, years, she had normal PAP smears, gyne- Leser (1853-1916) and Ulysse Trélat (1827- it has been suggested that the length of the cological exams, and mammograms. She 1890). Leser was a German surgeon, and eruptive period and the number of lesions denied ever having had a colonoscopy. Trélat was a French professor of surgery.2,8 required for the diagnosis of Leser-Trélat is Both Leser and Trélat were actually studying not a reliable indicator due to the variable cherry in cancer patients when course of patients.2 Our patient also had Discussion they discovered the Sign of Leser-Trélat, intense itching associated with her lesions making it a misnomer. It was actually in and sometimes would try to remove them Seborrheic keratoses (SKs) are one of 1900 when Holländer first linked internal herself prior to coming in for treatment. the most common benign cutaneous neo- 1 malignancy with seborrheic keratoses. The An important indicator of Leser-Trélat is plasms. In fact, it is said that most people most common internal malignancy associ- intense pruritus of the lesions. On physical will develop at least one SK in their lifetime. ated with the Sign of Leser-Trélat is ade- exam, acanthosis nigricans was not present. SKs were once thought to only occur in nocarcinoma (69%) in the gastrointestinal Although our patient had many the elderly and were formerly referred to tract and stomach (40%).1 About 20% of characteristics that supported the Sign of as senile keratoses, but this has since been patients have an associated lymphoma or Leser-Trélat, she also displayed characteris-

Winkelman, steinberg 69 tics that opposed this diagnosis. Normally, (Figure 4) on raised lesions and is therefore with a pale pink scar that faded over time. multiple eruptive SKs tend to occur in older reserved for small, thin lesions on certain This type of treatment is an efficient means patients, as does malignancy. Therefore, it areas of the body like the trunk and back. of removal for both the physician and is difficult to describe an underlying con- Scalpel excision is also an option for lesions patient, as the end result leaves less scar- nection between the two without extensive that are difficult to curette or are located ring. In addition, the results satisfied the accurate history, examination, and follow- on areas such as the eyelids. Scalpel exci- up appointments. Actually, the cause of sion was performed on two lesions on the Leser-Trélat is unknown, but it has been back, as shown in Figure 5 with Band-Aids. postulated that the underlying Another new treatment that we have found secretes growth factors that eventually alter to be very successful is laser therapy with the extracellular matrix, possibly resulting in the Matrix® fractional CO-2 laser (Figure 4) the formation of SKs. In fact, Ellis and Yates through fractional photothermolysis. First, performed a study which suggested that in after disinfecting the area with 70% isopro- genetically predisposed patients, the sign of pyl rubbing alcohol, the lesions were anes- Leser-Trélat is the result of a growth factor thetized with 2% lidocaine and 1:100,000 (transforming growth factor-α) reaching a epinephrine. Next, safety goggles were critical level in the body and eventually pro- applied, and the lesions were lasered with ducing the sudden eruption of SKs.2 Other continuous wave (CW) pattern at 5 watts. studies have tried to reproduce this postu- Then, the lesions were curettaged to remove lation, but have been unsuccessful. It has them. Antibiotic ointment (Bacitracin) and been suggested that Leser-Trélat is a cuta- Band-Aids were applied. Figure 3 - Seborrheic keratosis measuring neous that can The patient usually healed quickly, 4 cm on left flank appear before or concurrently with internal malignancy.1 The only concrete data known is that the Sign of Leser-Trélat seems to demonstrate a familiar trait with an auto- somal-dominant mode of inheritance. Furthermore, a genetically determined pre- disposition with an aberrant response to an epidermal chalone has been proposed.4 Robert A. Schwartz, M.D., shows that mul- tiple SKs are common, have an autosomal- dominant inheritance, and are usually not associated with cancer.2 However, he indicates that if cancer occurs, there are associated sudden and eruptive seborrheic keratoses. He also indicates that if cancer occurs, SKs are often seen with acanthosis Figure 4 - back of patient after cyrother- nigricans and florid cutaneous papilloma- apy, leaving hypopigmented areas (white 2 tosis. If the Sign of Leser-Trélat actually Figure 1 - Typical raised seborrheic kera- arrow), and treatment with the Matrix® exists, then tumors associated with SKs that tosis fractional CO2 laser, showing healing, are malignant behave aggressively, and the pale pink areas (black arrow) average life expectancy after diagnosis is 10.6 months. It has been said that the SKs often parallel the course of the malignancy, and when the malignancy is treated, the SKs regress in size and number.1 Our patient had a gradual onset of SKs as opposed to a sudden onset, which is one of the major hallmarks as described by the Sign of Leser-Trélat. She also had routine blood and chemistry tests, and other tests including a chest X-ray, endoscopy, colonoscopy, and mammography, which have all been negative for malignancy. In addition, other conditions co-exist with the eruption of SKs, like , eczema, or acanthosis nigricans, all of which our patient did not have. Treatment for Leser-Trélat involves identifying and treating the underlying malignancy. The associated SKs are usually treated for cosmetic reasons with various methods. Most of the time, these lesions are friable and can be peeled off on their own, so removal with cryotherapy or curette is acceptable. However, cryotherapy can leave Figure 5 - Back of patient post-scapel hyperpigmented or hypopigmented scars6 Figure 2 - Multiple gargantuan seborrheic excision of two lesions, covered with keratoses on the back Band-Aids 70 A Case of Multiple Gargantuan Seborrheic Keratoses patient, and she is now happier and has bet- ter self-esteem. Of course, multiple treat- ments need to be performed in order to clear her entire back and body of the SKs. Post-treatment care included cleaning the area with 70% isopropyl rubbing alcohol and applying antibiotic ointment twice a day for one week. Close monitoring will be performed at our office as well as with the patient’s primary care physician. Conclusion:

The suspicion for the sign of Leser-Trélat is low in this particular case when taking into account the history and clinical find- ings. It is reasonable to be suspicious for malignancy in this case, particularly because the patient is elderly and does have a cuta- neous finding, but it is low. Furthermore, she did not have a sudden eruption of SKs, which is paramount with Leser-Trélat. Her clinical and diagnostic testing also proved negative for the presence of internal malig- nancy. The patient was made aware of and educated about the Sign of Leser-Trélat and was informed to follow-up with her primary physician for regular visits and if any associ- ated signs or symptoms of cancer appear. The patient was satisfied with the treatment thus far, and is currently continuing to have as many lesions removed as possible. She expressed feeling less depressed and more satisfied overall.

REFERENCES: 1. Habif TP. Clinical Dermatology: A Color Guide to Diagno- sis and Therapy. 4th ed. Philadelphia, PA: Mosby, Inc. 2004:698, 705, 893-896. 2. Schwartz RA. Sign of Leser-Trélat. Journal of the Ameri- can Academy of Dermatology. 1996;35(1):88-95. 3. Fanti PA, et al. The Sign of Leser-Trélat associated with malignant melanoma. Cutis. 1989;44(1):39-41. 4. Di Benedetto G, Pierangeli M, Bertani A. A Peculiar Case of Multiple Gigantic Seborrheic Keratoses. Plastic & Reconstructive Surgery. 1997;99(5):1466-1467. 5. Murphy M, Watson R, Sweeney E, Barnes L. Accuracy of Diagnosis of SK’s in a Dermatology Clinic. Archives of Dermatology. 2000;136:800-801. 6. Habif TP, et al. Dermatology DDxDeck – Seborrheic Kera- toses. Philadelphia, PA: Mosby, Inc. 2006:115. 7. Lynch HT, Fusaro RM, Pester JA, Lynch JF. Leser-Trélat sign in mother and daughter with breast cancer. Journal of Medical Genetics. 1982;19:218-221. 8. Ronchese F. Keratoses, Cancer and “The Sign of Leser- Trélat.” Cancer. 1965;18:1003-1006.

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