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Volume 34

JAOCDJournalJournal OfOf TheThe AmericanAmerican OsteopathicOsteopathic CollegeCollege OfOf DermatologyDermatology

Metastatic Squamous Cell Updated Staging Guidelines and Prognostic Factors for “High-risk” SCC

Also in this issue: Delineating the Perforating Dermatoses A Rare Case of Cogan’s Syndrome with Cutaneous Findings Rhomboid Flaps and Their Modern Modifications last modified on February 17, 2016 8:09 AM

JOURNAL OF THE AMERICAN OSTEOPATHIC COLLEGE OF DERMATOLOGY Page 1 Journal of the American Osteopathic College of Dermatology

2015-2016 AOCD OFFICERS

PRESIDENT Alpesh Desai, DO, FAOCD

PRESIDENT-ELECT Karthik Krishnamurthy, DO, FAOCD

FIRST VICE-PRESIDENT Daniel Ladd, DO, FAOCD

SECOND VICE-PRESIDENT John P. Minni, DO, FAOCD

THIRD VICE-PRESIDENT Reagan Anderson, DO, FAOCD

Editor-in-Chief SECRETARY-TREASURER Karthik Krishnamurthy, DO Steven Grekin, DO, FAOCD TRUSTEES Danica Alexander, DO, FAOCD (2015-2018) Michael Whitworth, DO, FAOCD (2013-2016) Tracy Favreau, DO, FAOCD (2013-2016) David Cleaver, DO, FAOCD (2014-2017) Sponsors: Amy Spizuoco, DO, FAOCD (2014-2017) Peter Saitta, DO, FAOCD (2015-2018)

AuroraDx Immediate Past-President Ranbaxy Rick Lin, DO, FAOCD EEC Representatives Valeant James Bernard, DO, FAOCD Michael Scott, DO, FAOCD

Finance Committee Representative Donald Tillman, DO, FAOCD

AOBD Representative Michael J. Scott, DO, FAOCD

Executive Director Marsha A. Wise, BS AOCD • 2902 N. Baltimore St. • Kirksville, MO 63501 800-449-2623 • FAX: 660-627-2623 • www.aocd.org COPYRIGHT AND PERMISSION: Written permission must be obtained from the Journal of the American Osteopathic College of Dermatology for copying or reprinting text of more than half a page, tables or figures. Permissions are normally granted contingent upon similar permission from the author(s), inclusion of acknowledgment of the original source, and a payment of $15 per page, table or figure of reproduced material. Permission fees are waived for authors wishing to reproduce their own articles. Request for permission should be directed to JAOCD c/o AOCD, PO Box 7525, Kirksville, MO 63501. Copyright © 2003 by the Journal of the American Osteopathic College of Dermatology Print and layout by: S&S Printing and Graphics LLC, 701 N. Marion St., Kirksville, MO 63501 Copy editing by: Julia Layton, Freelance Writing and Editing

Page 2 JOURNAL OF THE AMERICAN OSTEOPATHIC COLLEGE OF DERMATOLOGY Journal of the American Osteopathic College of Dermatology Table of Contents Volume 34 JAOCD Editors...... 4 Letter from the Editor-in-Chief...... 5 Letter from the President...... 6 Letter from the Executive Director...... 7

FEATURE ARTICLE: A Rare Case of Metastatic : A Case Presentation and Discussion of Updated Staging Guidelines and Prognostic Factors...... 12 Steven Brandon Nickle, DO, Nicole Arnold, DO, J Ryan Jackson, DO, Tracy Favreau, DO, FAOCD

EDITOR’S PICKS: Review of Rhomboid Flaps and Their Modern Modifications...... 16 Alexandra Grammenos, MS, Ana M. Rivas, BS, Jacqueline A. Thomas, DO, David L. Thomas, MD, JD, EdD Delineating the Perforating Dermatoses: Case Reports and a Review of the Literature...... 20 Richard Limbert, DO, Rachel White, BA, Richard Miller, DO, FAOCD Cogan’s Syndrome with Cutaneous Findings: A Case Report and Review of Dermatologic Manifestations...... 25 Khasha Touloei, DO, Emily Tongdee, BS, Brittany Smirnov, DO, Tracy Favreau, DO, Leeor Porges, DO

ORIGINAL ARTICLES AND CASE REPORTS: Cutaneous : A Case Study and Literature Review...... 30 Mayha Patel, DO, Anne Nguyen, BS, David Horowitz, DO, FAOCD, Paul Shitabata, MD Bacterial Pseudomycoses of the Skin: A Case Report...... 32 Robert Lin, DO, Alpesh Desai, DO, FAOCD Favre-Racouchot Syndrome in a Unilateral, Perioral Distribution Associated with Tobacco Use: A Case Report and Review...... 34 Mitchell R. Manway, DO, Joseph M. Dyer, DO, Joshua D. Gapp, MD, Melinda F. Greenfield, DO Lymphadenopathic Form of Endemic Kaposi Sarcoma in an HIV-negative Gambian Male ...... 36 Eugene Sanik, DO, Ryan Schuering, BS, Marcus B. Goodman, DO, FAOCD Coexisting confluent and reticulated papillomatosis and terra firma-forme dermatosis...... 40 Claire Otteni, BA, Laura F. Sandoval, DO, Jonathan S. Crane, DO, FAOCD A Case of Pili Annulati Following Resolution of ...... 42 Karan Lal, BS, Charlotte Noorollah, DO Two Cases of Pediatric Acral Cutaneous Calcinosis with Transepidermal Elimination Presenting as Skin-colored Papules...... 44 Gabriela Maloney, DO, Rohini Chennuri, MD, Patricia Dymek, MD, Marylee Braniecki, MD Recurrent Basal Cell Carcinoma with Perineural Invasion: A Case Report and Review...... 46 Shana Rissmiller, DO, Alecia Folkes, MS, Indira Krishnarao, MD Atypical presentation of Sézary Syndrome with CD4+/CD7+/CD26- T-cells and marked epidermotropism: A case report and literature review...... 49 Gabriela Maloney, DO, Sujata Gaitode, MD, Igor Altman, MD, Marylee Braniecki, MD A Rare Case of Tumid Coexisting with Systemic Lupus Erythematosus: A Case Presentation and Discussion.....52 Jennifer Moscoso Conde, DO, Simona Bartos, MPH, John Howard, DO, Jacqueline Thomas, DO, FAOCD A Vesiculobullous Eruption Following Solid Organ Transplantation...... 54 Nadine George, DO, Ann Reed, DO, Frank Don, DO, FAOCD, Stanley Skopit, DO, MSE, FAOCD A rare case of verrucous in young female: A case report and review of clinicohistologic presentation and variable therapeutic response...... 56 John Moesch, BA, Jessica Mercer, MD, Jennifer B. Sissom, PA-C, Jonathan S. Weiss, MD

JOURNAL OF THE AMERICAN OSTEOPATHIC COLLEGE OF DERMATOLOGY Page 3 Editor-In-Chief Founding Editor Assistant Editor Karthik Krishnamurthy, DO Jay Gottleib, DO Julia Layton, MFA

Associate Editors

Derrick Adams, DO Aaron Bruce, DO Jonathan Crane, DO Peter Saitta, DO Michael Scott, DO Red Bluff, CA Bozeman, MT Wilmington, NC Brooklyn, NY Seattle, WA Editorial Board Sami Abbasi, DO Marcus Goodman, DO Scott Lim, DO Andrew Racette, DO Brownstown, MI Roswell, GA Erie, PA Phoenix, AZ

Brett Bender, DO Melinda Greenfield, DO Chava Lustig, DO Richard Rudnicki, DO Farmington Hills, MI Albany, GA Weston, FL Mesquite, TX

Ryan Carlson, DO Denise Guevara, DO Jere Mammino, DO Amara Sayed, DO Hilliard, OH Weston, FL Winter Springs, FL San Marcos, TX

Igor Chaplik, DO Andrew Hanly, MD John Minni, DO Joseph Brant Schneider, DO Aventura, FL Miami, FL Port St. Lucie, FL Shawnee Mission, KS

Michael P. Conroy, MD Joel Harris, DO Tony Nakhla, DO Gregg Severs, DO Columbus, OH Madison Heights, MI Orange County, CA Scranton, PA

John Coppola, DO Heather Higgins, DO Navid Nami, DO Sean Stephenson, DO Ormond Beach, FL Troy, MI Newport Beach, CA Troy, MI

Matthew Elias, DO David Horowitz, DO Jon Keeling, DO Jacqueline Thomas, DO Lighthouse Point, FL Torrence, CA Lexington, KY Fort Lauderdale, FL

Merrick Elias, DO Mark Lebwohl, MD Dimitria Papadopoulos, DO Jim Towry, DO Delray Beach, FL New York, NY Bellmore, NY Ocala, FL

Michelle Foley, DO Angela Leo, DO John Perrotto, DO Scott Wickless, DO Ormond Beach, FL New York, NY West Palm Beach, FL Dallas, TX

Page 4 JAOCD EDITORS Letter from the Editor-in-Chief

Karthik Krishnamurthy, DO, FAOCD Editor-in-Chief

Dear Readership, Medscape recently published its 2015 “Why Most Doctors Get Sued” report. As I clicked on the link in my email, I held my breath in anticipation of a report confirming what I already knew: Dermatologists get sued more than other specialties. As the slideshow loaded, I reviewed the of Erb’s point in my mind. When it finished loading, I saw that 47% of all doctors had been named in a lawsuit during their careers. Okay… that’s bittersweet. Should we be relieved that there would be kindred spirits, or alarmed that there is a coin-toss chance of being sued? At the next slide, I let out a sigh of relief. Dermatology was not in the list of the top seven specialties sued: OBs (85%), (83%), Orthopedics (79%), Radiology (72%), Anesthesiology (58%), IM/FM (46%), and (34%). If we’re below Oncology, I thought, we’re down to a one-in-three shot, at worst. As the report continued, I was drawn in to find out the reasons why physicians were sued, and what effect it had on them. I continued to read, but with a different attitude… what could I be doing differently or better in order to avoid harm or potential harm to my patients? “Failure to diagnose” was the leading cause of suits (31%). “Poor documentation” and “consent” issues together made up about 10% of suits. Then, I got worried again. More than 50% of responders had reported that the threat of malpractice influenced their care. Almost all responders reported that there are flaws in the way suits are handled in our legal system, with lack of peer review for merit. Seventy percent were surprised when they were sued; they weren’t expecting it. Most reported more than 100 hours in preparation, court, and trial-related meetings, and almost half the suits lasted longer than three years. More than half of responders stated that the long-term term emotional and financial effects were severely disruptive. Then things got a little brighter. About half of all cases were dismissed. Of the suits that were not settled before trial, only about 3% went against the physician. More than half the physicians who were sued stated that they would not have changed a thing in their care. More than half of the monetary awards for all cases were $0. Eighty-one percent of responders felt that saying “I’m sorry” would not have helped the outcome. I went to bed ambivalent-to-slightly-relieved. When I woke up the next morning, I knew I could shift my focus back to prior authorizations, step-therapy, and automated 1-800 insurance operators. Yours, Karthik Krishnamurthy, DO, FAOCD Editor-in-Chief, Journal of the American Osteopathic College of Dermatology

LETTER FROM THE EDITOR -IN-CHIEF Page 5 Letter from the President

Alpesh Desai, DO, FAOCD President, AOCD

Greetings from Houston, Texas! As President of the AOCD, I welcome you to another edition of the Journal of the American Osteopathic College of Dermatology. I would be remiss in not recognizing the Editor-in-Chief of this powerful publication, Karthik Krishnamurthy, DO. His commitment to the College and willingness to go above and beyond is admirable. Thank you, Dr. Krishnamurthy. I also want to express my appreciation to Dr. Lin, our Immediate Past President, for his tireless efforts on behalf of the College. His friendship and his willingness to continue participating in a meaningful way will only make this year more successful. I think it most important that we honor our heritage, and to that end, I want to express my deepest appreciation to Dr. Jay Gottlieb for his vision and wisdom in launching the JAOCD. I appreciated our time together in Orlando on a number of levels. First, the friendships that continue and the opportunity to develop new friendships and relationships are vital to our personal growth and development. Second, hearing new ways of doing things, discussing similar challenges, and hearing solutions to many old challenges was powerful. Finally, I believe there are no words to describe how special Orlando was personally to me. The attendees were so very caring! There is, inherent in this great organization, a camaraderie blended with the desire to help others. The kindnesses shown to me during this conference will linger long in my memory. The year 2016 is upon us. It seems only yesterday I was entering the Kansas City University of Medicine and Biosciences, followed by my internship and residency. Soon another cycle will pass. New, excited doctors will emerge and enter residencies in dermatology. As Director of the South Texas Dermatology Residency Program in Houston, I have borne witness to fine physicians honing their skills and expanding their knowledge in anticipation of launching their medical careers. We need to be mindful that the future of our organization rests squarely upon the shoulders of these new physicians we train. It is to the great benefit of the AOCD that we serve not only as mentors but also remain active in their development in both practice and science. Our future residents and fellows will be entering a new environment, working within a single accreditation system for graduate medical education programs in the United States. When the new system is fully implemented in July 2020, the graduates of osteopathic and allopathic medical schools will complete their residency and/or fellowship education in ACGME-accredited programs and demonstrate achievement of common milestones and competencies. No longer will there be a great divide in the practical training of DOs and MDs. Clearly our world is changing! I suppose the greatest morsel I could share with you comes from one of my mentors, who said, “Today, at this moment, we are living in yesterday’s future.” The changes in our practice of dermatology and medicine in general are profound. We spend great swaths of time dealing with electronic medical records and ICD 10. My challenge to you is to pause and remember why you chose medicine, and particularly why you chose dermatology. Then look at your patients through a lens tinted with that memory. While we must tend to the busyness of EMRs, we must not forget our patients. I look forward to serving you and the opportunity to meet all of you as you attend our meetings. Alpesh Desai, DO, FAOCD President, American Osteopathic College of Dermatology

Page 6 LETTER FROM THE PRESIDENT Letter from the Executive Director

Marsha Wise Executive Director, AOCD

Greetings, Everyone! The year is quickly coming to an end, and it has been a very busy one. We had a great meeting in Orlando, with 550 registered! It was our highest attendance ever! December 31, 2015, is the end of the current CME cycle. The new cycle begins January 1, 2016. I encourage everyone to check your CME reports and to monitor the AOA site for the new CME guide, which has not been published. We are hearing that there will be changes in the requirements for the new cycle. You can find that information here: http://www.osteopathic.org/ inside-aoa/development/continuing-medical-education/Pages/default.aspx. Many AOCD members have been inquiring about OCC and OCAT. If you have not already done so, you must register at http://www.osteopathic-cat.com (under “Register”). This is mandatory for recertification. If you have any questions please refer to the AOBD website at http://aobd.org/aobd/occ/aobd-occ-faqs. The Foundation for Osteopathic Dermatology is accepting applications for research grants. For more information, visit the Foundation page at https://aocd.site-ym.com/?page=Foundation. AOCD membership dues for 2016 are now due. The AOCD has made it easier for you to renew your dues by providing quick and secure renewal online. Just go to our web site, http://aocd.org, and log in. Your username is the email address you have on file with the AOCD, and your password is “Aocd” followed by your AOA# (case sensitive). Please contact our office if you have difficulty logging in. Also on that page is a form to update your database information. This database is maintained on our web site so you can make changes to your membership information at any time. All changes you make will be recorded in the database and will also update the “Find a DO” section of the web site. Although you will see all of your information in your personal file, inquiries will only generate your office address, office telephone number and office fax number. Save the Dates! The2016 Spring Meeting will take place from March 30th to April 3rd, 2016, at the Ritz Carlton Battery Park, New York, NY. The 2016 Fall Meeting will take place from September 15th to 18th, 2016, at the Loews Santa Monica, Santa Monica, CA. The 2017 Spring Meeting will take place from March 29th to April 2nd, 2017, at the Ritz Carlton Atlanta, Atlanta, GA. As always, if you have questions or concerns, please feel free to contact me (see “Contact Us” at AOCD.org), and I will be happy to assist you. We appreciate your continued support of the AOCD. Sincerely, Marsha Wise Executive Director, American Osteopathic College of Dermatology

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®/TMs are trademarks of Valeant Pharmaceuticals International, Inc. or its affiliates. Any other product or brand names and logos are the property of their respective owners. © 2015 Valeant Pharmaceuticals North America LLC. DM/RAM15/0007 Printed in USA. A Rare Case of Metastatic Squamous Cell Carcinoma: A Case Presentation and Discussion of Updated Staging Guidelines and Prognostic Factors

Steven Brandon Nickle, DO,* Nicole Arnold, DO,** J Ryan Jackson, DO,*** Tracy Favreau, DO, FAOCD****

*Dermatology Resident, 2nd year, Broward Medical Center, Fort Lauderdale, FL **Dermatology Resident, 1st year, Beaumont Medical Center, Farmington Hills, MI ***Traditional Rotating Intern, Sampson Regional Medical Center, Clinton, NC ****Director/Chairman of Dermatology, Nova Southeastern University College of Osteopathic Medicine/Broward General Medical Center, Fort Lauderdale, FL

Abstract Cutaneous squamous cell carcinoma (cSCC) is well recognized in the literature as a fairly common neoplasm that arises from a malignant proliferation of epidermal keratinocytes. Prognosis is typically favorable in cSCC, as it rarely metastasizes. However, the literature is unclear in regard to what defines “high risk” cSCC and what its prognostic indicators are. We report a case of a 68-year-old Caucasian female with metastatic cSCC and review the recent available guidelines regarding staging and major tumor characteristics associated with aggressive behavior and a poor outcome.

Introduction unknown duration. Cutaneous squamous cell carcinoma (cSCC) is Infectious was consulted for potential the second most common human cancer, with superimposed infection of the left upper scapular an estimated annual incidence of 186,157 to mass. The patient was started on vancomycin 419,843 cases in the United States.1 While tumor and piperacillin/tazobactam with preliminary recurrence, , and death occasionally microbiology Gram stain for Gram-positive occur, prognosis is typically excellent, as these cocci and Gram-negative rods. We recommended complications only occur approximately in 1% a wide excision of the left upper-back mass to to 5% of cases.2-6 Current literature supports a rule out angiosarcoma versus squamous cell correlation between certain pathological and carcinoma, along with an excision of the right clinical features, aggressive tumor behavior, and upper-back mass to rule out melanoma. increased risk of metastasis. However, there Upon completion of the excisions, the histologic are disputes over the definition of “high-risk examination of the left upper-back wide- cSCC” and its appropriate prognostic indicators. excision specimen revealed a necrotic, poorly Without a prognostic model, clinicians lack differentiated neoplasm with epidermoid and evidence to guide decisions regarding appropriate sarcomatoid components with blood-vessel nodal staging and adjuvant therapy. We report invasion. The following stains were performed a 68-year-old Caucasian female with metastatic on the left upper-back tissue specimen: p63 (+), cutaneous SCC and review the most up-to- p16 (+), Pan-K (+), HMB45 (-), MART1 (-), date guidelines regarding staging and major vimentin (+) (Figures 2, 3). The clinical and tumor characteristics associated with aggressive histopathologic exam favored a diagnosis of the behavior and a poor outcome. left upper-back as sarcomatoid squamous cell Figure 1. Left scapular fungating mass with carcinoma. Histologic examination of the right Case Report central erosions. upper-back lesion demonstrated malignant A 68-year-old Caucasian female presented to melanoma in situ with benign margins. After the emergency room (ER) with a left scapular mass on her left scapula (Figure 1) that was surgery, it was recommended that the patient mass that had been present for approximately tender to palpation and symmetrical with central be followed by oncology for further adjunctive six months per patient recollection. The initially erosion, surrounding erythema and malodorous therapy. small, pruritic papule had enlarged, become discharge; and a single, 3 cm x 2 cm, variegated Months later, the patient presented again to the tender and eventually ruptured. The rupture multi-toned brown to black, isolated patch ER due to extreme weakness and fatigue. The left produced a malodorous purulent discharge that with irregular borders, focal hyperpigmentation axillary mass measured 16 cm in size and had prompted her to seek medical attention. and slight elevation on the right upper back of become necrotic (Figure 4). A core biopsy of Past medical history was significant for 10 or more blistering without sunscreen as a child, hypertension, dyslipidemia and mellitus. Family history was significant for melanoma in two out of her six sisters. Surgical history consisted of a hysterectomy and cholecystectomy. The patient lived at home and was cared for by her son. The patient denied any weight change, fever or chills. On physical exam, temperature was 98.4 F (36.9 C), heart rate 66, respiratory rate 20, blood pressure 166/76 and oxygen saturation at 95% on room air. The patient had a firm, left axillary node that had been present for an unknown Figures 2 and 3. Left upper back tissue specimen: p63 (+), p16 (+), Pan-K (+), HMB45 (-), MART1 (-), vimentin (+). duration of time; a 12 cm x 10 cm fungating

Page 12 A RARE CASE OF METASTATIC SQUAMOUS CELL CARCINOMA: A CASE PRESENTATION AND DISCUSSION OF UPDATED STAGING GUIDELINES AND PROGNOSTIC FACTORS the left axillary mass was conducted and revealed High-risk Characteristics overexpression have shown aggressive metastasis.7 metastatic squamous cell carcinoma with an The American Joint Committee on Cancer H&E stain that demonstrated multiple spindle- (AJCC) substantially altered the staging of Prognosis shaped, atypical cells (Figure 5). The axillary cSCC in 2010 with the 7th edition of its staging Currently, the nodal classification used in staging mass most likely represented an enlargement manual.10 The new edition aimed to create is divided into N1, N2, and N3, with further of the initial left axillary node, which had now congruence by replicating the staging system for subdivision of the N2 component into a, b, and infiltrated into major blood vessels and other the mucosal squamous cell cancer variant. The c based on ipsilateral vs. contralateral nodes. structures, making surgical treatment impractical. TNM classification and staging system remains From a retrospective study of 603 patients, Clark The patient elected at that time for palliative with many changes. Perhaps the most important et al. found that stages N2a, N2c, and N3 of the radiation therapy. of these components is the high- and low-risk AJCC staging system contained less than 10% of 10 designations. T1 and T2 are defined as a lesion patients exclusive of any prognostic relevance. < 2 cm or > 2 cm, respectively. However, if there This assessment calls into question the validity are more than two high-risk characteristics, of the classification and the overall utility of the regardless of tumor size, it is designated as system. T2 and stage 2. These characteristics include: Further research on patient outcomes from clinical tumor diameter 2 cm or greater, Breslow cutaneous SCC will prove useful for verifying thickness greater than 2 mm, poor differentiation, which adjustments to the AJCC staging system perineural invasion, Clark level IV or higher, and are indicated. Histologic features consisting of primary location on the external ear or non- 3,7,9,11,12 a poorly differentiated tumor, Breslow depth glabrous . However, in a prospective greater than 2 mm, and the presence of study, Veness et al. examined 266 patients with involvement negatively influence the prognosis.14 cSCC that metastasized to parotid or cervical Approximately 75% of recurrences or metastases lymph nodes and found that 70% of the lesions of cSCC occur within two years after therapy, and measured ≤ 2 cm, indicating that factors other Figure 4. Left axillary necrotic mass with approximately 95% occur within five years. Thus, than tumor size likely contribute to metastatic 5 purulent discharge. 13 close follow-up is indicated. The risks for local risk. A review by Matorell-Calatayud et al. recurrence and distant metastasis are impacted by suggests other high-risk cSCC characteristics to tumor characteristics and patient characteristics. be included in the discussion of prognosis and Both regional lymph node and distant metastases treatment. These high-risk cSCC characteristics are associated with a markedly increased risk of include: genetic disorders (xeroderma disease-related mortality. Overall survival rates pigmentosum, epidermodysplasia verruciformis, for patients with regional lymph node metastases oculocutaneous albinism, dyskeratosis congenita, are about 25% to 35% at five years and less than and recessive dystrophic epidermolysis bullosa.), 20% at 10 years.5,15-18 In patients with distant cSCC arising at the site of a pre-existing lesion metastases, the five-year survival rate is less than (, burn sites, ulcers that are slow growing, 10%.5,18 chronic radiation ), immunosuppression and transplantation, and molecular markers. Sentinel lymph node (SLN) biopsy is a surgical For example, EFGR overexpression has been procedure utilized to detect subclinical nodal linked to early metastasis, and lesions with p16 metastasis malignancies. High-quality studies

Figure 5. Core biopsy from left axillary mass Table 1. AJCC tumor (T) staging and “high risk” features (H&E): Multiple spindled-shaped atypical cells present. Designation Description TX Primary tumor cannot be assessed T0 No evidence of primary tumor Discussion Cutaneous squamous cell carcinoma (cSCC) Tis Carcinoma in situ is a fairly common malignancy with an average T1 Tumor 2 cm or less in greatest dimension with fewer than 2,7 lifetime incidence greater than 10%. The two high-risk features majority of patients with cSCC present with a localized disease that is cured with local treatment; T2 Tumor > 2 cm in greatest dimension, or tumor of any size however, tumor recurrence, metastasis, and death with two or more high-risk features from this disease occasionally occur. Tumors that T3 Tumor with invasion of maxilla, , orbit or are associated with an increased risk of aggressive temporal bone behavior and demonstrate clinical or histological features have been termed “high-risk.” T4 Tumor with invasion of skeleton (axial or appendicular) or The mortality rate for disease-specific death perineural invasion of skull base from cSCC is 2.1%, with more deaths occurring High-risk Features annually from cSCC than melanoma due to the 8,9 Designation Description higher prevalence of the disease. Adequate > 2 mm classification and staging of cSCC is necessary Depth/Invasion in order to accurately predict a prognosis and Clark level ≥ IV appropriately develop a treatment plan. The Perineural invasion difficulties lay in the controversy regarding the Primary site: ear newest staging system and a lack of conclusive, Anatomic Location evidence-based research regarding high- Primary site: -bearing lip risk characteristics, prognosis, and treatment Differentiation Poorly differentiated or undifferentiated efficacy.2,9

NICKLE, HACKERT, JACKSON, FAVREAU Page 13 Table 2. NCCN guidelines for “high-risk” cSCC24 • Poorly differentiated histologic characteristics Factors indicating “high-risk” cSCC* • Perineural invasion (of any caliber) Area M ≥ 10 mm** • Tumor invasion beyond the subcutaneous fat Area H ≥ 6 mm*** (excluding bone invasion, which automatically upstages tumors to alternative stage T3). Poorly defined This alternative T-staging system differs from Recurrence 2010 AJCC tumor staging in the following Immunosuppression regards: Site of prior RT or chronic inflammatory process • Stage T1 comprises tumors that have no risk Rapidly growing tumor factors. Neurologic symptoms • Stage T2 tumors are categorized into two Moderately or poorly differentiated histology substages based on number of risk factors. Acantholytic, adenosquamous, or desmoplastic subtypes • Stage T3 includes all cases of bone invasion as well as tumors without bone invasion but Depth: ≥ 2 mm or Clark levels IV, V with all four risk factors. Perineural or vascular involvement • There is no stage T4 in the alternative staging. • Location on the ear and vermillion lip are not *High-risk = ≥1 of 12 risk factors considered risk factors. **M = Medium risk: forehead, scalp, cheek, ***H = High risk: “masked areas” of face, central face, ears, periauricular, eyelids, periorbital, nose, • Breslow (millimeter) tumor depth was not temple, used as a risk factor. Note: Low risk: trunk and extremities • Invasion beyond subcutaneous fat was the best prognostic cutpoint in this data set evaluating the use of SLN biopsy in high-risk skin, 9% presented with more than one cSCC, defining elevated risk of poor outcomes. cutaneous SCC are lacking.19,20 The effect of this and 33% had known risk factors such as psoriasis, procedure on patient survival is unclear. , radiation dermatitis, and arsenic • Stage T2b tumors are responsible for most exposure. poor outcomes. Treatment efficacy The proposed alternative tumor-staging system The most appropriate management of high- Tumors have been classified according to the 2010 AJCC T-stage guidelines (Table 1).23 provides improved prognostic discernment via risk cSCC remains unknown. However, stratification of stage T2 tumors. However, current treatment guidelines from the Along with the AJCC, the National validation in other cohorts is still needed. National Comprehensive Cancer Network, Comprehensive Cancer Network (NCCN) established in 2010, use a similar list of high- guidelines (Table 2) have been proposed to help risk criteria to determine appropriateness of in the assessment and classification of “high- Conclusion excision and the necessary margins, including risk” cSCCs.24 However, analysis from Melinda Cutaneous squamous cell carcinoma is a previous radiation, chronic inflammation, and et al. demonstrates discordance between their challenging neoplasm to classify and treat. This immunosuppression.7,21 If a lesion has one of these definitions of “high-risk” cSCC.25 challenge is largely due to the lack of substantial characteristics, excision with 10 mm margins or prospective studies regarding disease-specific In a retrospective cohort study, Jambusaria- survival. It is necessary for practitioner to be is indicated. The National Cancer Pahlajani et al. proposed an alternative tumor- Institute recommends the use of 6 mm to 10 mm vigilant regarding these high-risk characteristics staging system to identify risk factors for poor by promoting close follow-up with these margins for lesions > 20 mm or exhibiting high- outcomes in cSCC and evaluate the 2010 risk characteristics.22 patients due to the higher risks of recurrence and AJCC tumor-staging system’s ability to stratify metastasis. Although Mohs surgery is recommended for occurrence of these outcomes.12 The results for high-risk cSCC cases, ideal management has AJCC tumor stages T2 to T4 were statistically not yet been defined for this group, and a lack indistinguishable. Consequently, the majority of of randomized controlled trials subsequently poor outcomes occurred in AJCC stage T2 cases. leads to the management of patients not being The Jambusaria-Pahlajani et al. staging system uniform. 22 A retrospective study by Mullen et (Table 3) prognostically stratifies the stage T2 al. suggests that favorable outcomes can result in group, since most outcomes of interest (87%) patients with advanced disease or drastic surgical occurred in AJCC stage T2. 12 The alternative procedures (e.g., extremity amputation and/or tumor-staging system is based on four risk factors lymph node dissection).2 From this study, a list of that were highly predictive of at least two end characteristics that increase metastatic potential points of interest. These risk factors include: was developed. In individuals with metastasis, • Tumor diameter of 2 cm or greater 12.5% had primary lesions in previously injured

12 Table 3. Alternative T-staging system by Jambusaria-Pahlajani, et al. Alternative T-staging System Definition T0 In situ SCC T1 0 risk factors T2a 1 risk factor T2b 2-3 risk factors T3 4 risk factors or bone invasion

Page 14 A RARE CASE OF METASTATIC SQUAMOUS CELL CARCINOMA: A CASE PRESENTATION AND DISCUSSION OF UPDATED STAGING GUIDELINES AND PROGNOSTIC FACTORS References perineural invasion: an investigator-blinded 1. Karia PS, Han J, Schmults CD. Cutaneous retrospective cohort study. Dermatol Surg. squamous cell carcinoma: estimated incidence of 2009;35:1859. disease, nodal metastasis, and deaths from disease 15. Joseph MG, Zulueta WP, Kennedy PJ. in the United States, 2012. J Am Acad Dermatol Squamous cell carcinoma of the skin of the trunk 2013;68:957. and limbs: the incidence of metastases and their 2. Mullen JT, Feng L, Xing Y, et al. Invasive outcome. Aust N Z J Surg. 1992;62:697. Squamous Cell Carcinoma of the Skin: 16. Kwa RE, Campana K, Moy RL. Biology of Defining a High-Risk Group. Ann Surg Oncol. cutaneous squamous cell carcinoma. J Am Acad 2006;13:902-9. Dermatol. 1992;26:1. 3. Brantsch KD, Meisner C, Schönfisch B, et al. 17. Kraus DH, Carew JF, Harrison LB. Regional Analysis of risk factors determining prognosis of lymph node metastasis from cutaneous squamous cutaneous squamous-cell carcinoma: a prospective cell carcinoma. Arch Otolaryngol Head Neck study. Lancet Oncol. 2008;9:713. Surg. 1998;124:582. 4. Farasat S, Yu SS, Neel VA, et al. A new 18. Alam M, Ratner D. Cutaneous squamous-cell American Joint Committee on Cancer staging carcinoma. N Engl J Med. 2001;344:975. system for cutaneous squamous cell carcinoma: 19. Kwon S, Dong ZM, Wu PC. Sentinel lymph creation and rationale for inclusion of tumor node biopsy for high-risk cutaneous squamous (T) characteristics. J Am Acad Dermatol. cell carcinoma: clinical experience and review of 2011;64:1051. literature. World J Surg Oncol. 2011;9:80. 5. Rowe DE, Carroll RJ, Day CL Jr. Prognostic 20. Ross AS, Schmults CD. Sentinel lymph node factors for local recurrence, metastasis, and biopsy in cutaneous squamous cell carcinoma: survival rates in squamous cell carcinoma of a systematic review of the English literature. the skin, ear, and lip. Implications for treatment Dermatol Surg. 2006;32:1309. modality selection. J Am Acad Dermatol. 1992;26:976. 21. Roozeboom MH, Lohman BP, Westers- Attema A, et al. Clinical and Histological 6. Brougham ND, Dennett ER, Cameron R, Tan Prognostic Factors for Local Recurrence and ST. The incidence of metastasis from cutaneous Metastasis of Cutaneous Squamous Cell squamous cell carcinoma and the impact of its Carcinoma: Analysis of a Defined Population. risk factors. J Surg Oncol. 2012;106:811. Acta Dermato-Venereologica. 2013;93(4):417- 7. Martorell-Calatayud A, Sanmartin Jimenez O, 21. Cruz Mojarrieta J, et al. Cutaneous Squamous 22. Jambusaria-Pahlajani A KK, Hess, SD, Cell Carcinoma: Defining the High Risk Variant. Berg D, Schmults CD. Uncertainty in the peri- Actas Dermosifiliogr. 2013;367-79. operative management of high-risk cutaneous 8. Clayman GL, Lee JJ, Holsinger CF, et al. squamous cell carcinoma among Mohs surgeons. Mortality Risk From Squamous Cell Skin Arch Dermatol. 2010 Nov;146(11):1225-31. Cancer. J Clin Oncol. 2005;23(4):759-65. 23. Edge SB, Byrd DR, Compton CC, Fritz AG, 9. Schmults CD, Karia PS, Carter JB, et al. Greene FL, Trotti A III, Eds. AJCC Cancer Factors Predictive of Recurrence and Death Staging Manual. 7th ed. New York, NY: Springer; From Cutaneous Squamous Cell Carcinoma. 2010. JAMA Dermatology. 2013;149(5):541-7. 24. Edge SB, Byrd DR, Compton CC, Fritz AG, 10. Clark JR, Rumcheva P, Veness MJ. Analysis Greene FL, Trotti A III, Eds. AJCC Cancer and Comparison of the 7th Edition American Staging Manual. 7th ed. New York, NY: Springer; Joint Committee on Cancer (AJCC) Nodal 2010. Cutaneous squamous cell carcinoma and Staging System for Metastatic Cutaneous other cutaneous ; p. 301–14. Squamous Cell Carcinoma of the Head and 25. Chu MB, Slutsky JB, Dhandha MM, et al. Neck. Ann Surg Oncol. 2012;19(13):4252-8. Evaluation of the Definitions of “High-Risk” 11. Zwald F. Toward a Better Definition of High- Cutaneous Squamous Cell Carcinoma Using Risk Cutaneous Squamous Cell Carcinoma. the American Joint Committee on Cancer JAMA Dermatology. 2013;149(5):547-8. Staging Criteria and National Comprehensive 12. Jambusaria-Pahlajani A, Kanetsky PA, Karia Cancer Network Guidelines. J . PS, et al. Evaluation of AJCC Tumor Staging 2014;2014:154340. doi: 10.1155/2014/154340. for Cutaneous Squamous Cell Carcinoma and Epub 2014 Sep 17. a Proposed Alternative Tumor Staging System. JAMA Dermatol. 2013;149(4):402-10. Correspondence: J. Ryan Jackson, MS; 13. Veness MJ, Palme CE, Morgan GJ. High- [email protected] risk cutaneous squamous cell carcinoma of the head and neck: results from 266 treated patients with metastatic lymph node disease. Cancer. 2006;106:2389. 14. Ross AS, Whalen FM, Elenitsas R, et al. Diameter of involved predicts outcomes in cutaneous squamous cell carcinoma with

NICKLE, HACKERT, JACKSON, FAVREAU Page 15 Review of Rhomboid Flaps and Their Modern Modifications

Alexandra Grammenos, MS,* Ana M. Rivas, BS,* Jacqueline A. Thomas, DO,** David L. Thomas, MD, JD, EdD***

*Medical Student, 2nd Year, Nova Southeastern University College of Osteopathic Medicine, Ft. Lauderdale, FL **Assistant Professor of Dermatology and Mohs Surgery, Nova Southeastern University College of Osteopathic Medicine, Ft. Lauderdale, FL ***Professor and Chair of Surgery, Nova Southeastern University College of Osteopathic Medicine, Ft. Lauderdale, FL

Abstract Background: First proposed by Alexander Limberg in 1945, the rhomboid flap has been modified to accommodate a variety of different surgical settings. Rhomboid flaps have proven to be integral in a variety of sub-specialties. Objective: The aim of this review is to examine the rhomboid flaps of Limberg, Dufourmentel, Webster, and Quaba and report the appropriate surgical context and advantages of each flap type. Methods & Materials: A literature search was performed of PUBMED, SCOPUS, and MEDLINE for articles assessing the proper surgical context and subsequent outcomes of the Limberg, Dufourmentel, Webster, and Quaba/Sommerlad flaps. Results: The use of rhomboid flaps proves optimal for closure of large defects because of the reduced risk of distal-end necrosis. Conclusion: This review details a thorough examination of modification of rhomboid flaps and their effectiveness as an alternative to primary closure. The original Limberg flap was further modified success, as compared to the width-to-length ratio Introduction by Richard Webster in 1960 to include a 30° of the pedicle as traditionally thought.10 Vascular Following the formation of a surgical defect, a 1,5 closure type is chosen to suit the surrounding transposition flap with an M-plasty closure. testing methods, such as dermal bleeding pricks The addition of the M-plasty allowed for a better and reperfusion time testing, are performed prior tissue characteristics and defect size. While 11 primary closure is often the first choice, simple distribution of tension, reducing the strain on to closure to ensure adequate perfusion. suturing may not be sufficient to appropriately the distal tip of the flap. In 1987, Awf Quaba close the defect. Size is the most common designed a modified rhomboid flap to address Discussion deterrent from primary closure, where the long or closing a circular defect with minimal healthy skin Limberg Flap short axes of the defect are either too long or too loss. While all four flaps are widely useful, it is The simplicity and efficacy of the Limberg flap wide, respectively.1,2 Rhomboid flaps maintain imperative to not distort the anatomy or maintain 3 makes it versatile, allowing for adequate cosmesis continuity of texture, color, and vascularity skin laxity. Limberg, Dufourmentel, Webster, with few complications. The excision is made up with the surrounding tissue, eliciting the most and Quaba flaps are types of transposition flaps of two equilateral triangles with 60° and 120° successful aesthetic outcome.3 Rhomboid flaps that are generally smaller in size than both the 7,8 angles, respectively. The flap is then created by are most commonly used for tumor resection in advancement and rotational flaps. extending a line of equal length from either of head and neck but are widely applicable The varieties of rhomboid flaps provide superior the 120° angles. At the end of this extended line, in fields such as general and plastic surgery, results when compared to skin grafts of similar a second line is created at an angle of 60° (Figure ophthalmology, and otolaryngology.1,3 size and location because the sub-papillary and 1a). It is important to ensure this line is parallel In 1946, Alexander Limberg first designed a sub-dermal vascular plexuses are maintained to the side of the rhomboid defect.2,12 The flap through the flap’s pedicle, which is absent in skin surgical protocol for transposition of a rhomboid 4,7 is then transposed and ready for closure (Figure flap 120° onto a proximal skin defect.4 This was grafts. The enhanced vascularization established 1b). innovative and successful due to the retention through the pedicle lends the rhomboid methods The placement of the Limberg flap greatly of local vascularity via the pedicle.5 Claude to successful treatment in post-burn defect 9 influences its survival and aesthetic appearance Dufourmentel later modified this in 1966, using treatment. Even when adequate blood supply (Figure 1c). The flap should be positioned in a reduced angle size to ≤ 60° to limit the amount is maintained, the surgeon must be cautious the direction of minimal tension and maximum of disruption of healthy tissue during closure of the tension on the distal end of the flap in 4 extensibility. The flexibility of the skin in the area while increasing pedicle width.1,2 This closure order to reduce the likelihood of necrosis. It 6 is important to note that the maintenance of to be excised can be inspected by pinching the is compared to that created by primary closure. 13 perfusion pressure is the critical aspect to flap skin with the forefinger and thumb. Placement A B C

Figures 1a - 1c. Steps employed in the Limberg flap.

Page 16 REVIEW OF RHOMBOID FLAPS AND THEIR MODERN MODIFICATIONS A B C

Figures 2a – 2c. Steps employed in the Dufourmentel flap. of the flap becomes more challenging on the face, flap does not require as great of a transposition modification to the Limberg flap is the excess where anatomical features may create boundaries. movement of the flap covering the primary defect healthy tissue that is lost.33 A study conducted The incisions should not be placed on relaxed as the Limberg method.7,18 If a defect is less than by Kaya proposed a modification to the Limberg skin tension lines; instead, incisions should be 60° and cannot be closed via primary closure, the flap that included a complete lateralization of the made parallel to the relaxed skin tension lines.13 defect angle is enlarged and a Limberg flap is rhomboid from the intergluteal cleft.32 Placement of incisions parallel to Langer’s lines employed. The Dufourmentel flap is also used for the allows the resulting to fall within the creases 34 Further alterations to the Dufourmentel flap treatment of pilonidal sinus disease. Yildar of the skin.12 A reduction in tension on the flap were applied to address certain limitations of this et al. applied a modified Dufourmentel flap for decreases the likelihood of necrosis of the donor type of transposition flap. One modification, a wider defects of pilonidal sinus disease. This tissue.14 The parallelogram-shaped defects are “diamond flap,” is used to decrease the amount modification involved using an S-type oblique ideal for the use of a Limberg flap.15 of healthy tissue excised from a Dufourmentel excision along with a modified Dufourmentel Limberg flaps have been used in a variety of flap.19 The diamond flap modified one of the acute flap that placed the excision lateral to the areas of the body. Particularly, this flap has been corners of the rhomboid excision following initial midline of the intergluteal sulcus.35 A modified, practical for defects on the face, neck, and back. completion of the Dufourmentel flap design. asymmetrical Dufourmentel flap can be used However, the usefulness of the Limberg flap One of the acute corners is transformed into a to treat pilonidal sinus disease with low rates of makes it easy to employ and modify for defects in circular shape. In order for the flap to close the necrosis and complications.36 other parts of the body, such as the , new circular shape, an arc of the same dimension 13,16,17 19 A literature review of pilonidal sinus surgery the floor and ala of the nose, and the lips. is created on the part of skin that is transposed. found the use of the Limberg flap to be the Dufourmentel Flap Advantages of Limberg and Dufourmentel quickest and least complicated treatment for The design of a Dufourmentel flap allows for Flaps wound healing.20-22 Pilonidal surgical procedures closure of rhomboid defects of differing angles, Considering the tension of the skin, primary that healed with tension-free primary closure had such as acute angle closure, when compared to closure can cause an increase in dehiscence greater disadvantages than wounds that healed closure with a Limberg flap.2 The angles of the and infection in defects.25 A similar trend was using the Limberg flap.23,24 rhomboid do not need to equal 60° as in the observed comparing secondary-intention healing 26 Webster Flap Limberg flap. Upon bisection of the parallelogram, and the use of the Limberg flap. Secondary The Webster flap was developed in 1960 as a a plumb line is placed at 90°. A second line is intention requires greater care and increases the further adaptation of the original Limberg flap, created parallel to one of the sides of the defect. risk of infection of the open wound compared to The angle that is created from the two extended the closed sutures of a Limberg flap. In areas of lines is bisected with a line that is the same length the body where skin may not have great laxity, as a side of the rhomboid. The bisected line creates secondary-intention closure may be preferred a smaller tip angle of the flap.7 From the end of the over a rhomboid flap such as the Limberg bisected line, another line is created that is parallel method.15 to the longitudinal axis of the parallelogram 2 The Dufourmentel flap is advantageous with This parallel line must still be equal 12 (Figure 2a). smaller defects because of the narrow flap. in length to a side of the rhomboid. The design Application of the Dufourmentel flap has shown of the Dufourmentel flap allows two flaps to be satisfactory cosmetic results with a decrease in created from each of the four angles of a square flap rotation, compared to the Limberg flap, and defect. In the case of an asymmetrical rhomboid, adequate survival from vascularity from sub- four flaps can be created from a rhomboid defect dermal plexus.27,28 (Figures 2b-c).2 Rhomboid Flaps for Pilonidal Sinus Surgery The ideal scenario for the use of a Dufourmentel The Limberg flap has shown to be one of the flap is with an acute angle defect of greater than quickest and least complicated treatments for 60°. Other factors besides defect angle should be 29,30 wound healing in pilonidal sinus surgery. considered in the application of the Dufourmentel Through placement of the most inferior angle flap over other methods. The presence of laxity of of the rhomboid slightly lateral to midline, the the tissue favors the use of a Dufourmentel flap Figure 3. Initial step employed in the Webster recurrence and maceration of the defect was flap. over the simpler Limberg flap. A Dufourmentel decreased.31,32 A slight disadvantage of this GRAMMENOS, RIVAS, THOMAS, THOMAS Page 17 utilizing a 30° angle of rotation and an M-plasty A B closure at the base of the defect (Figure 3, p. 17).37 The original protocol describes the procedure of removing triangular-shaped areas of both skin and subcutaneous tissues along the nasolabial folds, allowing for medial movement of the cheek tissues.38 Webster flaps have commonly been used on the lower lip following carcinoma removal where the defect size is greater than 80% of the total area.39 This technique prevents and poor aesthetic outcomes, as well as maintaining good oral competence and sensation.10 Webster flaps retain good sensation and muscle tone of the upper lip, with special attention to retention of facial grooves and blood supply.9 With the reduction of the flap’s angle of rotation from 60° to 30°, there is less disruption and removal of healthy tissue when compared to the aforementioned flaps. Additionally, the utilization of the M-plasty closure allows for a more uniform distribution of tension across the flap. This reduction in tension promotes better revascularization to the most distal ends of the flap, ensuring a more rapid healing time with less Figures 4a – 4b. Steps employed in the Quaba/Sommerlad flap. chance of distal-flap necrosis. There have been several modifications of need to create a rhomboidal defect, and (2) a flap defects following skin-cancer excision. One study 42 the Webster flap technique described in the smaller than the defect size. The predominate by Murillo et al. examined the use of skin-cancer literature, all of which utilize the reduced angle advantage to this is a reduced sacrifice of healthy ablation in conjunction with flap transposition of rotation for more favorable surgical outcomes. donor tissue. In the case of Quaba/Sommerlad, a for complete resection of the malignancy while 44 One such modification is the combination of the diagonal is extended to be two-thirds the size of maintaining optimal aesthetic outcomes. Due to 39 Webster and Johanson techniques for closure of the defect (Figure 4b). Although most simple the variety of skin thicknesses and compositions defects greater than 80% with a staircase scar. The to achieve, the Quaba/Sommerlad flap taken throughout the head and neck region, this study Johanson technique was originally designed as a from shortest diagonal does not always achieve mapped the anatomical areas and based closure 39 staircase suture for a defect no larger than two the most aesthetically pleasing outcome. In protocols on where the cancer was located. For thirds of the total area with improved scarring contrast to the other rhomboid flap designs, the instance, a rhomboid flap was utilized in the aesthetic when compared to the linear suture Quaba/Sommerlad flap is raised less than the medial aspects of the cheek because of the ease .44 of Webster.10 As with rhomboid flaps, the step size of the defect and donor tissue is allowed of transposition of the attached skin Closure of technique described by Johanson is of clinical to contribute to the wound closer. Key stitch these defects produced great aesthetic outcomes. importance due to maintenance of tissue texture locations are integral to adequately distribute between the donor and lesion sites, retention the tension to ensure good vascularization to the Conclusion 39 of intact muscle fibers and innervation, and distal aspects of the flap. The extensive application and versatility of rhomboid flaps contributes to their success better aesthetic outcomes along the lateral The Quaba/Sommerlad method has been 40 and popularity among physicians. Several lower lip. The proposed modification allows especially helpful in the closure of hand defects for the combination of closure of a larger defect where the cutaneous branch of the dorsal different types of and modifications to flaps (Webster) with the more aesthetically pleasing metacarpal artery serves as the perforator artery better tailor this small surgical procedure for staircase sutures ( Johanson). supplying blood to the flap from the pedicle.43 In certain defects. The Limberg flap was the initial flap used for rhomboid defects, with effective In 2011, Minagawa et al. further modified the hand surgery, in order to increase flap vascularity, Webster flap, altering the flap formation itself, Bailey et al. prosed a modification that starts the healing and acceptable cosmetic appearance. including the formation of the flap on the perforator artery at the junction of the dorsal The simple design of a Limberg flap gave rise contralateral side of the defect versus bilaterally in metacarpal artery and the dorsal communicating to more advanced and complex flaps such as 37 concert with a nasolabial flap.41 The combination branch of the common digital artery. This the Dufourmentel, Webster, and Quaba flap. of closure via the modified Webster method increases the ability to cover the dorsal aspect of Rhomboid flaps have shown great effectiveness and nasolabial flap ensured optimal aesthetic the finger past the proximal interphalangeal joint. over alternative methods of healing such as 45,46 outcome of the lower lip with good donor site The increased blood flow makes this technique primary closure. Such advantages propel their matching in color and texture. The unaffected especially helpful when treating defects on use and are a common reason why these flaps 37 oral commissure remained untouched, and the burned or grafted areas. are one of the first techniques used by surgeons. formation of horizontal suturing between the Advantages of the Quaba/Sommerlad Flap While certain closure techniques are invasive mouth and nasolabial groove was avoided.38 and involved, rhomboid flaps are associated There are numerous advantages to the Quaba/ 47 Quaba/Sommerlad Flap Sommerlad flap, the most obvious being the with a good prognosis and rapid healing time. The Quaba/Sommerlad flap was first described in decrease in excision of healthy donor tissue when Continued modifications and advances in 39 1987 as a rhomboid-flap modification for closure raising the flap. In addition, this protocol dermatologic surgery will further improve the of circular defects (Figure 4a). Because circular permits more variability of the donor site, outcomes of rhomboid flaps. 39 defects are the most common types encountered allowing for better concealment of scarring. in facial surgeries, their closure is of great clinical 19 Ablation and Rhomboid Flaps significance. This flap uses the basis of the Rhomboid flaps are commonly used for closure of Limberg flap with two key modifications: (1) no

Page 18 REVIEW OF RHOMBOID FLAPS AND THEIR MODERN MODIFICATIONS References 20. Sit M, Aktas G, Yilmaz E. Comparison of the 37. Webster RC, Coffey RJ, Kelleher RE. Total 1. Aydin O, Tan O, Algan S, et al. Versatile use of three surgical flap techniques in pilonidal sinus and partial reconstruction of the lower lip with rhomboid flaps for closure of skin defects. Eurasian surgery. Am Surg. 2013;79(12):1263. innervated muscle-bearing flaps. Maxillofac Plast J Med. 2011;43:1-8. 21. Mentes O, Bagci M, Bilgin T, et al. Limberg flap Reconstr Surg. 1960;25:360-71. 2. Lister GD, Gibson T. Closure of rhomboid skin procedure for pilonidal sinus disease: results of 353 38. Hamahata A, Saitou T, Ishikawa defects: The flaps of Limberg and Dufourmentel. J patients. Langenbeck Arch Surg. 2008;393:185-9 M, et al. Lower lip reconstruction using Plast Reconstr Aesthet Surg. 1972;25:300-14. 22. Aslam M, Shoaib S, Choudhry A. Use of a combined technique of the Webster and Johanson methods. Ann Plast Surg. 2013;70:654-6. 3. Khan AAG, Shah KM. Versatility of Limberg Limberg flap for pilonidal sinus - A viable option. J flap in head and neck region. International Journal Ayub Med Coll Abbottabad. 2009;21(4):31-3. 39. Wechselberger G, Gurunluoglu R, Bauer T, et of Case Reports and Images. 2012;3(6):13-18. 23. Muzi MG, Milito G, Cadeddu F, et al. al. Functional lower lip reconstruction with bilateral cheek advancement flaps: Revisitation of Webster 4. Mathew J, Varghese S, Jagadeesh S. The Limberg Randomized comparison of Limberg flap versus modified primary closure for the treatment of method with a minor modification in the technique. flap for cutaneous defects - a two year experience. Aesthet Plast Surg. 2002;26:423-8. Indian J Surg. 2007;29:184-86. . Am J Surg. 2010;200(1):9-14. 24. Tavassoli A, Noorshafiee S, Nazarzadeh R. 40. Johanson B, Aspelund E, Breine U, et al. Surgical 5. Wong D. A practical approach to local flaps treatment of non-traumatic lower lip lesions with on the face after excision of small cancerous Comparison of excision with primary repair versus Limberg flap. Int J Surg. 2011;9(4):343-6. special reference to the step technique. Scandinavian skin lesions. Hong Kong J Dermatol Venereol. J Plast Reconstr Surg. 1974;8:232-40. 2012;20:171-74. 25. Okus A, Sevinc B, Karahan O, et al. Comparison of Limberg flap and tension-free primary closure 41. Minagawa T, Maeda T, Shioya, R. Esthetic 6. Lober C, Mendelsohn H, Fenske N. Rhomboid and safe lower lip reconstruction of an asymmetric transposition flaps. Aesthet Surg J. 1985;9(2):121-24. during pilonidal sinus surgery. World J Surg. 2012;36:431-5. defect due to cancer resection: A modified Webster 7. Rohrer TE, Bhatia A. Transposition flaps in method combined with a nasolabial flap. J Oral cutaneous surgery. Dermatol Surg. 2005;31(8):1014-23. 26. Jamal A, Shamim M, Hashmi F, et al. Open Maxillofac Surg. 2011;69:256-9. excision with secondary healing versus rhomboid 8. Imran D, Koukkou C, Bainbridge C. The excision with Limberg transposition flap in the 42. Quaba AA, Sommerlad BC. A square peg into rhomboid flap: A simple technique to cover the skin management of sacrococcygeal pilonidal disease. J a round hole: A modified rhomboid flap and its defect produced by excision of a mucous of a Pak Med Assoc. 2009;59(3):157-60. clinical applications.Br J Plast Surg. 1987;40:163- digit. J Bone Joint Surg Br. 2003;85:860. 70. 27. Nessar G, Kayaalp C, Seven C. Elliptical rotation 9. Ertas N, Kucukcelebi A, Erbas O, et al. Comparison flap for pilonidal sinus. Am J Surg. 2004;187:300-3. 43. Bailey SH, Andry D, Saint-Cyr M. The of elongations provided by subcutaneous pedicle dorsal metacarpal artery perforator flap: A case rhomboid flap and A-plasty in rat inguinal skin. 28. Jain V, Verma S, Verma A, et al. Basal cell report utilizing a Quaba flap harvested from a Plast Reconstr Surg Glob Open. 2006;117:486. carcinoma over chest wall (sternum) treated with previously skin-grafted area for dorsal 5th digit Dufourmentel flap: Report of a case with review of coverage. Hand. 2010;5:322-5. 10. Patel KG, Sykes JM. Concepts in local flap literature. J Cutan Aesthet Surg. 2012;3(2):115-8. design and classification. Oper Tech Otolaryngol - 44. Murillo W, Fernandez W, Caycedo D, et al. Head Neck Surg. 2011;22(1):13-23. 29. Tekin A. A simple modification with the Cheek and inferior eyelid reconstruction after skin Limberg flap for chronic pilonidal disease. J Surg cancer ablation. Clin Plast Surg. 2004;31:49-67. 11. Mishra S. A simple method for predicting Tech Case Rep. 2005;138:951-3. survival of pedicled skin flaps before completely 45. Defektlerinin C, Romboid O, Cok F, et al. raising them. Indian J Plast Surg. 2011;44:453-7. 30. Aithal SK, Rajan CS, Reddy N. Limberg flap Versatile use of rhomboid flaps for closure of skin for sacrococcygeal pilonidal sinus a safe and sound defects. Eurasian J Med. 2011;43:1-8. 12. Turan T, Kuran I, Ozcan H, et al. Geometric limit procedure. Indian J Plast Surg. 2003;75(4):298-301. of multiple local Limberg flaps: A flap design. Plast 46. Dass T, Zaz M, Rather A, et al. Elliptical Excision Reconstr Surg Glob Open. 1999;104(6):1675-8. 31. Akin M, Leventoglu S, Mentes B, et al. with Midline Primary Closure versus Rhomboid Comparison of the classic Limberg flap and Excision with Limberg Flap Reconstruction in 13. Chasmar L. The versatile rhomboid (Limberg) modified Limberg flap in the treatment of pilonidal Sacrococcygeal Pilonidal Disease: A prospective, flap. Plast Surg. 2007;15(2):67-71. sinus disease: A retrospective analysis of 416 Randomized Study. Indian J Surg. 2012;74:4 patients. Surg Today. 2012;40:757-62. 14. Pirozzi N, Pettorini L, Scrivano J, et al. Limberg 47. Shah A, Zoumalan R, Constantinides M. Skin Flap for Treatment of Necrosis and Bleeding at 32. Kaya B, Eris C, Atalay S. Modified Limberg Aesthetic Repair of Small to Medium-sized Nasal Haemodialysis Arteriovenous Angioaccess Puncture transposition flap in the treatment of pilonidal sinus Defect. Facial Plast Surg. 2008;24:1. Sites. Eur J Vasc Endovasc Surg. 2013;46(3):383-7. disease. Tech Coloproctol. 2012;16:55-9. 48. McCallum IJ, King PM, Bruce J. Healing by 15. Mathew J, Varghese S, Jagadeesh S. The Limberg 33. Afsarlar C, Yilmaz E, Karaman A, et al. primary closure versus open healing after surgery flap for cutaneous defects - a two year experience. Treatment of adolescent pilonidal disease with a new for pilonidal sinus: systematic review and meta- Indian J Plast Surg. 2007;69(5):184-6. modification to the Limberg flap: Symmetrically analysis. Br Med J. 2008;336:868-71. rotated rhomboid excision and lateralization 16. Chandrashekhar L, Gayathri G, Omprakash 49. Copcu E, Metin K, Aktas A, et al. Cervicopectoral TL, et al. Embedded toothbrush foreign body in of the Limberg flap technique. J Pediatr Surg. 2012;48:1744-9. flap in head and neck cancer surgery. World J Surg cheek - report of an unusual case. Eur Arch Paediatr Oncology. 2003;1:29. Dent. 2011;12(5):272-4. 34. Kayaalp C, Aydin C, Olmez A. Dufourmentel 50. Lee BT, Lin SJ, Bar-Meir ED, et al. Pedicle 17. Turan A, Tuncel U, Kostakoglu N. The use Rhomboid Flap for Pilonidal Disease. Dis Colon . 2009;52:169-70. perforator flaps: a new principle in reconstructive of single rhomboid flap in reconstruction of surgery. Plast Reconstr Surg. 2010;125:201-8. microstomia. Burns. 2012;38(7):e24-7. 35. Yildar M, Cavdar F, Yildiz M. The 18. Dionyssopoulos A, Mandekou-Lefaki I, Delli F, evaluation of a modified Dufourmentel flap et al. T- and B-cutaneous pseudolymphomas treated after S-type excision for pilonidal sinus disease. Correspondence: Jacqueline A. Thomas, DO; by surgical excision and immediate reconstruction. ScientificWorldJournal. 2013 Jun 17;2013:459147. Nova Southeastern University, 3200 South Dermatol Surg. 2006;32(12):1526-9. doi: 10.1155/2013/459147. Print 2013. 36. Friedl P, University Drive, Ft. Lauderdale, FL 33328; Ph: Rappold E, Jager, C. Effective and minimally painful 800-356-0026; F: 954-262-3981; 19. Tamborini F, Cherubino M, Scamoni S, et al. surgery of pilonidal sinus-asymmetric transposition [email protected] A modified rhomboid flap: The “diamond flap.” flap according to Dufourmentel. J Dtsch Dermatol Dermatol Surg. 2012;38(11):1851-5. Ges. 2011;9(4):333-5. GRAMMENOS, RIVAS, THOMAS, THOMAS Page 19 Delineating the Perforating Dermatoses: Case Reports and a Review of the Literature

Richard Limbert, DO,* Rachel White, BA,** Richard Miller, DO, FAOCD***

*Dermatology Resident, 3rd year, Nova Southeastern / Largo Medical Center, Largo, FL **Medical Student, 4th year, Philadelphia College of Osteopathic Medicine, Philadelphia, PA ***Program Director, Dermatology Residency, Nova Southeastern / Largo Medical Center, Largo, FL

Abstract Perforating dermatoses (PD) are a rare group of papulonodular skin with a distinct central keratotic core representing the transepidermal elimination of an altered dermal substance. Diagnosis is established via biopsy and histopathologic evaluation. The primary PD are best categorized into four groups: reactive perforating collagenosis (RPC), acquired perforating dermatosis (APD), elastosis perforans serpiginosa (EPS), and perforating calcific elastosis (PCE). The primary PD can be differentiated based on the perforating substance, the distribution of the lesions, and their unique associations. Diagnosis of a PD should prompt screening for underlying systemic disease. Treatment of the PD is often difficult, but numerous reports have shown success. Here we present our case reports and a thorough literature review incorporating all identified case reports and studies found on PubMed as of July 2015. Introduction follicular structures. Special stains may be used to Perforating dermatoses (PD) represent a rare help identify the perforating substance. group of papulonodular skin diseases with a The precise pathogenesis of the PD is unknown. It distinct central keratotic core. The core represents is postulated that the primary PD may be due to the transepidermal elimination of an altered abnormal dermal substances, whether genetically 1 dermal substance. Diagnosis is established altered or acquired. Other theories question via biopsy and histopathologic evaluation. whether the PD represent a unique pathologic Whereas primary PD are diseases chiefly process or are simply a result of mechanical characterized by transepidermal elimination, exposure of dermal substances.1 secondary PD are a group of unrelated Various classifications of the PD have been used disorders in which transepidermal elimination 1 in the literature, and various names have been is a minor phenomenon of another disorder. reported for each entity. This has led to ambiguity The primary PD are best categorized into four and confusion. A useful classification scheme of Figure 1. Dome-shaped papules with keratotic groups: reactive perforating collagenosis (RPC), 2 all PD was proposed by Patterson in 1984: core overlying the knuckles. acquired perforating dermatosis (APD), elastosis perforans serpiginosa (EPS), and perforating 1. Perforation as an incidental histologic finding calcific elastosis (PCE). The primary PD can be 2. Perforation associated with other cutaneous differentiated based on the perforating substance, and systemic disorders (secondary PD) the distribution of the lesions, and their unique associations (Table 1).1 Diagnosis of a PD 3. Disorders chiefly characterized by perforation should prompt screening for underlying systemic (primary PD) disease. Treatment of the PD is often difficult, but Even more numerous are the variations of the numerous reports have shown success. primary PD in the literature. The authors feel the Amongst the PD, a shared histopathologic best classification is outlined in Table 1 and will sequence occurs, and findings depend on the be discussed in this review. stage of evolution.1 First, a hyperkeratotic plug or crust forms. The plug enlarges, inducing Case Reports surrounding epidermal hyperplasia and occasional Case 1 dyskeratosis. Inflammatory cell aggregates may A 17-year-old Hispanic male presented with be seen in the plug and adjacent dermis. In Figure 2. Dome-shaped papules with keratotic a three-year history of spreading “.” He well-developed lesions, the plug contains the core overlying the elbow. denied pain, pruritus, or manipulation of lesions perforating substances: collagen, elastic fibers, and requested treatment for cosmetic concerns. amorphous degenerated material, and/or altered allergic rhinitis, and medulloblastoma. He Past medical history was significant for asthma, had attempted numerous over-the-counter Table 1. Primary perforating dermatoses treatments, including topical salicylic acid and Perforating Substance Location Associations cryotherapy, with no improvement. Reactive perforating Collagen Extremities, overlying None Physical exam revealed skin-toned, dome-shaped collagenosis sites of trauma papules with a central keratotic core concentrated over the dorsal hands (Figure 1), elbows (Figure Acquired Collagen, elastic fibers, Lower extremities or Pruritus, diabetes, 2), and knees. perforating or necrotic material generalized renal failure, liver dermatosis disease, malignancies, A punch biopsy of a representative lesion on the endocrinopathies elbow was taken (Figure 3). There was a cup- Elastosis perforans Elastic fibers Lateral neck, flexures Genetic diseases, shaped invagination of acanthotic epidermis with serpiginosa penicillamine a plug of keratin, collagen, and inflammatory debris. High magnification revealed Perforating calcific Calcified elastic fibers , periumbilical, Multiparity, vertically oriented collagen fibers undergoing elastosis areolar transepidermal elimination. Verhoeff-van

Page 20 DELINEATING THE PERFORATING DERMATOSES: CASE REPORTS AND A REVIEW OF THE LITERATURE A punch biopsy was taken from the lower leg, RPC is histologically characterized by a cup- screening labs were ordered, and the patient shaped invagination of acanthotic epidermis was started on 0.25% ointment containing a plug of vertically oriented collagen bid. The biopsy revealed a channel through fibers, keratin, and inflammatory debris. The an acanthotic epidermis filled with a plug of connective tissue surrounding the plug is amorphous, degenerated material with overlying typically unremarkable.6 After the plug falls off, parakeratosis and underlying neutrophils the epidermis atrophies.There is no gold standard (Figure 6). Verhoeff-van Gieson stain failed of treatment for RPC. Treatment is not necessary to demonstrate perforating elastic fibers. Labs since lesions may spontaneously resolve and are revealed a low hemoglobin and elevated alkaline largely asymptomatic.1 Yasmeen et al. compared phosphatase, AST, and ALT. treatment between 10 patients with RPC and report the most successful responses were with oral and topical tretinoin combined Figure 3. Invagination of acanthotic with emollients.5 Other treatments reported epidermis with a plug of keratin, collagen, and with varying levels of success include: topical inflammatory debris (H&E). steroids under occlusion, photochemotherapy, UVB phototherapy, cryotherapy, allopurinol, Gieson stain failed to demonstrate perforating methotrexate, and electrical nerve stimulation.1,8 elastic fibers. A diagnosis of reactive perforating Despite all treatment regimens, RPC often collagenosis was made. recurs.8 The patient was started on topical tretinoin 0.1% Acquired Perforating Dermatosis daily. He returned after three months for APD is overwhelmingly the most common follow-up and displayed moderate improvement, PD. This category includes all PD arising in but smooth papules remained. The patient noted adults that have been previously reported as that the lesions tended to recur and decided Figure 6. A channel through acanthotic acquired RPC, acquired EPS, Kyrle’s disease, against further treatment. 1 epidermis filled with a plug of amorphous and perforating , among others. degenerated material (H&E). Case 2 The splitting of this group reflects the variable A 42-year-old African American male presented histologic morphologies found in lesions of APD depending on the stage of development. A biopsy with an extremely pruritic, widespread eruption A diagnosis of acquired perforating dermatosis may reveal perforating collagen, elastic fibers, that had been worsening over three weeks. was established. The patient was referred to his amorphous degenerated material, and/or altered He tried over-the-counter creams and gastroenterologist for evaluation and treatment 9 follicular structures. emollients with no benefit. Past medical history of his anemia and hepatitis and was subsequently was significant for alcoholic hepatitis. He lost to follow-up. The classification of APD has changed over time, reported a similar eruption several years ago that and disagreement remains amongst authors. was successfully cleared with phototherapy. Discussion Kyrle’s disease was first described by Kyrle in Physical exam revealed hyperpigmented, 1916 as “follicular et parafollicularis in cutem keratotic papules scattered on the face, trunk, and Reactive Perforating Collagenosis penetrans” in a diabetic female with generalized RPC was first reported in a 6.5-year-old female hyperkeratotic nodules.10 Kyrle’s disease is extremities (Figure 4). Some lesions displayed a 3 strikingly linear pattern (Figure 5). by Mehregan et al. in 1967. It is a very rare, sometimes used synonymously with APD, and inherited disease thought to be caused by a genetic some describe it as the end stage of excoriated abnormality of collagen. Attempts to isolate the hyperplastic nodules of folliculitis. Patterson specific genetic defect have been unsuccessful et al. propose that perforating folliculitis and to date. RPC occurs in an autosomal-recessive acquired RPC are subsets of Kyrle’s disease.2 pattern, although there have been isolated reports Others suggest perforating folliculitis is not a 4 of autosomal-dominant inheritance. Onset is in specific disease, as perforation of follicles can childhood, with a mean age of 5.3 years, and there occur in any folliculitis regardless of the etiology. 5 is no gender or racial predilection. The term “acquired perforating dermatosis” was 10 Lesions present as 5 mm to 8 mm, flesh-colored first used by Rapini et al. in 1989. Kim et al. papules with a central keratotic core. They grow characterize the various APD lesions in a study over three to four weeks and may spontaneously of 30 cases as follows: KD-like hyperkeratotic resolve over six to 10 weeks, though some papules, PF-like follicular infiltrating papules, Figure 4. Keratotic papules scattered on the persist.1,6 Some lesions can grow up to 2 cm with EPS-like serpiginous hyperkeratotic papules, or trunk. increased age and a lack of treatment.4 There RPC-like keratotic plugged umbilicated papules 11 may be only a few localized lesions, or lesions (most common: 66.7%). can be more widespread and numerous. RPC APD occurs in middle-aged adults, with no can remain quiescent for long periods of time, 1,11 7 gender or geographic predilection. In the but a relapsing-remitting course is common. largest study to date, Kim et al. report a mean age RPC occurs in areas of superficial trauma and of onset of 55.5 years.11 APD generally presents Koebnerizes more than any other PD.2,5 The most as umbilicated papules and nodules with a central frequently affected areas include the dorsal hands, white keratotic core. The core is sometimes forearms, elbows, and knees.3,5,6 Some reports picked and physically removed by patients. Giant have associated exacerbations with cold weather variants have been reported where lesions are 2 in the winter months. It is postulated that the 12 cm. Lesions can be found on any cutaneous cold may induce degeneration of collagen and 5,8 surface, but the extensor lower legs are most Figure 5. Linear keratotic papules on the leg. thinning of the epidermis. Pruritus is not common, and many cases are generalized and prominent but has been reported in less than half 5 diffuse. Koebner’s phenomenon is occasionally of patients.

LIMBERT, WHITE, MILLER Page 21 seen, resulting in a linear configuration.11 Mucous four patients with APD. Schreml et al. agree that hydroxyapatite, or silicon, and metabolic membranes, palms, and soles are generally spared, all APD have similar pathogeneses because all disturbances leading to alteration of fibers, but there has been a report of conjunctival and eliminated materials, including collagen, elastin prompting their elimination.1,11 Another theory buccal involvement.11 Lesions persist anywhere and keratin, have been noted in one patient.17 proposes a role of abnormal vitamin A or D.6 from one month to five years, with an average On the contrary, Saray et al. propose that APD Anecdotal success of for treatment has duration reported by Kim et al. of 7.8 months. represent a broad spectrum and are not variants led to the idea of a possible infectious etiology.23,24 13 The most common reported associated symptom of the same process. Kim et al. also did not There are also familial reports of APD. One is pruritus, and few report pain.11 Rarely, a observe overlapping histologic features in the 11 family in India has 22 members afflicted with secondary infection may occur from (S. same patient. 25 so-called Kyrle’s disease over five generations. aureus), atypical mycobacteria (M. abscessus), or There is also debate as to whether perforation Unique features are also noted within the affected fungi (Mucor sp.).1 actually exists. Schreml et al. point out that family members, including eye changes and APD is most commonly associated with diabetes scratching may lead to epidermal gaps that expose palmoplantar lesions.There are no clinical studies or chronic renal failure (CRF). APD is also subepithelial contents, which may appear as conducted regarding treatment for APD, and associated with numerous other underlying perforation.17 Therefore, they advocate obtaining therefore there is no gold standard. Conventional systemic diseases, particularly ones that cause continuous imaging of the evolving lesions to treatments have been derived from case reports. pruritus.1 Saray et al. report that 86.4% of APD guide understanding of the pathohistologic Kim et al. report 93.3% of patients responding patients have at least one systemic disease.13 An mechanism; however, that is not possible at this to topical steroids and 80% responding to estimated 90.9% of diabetic patients with APD point.APD is proposed to originate from pruritus antihistamines to decrease pruritus.11 Control of have an associated nephropathy, but non-diabetic resulting in chronic scratching and epidermal pruritus and treating any underlying disease is CRF has been reported as well. Further, most hyperplasia. A similar is process is seen in prurigo the key to treatment. Other commonly reported patients with CRF are on dialysis, but it can nodularis, a common concomitant condition treatments include intralesional steroids and occur earlier in the disease course prior to dialysis seen with APD.11 This theory is supported by topical retinoids. Other reported treatments initiation. Approximately 10% of dialysis patients the presence of Koebnerization. Fujimoto et al. include: UVB, PUVA, oral retinoids, and develop APD. 11 Other reported associations propose that scratching exposes keratinocytes to methotrexate.11 Some dialysis patients have been include liver disease (primary biliary cirrhosis, advanced glycation end product (AGE)-modified cured of disease after transplant.27 hepatitis, alcoholic cirrhosis), malignancies extracellular matrix proteins, specifically collagen Allopurinol has recently emerged as a useful 18 The interaction leads to terminal (Hodgkin’s lymphoma, , types I and III. treatment of APD. Hoque et al. successfully differentiation of keratinocytes via AGE receptor thyroid cancer, acute leukemia), endocrinopathies treated four patients with a giant variant with (CD 36) and results in keratinocytes along 12 (hypothyroidism, hyperparathyroidism), allopurinol. The theory behind the use of a infections/infestations (, aspergillosis, with glycated collagen moving upward through xanthine oxidase inhibitor is that it reduces herpes zoster, ), congestive heart epidermis. oxygen free radicals, which cause collagen damage failure, neurodermatitis, , and 1 Other studies suggest that the interaction of and skin necrosis. Allopurinol is also reported to Kim et al. reported a pregnant APD 28 AIDS. keratinocytes with altered structural proteins inhibit neutrophil activity. case with no associated DM, CRF or previous plays a role. Fibronectin is increased in both the cutaneous disease.11 APD has also associated with Antibiotics have been used to treat culture- serum and lesional skin of diabetic and renal- negative APD. Clindamycin is reported to have TNF alpha inhibitors, bevacizumab, sirolimus, 18 Fibronectin is an 13 failure patients with APD. cleared a case after Kasiakou et al. noted the and indinavir. extracellular matrix protein involved in epithelial inflammatory histologic findings and suspected An extremely rare variant of APD called cell signaling, movement, and differentiation. It an infectious cause, thought to be anaerobic verrucous perforating collagenomas is reported binds collagen IV and keratinocytes and may 24 bacteria. Doxycycline has also been used in the literature but not well understood. It induce epithelial proliferation and transepidermal successfully in cases of APD.29 Metronidazole 19 One study identified type IV is characterized by verrucous papules with elimination. was successfully used in another case in which collagen from the basement membrane as transepidermal elimination of collagen. It occurs biopsy showed inflammatory infiltration in the 9 the specific type of collagen eliminated.20 after severe trauma. lesion. As opposed to clindamycin, metronidazole Other proteins overexpressed in APC include: Acquired perforating calcific collagenosis is an β does not have any anti-inflammatory properties, transforming growth factor beta-3 (TGF -3), 23 APD variant that develops after topical calcium which supports an infectious etiology. ) exposure. In certain cultures, matrix metalloproteinase-1 (MMP-1), and tissue chloride (CaCl2 A vitamin D3 synthetic analogue, tacalcitol, used CaCl is used to treat dermatitis and pruritus. inhibitor of metalloproteinase-1 (TIMP-1); 2 however, this may simply reflect normal wound in the treatment of psoriasis has also been used to Lee et al. report two patients exposed to a CaCl - 30 2 17,21 treat APD. Tacalcitol inhibits the proliferation containing emulsion, used to produce bean curd, healing in these sites. 14 of keratinocytes and simultaneously modifies who developed coalescing umbilicated papules. An abundance of neutrophil remnants has inflammatory mediators. Since APD lesions Histologically, the lesions show transepidermal been found in early lesions of APD, leading contain significant inflammation and epidermal elimination of calcified collagen and elastic tissue. some to believe that proteolytic enzymes, such hyperplasia-like psoriatic lesions, Escribano- 17 The The authors were able to experimentally induce as collagenase and elastase, play a role. Stablé et al. decided to use this treatment on a case enzymes may transgress the epidermis and digest 30 similar phenomena in guinea pigs. Patel et al. refractory to topical steroids and antihistamines. extracellular matrix components, leading to report similar findings in a patient exposed to They report achieving complete remission after 14-16 It also destruction of anchoring fibrils and collagen IV, rock salts containing calcium chloride. two months. has been described in oil field workers exposed to ultimately resulting in their elimination.Another the chemical.14 theory pinpoints diabetic microvasculopathy 11,22 Elastosis Perforans Serpiginosa Histologically, APD shows cup-shaped as the culprit. Microvasculopathy leads to Lutz first described EPS in 1953 and termed the dermal necrosis by hypoxia. This would incite the invagination of epidermis plugged with disease “ follicularis serpiginous” based 31 amorphous, degenerated material and elimination of the necrotic dermal material.This on the unique configuration. In 1955, Miescher inflammatory cell debris.10 Rapini et al. originally mechanism is supported by positive periodic acid- characterized the specific pathologic finding of proposed that the histologic findings represent Schiff staining of thickened blood vessel walls in perforating elastic fibers and termed the disease 32 different stages or different types of lesions the upper dermis in diabetic patients with APD. “elastoma intrapapillare perforans verruciform.” within the same pathologic process.10 They report Other proposed hypotheses involve deposition Dammert and Putkonen coined the current name 33 elimination of both collagen and elastic fibers in of substances such as calcium salts, uric acid, in 1958. EPS can either be idiopathic (most

Page 22 DELINEATING THE PERFORATING DERMATOSES: CASE REPORTS AND A REVIEW OF THE LITERATURE common), drug-induced, or reactive. There are influence the differentiation of keratinocytes.42 calcified elastic fibers in the upper reticular and also few familial reports of EPS.34,35 They propose that altered elastic fibers papillary dermis.48 The pathogenesis of PCE is It is reported that 40% of EPS patients have an accumulate in the dermis and induce upward unknown. Pruzan et al. propose lesions originate movement and differentiation of keratinocytes from repeated stretching of the skin from underlying genetic disorder involving fibrous 46 tissue including: Down syndrome, Ehlers- via elastin-receptor protein, 67 kDa. Expression multiparty, obesity, ascites, or surgery. Danlos syndrome, osteogenesis imperfecta, of 67 kDa elastin-binding protein has not been No successful treatments have been identified for Marfan syndrome, pseudoxanthoma elasticum reported in normal epidermal keratinocytes but PCE. Failed treatments include topical tretinoin (PXE), , Rothmund-Thomsonis overexpressed in elastin-rich connective tissue. and topical steroids.48,52 1,33 Other reports have implicated immunologic syndrome, acrogeria, and Moyamoya disease. 33 An extensive history and physical exam should dysfunction like that seen in Down syndrome. Secondary Perforating Dermatoses be performed when establishing the diagnosis. Reports of EPS implicating dysfunctional Secondary perforating dermatoses are a group However, pediatric dermatologists collectively do epidermal barrier from mechanical trauma, of unrelated disorders in which a substance not routinely perform genetic testing on the sole chemicals like calcium chloride salt water, and is transepidermally eliminated as a minor basis of EPS in an otherwise healthy child.36 scabies are best classified as APD.14,15,33 phenomenon of another disorder. As with the primary PD, the epidermis becomes hyperplastic, EPS has a predilection for males in a 4:1 ratio As with other perforating disorders, there are surrounds the substance being eliminated, and and most commonly occurs in the second decade no clinical trials or gold standards for treatment. 33,37 causes the upward extrusion via keratinocyte of life. EPS is characterized by 2 mm to 5 Several treatments are described with mixed 1 maturation. Secondary PD include substances mm, keratotic papules in a serpiginous or annular efficacy and poor long-term success. Destructive that are endogenous (chondrodermatitis 1 Rings of papules may be up to configuration. modalities attempted include cryotherapy, nodularis helicis, hematomas, , several centimeters in diameter. Lesions are most curettage, electrocautery, dermabrasion, excision, lichen nitidus, papular mucinosis, amyloidosis), commonly located on the lateral neck but can also tape stripping, topical salicylic acid, and CO2 exogenous foreign materials (silica, wood, suture), appear on the face and flexural extremities.1 There laser.1 Caution is advised, as there is risk of infectious organisms (chromoblastomycosis, are isolated case reports of EPS on the axilla and scarring with these modalities. Furthermore, 33 , schistosomiasis, tuberculosis, glans penis. EPS is typically asymptomatic. treatment is not necessary, as EPS remains leishmaniosis), ( annulare, Diagnosis is established through biopsy. EPS localized and asymptomatic. Mixed results are lipoidica, sarcoidosis, rheumatoid lesions show eosinophilic elastic fibers and also reported using topical and intralesional nodules, tophaceous gout), and neoplastic cells steroids, UVB, erbium-doped yttrium aluminium other basophilic debris filling tortuous channels 43 (melanoma, Paget’s disease, mycosis fungoides, Successful 1,53 that span from the papillary dermis to the (Er-YAG) laser, and pulsed dye laser. pilomatricoma, nevus sebaceous). Perforation case reports are described using topical epidermis. In adjacent dermal tissue there are in these dermatoses is best considered an imiquimod, topical calcipotriene ointment, and many inflammatory cells including lymphocytes, incidental finding. systemic isotretinoin.43 Topical tazarotene was macrophages, and multinucleated giant cells and 33 used with remission of lesions that recur when also altered elastic tissue. Elastic fibers are best highlighted by special stains like Verhoeff-van medication was discontinued. Phenytoin was Conclusion tried in one case with no success.33 There are also The PD have been classified and named in Gieson, which stains elastin black. reports of successful treatment of resistant cases numerous ways in the literature, which has led Pass et al. documented the first drug-induced with photodynamic therapy and topical allium to confusion. This thorough literature review EPS in a patient with Wilson’s disease on cepa-allantoin-pentaglycan gel.43 attempts to compile all available case reports long-term treatment with penicillamine.38 EPS and studies of the PD from PubMed. The has also been documented in patients taking Perforating Calcific Elastosis primary PD are best organized into four groups. penicillamine for cystinuria. Thirty-three percent PCE is an exceedingly rare disease and is both Diagnosis of a PD should prompt the evaluation of patients on high-dose therapy will develop histologically and clinically similar to PXE. for underlying disease. Further studies are needed EPS.39 EPS has also been recognized in patients Some authors argue PCE is a localized form of to elucidate effective treatment options. on low-dose treatment for rheumatoid arthritis, PXE, while others say it is a separate entity.44 primary biliary cirrhosis, and scleroderma. Still, PCE is acquired and localized, whereas PXE is penicillamine-induced EPS accounts for only an autosomal-recessively inherited, multi-organ References 40 1. Bolognia JL, Jorizzo JL, Schaffer JV, editors. 1% of all EPS cases. The elastic fibers seen in systemic disease. PCE has also been reported Dermatology. 3rd rev. ed. Philadelphia: Elsevier 46 these cases have a distinct lumpy appearance as “periumbilical perforating PXE.” The first Limited; 2012. p. 1599. with lateral buds. Penicillamine is hypothesized case of PCE was diagnosed as EPS with PXE 47 2. Patterson JW. The perforating disorders. J Am to disrupt desmosine crosslinks within elastin by Schutt in 1965. Lund and Gilbert reported 40 Acad Dermatol. 1984 Apr;10(4):561-81. by inhibiting the enzyme lysyl oxidase. The PCE as a separate entity in 1976, terming it damaged elastic tissue is then eliminated through “perforating PXE,” and Lever and Schaumburg- 3. Mehregan AH, Schwartz OD, Livingood CS. the epidermis. Theories regarding the role of Lever coined the term “PCE” in 1989.48,49 Reactive perforating collagenosis. Arch Dermatol. 1967 Sep;96(3):277-82. copper metabolism in EPS are debunked by the PCE occurs most commonly in middle-aged, presence of EPS in patients taking penicillamine obese, multiparous African-American females.1 4. Kumar V, et al. Familial reactive perforating for diseases other than Wilson’s. Penicillamine Woo and Rasmussen reviewed 22 cases of PCE collagenosis. J Dermatol. 1998 Jan;25(1):54-6. has also been shown to cause other cutaneous and reported an 82% female preponderance with 5. Bhat YJ, Manzoor S, Qayoom S, Wani R, Baba changes like pseudo-PXE and acquired cutis a mean age of onset of 43 years.50 PCE presents AN, Bhat AH. Familial Reactive Perforating 33,39 Furthermore, laxa by damaging elastic tissue. as yellowish verrucous plaques with keratotic Collagenosis. Indian J Dermatol. 2009;54(4):334- penicillamine has been found in the skin of an papules scattered at the periphery. Lesions are 7. EPS patient 25 years after discontinuation of usually exclusively distributed on the abdomen, the drug. This may explain why discontinuing 6. James WD, Elston DM, Berger TG, Andrews especially periumbilically; however, there is a GC, editors. Andrews’ Diseases of the skin: Clinical penicillamine does not prevent more EPS lesions 41 report of lesions on periareolar skin in one patient Dermatology. London: Saunders/Elsevier; 2011. p. from developing. 45,50,51 and on the axilla of another. 497-505. Most theories for EPS pathogenesis focus on Histologically, PCE shows short, thick, 7. Ramesh V, Sood N, Kubba A, Singh B, Makkar altered elastic fibers. A hypothesis presented basophilic, calcified elastic fibers residing in R. Familial reactive perforating collagenosis: a by Fujimoto et al. through in vitro studies the lower dermis. EPS, in contrast, reveals non- clinical, histopathological study of 10 cases. J Eur demonstrated that elastic fibers interact with and

LIMBERT, WHITE, MILLER Page 23 Acad Dermatol Venereol. 2007 Jul;21(6):766-70. Metin A. Clinicopathological features of 25 and brief review of such dermatoses. J Dermatol. patients with acquired perforating dermatitis. Eur 1997 Jul;24(7):458-65. 8. Pai VV, Naveen KN, Athanikar SB, Shastri DU, J Dermatol. 2013 Nov-Dec;23(6):864-71. Rai V. Familial reactive perforating collagenosis: 40. Boccaletti VP, Ricci RR, De Panfilis G. a report of two cases. Indian J Dermatol. 2014 23. Khalifa M, Shim I, Kaabia N, Bahri F, Trabelsi Unknown: papules on the knees. Dermatol May;59(3):287-9. A, Letaief AO. Regression of skin lesions of Kyrle’s Online J [Internet]. 2011 May 15 [cited 2015 disease with metronidazole in a diabetic patient. J Jan];17(5):12. Available from: http://escholarship. 9. Delacrétaz J, Gattlen JM. Transepidermal Infect. 2007 Dec;55(6):e139-40. org/uc/item/3md9m666. elimination of traumatically altered collagen. Report of three cases and consideration on the 24. Kasiakou SK, Peppas G, Kapaskelis AM, 41. Neri I, Gurioli C, Raggi MA, et al. Detection of relationship between ‘collagenome perforant Falagas ME. Regression of skin lesions of Kyrle’s D-penicillamine in skin lesions in a case of dermal verruciformé’ and reactive perforating collagenosis. disease with clindamycin: implications for an elastosis after a previous long-term treatment for Dermatologica. 1976;152(2):65–71. infectious component in the etiology of the disease. Wilson’s disease. J Eur Acad Dermatol Venereol. J Infect. 2005 Jun;50(5):412-6. 2015 Feb;29(2):383-6. 10. Rapini RP, Herbert AA, Drucker CR. Acquired perforating dermatosis. Evidence for 25. Shivakumar V, Okade R, Rajkumar V, Prathima 42. Fujimoto N, Tajima S, Ishibashi A. Elastin combined transepidermal elimination of both KM. Familial Kyrle’s disease: a case report. Int J peptides induce migration and terminal collagen and elastic fibers. Arch Dermatol. 1989 Dermatol. 2007 Jul;46(7):770-1. differentiation of cultured keratinocytes via 67 kDa Aug;125(8):1074-8. elastin receptor in vitro: 67 kDa elastin receptor is 26. Viswanathan S, Narurkar SD, Rajpal A, Nagpur expressed in the keratinocytes eliminating elastic 11. Kim SW, Kim MI, Lee JH, et al. A NG, Avasare SS. Rare presentation of Kyrle’s disease materials in elastosis perforans serpiginosa. J Invest clinicopathologic study of thirty cases of acquired in siblings. Indian J Dermatol. 2008;53(2):85-7. Dermatol. 2000 Oct;115(4):633–9. perforating dermatosis in Korea. Ann Dermatol. 27. Saldanha LF, Gonick HC, Rodriguez HJ, et 2014 Apr;26(2):162-71. 43. Campanati A, Martina E, Giuliodori K, al. Silicon-related syndrome in dialysis patients. et al. Elastosis perforans serpiginosa: a case 12. Hoque SR, Ameen M, Holden CA. Acquired Nephron. 1997;77(1):48–56. successfully treated with intralesional steroids reactive perforating collagenosis: four patients 28. Shih CJ, Tsai TF, Huang H, Ko WC, Hung CM. and topical allium cepa-allantoin-pentaglycan with a giant variant treated with allopurinol. Br J Kyrle’s disease successfully treated with allopurinol. gel. Acta Dermatovenerol Alp Pannonica Adriat. Dermatol. 2006 Apr;154(4):759-62. Int J Dermatol. 2011 Sep;50(9):1170-2. 2014;23(2):39-41. 13. Saray Y, Seçkin D, Bilezikci B. Acquired 29. Gonul M, Cakmak SK, Gul U, et al. Two 44. Schwartz RA, Richfield DF. Pseudoxanthoma perforating dermatosis: clinicopathological features cases of acquired perforating dermatosis treated elasticum with transepidermal elimination. Arch in twenty-two cases. J Eur Acad Dermatol Venereol. with doxycycline therapy. Int J Dermatol. 2006 Dermatol. 1978 Feb;114(2):279–80. 2006 Jul;20(6):679-88. Dec;45(12):1461-3. 45. Lopes LC, Lobo L, Bajanca R. Perforating 14. Lee SJ, Jang JW, Lee WC, et al. Perforating 30. Escribano-Stablé JC, Doménech C, calcific elastosis. J Eur Acad Dermatol Venereol. disorder caused by salt-water application and its Matarredona J, et al. Tacalcitol in the treatment 2003 Mar;17(2):206-7. experimental induction. Int J Dermatol. 2005 of acquired perforating collagenosis. Case Rep Mar;44(3):210-4. 46. Pruzan D, Rabbin PK, Heilnian ER, et Dermatol. 2014 Feb 27;6(1):69-73. al. Periumbilical perforating pseudoxanthoma 15. Knox JM, Dinehart SM, Holder W, et al. 31. Lutz W. Keratosis follicularis serpiginosa. elasticum. J Am Acad Dermatol. 1992 Acquired perforating disease in oil field workers. J Dermatologica. 1953;106(3-5):318-9. Apr;26(4):642-4. Am Acad Dermatol. 1986 Apr;14(4):605–11. 32. Miescher G. Elastoma intrapapillare perforans 47. Schutt DA. Pseudoxanthoma elasticum and 16. Patel RR, Zirvl M, Walters RF, Kamino H. verraciforme. Dermatologica. 1955 Mar- elastosis perforans serpiginosa. Arch Dermatol. Acquired perforating calcific collagenosis after May;110(3-5):254-66. 1965 Feb;91:151–2. topical calcium chloride exposure. J Cutan Pathol. 2010 May;37(5):593-6. 33. Kassardjian M, Frederickson J, Griffith J, 48. Budania A, De D, Saikia UN, Kanwar AJ, Shitabata P, Horowitz D. Elastosis perforans Mahajan R, Yaday S. Periumbilical perforating 17. Schreml S, Hafner C, Eder F, Landthaler M, serpiginosa in association with scabies mite. J Clin pseudoxanthoma elasticum--an acquired Burgdorf W, Babilas P. Kyrle disease and acquired Aesthet Dermatol. 2013 Oct;6(10):36-40. perforating disorder. Int J Dermatol. 2012 perforating collagenosis secondary to chronic renal Apr;51(4):439-41. failure and diabetes mellitus. Case Rep Dermatol. 34. Langeveld-Wildschut EG, Toonstra J, van 2011 Sep;3(3):209-11. Vloten WA, Beemer FA. Familial elastosis 49. Lever WF, Schaumburg-Lever G. perforans serpiginosa. Arch Dermatol. 1993 Histopathology of the skin. 7th ed. Philadelphia, 18. Fujimoto E, Kobayashi T, Fujimoto N, et Feb;129(2):205-7. PA: JB Lippincott & Co; 1989. p. 466. al. AGE-modified collagen I and III induce keratinocyte terminal differentiation through AGE 35. Ayala F, Donofrio P. Elastosis perforans 50. Woo TY, Rasmussen JE. Disorders of receptor CD36: epidermal-dermal interaction in serpiginosa. Report of a family. Dermatologica. transepidermal elimination. Int J Dermatol. 1985 acquired perforating dermatosis. J Invent Dermatol. 1983;166(1):32-7. Jun;24(5):267–79. 2010 Feb;130(2):405-14. 36. Vearrier D, Buka RL, Roberts B, et al. What is 51. Bressan AL, Vasconcelos BN, Silva RS, Alves 19. Bilezikçi B, Seckin D, Demirhan B. Acquired the standard of care in the evaluation of elastosis Mde F, Gripp AC. Periumbilical and periareolar perforating dermatosis in patients with chronic perforans serpiginosa? A survey of pediatric perforating pseudoxanthoma elasticum. An Bras renal failure: a possible role for fibronectin. J Eur dermatologists. Pediatr Dermatol. 2006 May- Dermatol. 2010 Sep-Oct;85(5):705-7. Acad Dermatol Venereol. 2003 Mar;17(2):230-2. Jun;23(3):219–24. 52. Kocatürk E, Kayala M, Zindanci I, Koç M. 20. Herzinger T, Schirren CG, Sander CA, et 37. Lewis KG, Bercovitch L, Dill SW, Robinson- Periumibilical perforating pseudoxanthoma al. Reactive perforating collagenosis – Bostom L. Acquired disorders of elastic tissue: elasticum. Indian J Dermatol Venereol Leprol. transepidermal elimination of type IV collagen. Clin part I. Increased elastic tissue and solar elastotic 2009 May-Jun;75(3):329. Exp Dermatol. 1996 Jul;21(4):279-82. syndromes. J Am Acad Dermatol. 2004 Jul;51(1):1– 53. Karpouzis A, Giatromanolaki A, Sivridis E, 21; quiz 22-4. 21. Gambichler T, Birkner L, Stucker M, et Kouskoukis C. Acquired reactive perforating al. Up-regulation of transforming growth factor- 38. Pass F, Goldfischer S, Sternlieb I, Sheinber collagenosis: current status. J Dermatol. 2010 beta3 and extracellular matrix proteins in acquired IH. Elastosis perforans serpiginosa during Jul;37(7):585-92. reactive perforating collagenosis. J Am Acad penicillamine therapy for Wilson disease. Arch Dermatol. 2009 Mar;60(3):463-9. Dermatol. 1973 Nov;108(5):713–5. Correspondence: Richard Limbert, DO; 22. Akoglu G, Emre S, Sungu N, Kurtoglu G, 39. Iozumi K, Nakagawa H, Tamaki K. Penicillamine induced degenerative dermatoses: Report of a case [email protected] Page 24 DELINEATING THE PERFORATING DERMATOSES: CASE REPORTS AND A REVIEW OF THE LITERATURE Cogan’s Syndrome with Cutaneous Findings: A Case Report and Review of Dermatologic Manifestations

Khasha Touloei, DO,* Emily Tongdee, BS,** Brittany Smirnov, DO,*** Tracy Favreau, DO,**** Leeor Porges, DO*

*Second-year Dermatology Resident, Nova Southeastern University College of Osteopathic Medicine / Broward General Medical Center, Ft. Lauderdale, FL **Third-year Medical Student, Florida International University Herbert Wertheim College of Medicine, Miami, FL ***First-year Dermatology Resident, Nova Southeastern University College of Osteopathic Medicine / Broward General Medical Center, Ft. Lauderdale, FL ****Director/Chairman of Dermatology, Nova Southeastern University College of Osteopathic Medicine / Broward General Medical Center, Ft. Lauderdale, FL

Abstract Cogan’s syndrome (CS) is a rare autoimmune disease characterized by ocular and vestibuloauditory symptoms, occasionally presenting with vasculitis. Although rare, dermatologic manifestations often compel patients to seek medical attention. Classically associated with vasculitis, cutaneous findings vary widely, making it vital for dermatologists, neurologists, rheumatologists, and primary care physicians alike to consider CS in any patient with ocular and vestibuloauditory symptoms, especially with dermatologic findings. We report a rare case of CS with dermatologic findings, reviewing the literature for its classification, epidemiology, etiology, pathophysiology, and current therapeutic approaches. We emphasize the spectrum of cutaneous findings, which spans from non-specific skin and urticarial vasculitis to palpable purpura and gangrenosum. Coexisting cutaneous conditions can delay diagnosis, affecting patient outcome particularly in reference to permanent sensorineural hearing loss. Irreversible loss of visual acuity can also result from delayed treatment. Dermatologic findings may direct physicians to CS and prevent severe negative outcomes.

headache and a that developed over six days on the dorsum of his hands bilaterally (Figure 1). The patient reported that similar symptoms initially began one year prior, during which time he presented to and was discharged from the emergency room without intervention. The patient reports that the rash began as a single papule on the left lateral hand, enlarged and then eventually ulcerated to become what he described as looking like a “cigarette burn.” Review of

Figure 1. Erythematous, crusted papules and plaques.

both anti-neutrophilic cytoplasmic antibodies Introduction 1,2,8,9 The first case of non-syphilitic keratitis in (ANCA) and anti-endothelial antibodies. association with audiovestibular symptoms was CS has been described most commonly in 1 reported in 1935 by Morgan and Baumgartner. Caucasians, with no reported sex predisposition.6,7 In 1945, David Cogan reported four additional Pediatric Cogan’s syndrome, however, affects cases, and the syndrome was hence termed males more than females by a ratio of 2:1.4 Both 2 Cogan’s syndrome (CS). CS is a rare vasculitis typical and atypical CS generally present between whose hallmark features are non-syphilitic the second and fourth decades of life, although interstitial keratitis and audiovestibular symptoms other sources suggest the first three decades.3,4 similar to Meniere’s syndrome, including hearing The age of onset of pediatric CS cannot be 4 loss, tinnitus, and vertigo. By 1980, Haynes specified due to the low number of cases reported 4 et al. defined atypical CS, a variant wherein in the literature. Disease course varies, but it most patients present with ocular and audiovestibular often becomes chronic and slowly progressive symptoms other than the interstitial keratitis and following an initial flare.10 This article will focus Meniere’s-type symptoms characteristic of the on both variants of CS and review the literature 5 typical variant. of dermatologic findings in CS. The pathophysiology of CS is believed to be autoimmune in nature, initially supported by the Case Report positive response to .3 Western A 47-year-old Trinidadian male presented Figure 2. Light brown, reticulated blots and immunofluorescence eventually with a two-month history of progressive loss hyperpigmentation with splinter hemorrhages revealed autoantibodies to the inner ear, including of visual acuity and bilateral hearing, as well as and petechiae. TOULOEI, TONGDEE, SMIRNOV, FAVREAU, PORGES Page 25 systems was positive for pruritus and vertigo. of the limbs, genitals or mouth, pyoderma antibodies against the inner ear were identified 10,24,29-31 In an Physical examination revealed a Fitzpatrick 3 gangrenosum, and limbal erythema. in CS patients, in addition to IgG, IgM, and analysis of 24 pediatric cases, only three presented 12-14 Other patient with erythematous, crusted papules and IgA antibodies against the cornea. with cutaneous manifestations of skin rash and autoantibodies, such as ANCA and rheumatoid plaques on the dorsal lateral hands and digits urticarial vasculitis.4 Although musculoskeletal, factor (RF), have also been reported but remain and light brown, reticulated hyperpigmentation ocular, and vestibular symptoms improved non-specific due to their prevalence in other on bilateral lower extremities, with splinter throughout the disease course, cardiovascular rheumatologic and autoimmune conditions.3 hemorrhages on the right hallus and petechiae and skin manifestations did not. In this study, on the bilateral toes (Figures 1, 2). Ocular One study found an immunodominant a delayed diagnosis was related to a worse examination revealed bilateral inferior autopeptide common among eight CS patients outcome. Additionally, among 50 case reports conjunctival erythema. Ophthalmologic that showed similarities to antigens such as SSA/ of CS, only four presented with dermatologic consultation diagnosed the patient with anterior Ro and the reovirus III major core protein lambda findings. These findings included a transient 15 scleritis and scleromalacia. 1. The autopeptide was also similar to cell- macular rash, a hemorrhagic, ulcerated vasculitis density enhanced protein tyrosine phosphatase-1 Two biopsies were performed for hematoxylin rash, and two cases complicated with pyoderma (DEP-1/CD148), a protein expressed on sensory and eosin (H&E) staining as well as a lesional 6,29,30,32 One case emphasized the gangrenosum. epithelia of the inner ear and on endothelial cells. direct immunofluorescence (DIF) to rule out significance of an early diagnosis to prevent In CS, IgG antibodies bind to cells expressing Buerger’s disease or any other form of vasculitis. hearing loss, while another highlighted how 15 DEP-1/CD148 and inhibit cell proliferation. Biopsy revealed spongiotic dermatitis with isolated systemic manifestations may delay Antibodies targeting heat shock proteins 70 overlying crust, and DIF was negative and thus diagnosis if ocular and audiovestibular symptoms and 68kDa derived from bovine inner ear have non-diagnostic (Figure 3). An extensive workup 32,33 are absent. also been reported.16 All the aforementioned was performed to rule out vasculitis, with all A common problem in the diagnosis of CS patients cochlear-targeting autoantibodies were originally studies being negative. An autoimmune workup is the variability of disease progression over time. thought to be specific for CS but were later found for lupus was negative. Additionally, the patient As evidenced by Zulian et al., hallmark symptoms in children with idiopathic sensorineural hearing was negative for HIV and RPR. MRI scan of the do not follow a chronological timeline.30 In that loss.17 brain revealed a right basal ganglia, left external study, a 4-year-old Caucasian boy developed capsule, and left central semiovale infarct. The conjunctivitis 10 days prior to admission. Etiology constellation of ocular inflammation (diagnosed Although hallmark symptoms may occur within The exact etiology of CS remains unknown; as scleritis), bilateral hearing loss, thrombocytosis, years of one another, this patient developed however, various hypotheses have been proposed. pruritic skin lesions, and elevated ESR and CRP sensorineural hearing loss soon after admission. It is possible that an infection may trigger CS, was consistent with CS. However, in many cases it is not until much time given that upper respiratory tract infections 4 has passed, often after many misdiagnoses, that precede 21% of cases. CS may also be associated the patient finally presents with the second of the with infections or tuberculosis 18,19 two hallmarks. By that time, physicians may not vaccination. In support of the theory of associate the two symptoms, making it difficult infection, some HLA loci, including HLA-B17, to diagnose the symptoms as a syndromic event, HLA-A9, HLA-Bw35, and HLA-Cw4, 20 let alone as a rare condition such as CS. Despite correlate with CS. being an uncommon presentation, dermatologic manifestations can help clue physicians in to Presentation CS, especially when the patient does not have a CS primarily presents with bilateral interstitial history of both hallmark features. keratitis with audiovestibular symptoms. In addition to its hallmark features, CS may also The significance of early diagnosis cannot be present with systemic, cardiovascular, neurologic, stressed enough, especially in pediatric cases of and gastrointestinal manifestations.3 Skin CS. This is due to the positive outcomes associated manifestations are not commonly seen but do Figure 3. H&E biopsy from the right dorsal with early treatment via immunosuppression. occur rarely.4 hand. Systemic symptoms tend to fully resolve upon treatment. Most important, though, vision and The presentation varies slightly between typical hearing loss can be reversible or irreversible and atypical CS. Discussion depending on the extent of delay from illness onset The clinical criteria for typical CS include non- CS is a clinical diagnosis based on ocular to time of treatment. Orsoni et al. present a case syphilitic interstitial keratitis, audiovestibular inflammation, audiovestibular symptoms, report of two children with CS, both treated with symptoms similar to Meniere’s syndrome, and negative serologic tests, and histological 31 27 -sparing immunosuppression. an interval between the onsets of the first two evidence of vasculitis. However, due to the 3 While both children’s systemic symptoms criteria of less than two years. Ocular symptoms variability of symptoms and lack of specific resolved, one child’s visual acuity and hearing loss are usually bilateral. Audiovestibular symptoms tests, CS is best retrospectively diagnosed after 28 improved whereas the second child had no ocular can develop at any time throughout the disease responsiveness to corticosteroid treatment. or auditory improvement. Given the devastating course and commonly include hearing loss, Dermatologic symptoms can be the impetus for effects of irreversible deafness and vision loss, vertigo, tinnitus, ataxia, and oscillopsia.3 Systemic CS patients seeking treatment, so the condition awareness of less-common presentations, such manifestations may be present secondary to should be considered when certain dermatologic as those of the skin, can decrease the occurrence vasculitis of all vessel sizes, with complaints findings present along with the constellation of not just negative outcomes, but permanent of headache, arthralgia, fever, arthritis, and of symptoms characteristic of CS (keratitis, negative outcomes. myalgia being most common.9,21,22 Aortitis with scleritis, vertigo, and hearing loss). Although aortic insufficiency is a major cardiovascular Pathophysiology 10,23 our patient presented with a biopsy indicating manifestation that occurs in 10% of patients. CS is mediated by lymphocytic and plasma-cell hemorrhagic crusts and scabs, other dermatologic 11 Neurological symptoms include sensorineural findings have also been documented. The few infiltration of the corneal and cochlear tissue. hearing loss but also extend to hemiparesis or skin manifestations reported among CS patients Autoantibodies targeting corneal, inner ear, hemiplegia secondary to a cerebral vascular and endothelial antigens have been found to have varied from non-specific erythematous or 1,2,8,9 accident and aphasia secondary to a transient 6,24,25 be specific to CS. More specifically, IgG urticarial rash, purpura, nodules or ulceration ischemic event. Finally, gastrointestinal

Page 26 COGAN’S SYNDROME WITH CUTANEOUS FINDINGS: A CASE REPORT AND REVIEW OF DERMATOLOGIC MANIFESTATIONS Table 1. Summary of prior case reports of CS with dermatologic manifestations.

Case Report Dermatologic Findings Notes Review of clinical features of CS Three of 23 patients had skin manifestations: Of the various manifestations of CS, only skin and among 23 children with CS cardiovascular manifestations did not improve over 4 (Paginini, et al. ) 1) 9-year-old female: maculopapular rash resembling marginated time. erythema of parvovirus B-19 infection on the lower limbs.

2) Previously healthy 4-year-old Caucasian male: developed transient macular rash after admission to the hospital.

3) Only one patient developed a skin rash over the course of the disease. Case report of pediatric CS (Podder, A 4-year-old female developed cutaneous manifestations over the Cutaneous manifestations need not appear at disease et al.29) course of her diseases, characterized by a vasculitic rash on her onset and may evolve as the disease progresses. that was initially hemorrhagic. The rash progressed to ulceration and was slow to heal. Ophthalmic, audiovestibular, and A 57-year-old Caucasian female with a history of vestibuloauditory This patient sought treatment due to her dermatologic systemic manifestations of CS symptoms presented with two months of progressively worsening symptoms, which permitted the eventual diagnosis and (Boulingez et al.6) ulcerations on the leg despite treatment. 0.5 cm pustular treatment of and CS. lesions were visible on the shins, some of which were deep and ulcerative. Blisters were also present on the left calf and foot. The right ankle was transitioning into superficial ulcerations with dark blue borders and surrounding erythema. After serological testing, histological examination, and slit lamp examination, she was diagnosed with pyoderma gangrenosum occurring within CS, both of which healed dramatically with oral minocycline therapy (although deafness remained). Case report of pediatric CS (Zulian, A 4-year-old Caucasian boy presented 10 days after an upper CS can present as a constellation of systemic et al.29) respiratory tract infection having developed bulbar conjunctivitis, symptoms that do not necessarily appear fever, and arthralgias. After admission to the hospital, he developed simultaneously. The ability to recognize both common sensorineural hearing loss and a transient macular rash and arthritis and rare symptoms despite separation through time on his right, eventually diagnosed as CS. can allow an early diagnosis and treatment – especially important in the prevention of loss of visual acuity and sensorineural hearing. Case report of atypical CS with An 18-year-old black female with atypical CS presented with Urticarial vasculitis is reported as a new manifestation urticarial vasculitis (Ochonisky, et al.34) urticarial vasculitis. This is the first case report emphasizing urticarial of atypical CS. vasculitis as a new manifestation of atypical CS. Ochonisky further explains the significance of the patient’s high levels of Chlamydia trachomatis antibodies in the pathogenesis of CS. Case report of symptoms post- A patient with atypical CS was proposed to have developed palpable Wohlgethan discusses the importance of recognition of splenectomy in atypical CS purpura and uveitis, with splenectomy as the trigger. precipitating factors rather than CS as the sole primary (Wohlgethan, et al.35) cause of skin manifestations. Two cases of pediatric CS (Orsoni, et A 13-year-old presented with limbal hyperemia and edema in one This case emphasizes the importance of early al.31) knee. A 9-year-old presented without skin manifestations. Both diagnosis and treatment to prevent permanent patients had a history of ocular and vestibulocochlear symptoms that amblyopia and profound deafness. The commonality presented at separate times throughout the disease progression. Other of the underdiagnosis of CS should also be noted, symptoms included headache, asthenia, arthritis, and splenomegaly. as ophthalmic and otologic symptoms often do not Following corticosteroid-sparing immunosuppressive drug therapy, occur simultaneously, rendering diagnosis more symptoms (excluding ocular inflammation and hearing loss) resolved difficult. Orsoni et al. state the need for a broad in both patients. Hearing loss and visual acuity improved significantly multidisciplinary approach to optimize early diagnosis, in the 13-year-old, with best-corrected visual acuity improving from especially in systemic autoimmune diseases such as 21/200 to 21/100. The 9-year-old, however, incurred irreversible ocular CS.31 This underlines the benefits of physicians being and otologic damage. aware of possible skin manifestations to use as a clue in CS when the hallmark symptoms have not fully manifested yet. manifestations may range from diarrhea and due to variability in the progression of the disease. Furthermore, Meniere’s does not present with melena to abdominal pains, presumed to be due However, systemic manifestations occur more ocular symptoms. VKH is a multisystem disease to mesenteric arteritis.26 often in atypical CS and can thus be used to that includes uveitis, leukoderma, sensorineural 3 The clinical criteria for atypical CS include various distinguish between the two. deafness, alopecia, and poliosis. CS does not More important, inflammatory ocular symptoms (with or without present with alopecia or poliosis. VKH presents with a severe exudative uveitis interstitial keratitis), audiovestibular symptoms not seen in CS.24 Finally, syphilis mimics CS unlike Meniere’s syndrome, and more than two 3 with an acute onset of bilateral audiovestibular years between the onsets of the first two criteria. CS needs to be diagnosed early to prevent the onset 24 29 Ocular manifestations that separate atypical from of severe hearing loss. The differential diagnosis symptoms. However, the interstitial keratitis in syphilis is chronic, not acute, and does not typical CS include acute closure angle glaucoma, of CS includes syphilis, Vogt-Koyanagi-Harada 24 show active inflammatory changes. Upon slit- retinal vasculitis, papillitis, central vein occlusion, (VKH) syndrome, and Meniere’s syndrome. 22 lamp examination of the deep cornea, a vascular vasculitic optic neuropathy, and papilledema. Diagnosis may be difficult during the onset of CS The systemic vasculitis of atypical CS involves the due to audiovestibular similarities to Meniere’s infiltrate can be seen as ghost vessels in patients A significant difference between CS cardiovascular, neurological, and gastrointestinal syndrome. The loss of balance and ataxia present with syphilis. 24 and syphilis is that patients with syphilis present systems, unlike in typical CS. Differentiation in CS differ from the typical vertigo of Meniere’s 24 between typical and atypical CS may be difficult syndrome, which can help differentiate the two. with infiltrate more central to the cornea.

TOULOEI, TONGDEE, SMIRNOV, FAVREAU, PORGES Page 27 Other Cases likely of systemic manifestations, dermatologic 2002;360:915–22. findings are often the impetus for patients to Although CS is not characteristically described to 16. Naumann A, Hempel JM, Schorn K. seek healthcare, highlighting the importance of present with dermatologic manifestations, there Detection of immune response to the inner ear recognizing these presentations of CS. have been several reports. Table 1 summarizes proteins in patients with sensorineural hearing dermatologic symptoms described among various loss. Laryngorhinootologie. 2001;80:237–44. case reports of CS. References 17. Berti E, Vannucci G, Lunardi C, Bianchi 1. Morgan RF, Baumgartner CJ. Meniere’s Treatment B, et al. Identification of autoantibodies against disease complicated by recurrent interstitial Medical treatment varies based on symptom inner ear antigens in a cohort of children keratitis: excellent results following cervical severity and the extent of the disease. Steroid with idiopathic sensorineural hearing loss. ganglionectomy. West J Surg. 1934;42:628. treatment is the common therapy no matter the Autoimmunity. 2013;46:525–31. 2. Cogan DG, Dickersin GR. Non-syphilitic degree of severity. Mild eye symptoms warrant the 18. Darougar S, John AC, Viswalingam M, 3 interstitial keratitis with vestibuloauditory use of topical and cycloplegiics. Cornell L, et al. Isolation of Chlamydia psittaci symptoms—a case with fatal aortitis. Arch Topical cyclosporine A has also been found from a patient with interstitial keratitis and uveitis to be effective in severe anterior segment Ophthalmol. 1949;42:42-9. 35 associated with otological and cardiovascular inflammation. However, when there is posterior 3. Kessel A, Vadasz Z, Toubi E. Cogan syndrome— lesions. Br J Ophthalmol. 1978;62709-14. segment inflammation, systemic treatment is pathogenesis, clinical variants and treatment 19. Ndiaye IC, Rassi SJ, Wiener-Vacher SR. the preferred treatment of choice. Due to the 2014; pathophysiology of CS, which involves various approaches. Autoimmun Rev. 13(4):351-4. Cochleovestibular impairment in pediatric organs (primarily the inner ear, the eye, and/or 4. Pagnini I., Zannin ME, Vittadello F, Sari M, Cogan’s syndrome. Pediatr. 2002;109:E38. systemic vasculitis), immunosuppressive therapy et al. (2012). Clinical features and outcome of 20. Ferri F. Cogan’s syndrome. In: Ferri’s Clinical is the goal. Systemic corticosteroids are the gold Cogan syndrome. J Pediatr. 2012;160(2):303-7. Advisor 2015. Philadelphia, PA: Elsevier; 2014. standard of care.3 5. Haynes BF, Kaiser-Kupfer MI, Mason P, 21. Greco A, Gallo A, Fusconi M, Magliulo G, et As previously mentioned, early treatment Fauci S. Cogan syndrome: studies in thirteen al. Cogan’s syndrome: an autoimmune inner ear is important in CS due to the progressive patients, long-term follow-up, and a review of the disease. Autoimmun Rev. 2013;12:396–400. audiovestibular degradation that may be literature. Medicine. 1980;59:426-42. irreversible if left untreated for too long. The 22. Gluth MB, Baratz KH, Matteson EL, Driscoll moment audiovestibular dysfunction is noted, 6. Chynn EW, Jakobiec FA. Cogan’s syndrome, CLW. Cogan syndrome: a retrospective review of high-dose corticosteroids should be administered ophthalmic, audiovestibular and systemic 60 patients throughout a half century. Mayo Clin (1 mg/kg to 1.5 mg/kg of daily).3 manifestations and therapy. Int Ophthalmol Clin. Proc. 2006;81(4):483–8. Signs of reversal of audiovestibular symptoms 1996;37:61-72. 23. Ferrari E, Taillan B, Garnier G, Dor V, et al. 24,36 should be noticed within two to three weeks. 7. Cundiff J, Kansanal S, Kumar A, Goldstain Manifestations cardiovasculaires du syndrome Following improvement, the steroid dose should D, Tessler HH. Cogan’s syndrome: a cause of de Cogan. A propos d’un cas. Arch Mal Coeur. be slowly decreased and continued for two to six progressive hearing deafness. Am J Otolaryngol. 1992;85:913–6. months.3 Infliximab in particular seems effective 2006;28:68-70. 24. Vollertsen RS, McDonald TJ, Younge BR, if started during the beginning of inner-ear Banks PM, et al. Cogan’s syndrome: 18 cases damage. It has also been useful in maintenance 8. Benett FM. Bilateral recurrent episcleritis and a review of the literature. Mayo Clin Proc. of remission in CS patients with treatment associated with posterior corneal changes, 37,38 1986;61:344–61. failure. If sensorineural hearing loss progresses vestibuloauditory symptoms and rheumatoid due to treatment failure, cochlear implant surgery arthritis. Am J Ophthalmol. 1963;55:8158. 25. Bicknell JM, Holland JV. Neurologic 3 is suggested. 9. Cheson BD, Bluming AZ, Alroy J. Cogan’s manifestations of Cogan’s syndrome. Neurol. 1978;29:278–81. If corticosteroid therapy is contraindicated syndrome: a systemic vasculitis. Am J Med. or the treatment regimen fails, other 1976;60:549-55. 26. Ho AC, Roat MI, Venbrux A, Hellmann immunosuppressants, such as cyclophosphamide, 10. Grasland A, et al. Typical and atypical DB. Cogan’s syndrome with refractory aortitis azathioprine, methotrexate, cyclosporine and Cogan’s syndrome: 32 cases and review of the and mesenteric vasculitis. J Rheumatol. tumor necrosis factor-alpha blockers, should be 1999;27:1404–7. 39,40-42 literature. Rheumatology. 2004;43(8):1007-15. used. 27. Van Doornum S, McColl G, Walter M, 11. St. Clair EW, McCallum RM. Cogan’s Jennens I, et al. Prolonged prodrome, systemic syndrome. Curr Opin Rheumatol. 1999;11:47– vasculitis, and deafness in Cogan’s syndrome. Conclusion 52. Skin manifestations among CS patients are rare; Ann Rheum Dis. 2001;60:69–71. 12. Arnold W, Gebbers JO. Serum antibodies nevertheless, it is important to report unusual 28. Broughton SS, Meyerhoff WE, Cohen against corneal and internal ear tissues in Cogan’s cases such as this one, especially with less SB. Immune-mediated inner ear disease: 10- common findings, as they add to the pre-existing syndrome. Laryngol Rhinol Otol. 1984;63:428– year experience. Semin Arthritis Rheum. pool of literature and further the understanding 33. 2004;35:544–8. and identification of varying presentations of 13. Arnold W, Pfaltz R, Altermatt HJ. Evidence such a rare condition. 29. Podder S, Shepherd RC. Cogan’s syndrome: of serum antibodies against inner ear tissues in a rare systemic vasculitis. Arch Dis Child. Cutaneous manifestations of CS present along the blood of patients with certain sensorineural 1994;71(2):163-164. a spectrum, from non-specific skin rashes and hearing disorders. Acta Otolaryngol. urticarial vasculitis to palpable purpura and 1985;99:437–44. 30. Zulian F, Sari M, Filippis C. Otolaryngological pyoderma gangrenosum. These coexisting manifestations of rheumatic diseases in children. 14. Helmchen C, Arbusow V, Jager L, Strupp M, Int J Pediatr Otorhinolaryngol. 2009;73:56-60. conditions can delay diagnosis, which can et al. Cogan’s syndrome: clinical significance of profoundly affect the patient outcome, particularly antibodies against the inner ear and cornea. Acta 31. Orsoni J, Zavota L, Vincenti V, Pellistri I, et in reference to permanent sensorineural hearing Otolaryngol. 1999;119(5):528-37. al. Cogan syndrome in children: early diagnosis loss. Irreversible loss of visual acuity can also and treatment is critical to prognosis. Am J result from delayed diagnosis and subsequent 15. Lunardi C, Bason C, Leandri M, Navone R, Ophthalmol. 2004;137(4):757-8. delayed treatment. Although they are the least et al. Autoantibodies to inner ear and endothelial antigens in Cogan’s syndrome. Lancet. 32. Bodemer C, Teillac-Haml D, Virelizier, et al. Page 28 COGAN’S SYNDROME WITH CUTANEOUS FINDINGS: A CASE REPORT AND REVIEW OF DERMATOLOGIC MANIFESTATIONS Syndrome de Cogan. Ann Dermatol Venereol. 1984;111:673-4 33. Shahid FL, Mukherjee R, Knapp C. Cogan’s Syndrome Associated with Orbital Inflammation. Orbit. 2013;33(3):206-7. 34. Ochonisky S, Chosidow O, Kuentz M, Man N, et al. Cogan’s syndrome. An unusual etiology of urticarial vasculitis. Dermatologica. 1991;183:218-21. 35. Shimura M, Yasuda K, Fuse N, Nakazawa M, et al. Effective treatment with topical cyclosporine A of a patient with Cogan syndrome. Ophthalmologica. 2000;214:429-33. 36. Haynes BF, Pikus A, Kaiser-Kupfer M, Fauci AS. Successful treatment of sudden hearing loss in Cogan’s syndrome with corticosteroids. Arthritis Rheum. 1981;25:501-3. 37. Ghadban R, Couret M, Zenone T. Efficacy of infliximab in Cogan’s syndrome. J Rheumatol. 2008;36:2456-8. 38. Fricker M, Baumann A, Wermelinger F, Villiger PM, et al. A novel therapeutic option in Cogan disease? TNF-alpha blockers. Rheumatol Int. 2007;28:493-5. 39. Allen NB, Cox CC, Cobo M, McCallum RM, et al. Use of immunosuppressive agents in the treatment of severe ocular and vascular manifestations of Cogan’s syndrome. Am J Med. 1990;88:296-301. 40. Riente L, Taglione E, Berrentini S. Efficacy of methotrexate in Cogan’s syndrome. J Rheumatol. 1996;24:1830-1. 41. Touma Z, Nawwar R, Hadi U, Hourani M, et al. The use of TNF-alpha blockers in Cogan’s syndrome. Rheumatol Int. 2007;28:995-6. 42. Weyn T, Haine S, Conraads V. Cogan’s syndrome with left main coronary artery occlusion. Cardiol J. 2009;16:573-6.

Correspondence: Emily Tongdee, BS; [email protected]

TOULOEI, TONGDEE, SMIRNOV, FAVREAU, PORGES Page 29 Cutaneous Adenosquamous Carcinoma: A Case Study and Literature Review

Mayha Patel, DO,* Anne Nguyen, BS,** David Horowitz, DO, FAOCD,*** Paul Shitabata, MD**** *Dermatology Resident, PGY-2, Western University of Health Sciences, College Medical Center, Long Beach, CA **4th-year Medical Student, Western University of Health Sciences, College of Osteopathic Medicine of the Pacific, Pomona, CA ***Dermatology Residency Program, Western University of Health Sciences, College Medical Center, Long Beach, CA ****Director of Dermatopathology, Harbor-UCLA Medical Center, Torrance, CA; Dermatology Associate Clinical Professor of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA

Abstract Cutaneous adenosquamous cell carcinoma (ASC) is a rare variant of squamous cell carcinoma. It is an aggressive tumor with a tendency for local invasion, recurrence, and metastasis, so there is a great need for providers to recognize and understand this entity. Here we present the case of an 85-year-old Caucasian male with a rapidly growing lesion of the mandible. The pathogenesis, clinical manifestations, diagnostic evaluation, and treatments of ASC are discussed. Introduction Adenosquamous carcinoma (ASC) occurs primarily in the elderly population and has a slight male predominance.1-3 Fair-skinned individuals in areas of sun exposure and immunosuppressed patients are at greater risk.2-4 The lesion presents as a singular, erythematous, indurated, keratotic plaque often arising within actinic keratoses primarily on the head and neck.1,2,5 Lesions have, however, been described on the hand, foot, and thigh.3 The tumors are aggressive and can cause local ulceration, extensive destruction to the surrounding tissues, and in some instances metastasis that leads to death. In a case series by Banks and Cooper, five patients passed away from uncontrolled local recurrence, and two are alive with widespread disease and clinical evidence of Figure 4. Mucicarmine stain showing lymph node involvement.2 In one patient the Figure 2. Atypical keratinocytes in the intraluminal mucin present in the dermis (40x). lesion caused fatal hemorrhage, and in another epidermis with acantholysis and multiple foci death by direct extension into the CNS. Wiedner of ductal differentiation in the dermis (10x). foci of ductal differentiation (Figures 2 and 3). A and Foucar describe a similar case in which a mucicarmine stain confirmed mucin within the recurrent lesion eroded the orbit.3 ducts (Figure 4). Clinical and histopathologic evidence supported Case Report a diagnosis of cutaneous adenosquamous An 85-year-old Caucasian male presented to carcinoma. our clinic with a reported two-week history of a smooth, dome-shaped, pink-to-erythematous, 0.6 cm x 0.6 cm nodule on the right superior Discussion mandible (Figure 1). Upon examination, the Cutaneous adenosquamous carcinoma is a rare patient admitted to rapid growth of the lesion malignant neoplasm with mixed glandular and and a tendency to bleed. squamous differentiation and a propensity for local invasion, recurrence, and distant metastasis. Our clinical differential diagnosis included ASC was first described in 1985 by Weidner and Foucar, who agreed with the view that ASC is best classified as a high-grade variant of cutaneous squamous cell carcinoma.3 Histologically, adenosquamous carcinomas often Figure 3. Multiple foci of ductal differentiation appear on a background of intense solar elastosis.4 in the dermis (20x). There are features typical of classic squamous cell carcinoma, such as irregular anastomosing islands desmoplastic trichoepithelioma, basal of squamous cells originating from the epidermis, cell carcinoma, cutaneous metastasis and keratin pearls, and intercellular bridges. The . atypical squamous sheets are connected to the epidermis with intervening areas that are A biopsy was taken, and histopathological 2 examination revealed an epidermis that was non-dysplastic. These squamous cells often exhibit a sclerosing pattern and can involve the replaced by atypical keratinocytes with nests 1-4 extending into the underlying dermis. Solar as well as skeletal muscle. Figure 1. Ulcerated, erythematous, scaling elastosis was also present. The squamous cells There is true glandular differentiation with cystic spaces lined by low, columnar-to-cuboidal papule of the right mandible. demonstrated acantholysis as well as multiple

Page 30 CUTANEOUS ADENOSQUAMOUS CARCINOMA: A CASE STUDY AND LITERATURE REVIEW Table 1. Differential Diagnosis of ASC with Histopathological and Immunohistochemistry Features References Diagnosis Histopathology and Immunohistochemistry Features 1. Azorín D, López-ríos F, Ballestín C, Barrientos N, Rodríguez-Peralto JL. Primary cutaneous Primary cutaneous SCC , full-thickness atypia of epidermis, adenosquamous carcinoma: a case report invasion of dermis by atypical keratinocytes and review of the literature. J Cutan Pathol. Metastatic carcinoma ER PR surfactant thyroglobulin CA 199 2001;28(10):542-5. Acantholytic SCC Pseudoglandular formation, PAS-negative 2. Banks ER, Cooper PH. Adenosquamous MEC Patchy and focal p63 and cytokeratin 5/6 staining carcinoma of the skin: a report of 10 cases. J Cutan Pathol. 1991;18(4):227-34. Cutaneous adenosquamous carcinoma Diffuse p63 and cytokeratin 5/6 staining, CEA+, keratin 7+ 3. Weidner N, Foucar E. Adenosquamous carcinoma of the skin. An aggressive mucin- epithelial cells secreting mucin with ductular and gland-forming squamous carcinoma. Arch Treatment Dermatol. 1985;121(6):775-9. differentiation, sometimes highlighted by an Most cases report a surgical approach with eosinophilic cuticle.1-4 High-grade atypia with 2 Mohs microscopic surgery, in some instances 4. Fernández-Figueras MT, Fuente MJ, Bielsa frequent mitotic figures is characteristic. followed by radiation and chemotherapy as I, Ferrándiz C. Low-grade mucoepidermoid There are currently only a few cases of ASC regional recurrence is common.2,12 There are also carcinoma on the vermilion border of the lip. Am described in the literature, though some reports on the use of cetuximab as an adjunctive J Dermatopathol. 1997;19(2):197-201. authors refer to previously described cutaneous therapy for the treatment of ASC. The efficacy 5. Johnson DS, Solomon AR, Washington CV. mucoepidermoid carcinomas (cMEC) as the of this recombinant human and mouse chimeric Mucoepidermoid/adenosquamous carcinoma same entity.6 There is controversy over whether antibody against the epidermal growth factor of the skin: presentation of two cases. Dermatol they should be regarded as singular or distinct receptor as treatment for locally advanced Surg. 2001;27(12):1046-8. entities. Both lesions exhibit squamous as well as cutaneous ASC is still under exploration.12 adenomatous differentiation.1,3 6. Fu JM, McCalmont T, Yu SS. Adenosquamous Carcinoma of the Skin: A Case Series. Arch Although exceedingly rare in the skin, MECs Conclusion Dermatol. 2009;145(10):1152-8. are commonly found in other organs, such as In summary, adenosquamous carcinoma is best salivary glands, lungs, and the female genital considered a locally aggressive, high-risk subtype 7. Landman G, Farmer ER. Primary cutaneous 8 tract, and are of sweat gland origin. MECs are of cutaneous squamous cell carcinoma. Due : report of a case. J low-grade, indolent neoplasms with extremely to the invasive and sclerosing pattern of these Cutan Pathol. 1991;18(1):56-9. low metastatic potential.7,8 ASCs, on the other lesions, surgical resection can be difficult, but it is 8. Gartrell R, Pauli J, Zonta M. Primary hand, are not only aggressive but exhibit high 3 1-3 the treatment of choice. It is important to take Cutaneous Mucoepidermoid Carcinoma: A Case rates of both recurrence and metastasis. The a thorough history and perform full body scans Study with a Review of the Literature. Int J Surg reigning opinion is that ASC, due to its highly in order to rule out an alternative primary tumor Pathol. 2015 Apr;23(2):161-4. aggressive nature, should be considered separate 13 1-3,5,7,8 origin. Clinicians may also consider testing from MEC for prognostic purposes. Even for the estrogen receptor, receptor, 9. Riedlinger WF, Hurley MY, Dehner LP, Lind so, the terms “ASC” and “MEC” continue to be surfactant, thyroglobulin, and CA199 antigens in AC. Mucoepidermoid carcinoma of the skin: a used interchangeably, leading to much confusion. order to further rule out metastatic disease.1 distinct entity from adenosquamous carcinoma: This highlights the unanswered need to establish a case study with a review of the literature. Am J a more definitive classification system.2,3,9 Surg Pathol. 2005;29(1):131-5. ASC can resemble several other entities and must 10. Caputo V, Colombi R, Ribotta M, Rongioletti be discriminated due to differences in biological F. Cutaneous squamous cell carcinoma with behavior and treatment approaches. Basal cell and mucinous metaplasia on the sole associated with squamous cell carcinomas are the most common high-risk human papillomavirus type 18. Am J 3 leading diagnoses submitted to pathologists. It is Dermatopathol. 2011;33(3):317-22. important to differentiate ASC from metastasis, microcystic adnexal tumor, MEC as an extension 11. Ko CJ, Leffell DJ, McNiff JM. Adenosquamous of a primary salivary gland tumor, and primary carcinoma: a report of nine cases with p63 MEC (Table 1).2,8 and cytokeratin 5/6 staining. J Cutan Pathol. 2009;36:448–52 Histologically, ASC and MEC exhibit several mutually exclusive features. Unlike MEC, ASC 12. Nouri K, Trent JT, Lowell B, Vaitla R, is intraepidermal, well differentiated, and displays Jimenez GP, Mucoepidermoid carcinoma high-grade nuclear features. MEC is a dermal- (adenosquamous carcinoma) treated with based, solid or cystic tumor and has papillary Mohs micrographic surgery. Int J Dermatol. features, mucogenic cells, and peritumoral 2003;42:957-9. 9 fibrosis. Stains and immunohistochemistry 13. Suárez-Peñaranda JM, Vieites B, Valeiras can further assist in finding the right diagnosis. E, Varela-Duran J. Primary mucoepidermoid ASC mucin is sensitive to sialidase and resistant carcinoma of the skin expressing p63. Am J 3 to hyaluronidase, indicating epithelial mucin. Dermatopathol. 2010;32(1):61-4. The cells lining the glandular spaces stain with CEA or mucicarmine and keratin 7, suggesting 1,2,10 glandular differentiation. In addition, Correspondence: Mayha Patel, DO; diffuse staining for both p63 and cytokeratin [email protected] 5/6 supports a primary cutaneous origin over metastatic . MEC also stains positive for p63 and cytokeratin 5/6, but it is focal and patchy, not diffuse.11

PATEL, NGUYEN, HOROWITZ, SHITABATA Page 31 Bacterial Pseudomycoses of the Skin: A Case Report

Robert Lin, DO,* Alpesh Desai, DO, FAOCD**

*2nd-year resident, South Texas Osteopathic Dermatology Residency Program, Houston, TX **Program Director, South Texas Osteopathic Dermatology Residency Program, Houston, TX

Abstract Clinicians in all scopes of medicine are no strangers to misnomers. The inaccurate naming of diseases and organisms oftentimes results from their resemblance to other entities and has been known to mislead physicians regarding etiologies and histopathologies. In the field of dermatology, certain skin infections have been mislabeled to be fungal when they are actually bacterial in nature. In order to further understand the origins and development of these infectious misnomers, we present a patient diagnosed with an unusual condition involving three different pseudomycotic skin infections. We also discuss the clinical features shared between these three bacterial pseudomycoses and identify the features that differentiate them from one another histopathologically. Introduction Histologic findings of these specimens were the diagnosis of actinomycetoma, , Pseudomycotic infections of the skin are a subset consistent with the diagnoses of , and botryomycosis, all are infections of the of bacterial infections that produces lesions with actinomycosis, and actinomycetoma pending the skin caused by specific types of bacteria. These clinically fungal features.1 Often, additional results of the tissue culture. conditions are differentiated from one another depending on the appearance and size of the tests would be required to isolate the causative Figure 2 organism, thus delaying appropriate treatment. bacteria associated with the disease (Table 1). If In order to increase the dermatologic awareness histologic findings prove to be inconclusive, then of these infections, we present an unusual additional stains and studies can be performed case of a patient with three different bacterial depending on the species of bacteria involved 2 pseudomycoses of the skin and discuss the clinical (Table 2). features, microbiology, histology, and treatment of these rare entities. Actinomycetoma Actinomycetoma is a chronic cutaneous infection of the skin caused by aerobic, Gram- Case Presentation positive Actinomycetales order of bacteria such A 66-year-old Hispanic male presented with a as Nocardia brasiliensis. These organisms are 12-year history of multiple dark nodules to his phylogenetically diverse but morphologically body that appeared to be getting progressively Figure 3 similar, exhibiting characteristic filamentous worse. Despite receiving treatment with various branching into both bacillary and coccoid forms. antibiotics, antifungals, and topical creams, Nocardia can be differentiated from Actinomyces his condition persisted without any signs of by the acid-fast staining and aerobic properties improvement. Physical examination revealed of Nocardia.3 several non-tender, erythematous, firm nodules mixed with some largely indurated plaques After the organism is inoculated into the skin, diffusely wrapped around his lower abdomen and a pyogenic response ensues with formation of a back (Figure 1). painless nodule at the site of entry. As the nodule enlarges, a chronic inflammatory response occurs, Figure 1 which can remain localized or extend to involve muscle and bone.4 Diagnosis of actinomycetoma is made In order to cover for all bacterial species involved, histologically with or by culturing of the patient was placed on a prolonged course infected lesions. Histopathologic appearance of of amoxicillin with clavulanic acid for at least this condition is characterized by the appearance six months until complete resolution of his of delicate, filamentous Gram-positive branching. condition. He responded very well to treatment These organisms were once considered fungi without any signs of recurrence to this date. because of their hyphal-like appearance, but molecular analysis of their cell wall has confirmed 3,4 Discussion their classification as bacterial. Despite the presence of fungal nomenclature in Management of this condition usually

Table 1. Appearance and size of associated bacteria

Multiple punch biopsies obtained from Actinomycetoma Actinomycosis Botryomycosis these lesions displayed areas of suppurative granulomatous fibro-inflammatory response Appearance Filamentous Filamentous Cocci consistent with an infectious process. Gram staining performed on these lesions revealed Grain Size 40-80 μm 1-3 mm 0.5-1 mm several foci of admixed Gram-positive bacterial cocci in addition to numerous filamentous rods Organism Nocardia brasiliensis Actinomyces israelii Staphylococcus aureus in the deep dermal tissues (Figures 2 and 3). Page 32 BACTERIAL PSEUDOMYCOSES OF THE SKIN: A CASE REPORT Table 2. Additional diagnostic stains and studies

Actinomycetoma Actinomycosis Botryomycosis References Basophilic mass of Basophilic mass of Eosinophilic periphery 1. Savitha SA, Sacchidanand SA, Gowda SK. Hematoxylin and eosin microfilaments microfilaments and basophilic center Misnomers in dermatology: An update. Indian J Dermatol. 2013;58:467-74. Grocott-Gomori Positive Positive Negative 2. Padilla-Desgarennes C, Vazquez-Gonzalez D, Bonifaz A. Botryomycosis. Clin Dermatol. 2012 Periodic acid-Schiff Positive Positive Positive Jul-Aug;30(4):397-402. 3. Beaman BL, Beaman L. Nocardia species: Positive Positive Positive and negative Gram filaments filaments clusters host-parasite relationships. Clin Microbiol Rev. 1994;7:213. Ziehl-Neelsen Partially positive Negative Negative 4. Murray PR, Baron EJ, Jorgensen, JH, Pfaller MA, Yolken RH, editors. Manual of Clinical involves antibiotics alone. Trimethoprim- organism cultured from lesions of botryomycosis, Microbiology, 9th edition. Washington: sulfamethoxazole with or without dapsone is although it is not the only organism that can American Society for Microbiology; 2007. p. 515. commonly used for disease of short duration, of cause this particular type of condition. These 5. Ameen M, Arenas R, Vásquez del Mercado E, limited extent, and with low risk of dissemination. pathogens may include, but are not limited to, et al. Efficacy of imipenem therapy for 6. Nocardia For patients with more severe disease, longer- organisms such as Pseudomonas aeruginosa, actinomycetomas refractory to sulfonamides. J duration disease, or disease that is refractory to Escherichia coli, Serratia, and Proteus. Cutaneous Am Acad Dermatol. 2010;62:239. sulfonamides, consideration should be given to botryomycosis is the most common form of 6. Belmont MJ, Behar PM, Wax MK. Atypical intravenous imipenem alone or in combination botryomycosis and usually occurs following 5 presentations of actinomycosis. Head Neck. with amikacin. cutaneous inoculation of bacteria due to trauma, 1999;21:264. surgery, or presence of a foreign body. Lesions Actinomycosis typically develop very slowly and may evolve to 7. Lerner PI. The lumpy jaw. Cervicofacial Actinomycosis is a chronic cutaneous infection form multiple large, subcutaneous nodules for actinomycosis. Infect Dis Clin North Am. characterized by formation, draining sinus several months to years.9 1988;2:203. tracts, fistulas, and tissue fibrosis. This condition Diagnosis of botryomycosis can be established 8. Martin MV. The use of oral amoxicillin for the is most commonly caused by Gram-positive, histopathologically with skin biopsy or by treatment of actinomycosis. A clinical and in vitro anaerobic bacteria such as Actinomyces israelii. culturing the bacteria from ulcers of infected study. Br Dent J. 1984;156:252. The name reflects its characteristic filamentous, lesions. Histopathologic appearance of this fungal-like appearance in infected tissues. 9. Mehregan DA, Su WP, Anhalt JP. Cutaneous condition is characterized by a central focus of However, Actinomyces are true bacteria, with botryomycosis. J Am Acad Dermatol. 1991 necrosis surrounded by a chronic inflammatory filaments much narrower than fungal hyphae Mar;23(3):393-6. reaction containing histiocytes, epithelioid cells, noted for forming discrete, macroscopic grains multinucleated giant cells, and fibrosis. Gram 10. Vasishta RK, Gupta N, Kakkar N. of hard consistency, anywhere from 1 mm to 3 staining or silver-nitrate staining is the preferred Botryomycosis--a series of six integumentary mm in diameter, visible to the naked eye. While method of identifying these causative pathogens, or visceral cases from India. Ann Trop Med these species capitalize on tissue injury to invade which may be distinguished from actinomycosis Parasitol. 2004;98:623. the skin, pain is generally an uncommon feature, 6 or actinomycetomas by the variable sizes and particularly in chronic cases. 11. Neafie RC, Marty AM. Unusual infections in shapes of the granules. These Gram-positive cocci humans. Clin Microbiol Rev. 1993;6:34. Histologic findings typically reveal acute or are oftentimes larger than 1 micron in diameter, chronic inflammatory granulation tissue with in contrast to the branching, filamentous bacteria infiltration by neutrophils, foamy macrophages, less than 1 micron in size for actinomycosis and Correspondence: Robert Lin, DO; plasma cells, and lymphocytes with a surrounding actinomycetoma.10 [email protected] dense fibrosis. Filaments of Nocardia and Treatment of this condition is dependent on Actinomyces species are next to impossible to the causative organism and severity of the differentiate by conventional methods such infection. For Gram-positive infections such as Grocott-Gomori and hematoxylin-eosin as Staphylococcus aureus, oral trimethoprim- staining. However, Nocardia species are typically sulfamethoxazole, clindamycin, doxycycline, acid-fast aerobic organisms, while Actinomyces 7 or cephalexin can be used. For Gram-negative are not. infections such as Pseudomonas aeruginosa, Treatment of choice for actinomyces often intravenous ceftazidime, ciprofloxacin, aztreonam, requires prolonged courses of antibiotics such as or imipenem can be effective.11 high-dose penicillin and amoxicillin. Acceptable alternatives include tetracyclines, erythromycin, and clindamycin.8

Botryomycosis Botryomycosis is a rare, chronic, suppurative disease that is often mistaken clinically for a fungal infection. The term was coined because the infection granules appeared to be grouped together, resembling bunches of grapes (botrys in Greek), and behaved like a (mycosis). Staphylococcus aureus is the most common

LIN, DESAI Page 33 Favre-Racouchot Syndrome in a Unilateral, Perioral Distribution Associated with Tobacco Use: A Case Report and Review

Mitchell R. Manway, DO,* Joseph M. Dyer, DO,** Joshua D. Gapp, MD,*** Melinda F. Greenfield, DO****

*Dermatology Research Fellow, Center for Clinical and Cosmetic Research, Aventura, FL **Dermatology Resident, 2nd year, Largo Medical Center/NSUCOM, Largo, FL ***Board-certified Dermatopathologist, Alabama Pathology Associates, PC, Montgomery, AL **** Board-certified Dermatologist, Albany Dermatology Clinic, Albany, GA

Abstract The development of Favre-Racouchot syndrome (FRS) has been well described in dermatologic literature as having a strong association with chronic sun exposure and damage, which result in the classic appearance of solar elastosis and dilated open comedones in a bilateral periorbital distribution. However, frequently lacking in the literature is mention of another potential risk factor: tobacco use. The authors report a unique case presentation of FRS in a unilateral perioral distribution in a 66-year-old African American female without history of chronic sun exposure, but rather associated with preferential one-sided placement of her cigarettes. It is hoped that this case report will serve to strengthen the evidence that tobacco use may be implicated in the development of FRS. Introduction of Favre-Racouchot Syndrome with long- The patient denied use of hormone replacement Favre-Racouchot syndrome (FRS) has been term tobacco use as described in a unique case therapy, lithium, or epidermal growth factor estimated to affect up to 6% of individuals over presentation. So far, there have been very few but receptor inhibitors. Furthermore, she denied the age of 50 and presents most commonly in significant publications that have investigated occupational exposure to halogenated compounds. Caucasian males.1 It has been well established the association of skin changes consistent with The patient admitted a 58-year history of by past literature that the development of the FRS and smoking. This case report is noteworthy cigarette smoking, where she preferentially and condition possesses a strong association with due to the unique presentation of the patient, incessantly held the cigarette on the right side of history of exposure to solar radiation and actinic who had no other major risk factors for the her mouth. She denied alcohol consumption or damage. Indeed, in addition to the presence of development of FRS and who also had skin any illicit drug use. solar elastosis, one of the hallmark characteristics changes that were consistent with the perioral On physical exam, the patient was a well- of the disease, numerous periorbital open location of her tobacco habit. It is hoped that this developed, well-nourished female with comedones, have been referred to specifically as article will emphasize that FRS, which is most Fitzpatrick skin type V. Inspection of the right 2,3 “solar comedones.” FRS has also been described often thought to result from solar/UV-induced lower cutaneous lip revealed small and open in a patient following cancer radiation treatments, damage, is undoubtedly a disease of multifactorial comedones in an agminate arrangement (Figure thought to result from similar pathogenesis origin with a potentially strong association with 1). There was mild hyperpigmentation but no involving the interruption of keratinization of the tobacco use. associated solar elastosis. The remainder of the 4 pilosebaceous follicle. Yet, the exact pathogenesis facial skin, including the periocular region, was of this disease remains poorly understood, as does Case Report free of similar findings. the potential for other significant contributive or A 66-year-old African American female with A shave biopsy was obtained and demonstrated causative factors. history of considerable cigarette use presented two mildly inflamed comedonal cysts embedded with a skin eruption, which she described as The authors attempt to demonstrate a rarely in a dermis with evidence of severe nodular solar “brown bumps,” under the right side of her mouth emphasized association of the development elastosis (Figures 2 and 3). for eight months’ duration. She had previously sought treatment by her primary care physician. Despite the unusual location and lack of Although she denied any history of herpes chronic actinic damage, a diagnosis of Favre- labialis, she had been treated presumptively Racouchot syndrome was made on the basis with a course of oral acyclovir, resulting in no of clinicopathologic findings. The patient was improvement in appearance. The lesions were treated topically with tretinoin 0.04% gel and asymptomatic but aesthetically displeasing to counseled on smoking cessation. At three-month the patient, and therefore she sought further follow-up, she reported mild improvement in treatment by a dermatologist. appearance of the perioral cysts and comedones.

Figure 2. Photomicrograph of skin containing Figure 3. Photomicrograph of the surrounding two mildly inflamed comedonal cysts dermis demonstrating severe nodular solar Figure 1. Small cysts and open comedones in embedded in a dermis with evidence of severe elastosis indicating significant prolonged sun an agminate arrangement post shave biopsy. solar damage (4x). exposure (20x).

Page 34 FAVRE-RACOUCHOT SYNDROME IN A UNILATERAL, PERIORAL DISTRIBUTION ASSOCIATED WITH TOBACCO USE: A CASE REPORT AND REVIEW Discussion knowledge of many potential harms. Ultimately, Simple Open Comedone Extraction Technique The relationship of FRS with smoking has sufficient research on the development of FRS for Favre-Racouchot Disease. Photodermatol been investigated in the past, but not to a large is lacking, and further clinical studies should be Photoimmunol Photomed. 2005;21(5):275-7. performed to gain a better understanding of the extent. Acting on a hypothesis based on clinical 14. Rai S, Madan V, August PJ, Ferguson JE. pathogenesis and disease factors. experience, one dermatology clinic performed Favre-Racouchot Syndrome: A Novel Two-step a retrospective study that revealed a statistically In reference to treatment, although benign, FRS Treatment Approach Using the Carbon Dioxide significant association between FRS and chronic can be aesthetically troubling to patients and has Laser. Br J Dermatol. 2014;170(3):657-60. 5 tobacco use. Furthermore, the authors found proved challenging to remedy. There have been the likelihood of developing FRS was dose- many proposed therapeutic modalities, including dependent when comparing heavy versus light Acknowledgements direct extraction, topical or oral retinoids, The authors of this case report would like to smokers. Drawing on this study’s conclusions, chemical peels, and microdermabrasion, as well acknowledge Dr. Paul Googe of Knoxville a subsequent publication asserted that smoking as investigations utilizing CO2 laser that have Dermatopathology Laboratory for the capture of holds a stronger association with development 13,14 resulted in good outcomes. histological images. of FRS than ultraviolet radiation.6 Despite this contention, FRS continues to be regarded as a predominantly sun-damage-induced disease Conclusion It is hoped that the information presented in process, and these authors could find no further this case report will encourage providers to studies investigating the relationship between Correspondence: Mitchell R. Manway, DO; acknowledge that emphasizing smoking cessation smoking and FRS development. Center for Clinical and Cosmetic Research, in patients is also an essential adjunct treatment 2925 Aventura Blvd., Suite 205, Aventura, FL This particular case presentation is noteworthy for the resolution of FRS and prevention of the 33180; Ph: 305.933.6716; Fax: 305.933.3853; due to the unique nature of a unilateral perioral disease process. [email protected] distribution of the disease, thought to be a direct result of the habitual preference of the patient to hold her lit cigarettes in her ipsilateral mouth. In References 1. Friedman SJ, Su WP. Favre-Racouchot support of this assumption, changes in the elastic syndrome associated with radiation therapy. tissue of non-sun-exposed areas in smokers that Cutis. 1983;31:306–10. resemble the histological findings of solar elastic tissue resulting from sun damage have been 2. Patterson WM, Fox MD, Schwartz RA. described.7 Past in vitro studies have indicated that Favre-Racouchot Disease. Int J Dermatol. tobacco-smoke extract impairs the production 2004;43(3):167-9. of collagen and increases the production of 3. Izumi AK, Marples RR, Kligman AM. tropoelastin and matrix metalloproteinases, Senile (Solar) Comedones. J Invest Dermatol. which in turn degrade matrix proteins and cause 1973;61(1):46-50. an abnormal production of elastosis material.8 Moreover, as the patient in this case report is 4. Breit S, Flaig MJ, Wolff H, Plewig G. Favre- African American, her skin possesses a higher Racouchot-like Disease after Radiation Therapy. concentration of melanin, which has been shown J Am Acad Dermatol. 2003;49(1):117-9. to be negatively associated with the development 5. Keough GC, Laws RA, Elston DM. Favre- 9 of UVR-induced solar elastosis. Complicating Racouchot Syndrome: A Case for Smokers’ the picture is whether exposure to tobacco smoke Comedones. Arch Dermatol. 1997;133(6):796-7. is solely responsible for the development of the 6. Chauhan V, Sharma R, Thakur S. Tell-tale Signs elastosis found in this patient or if the potential of a Chronic Smoker. Lung India. 2013;30(1):79. long-term exposure to heat (infrared radiation) from the lit cigarette also has impact. One study 7. Frances C, Boisnic S, Hartmann DJ, et al. investigated this question, exposing a group of Changes in the Elastic Tissue of the Non- albino guinea pigs to UVA and UVB radiation sun-exposed Skin of Cigarette Smokers. Br J with and without infrared radiation. The study Dermatol. 1991;125(1):43-7. found that the combination of UV and IR 8. Morita A. Tobacco Smoke Causes Premature radiation resulted in dense, mat-like elastic fiber Skin Aging. J Dermatol Sci. 2007;48(3):169-75. depositions that exceeded what was observed in either source of irradiation alone.10 9. Young AL, Levy S, Nighland M, et al. Are Dark-skinned People Really Protected from In addition to elastosis, other common Ultraviolet Radiation? Clin Exp Dermatol. histological findings of FRS include epidermal 2010;35(4):392-6. atrophy, basophilic degeneration of the upper dermis, and a decrease in the size of the 10. Kligman LH. Intensification of Ultraviolet- sebaceous glands with dilated and keratin-filled induced Dermal Damage by Infrared Radiation. pilosebaceous infundibulum.2 As to the unilateral Arch Dermatol Res. 1982;272(3-4):229-38. distribution of the patient’s disease, albeit rare, 11. Stefanidou M, Ioannidou D, Tosca A. unilateral temporal and periorbital presentations Unilateral Nodular Elastosis with Cysts and of FRS have been reported in the past linked Comedones (Favre-Racouchot Syndrome). with occupations involving chronic asymmetrical Dermatology. 2001;202(3):270-1. sunlight exposure.11,12 No similar reports of FRS in a unilateral, perioral distribution could be found, 12. Vogel S, Mühlstädt M, Molin S, et al. despite an extensive literature search. It is unclear Unilateral Favre-Racouchot Disease: Evidence why more individuals do not develop the skin for the Etiological Role of Chronic Solar findings this patient presented with, as tobacco Damage. Dermatology. 2013;226(1):32-4. use is still ubiquitous today despite widespread 13. Kaya TI, Tursen U, Yazici AC, Ikizoglu G. A MANWAY, DYER, GAPP, GREENFIELD Page 35 Lymphadenopathic Form of Endemic Kaposi Sarcoma in an HIV-negative Gambian Male

Eugene Sanik, DO,* Ryan Schuering, BS,** Marcus B. Goodman, DO, FAOCD***

*Dermatology Resident, 2nd year, PCOM/North Fulton Hospital Medical Campus, Roswell, GA **Medical Student, 4th year, Lake Erie College of Osteopathic Medicine, Bradenton, FL ***Program Director, Dermatology Residency Program, PCOM/North Fulton Hospital Medical Campus, Roswell, GA

Abstract Kaposi sarcoma (KS) is a multicentric neoplasm of vascular and lymphatic endothelial origin that can involve the skin, lymph nodes, and visceral organs. Human herpesvirus 8 has been implicated in the etiology of this disorder. Commonly seen in association with AIDS and an immunocompromised state, KS also occurs in HIV- seronegative, immunocompetent populations in parts of Africa. We report the case of a 21-year-old male from Gambia, West Africa, who presented with multiple painful nodules on the hands and feet. Histopathology confirmed a diagnosis of Kaposi sarcoma, whereas serology for HIV was negative. Positron emission tomography revealed higher-stage disease with uptake in retroperitoneal lymph nodes, also subsequently biopsy-confirmed. The patient received radiation therapy but continues to have a progressive disease course with development of new cutaneous lesions. Herein we provide a review of contemporary knowledge on the clinical features and management of this aggressive endemic subtype of Kaposi sarcoma. Introduction inflammatory dermatosis. However, on histology, tea tree oil, which had little effect on the lesions Kaposi sarcoma (KS) is a mesenchymal, there may be subtle indications of newly formed or his symptoms. Associated symptoms included angioproliferative, low-grade malignancy. ecstatic, vascular spaces with protrusion of native constant sweating in the feet and ankles and knee Although multi-focal, KS does not become vascular structures into these channels creating arthralgia bilaterally. Ibuprofen did not alleviate metastatic. KS is etiologically related to infection the characteristic promontory sign. The plaque- his joint pain. The patient’s past medical history by human herpesvirus 8 (HHV-8). HHV-8 stage lesions of KS are characterized by a more was unremarkable, and his immunizations were has been found in tissue biopsies of all stages diffuse dermal vascular infiltrate and greater up to date, per the patient. At the time of initial and epidemiological forms of KS. Aside from cellularity. Commonly, a phenomenon known as presentation, he was not on any medications. causing KS, this oncogenic virus also gives rise autolumination is seen, where an erythrocyte is The patient denied any recent fever, chills, nausea, to two other malignancies: a rare form of B-cell contained in a paranuclear vacuole in a spindled or vomiting. He had not had any excessive fatigue lymphoma called primary effusion lymphoma endothelial cell. Nodular-stage KS is more or weight loss. He denied noting any palpable or and a plasmablastic form of multicentric apparent in diagnosis, characterized by dermal tender lymph nodes. He had not appreciated any Castleman disease. HHV-8, however, is not expansion by variable cellular proliferation of gastrointestinal symptoms, including abdominal involved in epithelial tumors. Viral infection is neoplastic spindled cells. The viral load in lesions tenderness, distention, or generalized discomfort. correlates with the clinical progression through necessary for the occurrence of KS but not always 5,6 He denied any constipation, diarrhea, or blood in sufficient. HHV-8 seropositivity throughout the patch, plaque, and nodular stages. Staining the stool. the world has been found to be greater than the with antibodies to HHV-8 LNA-1 and lymphatic Skin examination revealed multiple prevalence of KS, with up to 80% seropositivity in endothelial cell marker D2-40 has proven useful 7 hyperpigmented, firm and hyperkeratotic papules, some parts of sub-Saharan and equatorial Africa. in the identification of early KS development. nodules, and small tumors on the dorsal and Consequently, it has been speculated that there There are myriad other histological KS variants, plantar surfaces of the feet and ankles (Figure are also ethnic and genetic cofactors involved in including those described in older literature, such 1). On the plantar surface of the right foot, there the development of KS.1,2 as anaplastic, lymphedematous, lymphangioma- were multiple well-circumscribed, exophytic, Kaposi sarcoma classically presents with the like, lymphangiectatic, bullous, and telangiectatic hyperkeratotic plaques in a cluster near the ball of cutaneous manifestations of discrete violaceous KS. Anaplastic KS is rare and poorly the foot (Figure 2). Smaller nodules were present patches, plaques, or nodules, most commonly on documented. Telangiectatic KS is identified on the hands and fingers (Figure 3). There was the lower extremities. The four most common in a single case report. More contemporary mild nonpitting edema up to the mid-calf. No clinical variants of the disease are classic KS, variants include hyperkeratotic (verrucous), other cutaneous lesions were noted elsewhere. African (endemic) KS, iatrogenic/transplant- keloidal, micronodular, - On general physical exam, the patient was associated KS, and AIDS-associated (epidemic) like, ecchymotic, intravascular, glomeruloid, fully alert and oriented, and in good spirits. KS. In 1982, Kaposi was the first to describe the pigmented, regressing KS (AIDS-treatment 7,8 No was noted in the neck, disease, which he called “sarcoma idiopathicum related), and KS with myoid nodules. multiple hemorrhagicum.” In 1912, Sternberg Figure 1 labeled this condition “Kaposi sarcoma.” Two Case Report A 21-year-old African male presented to our years later, in 1914, the first case of African or dermatology clinic with complaints of multiple endemic KS was described to be a more aggressive painful lesions on the hands and feet. The lesions form with a higher rate of extracutaneous had appeared about two years earlier. Before manifestations.3,4 the lesions appeared, he noticed swelling and KS classically progresses through three stages pain in his right foot, which started seven years representative of its morphological features: the prior. The pain was worst upon waking in the patch, plaque, and nodular stages. These stages morning and when weight bearing. Six weeks are common in all four of the clinical variants before presentation, the patient had emigrated mentioned and correspond to certain histological from Gambia, West Africa. His lesions had been features. The earliest phase of KS, the patch stage, evaluated by physicians in Africa, and, according is the most difficult to diagnostically identify, to the patient, they were unable to identify a manifesting as something more akin to a mild diagnosis. One of the treatments tried was 100%

Page 36 LYMPHADENOPATHIC FORM OF ENDEMIC KAPOSI SARCOMA IN AN HIV-NEGATIVE GAMBIAN MALE Figure 3 are seen in central and eastern Africa, where HIV infection rates are high. Across the entire continent, KS is the third most common cancer behind liver and prostate and is one of the leading causes of cancer death.11-13 In endemic areas like Uganda, for example, where the prevalence of HIV has reached up to 10%, the incidence of KS has increased tenfold compared with the pre- HIV/AIDS era.2,10,14 When regarding hospitals in and around Kenya, KS comprises 25% of all cutaneous malignancies, second only to squamous cell carcinoma (44%). Similar rates have been observed in studies in Nigeria.15,19,20 HHV-8, a virus that can be spread via saliva and semen, is the underlying culprit to all KS. However, as mentioned earlier, HHV- 8 seropositivity does not perfectly correlate with the appearance of KS. In fact, there are countries where HHV-8 seropositivity rates are high and KS is rarely reported. This includes Figure 2 Brazil, Thailand, Gambia, and the Ivory Coast.21 Investigators have struggled to identify additional abdomen, or inguinal regions. Heart rate was cell count of 6,500 per microliter, containing factors that may play a role in the manifestation of of regular rate and rhythm with no murmurs an elevated portion of lymphocytes (46.2%). KS. There are eight distinct subtypes distributed or gallops appreciated. Lungs were clear to The remainder of the values were within the over certain geographical regions: namely A/C, J, auscultation bilaterally with no wheezes or normal range for hemoglobin, hematocrit, mean K/M, D/E, B, Q, R, and N groups. Subtypes B, rhonchi. Vital signs were unremarkable. No corpuscular volume, mean corpuscular hematocrit N, Q, and R are found almost exclusively among tenderness, distention, or masses were noted in concentration, and platelet count. The complete the Sub-Saharan African cases, with subtype the abdomen. metabolic panel was unremarkable other than a B predominating. It is not certain whether the slightly elevated glucose level of 106 mg/dL. The 4,22 Prior to histological investigation, the subtypes have different pathogenic properties. patient underwent HIV testing, was found to be differential diagnosis included Kaposi sarcoma, A multitude of co-factors have been proposed seronegative, and was referred to oncology. acroangiodermatitis, , in the pathogenesis of endemic KS. One of the lymphatic filariasis, angiosarcoma, andDespite several rounds of radiation therapy, risk factors identified for endemic KS is barefoot disseminated mycobacterial infection. Two oncology noted new lesions developing on the exposure to wet soil. The proposed mechanisms 4-mm punch biopsies, one from the right foot right side of his neck and on the right hand. A are various and include the role of high iron levels and another from the left hand, were obtained for PET/CT scan was performed, which showed and quartzite content in African soils. In a clay hematoxylin-eosin (H&E) analysis. lymphadenopathy in the retroperitoneum. The emulsion, quartz particles of less than 2 um can largest lymph node measured 2.7 cm in diameter. Histopathologic findings revealed a “busy readily enter sweat glands of the feet. Quartz can Biopsy of the lymph nodes confirmed the dermis” with a proliferation of intersecting cause micro-abrasions when exposed to the skin presence of Kaposi sarcoma there as well. fascicles of spindle-shaped cells with poorly of the feet. These quartz particles may induce defined, slit-like vascular spaces containing lymphatic damage and fibrosis, resulting in an erythrocytes (Figures 4, 5). Some irregularly Discussion inflammatory response and local immune system Endemic KS is found most commonly in impairment.2 This lymphedematous region is shaped, dilated vascular channels were seen at the Uganda, the Congo, the Congo Republic, periphery of the tumor nodule. Also noted was 9,10 a predisposed environment for malignancy, Burundi, and Zambia. It comprises up to especially vascular tumors.23 a mild background inflammatory cell infiltrate 10% of malignancies in central Africa and has consisting predominantly of lymphocytes. a male-to-female ratio of nearly 15:1 in adults. After aluminum, iron is the most abundant Immunohistochemistry for human herpesvirus 8 Interestingly, the ratio of KS in children is nearly mineral in African clay soils. Multiple pathways detected positive staining of nuclei in spindle cells 1:1 male to female. The incidence of KS varies have been suggested for the role of iron. Iron and endothelial cells lining the vascular channels widely with the geographic variations of the may lead to immune impairment via inhibition (Figure 6). Based on these characteristic findings, HIV/AIDS epidemic, as approximately 80% of of CD4 lymphocytes and suppression of a diagnosis of Kaposi sarcoma was made. those presenting with KS are HIV positive.12,15-18 macrophages. It can also induce production of A complete blood count showed a white blood Consequently, the highest incidence rates of KS reactive oxygen species and even directly promote

Figure 4 Figure 5 Figure 6

SANIK, SCHUERING, GOODMAN Page 37 growth of spindle cells. Iron has also been found lymphedema of the leg, in addition to cutaneous bleomycin is first-line therapy for advanced to induce anti-apoptotic signals in endothelial features, would most likely fall into stage III of classic KS.10 Other chemotherapy agents cells that are potential progenitors for KS cells. the classification system. Of the clinical variants include liposomal anthracyclines, paclitaxel, oral Lastly, iron may be conducive to KS development of endemic KS mentioned, this patient may etoposide, and single-agent and combinations via increased host-cell production of viral nucleic fall into the lymphadenopathic form, although of doxorubicin, bleomycin, and vincristine. The acids.2,24-28 This theory is supported in part by the cutaneous features are present in this case. response rates for combination agents range observation that endemic KS in Africa seems to widely, from 25% to 88%, in treatment for AIDS- be in proximity to volcanoes.29 Similarly, higher Treatment KS. Liposomal anthracyclines are considered rates of KS have been seen in populations of The treatment options for endemic KS vary widely first-line treatment for advanced AIDS-KS. The southern Italy near Mount Vesuvius. However, due to its heterogeneity. There are no therapeutic use of doxorubicin is supported by the fact that further studies are warranted.30,31 guidelines. Local and topical therapies may be preclinical data shows PEGylated liposomes used in patients with minimal cutaneous disease, preferentially accumulate in KS lesions.37 Another potential co-factor is quinine and or reserved as palliative therapy for patients with Paclitaxel has shown a response rate of 59%.4 other drugs used for malaria treatment. KS aggressive, recalcitrant disease. Topical options and malaria show similar distribution patterns include retinoids, imiquimod, cryotherapy, Immunological agents such as interferon-alfa throughout sub-Saharan Africa, Italy, Greece, electrodessication, surgical excision, and laser and sirolimus have also been tried. In one study, and Asia. In addition, quinine, chloroquine, 6 sirolimus demonstrated complete regression of therapy. and hydroxychloroquine may decrease immune iatrogenic KS in 15 patients.38 Newer therapeutic response toward viruses. Chloroquine has been Local chemotherapy with intralesional vincristine approaches include anti-angiogenic agents, found to reduce the antibody response when has been commonly used for nodular lesions. VEGF inhibitors, tyrosine kinase inhibitors, given concomitantly with the rabies vaccine. Intralesional vinblastine and bleomycin have and matrix metalloproteinases. Irinotecan, an These medications have been used for their been used, but are more painful and less effective anticancer drug that targets DNA topoisomerase immunosuppressive properties in the treatment than vincristine. Traditional low-dose radiation I, has been used in advanced AIDS-KS.39 of lupus erythematosus and rheumatoid arthritis. therapy often produces good therapeutic results Antiviral therapy with cidofovir, foscarnet, or Quinine may act as an activating agent, converting by reducing pain and edema. However, one study ganciclovir has demonstrated a suppression of latent HHV-8 to its lytic form.4,32,33 has shown five-year survival rates of 46% for local HHV-8 replication.40 Even oral shark cartilage radiotherapy due to development of KS outside has been used as a treatment option.41 There are four clinical variants of endemic KS: 34 the local treatment region. In a two-year study, (1) benign nodular or chronic localized, which treating local KS lesions smaller than 2 cm with presents as classic KS; (2) locally aggressive, Conclusion high-dose-rate brachytherapy demonstrated Kaposi sarcoma is an HHV-8 associated invading soft tissue and bone (usually fatal in a complete response in all 16 patients, with neoplasm originating from vascular and five to seven years); (3) florid disseminated, no evidence of local recurrence or tumor lymphatic endothelium. Endemic KS is a more having skin and visceral involvement; (4) 35 progression. The recent use of chemotherapy aggressive form found most commonly in HIV- lymphadenopathic, rapidly disseminating to in combination with electroporation to enhance seronegative Africans. The etiology of disease is lymph nodes and visceral organs, in which drug uptake into tumor cells of patients with KS multi-faceted, given that HHV-8 seropositivity there is usually an absence of cutaneous features not treatable with radiotherapy or vincristine does not confer the disease state. There are (usually in children and usually fatal).29 KS can demonstrated a complete response rate of multiple proposed factors that potentially play a spread to the GI and respiratory tracts, but 36 9 60.9%. role in the development of endemic KS, including all visceral organs are potentially susceptible. HHV-8 subtypes, soil conditions, and drug In HIV-infected patients, highly active Visceral involvement is often symptomless. interactions, to name a few. The broad range of antiretroviral therapy (HAART) plays an However, gastric outlet obstruction, enteropathy, disease manifestations lends to the wide spectrum indispensable first-line role in management, and bleeding of ulcerated KS lesions has been of treatment options, and there is currently no 29 alone and in combination with other treatments. reported. Lymphadenopathy is present in about standard of care. 75% of KS patients.12 The reported mortality HAART exerts its therapeutic effects by rate in Togo for endemic KS after two years is inhibiting HIV replication and augmenting the immune response against HHV-8. Protease References 5%, compared to 45% for AIDS-associated KS 1. Iscovich J, Boffetta P, Franceschi S, Azizi E, 15,16 inhibitors have also been shown to have direct (no HAART). Locally aggressive KS has an Sarid R. Classic kaposi sarcoma: epidemiology 10 antiangiogenic effects. However, the KS may estimated three-year survival rate of 64%. and risk factors. Cancer. 2000;88(3):500-17. initially flare in patients with very low CD4+ Staging of KS has been difficult, and multiple T-cell counts, as a result of immune reconstitution 2. Ziegler JL, Simonart T, Snoeck R. Kaposi’s classification systems have been devised. The inflammatory syndrome. sarcoma, oncogenic viruses, and iron. J Clin Virol. classification system proposed by Schwartz et 2001;20(3):127-30. al. is shown in Table 1.10 Mortality rates and Systemic chemotherapy is reserved for cases prognoses do not appear to be available relative of disseminated, rapidly progressive, or life- 3. Rappersberger K, Tschachler E, Zonzits E, to these stages. The patient presented here, given threatening disease with visceral involvement. et al. Endemic Kaposi’s sarcoma in human the retroperitoneal lymph node involvement and Intra-arterial vinblastine in combination with immunodeficiency virus type 1-seronegative persons: demonstration of retrovirus-like Table 1. Classification system for Kaposi sarcoma particles in cutaneous lesions. J Invest Dermatol. 1990;95(4):371-81. Stage I Localized nodular KS, with ≤ 15 cutaneous lesions or involvement restricted to one bilateral anatomic site, and few, if any, gut nodules 4. Ruocco E, Ruocco V, Tornesello ML, et al. Stage II Includes both exophytic destructive KS and locally infiltrative cutaneous lesions and Kaposi’s sarcoma: etiology and pathogenesis, locally aggressive KS or nodular KS, or > 15 cutaneous lesions or involvement of more inducing factors, causal associations, and than one bilateral anatomic site, and few or many gut nodules treatments: facts and controversies. Clin Dermatol. 2013;31(4):413-22. Stage III (Generalized lymphadenopathic KS) Widespread lymph node involvement, with or without cutaneous KS, but with limited, if any, visceral involvement 5. Feller L, Lemmer J. Insights into pathogenic events of HIV-associated Kaposi sarcoma and Stage IV (Disseminated visceral KS) Widespread KS, usually progressing from stages II or III, immune reconstitution syndrome related Kaposi with involvement of multiple visceral organs with or without cutaneous KS sarcoma. Infect Agent Cancer. 2008;3:1.

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Offermann MK, Lin JC, Mar EC, Targeted therapy for Kaposi sarcoma. BioDrugs. Sarcoma. Am J Dermatopathol. 2010;32(3):244- et al. Antioxidant-sensitive regulation of 2009;23(2):69-75. 50. inflammatory-response genes in Kaposi’s39. Vaccher E, di Gennaro G, Simonelli C, sarcoma cells. J Acquir Immune Defic Syndr 9. Restrepo CS, Ocazionez D. Kaposi’s sarcoma: Schioppa O, Tirelli U. Evidence of activity of Hum Retrovirol. 1996;13(1):1-11. imaging overview. Semin Ultrasound CT MR. Irinotecan in patients with advanced AIDS- 2011;32(5):456-69. 25. Simonart T. Role of environmental factors in related Kaposi’s sarcoma. Aids. 2005;19(16):1915- the pathogenesis of classic and African-endemic 6. 10. Schwartz RA, Micali G, Nasca MR, Scuderi Kaposi sarcoma. Cancer Lett. 2006;244(1):1-7. L. Kaposi sarcoma: a continuing conundrum. J 40. Casper C, Krantz EM, Corey L, et al. Am Acad Dermatol. 2008;59(2):179-206; quiz 26. Simonart T, Noel JC, Andrei G, et al. Iron as a Valganciclovir for suppression of human 207-8. potential co-factor in the pathogenesis of Kaposi’s herpesvirus-8 replication: a randomized, double- sarcoma? Int J Cancer. 1998;78(6):720-6. blind, placebo-controlled, crossover trial. J Infect 11. Jamison DT, Feachem RG, Makgoba MW, Dis. 2008;198(1):23-30. Bos ER, Baingana FK, Hofman KJ, Rogo KO, 27. Drakesmith H, Prentice A. Viral infection eds. Disease and Mortality in Sub-Saharan and iron metabolism. Nat Rev Microbiol. 2008; 41. Hillman JD, Peng AT, Gilliam AC, Africa. 2nd ed. Washington DC: World Bank; 6(7):541-52. Remick SC. Treatment of Kaposi sarcoma with oral administration of shark cartilage in 2006. 28. Ye F, Zhou F, Bedolla RG, et al. Reactive oxygen a human herpesvirus 8-seropositive, human 12. Matondo P. Kaposi’s sarcoma in Africa. Clin species hydrogen peroxide mediates Kaposi’s immunodeficiency virus-seronegative homosexual Dermatol. 1999;17(2):197-207; discussion 105- sarcoma-associated herpesvirus reactivation from man. Arch Dermatol. 2001;137(9):1149-52. 6. latency. PLoS Pathog. 2011;7(5):e1002054. 13. Parkin DM, Bray F, Ferlay J, Jemal A. Cancer 29. Hengge UR, Ruzicka T, Tyring SK, et al. in Africa 2012. Cancer Epidemiol Biomarkers Update on Kaposi’s sarcoma and other HHV8 Correspondence: Eugene Sanik, DO; 2500 Prev. 2014;23(6):953-66. associated diseases. Part 1: epidemiology, Hospital Blvd, Suite 280, Roswell, GA 30076; Ph: environmental predispositions, clinical 770-754-0787; Fax: 866-763-0787; askeugene@ 14. Parkin DM, Sitas F, Chirenje M, et al. manifestations, and therapy. Lancet Infect Dis. gmail.com Part I: Cancer in Indigenous Africans-- 2002;2(5):281-92. burden, distribution, and trends. Lancet Oncol. 2008;9(7):683-92. 30. Pelser C, Dazzi C, Graubard BI, et al. Risk of classic Kaposi sarcoma with residential exposure 15. Mosam A, Aboobaker J, Shaik F. to volcanic and related soils in Sicily. Ann Kaposi’s sarcoma in sub-Saharan Africa: a Epidemiol. 2009;19(8):597-601. current perspective. Curr Opin Infect Dis. 2010;23(2):119-23. 31. Montella M, Franceschi S, Geddes M, Arniani S, Cocchiarella G. Classic Kaposi’s 16. Pitche PT, Kombate K, Owono F, Tchangai- sarcoma and volcanic soil in southern Italy. Walla K. Kaposi’s sarcoma in a hospital setting in Lancet. 1996;347(9005):905. Lome (Togo): a study of 93 cases. Int J Dermatol. 2007;46 Suppl 1:42-4. 32. Pappaioanou M, Fishbein DB, Dreesen DW, et al. Antibody response to preexposure human 17. Asuquo ME, Ebughe G. Cutaneous diploid-cell rabies vaccine given concurrently with in Calabar, Southern Nigeria. Dermatol Online chloroquine. N Engl J Med. 1986;314(5):280-4. J. 2009;15(4):11. 33. Ruocco V, Ruocco E, Schwartz RA, Janniger 18. Mwanda OW, Fu P, Collea R, Whalen C, CK. Kaposi sarcoma and quinine: a potentially Remick SC. Kaposi’s sarcoma in patients with overlooked triggering factor in millions of and without human immunodeficiency virus Africans. J Am Acad Dermatol. 2011;64(2):434- infection, in a tertiary referral centre in Kenya. 6. Ann Trop Med Parasitol. 2005;99(1):81-91. 34. Kigula-Mugambe JB, Kavuma A. Epidemic 19. Nthumba PM, Cavadas PC, Landin L. and endemic Kaposi’s sarcoma: a comparison Primary cutaneous malignancies in sub-Saharan of outcomes and survival after radiotherapy. Africa. Ann Plast Surg. 2011;66(3):313-20. Radiother Oncol. 2005;76(1):59-62. 20. Asuquo ME, Ebughe G. Major dermatological 35. Kasper ME, Richter S, Warren N, et al. malignancies encountered in the University of Complete response of endemic Kaposi sarcoma Calabar Teaching Hospital, Calabar, southern lesions with high-dose-rate brachytherapy: Nigeria. Int J Dermatol. 2012;51 Suppl 1:32-6, treatment method, results, and toxicity using 36-40. skin surface applicators. Brachytherapy. 21. Szajerka T, Jablecki J. Kaposi’s sarcoma 2013;12(5):495-9. revisited. AIDS Rev. 2007;9(4):230-6. 36. Curatolo P, Quaglino P, Marenco F, et 22. Zong JC, Kajumbula H, Boto W, Hayward al. Electrochemotherapy in the treatment of GS. Evaluation of global clustering patterns and Kaposi sarcoma cutaneous lesions: a two-center

SANIK, SCHUERING, GOODMAN Page 39 Coexisting confluent and reticulated papillomatosis and terra firma-forme dermatosis

Claire Otteni, BA,* Laura F. Sandoval, DO,** Jonathan S. Crane, DO, FAOCD***

*Medical student, 4th year, Philadelphia College of Osteopathic Medicine, Philadelphia, PA **Dermatology Resident, 1st year, Sampson Regional Medical Center/Campbell University School of Osteopathic Medicine, Clinton, NC ***Program Director, Sampson County Regional Medical Center/Campbell University School of Osteopathic Medicine, Clinton, NC; Dermatologist, DermOne, Wilmington, NC

Abstract Confluent and reticulated papillomatosis (CARP) is an uncommon skin disorder that usually affects young adults. The clinical presentation most often involves the upper trunk, commonly in the intermammary area or, less frequently, the interscapular and epigastric regions.1,2 The lesions usually appear as grayish brown, hyperkeratotic, verrucous papules and patches that are confluent centrally and reticulated peripherally. While usually asymptomatic, the eruption can present with mild pruritis.1 In addition, the eruption is often fairly symmetrical across the body and trunk. We present an unusual case of CARP coexisting with terra firma-forme dermatosis in a young male, with atypical features consisting of a significant unilateral distribution with a whorled appearance.

ConfluentIntroduction and reticulated papillomatosis of ACase 15-year-old Report male of Middle Eastern descent Gougerot and Carteaud (CARP) was first initially presented to our dermatology clinic described in 1927. This condition typically has with his mother with a four-year history of an an onset during puberty, and is usually sporadic unresolving rash. He noticed gradual progression although familial cases have been reported. Young of the lesions across his neck, chest and back. He women are affected 2.5 times more frequently denied any associated symptoms or precipitating than young men, and blacks are affected twice as factors, including recent infection, fever, chills, often as whites.1 joint aches, pain or pruritis. Past medical history There are several different theories surrounding and skin history were noncontributory. Cutaneous the pathogenesis of this skin disorder. Some examination revealed hyperpigmented, brownish- theorize underlying endocrine imbalance and black, warty papules and plaques, predominately unilateral, distributed across his right anterior insulin resistance, due to an association with Figure 3. Histopathology showing the epidermis diabetes, obesity, pituitary and thyroid disorders.1,3 neck, right chest, bilateral , epigastric skin, with slight acanthosis with papillomatosis and However, others theorize a keratinization defect and back in a whorled appearance. The anterior hyperkeratosis, and pityrosporum yeast in the or an association with , due to chest revealed a vertical linear demarcation, with Malassezia furfur cornified layer. successful treatment with retinoids and selenium the right chest affected to a greater extent than sulfide, respectively.1 the left (Figures 1, 2). At this time, the patient antibody, complete blood count, erythrocyte refused a biopsy as well as lab work. We initiated sedimentation rate, urinalysis, hemoglobin Terra firma-forme dermatosis is characterized by treatment with ointment 0.1%, A1C and carcinoembryonic antigen, which dirt-like plaques, occurring most often in children which he found to provide mild improvement of were all within normal limits. A biopsy of the or adolescents, that cannot be washed away with dyspigmentation. epigastric skin was also done at this time, which soap and water but can be removed with isopropyl revealed an epidermis with slight acanthosis alcohol. Differential diagnosis often includes The patient then presented a year later stating that with papillomatosis and hyperkeratosis, and CARP, pityriasis versicolor, and acanthosis the lesions were not improving to his satisfaction pityrosporum yeast in the cornified layer, nigricans.4,5 Misdiagnosis of this condition often and he would like to pursue more aggressive consistent with CARP ( ). We initiated leads to unnecessary workups including skin treatment. We ordered a comprehensive Figure 3 further treatment with doxycycline 100 mg biopsies and endocrine evaluations. metabolic panel, lipid panel, antinuclear

Figures 1 and 2. Hyperpigmented, brownish-black, warty papules and plaques, predominately unilateral and with a whorled appearance.

Page 40 COEXISTING CONFLUENT AND RETICULATED PAPILLOMATOSIS AND TERRA FIRMA-FORME DERMATOSIS orally once daily. At two-week follow-up, the of terra firma-forme dermatosis was made at a doxycycline and topical tacrolimus had resulted subsequent visit, we feel this was a secondary 1.References Bolognia JL, Jorizzo JL, Schaffer JV. in minimal improvement, and we therefore diagnosis to the CARP. Co-occurrence of these Dermatology. 3rd ed. London: Elsevier Limited; discussed other treatment options such as two conditions has previously been reported, 2012. isotretinoin, oral minocycline, and and distinguishing them can be difficult as they antifungals. The patient refused further treatment can present clinically and histologically alike.5,8 2. Min ZS, Tan C, Xu P, Zhu WY. Confluent and decided to continue with the doxycycline The papillomatous skin changes associated with and reticulated papillomatosis manifested as and topical tacrolimus. At this visit it was also CARP may trap debris, dirt, or sebum, resulting vertically rippled and keratotic plaques. Postepy discovered that some of the hyperpigmented in terra firma-forme dermatosis.9 Treatment of Dermatol Alergol. 2014 Oct;31(5):335-7. lesions could be wiped off with gauze soaked CARP has proven difficult, as it often does not 3. Bernardes FF, Quaresma MV, Rezende FC, in isopropyl alcohol, indicating a coexisting respond to therapeutic interventions or recurs Kac BK, Nery JA, Azulay-Abulafia L. Confluent diagnosis of terra firma-forme dermatosis after therapy has stopped. Many treatments and reticulate papillomatosis of Gougerot- (Figure 4). have been reported to achieve success, such as Carteaud and obesity: dermoscopic findings. An a variety of antibiotics, isotretinoin, acitretin, Bras Dermatol. 2014 May;89(3):507-9. salicylic acid, hydroquinone, antifungals and 5-fluorouracil, though no single therapy has 4. Duncan WC, Tschen JA, Knox JM. Terra been proven to be consistently successful.1,2 In firma-forme dermatosis. Arch Dermatol. 1987 our case, our patient had mild improvement of May;123(5):567-9. dyspigmentation with topical tacrolimus and 5. Berk DR. Terra firma-forme dermatosis: a oral doxycycline, but the treatment did not result retrospective review of 31 patients. Pediatr in full, desired improvement. While lesions Dermatol. 2012 May;29(3):297-300. of terra firma-forme dermatosis can be treated 6. Kalter DC, Griffiths WA, Atherton DJ. Linear successfully with cleansing with isopropyl and whorled nevoid hypermelanosis. J Am Acad alcohol, continued maintenance treatments may Dermatol. 1988 Dec;19(6):1037-44. be necessary when an underlying papillomatous condition such as CARP is also present. 7. Di LV. Linear and whorled hypermelanosis. Figure 4. Hyperpigmented lesions could be Pediatr Dermatol. 2007 May;24(3):205-10. wiped off with gauze soaked in isopropyl 8. Berk DR, Mutizwa MM. Comment regarding alcohol. WhileConclusion CARP has many characteristic clinical the histopathology of terra firma-forme features, there have been a variety of different dermatosis. J Cutan Pathol. 2012 Feb;39(2):300- manifestations reported.2 We report another 1. CARPDiscussion was first described in 1927. It is most manifestation of CARP, presenting primarily 9. Berk DR. Confluent and reticulated common in people in their late teens and early unilaterally with a whorled pattern and with the papillomatosis response to 70% alcohol 20s. CARP affects all racial groups but has been coexistence of terra firma-forme dermatosis. swabbing. Arch Dermatol. 2011 Feb;147(2):247- found to occur more frequently in blacks. The Familiarity with terra firma-forme can avoid 8. lesions begin as round, red-to-brown papules, unnecessary workups, but it is also important

1 mm to 2 mm in diameter, distributed across to recognize that papillomatous diseases such as CARP and can the intermammary region and, less commonly, Correspondence: Laura Sandoval, DO; the interscapular and epigastric regions. As possibly predispose patients to this entity. When 1099 Medical Center Dr., Wilmington, NC the disorder progresses, the lesions enlarge to CARP or acanthosis nigricans is suspected, 28401; Ph: 760-217-1457; F: 910-343-6006; 4 mm to 5mm and can become hyperkeratotic it may be prudent to first attempt wiping off [email protected] and verrucous. The lesions can coalesce, and the hyperpigmented lesions with isopropyl alcohol eruption tends to spread centrifugally, becoming at initial visit. However, as in the case of our confluent centrally and reticulated peripherally.1,2 patient, in the presence of terra firma-forme it is important to closely examine the skin for textural In our case, the lesions appeared as surface changes after lesions have been wiped hyperpigmented, brownish-black papules and away, because they may suggest a co-existing plaques distributed across the intermammary, papillomatous disease. epigastric and interscapular regions. The presentation of this eruption was unique due to its whorled appearance and unilateral distribution across the anterior chest. Due to these unique clinical features, our differential diagnosis was broad and included acanthosis nigricans, progressive cribriform and zosteriform hyperpigmentation, and linear and whorled nevoid hypermelanosis. Both clinically and histologically, this case resembled both acanthosis nigricans and CARP, but CARP was favored due to the distribution throughout the trunk as opposed to limited to intertriginous areas. Progressive cribriform and zosteriform hyperpigmentation was ruled out based on the presence of lesions on the bilateral back and bilateral arms. We also ruled out linear and whorled nevoid hypermelanosis due to the lack of lesions present in infancy, as well as the lack of epidermal melanosis on histology.6.7 While the diagnosis

OTTENI, SANDOVAL, CRANE Page 41 A Case of Pili Annulati Following Resolution of Alopecia Areata

Karan Lal, BS,* Charlotte Noorollah, DO**

*Medical Student, New York Institute of Technology College of Osteopathic Medicine, Old Westbury, NY **Dermatologist, Brooklyn Dermatology, Brooklyn, NY

Abstract Pili annulati (PA) is a primarily inherited condition that has been reported to occur concurrently with alopecia areata (AA) and following resolution of AA. PA represents a non-fragile hair disorder that becomes more evident in adulthood, allowing it to be missed in many patients. Microscopic examination of affected reveals a characteristic banded, alternating dark-and-light appearance. There is no formal treatment for PA, but proper hair care can prevent harm from external factors. Introduction Pili annulati (PA) is a rare, non-fragile hair disorder, often inherited in an autosomal- dominant fashion, though there are reports of sporadic cases. PA clinically presents as light spangled hair. Microscopically, it is characterized by alternating dark and light bands initiating from the hair sheath that are present in a random fashion along the length of the upper Figure 2. Microscopic examination revealing hair shaft with areas of alternating dark and light bands three quarters of the hair shaft.1,2 The condition with sharply cut edges. may be diagnosed in the beard, scalp, pubic 3-5 hair regrowth with only textural changes, and revealed any differences between PA and normal and axillary regions. The alternating dark and 1 therapy was discontinued (Figure hair specimens. However, antibodies to aspects light bands appear as such due to the presence 1). A hair sample was sent for pathological of the lamina densa, lamina lucida, and anchoring of air-filled pockets within the cortex of the hair 6 examination to rule out a structural hair-shaft fibrils have been noted on immunohistochemical shaft at varying locations. Upon microscopic deformity. Examination of the hair shaft under studies, which is supported by transmission examination, these pockets scatter light and polarized light revealed alternating dark and light electron microscopy of PA hair specimens that appear dark due to the decreased transmission of bands with sharp-appearing edges indicative of a demonstrate reduplication of the lamina densa light; however, clinically they correspond to the 8 diagnosis of pili annulati (Figure 2). in the hair root bulb. Linkage analysis within light strands, because under reflective light the families with autosomal-dominant PA has also “microscopically dark” areas actually reflect more 6 been performed, revealing a gene locus on 12q light. PA has been reported concomitantly in with specific linkage between 12q24.32–24.33 patients with alopecia areata (AA) and following 9,10 regions. Although no known mutations have the resolution of AA. been isolated, having this specific locus provides an opportunity for further exploration. Case Report The diagnosis of PA is often made by light A 6-year-old male presented to the dermatology microscopy, with increased sensitivity when office with the primary complaint of “hair not a liquid medium is used to fix the hair.11 The growing the way it used to.” Hair loss had been differential diagnosis of PA includes pseudopili occurring in a non-discrete pattern for two annulati and monilethrix. months’ duration. The patient reportedly had very thick hair, and changes were particularly notable Pseudopili annulati, a twisted-hair phenotype, after a recent haircut prior to presenting to the characteristically appears in an elliptical shape office. The patient had a past medical history of with a normal hair shaft under light microscopy, hay fever. Past surgical and family histories were Figure 1. Dark brown hairs exhibiting but clinically it displays banding.12 Monilethrix non-contributory. alternating shiny and dull segments along the is an inherited, autosomal-dominant condition shafts with a speckled appearance. that has an alternating node and constricted On physical examination, the patient had appearance on microscopy, resembling PA, but round patches of non-scarring alopecia with unlike PA it is a fragile hair disorder.13,14 mild scaling. A fungal culture was performed for suspected tinea capitis, and the patient was Discussion PA has been documented to appear in conjunction prescribed 2% topical lotion to be Hair abnormalities are subtle and therefore with AA and post AA, and has also been applied daily, pending cultures. require extensive investigation. Pili annulati is reported to disappear after resolution of AA. One a rare, autosomal-dominant hair shaft disorder, European study examined the presence of PA Baseline laboratory examination revealed a discovered in 1866, that has an unknown concomitant with AA and found a statistically mildly elevated white blood cell count, while the 1,7 pathogenesis. Possible explanations for significant 9% prevalence of concurrent AA in remainder of the exam was within normal limits. development of PA include a structural protein the PA group.15 The study, however, suggested Fungal cultures did not reveal any growth, at which defect within the extra cellular matrix, a basement that the concurrence was coincidental, as the point ketoconazole therapy was discontinued membrane zone defect, a cytokeratin abnormality genes identified in AA do not appear to have and triamcinolone 0.1% cream with twice daily and a genetic defect on the long of the a relationship to the gene locus identified in application was initiated for suspected alopecia th 1,8,9 12 chromosome. Immunohistochemical PA. 15 However, the study size was too small to areata. Further follow-up at two months revealed examination for cytokeratin anomalies have not determine an actual relationship. Our patient, on Page 42 A CASE OF PILI ANNULATI FOLLOWING RESOLUTION OF ALOPECIA AREATA the other hand, had PA after resolution of AA. References 17. Smith SR, Kirkpatrick RC, Kerr JH, et al. A similar case has been reported by Cruz et al., 1. Giehl KA, Dean D, Dawber RP, et al. Alopecia areata in a patient with pili annulati. J in which a 31-year-old female with severe AA in Cytokeratin expression in pili annulati hair Am Acad Dermatol. 1995;32(5, pt 1):816-8. locations of the scalp as well as other hair-bearing follicles. Clin Exp Dermatol. 2005;30:426-8. 18. Castelli E, Fiorella S, Caputo V. Pili Annulati areas had resolution of her AA after being Coincident with Alopecia Areata, Autoimmune treated with several courses of intramuscular 2. Streck AP, Moncores M, Sarmento DF, et al. Thyroid Disease, and Primary IgA Deficiency: triamcinolone. Hair shaft examination of this Study of nanomechanical properties of human Case Report and Considerations on the patient’s regrown hair revealed PA.16 In contrast, hair shaft in a case of pili annulati by atomic Literature. Case Rep Dermatol. 2012;4(3):250-5. a case has been reported of a patient with a past force microscopy. J Eur Acad Dermatol Venereol. history of PA who presented with hair loss, and 2007;21:1109-10. after treatment with intralesional triamcinolone 3. Amichai B, Grunwald MH, Halevy S. Hair Correspondence: Charlotte Noorollah, DO; and topical had re-growth of normal, abnormality present since childhood. Pili [email protected] non-PA hair.17 annulati. Arch Dermatol. 1996;132:575, 578. PA has also been identified in a patient with 4. Musso LA. Pili annulati. Australas J Dermatol. a complex condition of autoimmune disease 1970;11:67–75. comprised of IgA deficiency, thyroid disease, 5. Montgomery RM, Binder AI. Ringed hair. and AA. Although there may be no association Arch Dermatol Syphilol. 1970;58:177–9. between PA and AA, the presence of autoimmune diseases may relay some connection to antigenic 6. Moffitt DL, Lear JT, de Berker DA, Peachey changes within the hair root bulb and the RD. Pili Annulati Coincident with Alopecia polygenic nature of AA as well as the distinct Areata. Pediatr Dermatol.1998;15(4):271-3. locus of PA.18 7. Landois L. Das plötzliche Ergrauen Although there is no treatment for PA, patients der Haupthaare. Arch Path Anat Physio. with co-existing hair loss may benefit from topical 1866;35:575–99. minoxidil therapy, for it is thought to allow for 8. Giehl KA, Ferguson DJ, Dead D, et al. normal matrix production, which in turn could Alterations in the basement membrane zone in theoretically repair the structural defect.17 pili annulati hair follicles as demonstrated by electron microscopy and immunohistochemistry. Conclusion Br J Dermatol. 2004;150:722-7. Pili annulati is a rare hair phenotype that has been 9. Green J, Fitzpatrick E, De Berker D, Forrest documented to occur with AA, after resolution of SM, Sinclair RD. A Gene for Pili Annulati Maps AA, and in combination with other autoimmune to the Telomeric Region of Chromosome 12q. J disorders. Due to its inheritable nature, a Invest Dermatol. 2004;123(6):1070-2. family history of PA may warrant examination and education of patients affected with this 10. Giehl KA, Eckstein GN, Benet-Pages A, Tosti condition. Although no treatment exists, patients A, De Berker DA, et al. A Gene Locus Responsible should be reassured and taught proper hair care for the Familial Hair Shaft Abnormality Pili management for this non-fragile condition. Annulati Maps to Chromosome 12q24.32-24.33. J Invest Dermatol. 2004;123(6):1073-7. 11. Giehl KA, Ferguson DJ, Dawber RP, et al. Update on detection, morphology and fragility in pili annulati in three kindreds. J Eur Acad Dermatol Venereol. 2004;18:654-8. 12. Lee SS, Lee YS, Giam YC. Pseudopili annulati in a dark-haired individual: A light and electron microscopic study. Pediatr Dermatol. 2001;18:27–30. 13. Bindurani S, Rajiv S. Monilethrix with Variable Expressivity. Int J Trichology. 2013;5(1):53-5. 14. Rakowska A, Slowinska M, Kowalska- Oledzka E, Rudnicka L. Trichoscopy in Genetic Hair Shaft Abnormalities. J Dermatol Case Rep. 2008;2(2):14-20. 15. Giehl K, Schmuth M, Tosti A, De Berker D, et al. Concomitant Manifestation of Pili Annulati and Alopecia Areata: Coincidental Rather than True Association. Acta Derm Venereol. 2011;91(4):459-62. 16. Cruz AP, Liang CA, Gray JP, Robinson- Bostom L, et al. The Appearance of Pili Annulati Following Alopecia Areata. Cutis. 2012;89(3):145-7.

LAL, NOOROLLAH Page 43 Two Cases of Pediatric Acral Cutaneous Calcinosis with Transepidermal Elimination Presenting as Skin-colored Papules

Gabriela Maloney, DO,* Rohini Chennuri, MD,** Patricia Dymek, MD,*** Marylee Braniecki, MD**

*Traditional Rotating Intern, Largo Medical Center, Largo, FL **Pathology Department, University of Illinois Hospital & Health Sciences System, Chicago, IL ***Dermatology Department, University of Illinois Hospital & Health Sciences System, Chicago, IL

Abstract We present two pediatric cases of acral dystrophic calcinosis. Dystrophic cutaneous calcification can occur in a variety of disorders that are usually associated with prior skin damage. It represents the deposition of insoluble calcium salts in the presence of tissue damage without abnormal systemic calcium levels or defective calcium metabolic regulation. A papular or warty acral lesion in the pediatric population should prompt the diagnostic possibility of a localized acral dystrophic calcinosis, especially if there is a clinical history of multiple needle sticks. It is important that physicians are aware that prior needle prick trauma (i.e., neonatal) can result in cutaneous dystrophic calcification, and to consider this entity whenever confronting a warty or papular lesion located in an acral site in the pediatric population.1 Introduction The second case involves a 1-year-old female Many different pathological conditions can result with a 4 mm, white-tan papule on the left heel. in dystrophic cutaneous calcification; however, Differential diagnosis included verruca vulgaris most commonly they are associated with prior and cyst. Skin biopsy specimen showed only skin damage without abnormal systemic calcium stratum corneum, but revealed disrupted acral levels or defective calcium metabolic regulation.2 stratum corneum with intracorneal deposition of Deposition of insoluble calcium salts occurs in granular calcified material (Figures 2 and 3). damaged tissue, and when localized, it can result The pathologic diagnosis on both cases was in a warty papule with a clinical differential dystrophic cutaneous calcification (consistent diagnosis including periungual , cyst, with prior needle stick trauma). verruca vulgaris and fibrokeratoma, among other conditions.3 Identifying the correct lesion Figure 1. Biopsy from right-index-finger papule is important when determining the clinical of 11-month-old male (H&E, 40x). Discussion Dystrophic calcification represents the deposition management, as some lesions require treatment of insoluble calcium salts in the presence of (e.g., verruga vulgaris), some may need further tissue damage without abnormal systemic investigation (e.g., ruling out tuberous sclerosis calcium levels or defective calcium metabolic when periungual are present), and 4 regulation. Calcium is important in cellular some do not require further intervention, as with proliferation, differentiation and regulation of cutaneous dystrophic calcinosis. Prior needle cell-to-cell adhesion. When tissue is damaged, prick trauma (i.e., neonatal) has been reported to cellular membrane disruption can allow calcium result in cutaneous dystrophic calcification, and it influx and intracellular crystallization. The is important for physicians to consider this entity 1 acidity produced by cellular damage can also within the pediatric population. 2 inhibit anti-calcifying processes. Dystrophic cutaneous calcification can occur in a variety of Case Report disorders that are usually associated with prior We present two pediatric cases of acral dystrophic skin damage. Examples of these conditions calcinosis. Such lesions can clinically appear include autoimmune connective tissue diseases, warty or as a papules. This entity is probably a panniculitis, genetic disorders, infections and more common lesion then is actually reported. Figure 2. Biopsy from left-heel papule of neoplasms, among many others.2 Our patients, in A papular or warty acral lesion in the pediatric 1-year-old female (H&E, 200x). both cases, did not present with any biochemical, population should prompt the diagnostic metabolic or genetic abnormalities. possibility of a localized acral dystrophic The verrucous papule on the index finger (in calcinosis, especially if there is a clinical history the first case) and the papule from the heel (in of multiple needle sticks. the second case) both showed subepidermal The first case involves an 11-month-old male dystrophic calcification secondary to traumatic who presented with a flesh-colored papule on the needle-stick injury. A similar case of dystrophic right index finger since birth. The lesion began calcification secondary to needle-prick trauma has as two small white “dots” and had increased to been reported by Sakmann et al., who theorized the size of 5 mm x 4 mm. The clinical differential that the needle prick introduced epidermal diagnosis of this periungual, flesh-colored papule implantation cysts that led to dystrophic included periungual fibroma, fibrokeratoma, calcification of the cutaneous tissue.1The clinical pyogenic granuloma, connective tissue nevi, differential diagnosis of skin-colored papules myxoid cyst and verruca vulgaris. Tissue sections includes periungual fibroma, fibrokeratoma, from a biopsy revealed a distinct nodular mass connective tissue nevi, myxoid cyst and verruca. of subepidermal dystrophic calcification with Figure 3. Biopsy from left-heel papule of Periungual fibroma belongs to a group of lesions overlying reactive acanthosis and evidence of 1-year-old female (calcium [Von Kossa] stain, called cutaneous angiofibromas, which are dome- transepidermal elimination of calcific material 200x). shaped lesions composed of a collagenous stroma (Figure 1).

Page 44 TWO CASES OF PEDIATRIC ACRAL CUTANEOUS CALCINOSIS WITH TRANSEPIDERMAL ELIMINATION PRESENTING AS SKIN-COLORED PAPULES with increased dermal fibroblasts and dilated, thin-walled blood vessels. Periungual fibroma 1.References Sakmann S, DeSilva P. Neonatal heel-prick is considered a major diagnostic criterion for testing leading to dystrophic calcification. BMJ tuberous sclerosis, seen more commonly in Case Rep [internet]. 2013 May 31 [cited 2014 adults.5,6Fibrokeratomas are uncommon, benign March 3]. Available from http://www.ncbi.nlm. lesions that present in the finger of middle-aged nih.gov/pubmed/23729719. adults. They consist of solitary, pink to skin- 2. Bolognia JL, Jorizzo JL, Schaffer JV. colored, exophytic papulonodules that may be Dermatology. 3rd ed. Philadelphia. Elsevier slightly keratotic with a collarette of elevated skin. Saunders; 2012. Chapter 50, Calcifying and They are composed of blood vessels surrounding Ossifying Disorders of the Skin; p. 729-31. think collagen bundles.7Connective tissue nevi, also known as collagenomas, are thin, skin- 3. Alabaz D, Mungan N, Turgut M, Dalay C. colored papules, nodules or plaques that arise Unusual Idiopathic Calcinosis Cutis Universalis during childhood or can be present at birth. The in a Child. Case Rep in Dermatol 2009;1:16-22. histopathological evaluation consists of increased 4. Walsh JS, Fairley JA. Calcifying disorders of dermal collagen bundles without an increase in the skin. J Am Acad Dermatol. 1995;33:693-706. fibroblasts.6Myxoid cysts are the most common nail tumors, often seen in middle-aged women. 5. Hake S. Cutaneous manifestations of tuberous They are soft nodules located in the proximal nail sclerosis. The Oschner Journal. 2010;3:200-4. fold of fingernails that often drain spontaneously.8 6. Bolognia JL, Jorizzo JL, Schaffer JV. Verruca vulgaris, also known as common warts, Dermatology. 3rd ed. Philadelphia. Elsevier are exophytic, hyperkeratotic, dome-shaped Saunders; 2012. Chapter 118, Fibrous and papules or plaques that often present on the Fibrohistiocytic Proliferations of the skin and fingers or dorsum of the hands, but can occur ; p. 1961-77. anywhere in the skin surface, especially in trauma- 7. Adya KA, Palit A, Inamadar AC. Keratotic prone sites. They can have characteristic punctate papule with a collarette of skin. Indian J. black dots as a result from thrombosed capillaries. Dermatol. 2012;57(2):164-5. Elongated rete ridges, marked acanthosis, and parakeratosis overlying papillomatosis are seen 8. Cobos G, Braunstein I, Abuabara K, et al. on histopathological examination.9 Mucinous nevus: report of a case and review of the literature. JAMA Dermatol. 2014;150(9):1018-9. Histopathologic evaluation and a good history and physical examination and review of systems 9. Bolognia JL, Jorizzo JL, Schaffer JV. rd are very important when trying to distinguish Dermatology. 3 ed. Philadelphia. Elsevier between these conditions. Saunders; 2012. Chapter 79, Human Papillomaviruses; p. 1303-19.

Correspondence: Gabriela Maloney, DO; [email protected].

MALONEY, CHENNURI, DYMEK, BRANIECKI Page 45 Recurrent Basal Cell Carcinoma with Perineural Invasion: A Case Report and Review

Shana Rissmiller, DO,* Alecia Folkes, MS,** Indira Krishnarao, MD***

*Dermatology Resident, Second Year, West Palm Hospital, Palm Beach Consortium for Graduate Medical Education, West Palm Beach, FL **Medical Student, Third Year, Nova Southeastern University College of Osteopathic Medicine, Ft. Lauderdale, FL ***Dermatologist, Teaching Faculty, Veterans Affairs Medical Center, West Palm Beach, FL

Abstract While basal cell carcinoma (BCC) is the most common malignancy found in humans, the disease process remains localized in the great majority of cases. Recurrent, locally advanced, and metastatic disease can pose a significant management challenge. Herein, we present a case of recurrent BCC of the ear found to incidentally have perineural invasion. Identifying risk factors for recurrent and more advanced disease can aid the clinician in the early and appropriate management of patients with basal cell carcinoma. The relationship between the timing and amount Perineural invasion has an increased occurrence of ultraviolet radiation exposure has not been in male patients and has been linked to increased clearly established.1 Additional risk factors incidence of regional lymph node involvement.6 include history of exposure to ionizing radiation, Most metastatic and locally aggressive BCCs arsenic exposure, and immunosuppression.3 Basal originate from the head and neck, with a mean cell carcinoma may also develop in chronic scars, interval of initial presentation to discovery of ulcers, or burns. metastasis of approximately nine years.3 Recurrent Several genodermatoses are associated with skin cancers with prior resection and/or radiation an increased risk of basal cell carcinoma. These therapy are more commonly associated with perineural invasion than the primary untreated include oculocutaneous albinism, xeroderma 6 pigmentosum, epidermodysplasia verruciformis, skin cancer. and basal cell nevus syndrome (BCNS).3,4 Rombo, Bazex-Dupré-Christol, Brooke-Spiegler, Case Report Schopf-Schulz-Passarge, and Muir-Torre are A 65-year-old Caucasian male presented to the other rare syndromes associated with BCC.3,4 dermatology clinic for evaluation of a recurrent lesion involving the mid-helix of his right ear. There are many risk factors contributing to the He first noticed this growth approximately one development of recurrent, locally advanced, or month prior to presentation. He reported a history metastatic basal cell carcinoma. Anatomical of basal cell carcinoma of this site around 2008, locations with higher risk of recurrence include 3 which was treated by excision with subsequent the face, eyelid, nose, lip, ear, hands and feet. graft placement. In 2012, he developed recurrent Increased recurrence rates are further observed superficial spreading BCC. This was managed when poorly defined borders are present, with Mohs micrographic surgery. The surgical in tumors larger than 2 cm in diameter, in defect was repaired by plastic surgery, and the perineural involvement, and in prior history of 3 patient applied imiquimod 5% to the area after Figure 1. Right mid-helix: 6 mm papule with recurrent BCC. Patients who have had multiple healing from the procedure. There was no past central hyperkeratotic crust and rolled borders. lesions have a higher recurrence rate than those 5 medical history of immunosuppression, radiation with single lesions. Tumors around the medial exposure, or arsenic exposure. He did admit to canthus, nose, and ear are more likely to become Introduction 1 chronic sunlight exposure as a child and as an While basal cell carcinoma (BCC) is the most invasive compared to BCC of other sites. adult (working outdoors on heavy machinery). common malignancy found in humans, with The most likely lesions to metastasize include He denied a history of any other skin cancers. over 2 million cases diagnosed each year in the large tumors or those with more aggressive United States, the disease remains localized in histological phenotypes (morphemic, infiltrating, On physical examination, the right mid-helix 1 the great majority of cases.1 Locally advanced basosquamous). demonstrated a 6 mm papule with central hyperkeratotic crust and rolled borders (Figure and metastatic disease is quite rare, with Several host factors are associated with an 2 1). This was located along the edge of a smooth, an incidence ranging from 0.18% to 3%. increased risk for recurrent disease. Patients round cicatrix from prior graft. A shave biopsy of Complications of local disease include local who are diagnosed with BCC before the age the lesion was performed and demonstrated basal tissue destruction, functional impairment, and of 40, are immunosuppressed, have a genetic 3 cell carcinoma extending to the deep margin of cosmetic disfigurement. Metastatic disease syndrome and/or have a history of aggressively 3 the biopsy. The patient was then referred back for causes additional complications, with the most behaving tumors are at higher risk. With regard Mohs surgery. After performing two stages of frequently involved sites being the lymph nodes, to immunosuppression, this includes patients 1 Mohs, the margins were still found to be positive. bone, and lungs. with a history of transplant, those with leukemia/ The patient was very concerned about losing a The incidence of basal cell carcinoma increases lymphoma, and those on immunosuppressants 1,5 significant portion of his ear and was unwilling with age. While it is most frequently found for conditions such as rheumatoid arthritis. to continue with further excision. At that point, a in light-skinned individuals, all skin types are As previously mentioned, radiation therapy, wedge resection was performed to remove a little affected. The most common risk factor for BCC chronic scars, burns, or ulceration can make that more tissue, as well as allow for closure of the development is chronic UV exposure through particular area of the body more susceptible to 3 surgical defect. This tissue was sent for permanent sunlight, tanning booths, or UV light therapy.3 recurrence of BCC. processing. Hematoxylin and eosin stain (H&E)

Page 46 RECURRENT BASAL CELL CARCINOMA WITH PERINEURAL INVASION: A CASE REPORT AND REVIEW is an indirect sign of perineural spread.6 Plain radiographs and CT scan are used to visualize expansion of neural foramina and canals such as the inferior alveolar canal, infraorbital foramen, foramen rotundum or facial (Fallopian) canal.9 PET scan can also be used to visualize possible extension through the bone and foramina.3 In cases where the tumor has spread to regional lymph nodes, visualization can be seen on MRI. 9 Patients with nodal disease should undergo contrast-enhanced CT and/or ultrasound-guided fine needle aspiration cytology and/or sentinel lymph node biopsy.9 Figures 2 and 3. H&E stains of excision specimen demonstrating basal cell carcinoma surrounding There is no universally accepted protocol for the nerve sheath. treatment of basal cell carcinoma with perineural invasion. Treatment is mostly individualized, depending on the patient’s co-morbidities, anatomical location of the lesion, previous treatment history, patient preference, and other factors.1 Adequate surgical removal based on histologic findings is the primary treatment used with adjunctive radiotherapy.12 Surgical treatment methods include Mohs surgery, standard surgical excision, curettage alone, and curettage and electrodesiccation.3 Non-surgical methods include topical chemotherapy, radiation therapy, and photodynamic therapy.3 The five-year recurrence rates for recurrent basal cell carcinoma Figures 4 and 5. Ber-EP4 staining demonstrating basal cell carcinoma surrounding nerve sheath. are significantly higher than with primary BCC. They are estimated as follows: 5.6% with Mohs 9 identified areas of perineural invasion (Figures 2 and numbness. Perineural spread from the head surgery, 17.4% with surgical excision of the & 3). This was confirmed with Ber-EP4 staining and neck tends to involve the trigeminal nerve, tumor, 40% with curettage and electrodessication, (Figures 4 & 5). resulting in paresthesia. Facial nerve involvement and 13% with radiation therapy.3 results in palsy, as these nerves have a rich network The patient was sent for an MRI of the head and 10 Hedgehog pathway inhibitors, including of cutaneous endings. neck with and without contrast to evaluate for vismodegib, may have a potential role in the further extension of the carcinoma. An area of Identifying risk factors for recurrent and advanced treatment of advanced or metastatic cases of basal focal contrast enhancement within the adjacent disease can aid the clinician in the appropriate cell carcinoma when surgery is contraindicated subcutaneous fat deep to the helix was identified. management of patients with basal cell carcinoma. or deferred by the patient.1 A recent study of This was thought to represent postoperative The location of this patient’s basal cell carcinoma, 499 patients with advanced or metastatic disease enhancement along the surgical tract versus early the ear, is a site known to be associated with more who were ineligible for surgical treatment found tumor invasion. A positron emission tomography aggressive tumors. Studies suggest that there is that 302 of 453 patients with locally advanced (PET) scan was also performed and did not a preference for tumor cells to grow in this area basal cell carcinoma had an overall response to 13 demonstrate any areas of increased uptake. due to a larger degree of angiogenesis, making daily treatment with vismodegib. Of the 302 this an ideal environment for tumorigenesis and patients, 153 had a complete response, and 149 The patient was referred for localized radiation 11 treatments. He is currently awaiting a follow-up uncontrolled growth. This shows that there is a patients had a partial response. In addition, 11 of MRI. correlation between angiogenesis and increased 29 patients with metastatic basal cell carcinoma aggressiveness, requiring more Mohs stages to had an overall response (two complete responses, achieve tumor-free margins. nine partial responses). The long-term efficacy Discussion and tolerability of hedgehog pathway inhibitors Perineural invasion is characterized by growth Following the identification of perineural spread 1,13 is still being investigated. of tumor cells within any of the three layers of basal cell carcinoma, the patient should undergo of the nerve sheath.7 This is believed to be a additional studies to further delineate the extent In non-melanoma skin carcinomas, radiation result of reciprocal interactions between cancer of disease. A complete skin examination should can be used as primary treatment or as adjuvant cells and nerve elements.8 Perineural spread be performed, as patients often have additional therapy. Radiation works by inducing death 3 may by facilitated by neural secretion of glial- cancer at other sites. Any suspicious lesion of cancer cells present along the invading derived neurotrophic factor (GDNF), which requires a biopsy for definitive diagnosis. A nerve and can interrupt paracrine interactions phosphorylates the RET tyrosine kinase receptor, thorough history regarding paresthesias or palsy between cancer cells and nerves, in particular 8 triggering downstream signaling pathways that should be elicited, as the new onset or progression the GDNF-RET axis. There are three different promote cancer-cell migration and invasion.8 of paresthesias may be the only presenting sign radiation methods used: orthovoltage superficial High RET receptor expression has also been of perineural spread. Gadolinium-enhanced MRI X-rays, megavoltage electron-beam therapy, and 3 found in patients with pancreatic and prostate or MR neurography are the best imaging studies Brachytherapy. Radiotherapy can be low-energy, carcinomas, which are found to express perineural for the detection of perineural spread and are which treats superficial lesions, or high-energy, characteristics.8 used to assess the extent of disease spread along which can spare the skin and penetrate to deep- 6 the cranial nerves. Other signs of perineural seated lesions.14 Perineural invasion may be categorized as either invasion include enhancement with or without Patients with focal, incidental perineural invasion incidental invasion, which is asymptomatic, or enlargement of the nerve, mass in the cavernous 6 with negative margins, such as BCC that is not clinical perineural invasion, which presents with sinus or Meckel cave. Denervation of a group of adjacent to a major cranial nerve, are likely to cranial-nerve deficits such as paresthesia, pain, muscles innervated by the affected cranial nerve RISSMILLER, FOLKES, KRISHNARAO Page 47 9 be cured with surgery alone. However, those References 13. Basset-Seguin N, Hauschild A, Grob J, with multifocal perineural spread should be 1. Lear J, Corner C, Dziewulski P, Fife K, Ross Kunstfeld R, Dréno B, Mortier L, Ascierto considered for postoperative radiotherapy, G, Varma S, Harwood C. Challenges and new P, Licitra L, Dutriaux C, Thomas L, Jouary T, especially patients with recurrent cancers, those horizons in the management of advanced basal Meyer N, Guillot B, Dummer R, Fife K, Ernst who are immunocompromised due to solid organ cell carcinoma: a UK perspective. Br J Cancer. D, Williams S, Fittipaldo A, Xynos I, Hansson transplant and/or chronic lymphocytic leukemia, 2014 Oct 14;111(8):1476–1481. J. Vismodegib in patients with advanced basal and those with tumors in locations close to cranial cell carcinoma (STEVIE): a pre-planned nerves V and VII.9 Since patients with extensive 2. Bechert C, Stern J. Basal cell carcinoma interim analysis of an international, open-label microscopic BCC with perineural invasion have a with perineural invasion: reexcision perineural trial. Lancet Oncol. 2015 May 13. pii: S1470- high risk for recurrence, they should be considered invasion? J Cutan Pathol. 2010 Mar;37(3):376-9. 2045(15)70198-1. for radiotherapy as well.9 Radiotherapy can be 3. Kauvar A, Cronin T, Roenigk R, Hruza G, 14. Han A, Ratner D. What is the Role of effective in treating microscopic deposits of Bennett R. Consensus for Nonmelanoma Skin Adjuvant Radiotherapy in the Treatment cancer cells that remain after surgical removal of Cancer Treatment: Basal Cell Carcinoma, of Cutaneous Squamous Cell Carcinoma the tumor mass. It may also be used for tumor Including a Cost Analysis of Treatment Methods. with Perineural Invasion? Cancer. 2007 Mar destruction in places that are difficult to reach by Dermatol Surg. 2015 May;41(5):550-71. 15;109(6):1053-9. surgical excision. 4. Spitz, J. Genodermatoses: A Clinical Guide Not all patients with tumors characterized by nd to Genetic Skin Disorders. 2 ed. Philadelphia: : perineural invasion are able to receive adjuvant Lippincott Williams & Wilkins, 2005. p. 56-58, Correspondence Shana Rissmiller, DO; radiotherapy. Some patients are unable to tolerate 170-179. [email protected] the side effects, such as redness and irritation of the area treated. Recurrent lesions that are close 5. Bumpous J, Padhya T, Barnett S. Basal Cell to a site previously treated by irradiation can Carcinoma of the Head and Neck: Identification not be treated with radiotherapy due to risk of of Predictors of Recurrence. Ear Nose Throat J. necrosis.14 Radiotherapy can cause orbital and 2000 Mar;79(3):200-4. central nervous system damage as well as bone 6. Gaddikeri, Santhosh, Bhrany, Amit, Anzai, exposure, fistula formation, and wound infection. Yoshimi. Perineural Invasion of Skin Cancers in Patients with connective tissue diseases and those the Head and Neck: An Uncommon Phenomenon with genetic conditions that predispose them to Revisited. Otolaryngology. 2014;4:3. skin cancer, such as xeroderma pigmentosum, 7. Frunza A, Slavescu D, Lascar I. Perineural are more susceptible to radiation and therefore Invasion in Head and Neck Cancers - A Review. should not receive radiation treatment.14 J Med Life. 2014 Jun 15;7(2):121-3. 8. Bakst R, Lee N, He S, Chernichenko Conclusion N, Chen C, Linkov G, Le C, Koutcher J, Perineural invasion of basal cell carcinoma is Vakiani, Efsevia, Wong, Richard. Radiation a poor prognostic indicator, associated with Impairs Perineural Invasion by Modulating higher rates of morbidity and mortality.12 the Nerve Microenvironment. PLoS ONE. Management of advanced disease such as this can 2012;7(6):e39925. be challenging. This case study demonstrates a rare circumstance in which a basal cell carcinoma 9. Mendenhall W, Ferlito A, Takes R, Bradford C, located on a high-risk site recurred twice in a Corry J, Fagan J, Rinaldo A, Strojan P, Rodrigo J. patient with no known personal risk factors. Cutaneous Head and Neck Basal and Squamous Cell Carcinomas with Perineural Invasion. Oral Oncol. 2012 Oct;48(10):918-22. 10. Panizza B, Warren T. Perineural Invasion of Head and Neck Skin Cancer: Diagnostic and Therapeutic Implications. Curr Oncol Rep. 2013;15:128–33. 11. Mulvaney P, Higgins B, Dufresne R, Cruz A, Lee K. Basal Cell Carcinomas of the Ear Are More Aggressive Than On Other Head and Neck Locations. J Am Acad Dermatol. 2014 May;70(5):924-6. 12. DeAmbrosis K, De’Ambrosis B. Nonmelanoma Skin Cancer with Perineural Invasion: Report of Outcomes of a Case Series. Dermatol Surg. 2010;36(1):133-8.

Page 48 RECURRENT BASAL CELL CARCINOMA WITH PERINEURAL INVASION: A CASE REPORT AND REVIEW Atypical presentation of Sézary Syndrome with CD4+/CD7+/CD26- T-cells and marked epidermotropism: A case report and literature review

Gabriela Maloney, DO,* Sujata Gaitode, MD,** Igor Altman, MD,*** Marylee Braniecki, MD**

*Traditional Rotating Intern, Largo Medical Center, Largo, FL **University of Illinois Hospital & Health Sciences System, Wound Care, Chicago, IL ***University of Illinois Hospital & Health Sciences System, Dermatology Department, Chicago, IL

Abstract We present an atypical case of Sézary syndrome in a 46-year-old African American female who presented with tenderness, pruritus, hyperpigmented lesions and lymphadenopathy. Her condition was characterized by the retention of T-cell CD7 expression, significant atypical lymphocytic epidermotropism that histologically mimicked mycosis fungoides, and circulating Sézary cells ( CD4+/CD7+/CD26-) of fewer than 1000/uL. It is important to recognize this unique presentation and be able to differentiate it from mycosis fungoides (MF), as this can significantly alter the prognosis and treatment while having an impact on the patient’s life. Introduction Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma, accounting for approximately 50% of cases. It has three main clinical stages, including patch, plaque, and tumor, all with epidermotropic infiltrates of small- to medium-sized neoplastic T cells. Early MF tends to have neoplastic lymphocytes with an immunohistochemical profile positive for CD3, CD4 and CD45, and negative for CD7 and CD8.1Sézary syndrome (SS) is a rare, leukemic variant of cutaneous T-cell lymphoma characterized by cerebriform cells (Sézary cells), erythroderma and pruritus along with circulating, mature neoplastic T cells. Symptoms often Figure 1. Multiple breast erosions. develop insidiously, making the diagnosis very severe pruritic cutaneous lesions in both breasts Figure 2. Atypical lymphocytic infiltrates in difficult, often taking up to an average of 20.5 2 that started as bruises and progressed to erosions epidermis and dermis associated with erosion months from symptom onset to diagnosis. and sloughing of skin (Figure 1). She also had on breast skin (50x). Loss of CD7 expression has been reported small, erythematous, crusted papules on her as the most commonly used method for bilateral temples that extended down to the sides detection of cutaneous T-cell . of her neck and were accompanied by a severe However, CD7 expressivity has been reported burning sensation. The patient then progressed to to be highly variable.3-6 Studies have found that develop erythroderma covering 70% of her body some patients that were CD4+/CD7+ in early surface area. studies demonstrated loss of CD7 expressivity Skin biopsies of the breast were performed and over time, therefore making it a less reliable revealed a CD4-positive T-cell lymphoma with marker to separate normal from neoplastic cell foci of atypical cell aggregates within the epidermis populations.3,5 (epidermotropism and Pautrier microabscesses) associated with extensive papillary dermal involvement by atypical lymphoid infiltrate Case Report composed of small- to medium-sized cells Figure 3. Scalp with prominent epidermal and A 46-year-old African American female presented (Figure 2). The atypical lymphoid infiltrate was follicular involvement by atypical lymphocytes with tenderness, pruritus and hyperpigmented positive for CD4 and CD7, and negative for (50x). lesions on both breasts shortly after completing CD8. Direct immunofluorescence study for IgG, two months of radiation for breast cancer on the did not meet the criteria for Sézary syndrome. IgA, IgM, C3, and fibrinogen were all negative. left breast. She was staged T2N0M0, ER+, PR-, The neoplastic T-cells did not express CD56 or Because of the CD7 positivity, the patient was CD26. The clonal T-cell receptor gamma gene HER-2/neu- and Ki-67 30% and underwent tested for HTLV, which was negative. a lumpectomy, five months of chemotherapy rearrangement was detected, and the CD4:CD8 with doxorubicin and cyclophosphamide, and Biopsies of the scalp vertex and occipital scalp ratio was approximately 15:1 (Figure 6, p. 50). demonstrated similar morphologic findings with radiation. The patient also had breast tenderness, The patient was diagnosed with an atypical case a periadnexal and folliculotropic distribution warmth, peau d’orange appearance, and axillary of Sézary syndrome associated with a prominent (Figure 3). Immunophenotyping demonstrated lymphadenopathy, which raised a concern for CD4+/CD7+, “mycosis fungoides-like” cutaneous CD4, CD5 and CD7 positivity, with a marked mastitis. The patient did not respond to two histology. The presence of epidermotropism, increase of CD4:CD8 of approximately 10:1 courses of antibiotics. Breast biopsies showed atypical T-cell morphology and clonal T-cell (Figures 4 and 5, p. 50). Testing was negative for mild acute and chronic inflammation, with no rearrangement helped distinguish this case from CD8, CD10, CD30, CD56, and BCL6. signs of malignancy. Left axillary lymph-node reactive benign dermatoses. biopsy with flow cytometry demonstrated a Peripheral blood flow cytometry indicated The patient was staged IVA1. She was started peripheral T-cell lymphoma. atypical circulating T-cell lymphocytes that on bexarotene, prednisone, photophoresis and appeared Sézary by morphology, but the Sézary A few months later, the patient developed more topical . cell count was only 800 cells/uL and therefore MALONEY, GAITODE, ALTMAN, BRANIECKI Page 49 plaque stage is very similar but with elevation Epidermotropism is often absent or minimal Discussion and induration present, typically presenting in in SS; therefore, only approximately 60% of In the case presented here, the patient’s 2 initial cutaneous patches and the histological continuity with the patches. Tumors develop skin biopsies are diagnostic for SS. An atypical within the patches or plaques, but not all patients lymphocyte infiltrate at the dermoepidermal evaluation showing epidermotropism of atypical 1 lymphocytes lead to a possible diagnosis of progress to this stage. Histologically, neoplastic junction, eosinophilia, parakeratosis, acanthosis, mycosis fungoides. However, the patient’s rapid T-cell infiltrates appear within the superficial and spongiosis are the most common progression of skin involvement along with dermis accompanied by sparse epidermotropism histopathological features of SS. However, those and no spongiosis in the early stages of the findings are also commonly seen in many benign persistent CD7 expression on the lymphocytes 9 and presence of circulating atypical (CD4+/ disease. As the lesions progress, intraepidermal inflammatory conditions. CD7+/CD26-) lymphocytes in the blood collections of lymphocytes (Pautrier Sézary syndrome typically is diagnosed based supported the diagnosis of Sézary syndrome. microabscesses) and well-developed, band-like on evidence of molecular clonality of T-cell 1Early Mycosis fungoides (MF) is the most common lichenoid lymphocytic infiltrates are seen. gene rearrangement, absolute Sézary cell count MF tends to have neoplastic lymphocytes with an 3 type of cutaneous T-cell lymphoma, accounting greater than or equal to 1,000 cells/mm, a for approximately 50% of the cases. It has three immunohistochemical profile positive for CD3, CD4:CD8 ratio greater than or equal to 10 by primary, distinct clinical stages: patch, plaque, CD4 and CD45, and negative for CD7 and flow cytometry, >40% loss of CD7, >36% loss of and tumor. All stages are characterized by CD8. Even though the immunohistochemical CD26, and presence of CD25.9 epidermotropic infiltrates of small- to medium- profile of our patient was CD7+, there have been The differential diagnosis for Sézary syndrome sized neoplastic T cells. MF has a median age of reports of CD7+ MF reported in the literature. includes (but is not limited to) generalized atopic presentation of 57 years, affecting men more often T-cell clones are identified in anywhere from dermatitis, pityriasis rubra pilaris, erythrodermic than women with a 2:1 ratio. It is commonly seen 57% to 70% of cases. Loss of pan-T-cell antigens hypersensitivity reactions, parapsoriasis, DRESS in photoprotected areas, especially the buttocks, (CD2, CD5, and CD7) has also been reported 1 syndrome, , graft-versus-host- , upper thighs, breasts, and axilla. The in early patch stages of MF, which can be useful disease, generalized anaphylaxis, erythrodermic patch stage is characterized by 5 cm to 10 cm, to distinguish it from psoriasis and spongiotic dermatitis.3 Detection of the same clones from MF, acute or chronic leukemias, CTCL spectrum round, erythematous patches with a wrinkled 9 disease. Prognosis is generally poor, with a appearance and a fine overlying scale. The two different anatomical locations, as occurred in our case, has been shown to increase sensitivity median survival of four years from time of 10 and specificity when diagnosing MF.7Early diagnosis. Sézary syndrome has historically been MF can be very difficult to diagnose, often considered to arise from pre-existing MF, as an requiring years and many different biopsies. advanced systemic presentation. However, recent The differential diagnosis includes spongiotic lymphocyte studies suggest that SS and MF are dermatitis, psoriasis, dermatophytic infections, two distinct entities arising from two different 11 chronic actinic dermatitis, lymphomatoid contact subsets of atypical T-cells. CD26 is a dipeptidyl dermatitis, and lymphomatoid drug reactions. peptidase IV normally expressed in the majority Pagetoid reticulosis, primary cutaneous aggressive of T lymphocytes in the peripheral blood. It is epidermotropic CD8+ T-cell lymphoma, adult a surface proteolytic enzyme related to cellular T-cell leukemia/lymphoma (ATLL), and types activation, and its absence or decreased expression B and D lymphomatoid papulosis (LyP) are is highly characteristic of mycosis fungoides and Figure 4. Scalp showing atypical CD7+ lymphomas that may be nearly identical to MF Sézary syndrome. Jones et al. reported CD26 epidermotropic T cells (50x). histopathologically. Clinical presentation is most positivity ranging from 56% to 86% of CD4+ helpful in differentiating these cases, highlighting T-cells of healthy control subjects. They also the importance of good communication between reported loss of CD26 expressivity in 59 of 66 the dermatologist and dermatopathologist in this cases of MF or SS, with the remaining seven case.1 cases having only a dim expression of CD26. They concluded that absence of CD26 is a very useful A recent study demonstrated that only 9% of 4 marker when diagnosing MF or SS. CD7 is a the lesional lymphocytes are atypical and that glycoprotein belonging to the immunoglobulin reactive lymphocytes are also present in addition gene superfamily and is thought to be involved to the neoplastic cells, making architectural in signal transduction. It is expressed in almost all abnormalities more important than cytological CD8+ T cells and in approximately 90% of CD4+ 8,9Prognosis differences when diagnosing MF. T cells. CD7 expression in healthy subjects has varies according to the stage of the disease and been reported to be positive in 73% to 97% of the surface area involved. The risk of progression 4 Figure 5. Scalp with CD4+ uptake by non-neoplastic lymphocytes. The percentage of and visceral involvement tends to increase with lymphocytic infiltrate (30x). CD4+/CD7- T cells may correlate with Sézary- increasing surface area, presence of tumors cell counts in SS, but it is unknown whether and erythroderma. Subtypes of MF with no this is a result of neoplastic expansion of CD4+/ difference in prognosis include dyshidrotic MF, CD7- cells or aberrant loss of CD7 expressivity hypopigmented MF, and acanthosis-nigricans- in malignant T cells.5Loss of CD7 expression 1Sézary syndrome (SS) is a rare, leukemic like MF. has been reported to be the most commonly variant of cutaneous T-cell lymphoma. It is used method for detection of cutaneous T-cell characterized by cerebriform cells (Sézary cells), lymphomas. It is also believed that the size of the erythroderma, pruritus and circulating mature CD7- T cells correlates with disease progression neoplastic T-cells. Palmoplantar , 12 in MF and SS. However, CD7 expressivity has subungual hyperkeratosis, yellow discoloration, been reported to be highly variable: Studies have nail thickening, onychomadesis, alopecia, and found up to 50% of MF or SS patients with a ectropion are also distinguishing features of SS. positive CD7 marker in their neoplastic T-cells.3-6 Symptoms often develop insidiously, making the Jones et al. speculated that CD7 expression may diagnosis very difficult, often taking an average of Figure 6. Scalp with very limited CD8 uptake 2 be vulnerable to reactive T-cell populations, 4 (30x). 20.5 months from symptom onset to diagnosis. concurrent illness, and effects of treatments.

Page 50 ATYPICAL PRESENTATION OF SÉZARY SYNDROME WITH CD4+/CD7+/CD26- T-CELLS AND MARKED EPIDERMOTROPISM: A CASE REPORT AND LITERATURE REVIEW Studies have also found that some patients who were CD4+/CD7+ in early studies demonstrated References 3,5 1. Pincus LB. Mycosis Fungoides. Surg Pathol loss of CD7 expressivity over time. This could Clin. 2014;7(2)143-167. explain the highly variable CD7 expression in MF and SS and makes it a less reliable marker to 2. Booken N, Nicolay JP, Weiss C, et al. Cutaneous separate normal from neoplastic cell populations. tumor cell load correlates with survival in patients with Sézary syndrome. J Dtsch Dermatol Ges. It is possible that our patient presented with a 2013;11:67-79. very early stage of Sézary syndrome in which there has not been enough CD7 loss, but the 3. Florell SR, Cessna M, Lundell RB, fact that the patient did not express CD26 is a et al. Usefulness (or lack thereof) of confirmatory marker for the presence of Sézary immunophenotyping in atypical cutaneous T-cell syndrome. Failure to meet the required criterion infiltrates. Am J Clin Pathol. 2006;125:727-36. of 1000 Sézary cells/uL can also be attributed to 4. Jones D, Dang NH, Duvic M, et al. Absence of early stages of the disease. CD26 expression is a useful marker for diagnosis Some sources define a Sézary cell count of >500 of T-cell lymphoma in peripheral blood. Am J cells/uL as diagnostic “substantial peripheral Clin Pathol. 2001;115(6):885-92. blood involvement” when erythroderma is also 5. Vonderheid EC, Bigler RD, Kotecha A, et 4 present. al. Variable CD7 expression on T cells in the leukemic phase of cutaneous T cell lymphoma Conclusion (Sézary Syndrome). J Invest Dermatol. The overlapping features of mycosis fungoides 2001;117(3):654-62. and Sézary syndrome seen in this patient posed 6. Steinhoff M, Schopp S, Assaf C, et al. a diagnostic dilemma. The patient had severe Prevalence of genetically defined tumor cells pruritus and was initially diagnosed with a T-cell in CD7 as well as CD26 positive and negative lymphoma by axillary-node biopsy. Subsequent circulating T-cell subsets in Sézary Syndrome. skin biopsies showed significant atypical Leuk Res. 2009;33(1):88-99. lymphocytic epidermotropism and histologically appeared as mycosis fungoides, with a CD4:CD8 7. Thurber SE, Zhang B, Kim YH, et al. T-cell ratio of approximately 15:1 and T-cell clonal clonality analysis in biopsy specimens from two rearrangement. There was retention of T-cell different skin sites shows high specificity in the CD7 expression on the atypical lymphocytes, and diagnosis of patients suggested mycosis fungoides. the patient proceeded to develop erythroderma J Am Acad Dermatol. 2007;57:782-90. with evidence of circulating (CD4+/CD7+/ 8. Massone C, Kodama K, Kerl H, et al. CD26-) Sézary cells but did not fulfill the Histopathologic features of early (patch) lesions diagnostic criterion of a 1,000 cells/uL Sézary of mycosis fungoides: a morphologic study on cell count. 745 biopsy specimens from 427 patients. Am J This case was classified as “atypical” because the Surg Pathol. 2005;29:550-60. patient had clinical features of Sézary syndrome 9. Kubica AW, Pittelkow MR. Sézary Syndrome. with evidence of circulating (CD4+/CD7+/ Cutaneous Lymphomas. Surg Pathol Clin. CD26-) Sézary cells but also had significant 2014;7(2)191-202. epidermotropism, which is not typically seen 10. Kubica AW, Davis MD, Weaver AL, et al. with Sézary syndrome. Thus, a diagnosis of an Sézary syndrome: a study of 176 patients at Mayo atypical Sézary syndrome was favored, instead Clinic. J Am Acad Dermatol. 2012;67:1189-99. of erythrodermic MF, due to the advanced stage of disease at clinical presentation and rapid 11. Campbell JJ, Clark RA, Watanabe R, et al. progression of skin involvement. This case is Sézary syndrome and mycosis fungoides arise anticipated to undergo genotypic profiling to from distinct T-cell subsets: a biologic rationale better understand the complexity of the circulating for their distinct clinical behaviors. Blood. T cell (CD4+/CD7+/CD26-) subset seen in this 2010;116:767-71. patient with atypical Sézary syndrome. 12. Harmon CB, Witzig TE, Katzmann JA, et al. Detection of circulating T-cells with CD4+CD7- immunophenotype in patients with benign and malignant lymphoproliferative dermatoses. J Am Acad Dermatol. 1996;35:404-10.

Correspondence: Gabriela Maloney, DO; [email protected]

MALONEY, GAITODE, ALTMAN, BRANIECKI Page 51 A Rare Case of Tumid Lupus Erythematosus Coexisting with Systemic Lupus Erythematosus: A Case Presentation and Discussion

Jennifer Moscoso Conde, DO,* Simona Bartos, MPH,** John Howard, DO,*** Jacqueline Thomas, DO, FAOCD****

*Dermatology Resident, 1st year, Broward Health Medical Center/NSUCOM, Fort Lauderdale, FL **Medical Student, 3rd year, Nova Southeastern University College of Osteopathic Medicine, Fort Lauderdale, FL ***Intern, Broward Health Medical Center/NSUCOM, Fort Lauderdale, FL ****Clinical Assistant Professor, Nova Southeastern University, Fort Lauderdale, FL; Department of Dermatology, Physicians Regional Hospital, Naples, FL

Abstract Tumid lupus erythematousus (TLE) is an uncommon autoimmune condition that has infrequently been described in the literature and is difficult to distinguish from other cutaneous diseases. It is a subtype of discoid lupus erythematosus (DLE). TLE usually follows a favorable course and responds well to antimalarias, local corticosteroids and, more recently, photodynamic therapy and topical tacrolimus. Very rarely, TLE is associated with systemic lupus erythematosus (SLE). In the following case presentation, we describe an individual with a history of SLE and subsequent lupus nephritis presenting with worsening respiratory complaints. Further workup and CT imaging revealed lupus vasculitis with concomitant TLE. Even though these two conditions rarely coexist, it is important to raise awareness of this possible occurrence so that clinicians may reach the proper diagnosis and management. Introduction findings to severe organ system involvement opacities throughout both lung fields. Differential Lupus erythematosus (LE) is a disorder with such as in SLE. Cutaneous lupus erythematoses diagnoses included septic emboli, vasculitis, and varied manifestations ranging from cutaneous (CLE), such as discoid lupus erythematosus atypical infections causing multifocal pneumonia. (DLE), lupus panniculitis, hypertrophic LE, and A cardiac echocardiogram revealed no verrucous Figure 1 TLE, can be divided into acute, subacute, and (Libman-Sacks) or septic vegetations. Blood and chronic cutaneous LE. Patients with TLE rarely urine cultures were negative. A sputum culture present with other systemic or cutaneous disease was positive for rare Candida albicans, considered . It is a diagnostic challenge a contaminant. Toxicology screen was negative. to correctly identify TLE and accurately exclude Dermatology was consulted, and skin biopsy of other cutaneous diseases, which it mimics upper arm and thigh lesions revealed perivascular frequently. lymphocytic infiltration with lack of interface changes at the dermal-epidermal junction Case Presentation (Figure 3) as well as abundant mucin in the A 35-year-old male with a history of SLE and dermis (Figure 4), consistent with tumid lupus end-stage renal disease (ESRD) secondary to erythematosus. lupus nephritis on dialysis presented to the emergency department with fever and shortness of breath. He reported dyspnea, coughing, wheezing and malaise, which began four days prior to presentation. He was a boat mechanic and had been spending an extensive amount of time in the sun for the past couple of days. He had a similar episode of worsening shortness of breath and hemoptysis a few months prior, for which he was admitted to the hospital. Figure 2 In the emergency department, he was tachycardic at 112 beats per minute, tachypneic at 24 breaths per minute, hypertensive at 159/94 mm Hg and Figure 3. Perivascular lymphocytic infiltration febrile at 103 degrees Fahrenheit, with an oxygen saturation of 97% on 4 L/min nasal cannula. On with lack of interface changes at the dermal- physical exam, he demonstrated wheezing and epidermal junction. crackles bilaterally throughout. Cardiac exam revealed tachycardia, without murmurs, rubs or clicks. A left forearm fistula was present with an appreciable bruit, without erythema, tenderness or discharge. Skin examination revealed multiple erythematous and violaceous papules and plaques on his bilateral upper extremities (Figure 1), upper back, and thighs. Purpura was evident on his bilateral shins (Figure 2). An erythematous malar rash extending onto his nasal bridge as well as perioral erythema was evident on his face. Neurological, abdominal, musculoskeletal, and genitourinary exams were unremarkable. Further workup with a CT scan Figure 4. High power: Abundant mucin in the of the chest revealed multiple, subcentimeter dermis highlighted by alcian blue stain.

Page 52 A RARE CASE OF TUMID LUPUS ERYTHEMATOSUS COEXISTING WITH SYSTEMIC LUPUS ERYTHEMATOSUS: A CASE PRESENTATION AND DISCUSSION Antibiotics were initiated and then stopped, Tumid LE is very rarely associated with SLE, References as blood cultures were negative. At the time which presents with cutaneous manifestations 1. Alexiades-Armenakas MR, Baldassano of discharge, the patient was diagnosed with and/or affecting other organs such as the kidneys, M, Bince B, Werth V, Bystryn JC, Kamino concurrent SLE, lupus vasculitis and TLE. He lungs, and gastrointestinal organs. Tumid LE H, et al. Tumid lupus erythematosus: criteria improved with a tapering course of corticosteroids differs from SLE and other chronic cutaneous for classification with immunohistochemical and bronchodilators and was advised to follow up LE in that the cutaneous lesions of TLE are analysis. Arthritis Rheum. 2003;49(4):494-500. with the dermatologist as an outpatient. fixed and of long duration. The serologic profile is similar to other forms of chronic cutaneous 2. Kuhn A, Richter-Hintz D, Oslislo C, LE, with approximately half of patients having Ruzicka T, Megahed M, Lehmann P. Lupus Discussion low antinuclear antibody (ANA) titers (1:160) erythematosus tumidus--a neglected subset of Tumid LE, first described in 1909 by Eric cutaneous Lupus erythematosus: report of 40 Hoffman, is a rare autoimmune condition and a negative remaining autoantibody panel. cases. Arch Dermatol. 2000;136(8):1033-41. characterized by smooth, nonscarring, pink or The association with systemic disease is low. The erythematous papules, nodules or plaques usually female-to-male ratio in tumid LE, 8:7, is similar 3. Dekle CL, Mannes KD, Davis LS, Sangueza in a symmetric distribution. The lesions usually to that seen in the chronic cutaneous forms of LE OP. Lupus tumidus. J Am Acad Dermatol. present on sun-exposed areas such as the face, and is in contrast to the female predominance 1999;41(2 Pt 1):250-3. neck, arms and upper back and typically spare the observed in systemic LE, with a ratio of 8:1 1,7 4. Goerig R, Vogeler C, Keller M. Atypical lower extremities.1,2 to 10:1. Although the literature contains conflicting reports regarding the coexistence of presentation of cutaneous lupus mucinosis. J Clin TLE may resemble many other cutaneous TLE with SLE or other variants of cutaneous Aesthet Dermatol. 2013;6(4):37-40. dermatidities such as eczema, psoriasis, erythema lupus, there have been a number of case reports 5. Vincent JG, Chan MP. Specificity of dermal multiforme, urticarial , lymphocytic documenting this combination. mucin in the diagnosis of lupus erythematosus: infiltration of the skin, pseudolymphoma, graft- comparison with other dermatitides and normal versus-host disease, other lesions of cutaneous In the case presented here, the recent UV LE, or polymorphous light eruption. Due to its exposure was likely the trigger for the patient’s skin. J Cutan Pathol. 2015 Oct;42(10):722-9. rare occurrence, its varied clinical manifestations, new cutaneous eruption and the worsening of his 6. Verma P, Sharma S, Yadav P, Namdeo C, and scarcity of cutaneous findings, TLE is often systemic symptoms. The literature demonstrates Mahajan G. Tumid lupus erythematosus: an difficult to diagnose, and its precise definition that lupus photosensitivity may be caused by intriguing dermatopathological connotation 3 remains elusive. Multiple case reports of TLE an aberrant response of keratinocytes to UV treated successfully with topical tacrolimus have been described over time, and some studies injury, defective clearance of apoptotic cells or an and hydroxyxhloroquine combination. Indian J do offer criteria for definition and differential enhanced inflammatory response to these cells.8 Dermatol. 2014;59(2):210. diagnosis, delineated in Table 1. Therefore, a thorough education of the patient 7. Stead J, Headley C, Ioffreda M, Kovarik regarding UV exposure as a disease trigger is The histopathological characteristics of TLE C, Werth V. Coexistence of tumid lupus paramount. are dermal mucin deposition, usually with erythematosus with systemic lupus erythematosus an interstitial distribution, and perivascular and discoid lupus erythematosus: a report of lymphocytic infiltration. Tumid LE typically Conclusion two cases of tumid lupus. J Clin Rheumatol. lacks interface changes, although there are some Although TLE is rarely associated with SLE, the 2008;14(6):338-41. reports of focal interface changes at the dermal- astute clinician should maintain a high index of 4 8. Kuechle MK, Elkon KB. Shining light on follicular and dermal-epidermal junctions. suspicion when examining patients presenting lupus and UV. Arthritis Res Ther. 2007;9(1):101. Histopathological evidence of extensive with signs and symptoms of either condition. An neutrophilic infiltrates and abundant mucin established diagnosis of SLE should not preclude in the reticular dermis is present and usually additional cutaneous lupus findings. As in the sufficient to exclude other cutaneous conditions.5 Correspondence: Jennifer Moscoso Conde, DO; case presented, a patient may concomitantly Immunohistochemical evidence shows a T cell [email protected] manifest SLE nephritis, tumid lupus and lupus (CD3+) predominance. vasculitis. Given the rarity of TLE’s reported TLE usually follows a favorable course and association with systemic lupus erythematosus, it responds well to antimalarials and local is important that patients with a diagnosis of TLE corticosteroids. Recently, photodynamic therapy be followed closely for any signs or symptoms of and topical tacrolimus have shown good clinical systemic involvement. results.6

Table 1. Proposed criteria for TLE diagnosis1 Clinical Findings Papules, plaques, and/or nodules Pink-to-violaceous color Absence of surface changes Non-scarring Photodistribution Chronic (> 5 months)

Histopathologic Findings Moderate to dense, superficial and deep, perivascular, lymphocytic infiltrate Absent to focal dermo-epidermal junctional involvement Mucin deposition in papillary and reticular dermis

Immunohistochemical Predominantly T cells (CD3+) Findings CD4 predominant (> 68% of infiltrate) CD8 minority (< 50% of infiltrate) CD4:CD8 ratio > 2:1

CONDE, BARTOS, HOWARD, THOMAS Page 53 A Vesiculobullous Eruption Following Solid Organ Transplantation

Nadine George, DO,* Ann Reed, DO,** Frank Don, DO, FAOCD,*** Stanley Skopit, DO, MSE, FAOCD****

*3rd-year resident, Larkin Community Hospital/NSU-COM Dermatology Residency Program, South Miami, FL **2nd-year resident, Larkin Community Hospital/NSU-COM Dermatology Residency Program, South Miami, FL ***Dermatologist, Florida Academic Dermatology Center, Coral Gables, FL ****Program Director, Larkin Community Hospital/NSU-COM Dermatology Residency Program, South Miami, FL

Abstract Viruses are the most frequent cause of cutaneous infections in organ transplant recipients, and virus (HSV) is one of the most commonly implicated, especially in the first few months post-transplant. Given a nonspecific presentation in these patients, it is essential to confirm the diagnosis with further laboratory testing. Notably, cutaneous cytomegalovirus (CMV) infection may mimic HSV or may co-infect affected skin lesions. Cutaneous CMV is present in approximately 20% of systemic CMV infections, and if left untreated it has a high mortality rate due to increased risk of graft rejection and other secondary infections. We describe a case of a chronic vesiculobullous eruption in a 75-year-old liver transplant recipient whose diagnosis of HSV was determined during her initial office visit using the reliable Tzanck smear, therefore allowing for rapid initiation of antiviral treatment. Confirmatory viral cultures were also performed to verify the causative agent and to rule out the possibility of co-infections. Introduction diagnosis and prompt treatment to prevent Discussion Herpes simplex virus infection is usually a relatively dissemination to visceral organs. Moreover, other Organ transplant recipients are prone to straightforward diagnosis to make. However, viral infections, such as cytomegalovirus, must developing a variety of skin diseases secondary organ transplant recipients or immunosuppressed be excluded from the diagnosis as they often to the potent immunosuppressive agents used to patients may present with clinically atypical significantly increase morbidity and mortality in guarantee long-term graft survival and prevent lesions, necessitating the need for accurate organ transplant recipients. organ rejection.1 Cutaneous infections occur in up to 80% of organ transplant recipients, Figure 1 Case Report and viral infections are the most common A 75-year-old Hispanic female presented to our of these.2 The herpes simplex virus (HSV) outpatient dermatology clinic complaining of a types 1 and 2 are members of the Herpesvirus three-week history of a burning, painful eruption family and are distinguished by their ability to on her buttocks. She admitted that this had been remain latent within a host and spontaneously occurring intermittently for years. Her past medical reactivate with trauma, UV exposure, fever, or history was significant for hypertension and a immunosuppression. The latent virus travels liver transplant in 1998 secondary to autoimmune from the nerve root to innervated skin regions. hepatitis. At the time of her presentation, the Transplant patients can be infected with HSV-1, patient was on several immunosuppressive agents HSV-2, or both types, with prevalence similar to including mycophenolate mofetil, cyclosporine, the distribution by age in the general population.3 and prednisone. Other medications included Typically, reactivated, localized HSV infections valsartan, bisoprolol, and folic acid. A review occur within the first few weeks of transplantation, of systems was negative for any fever, malaise, and mucocutaneous lesions of the oropharynx or vision change, shortness of breath, chest pain, and genital regions are the most common presentation gastrointestional disturbances. in organ transplant recipients.1,4 Compared to the general population, manifestation of HSV On physical examination, there were multiple Figure 2 reactivation in immunosuppressed patients results shallow ulcers and grouped vesicles on in chronic, larger, slower-healing ulcers with the buttock region (Figures 1 and 2). The greater potential for dissemination to visceral patient had no mucous membrane or other organs.1,2 Systemic involvement may manifest cutaneous involvement. There was no inguinal as fever, leukopenia, esophagitis, hepatitis, lymphadenopathy. Our initial differential diagnosis included a viral such as Figure 3 HSV types 1 and 2, varicella-zoster virus (VZV), and cytomegalovirus (CMV). Other diagnostic considerations were and bullous allergic . A Tzanck smear was performed and showed characteristic multinucleated giant cells (Figure 3). Therefore, a presumed diagnosis of herpes simplex infection was made, later confirmed by viral culture. A skin biopsy was not performed. The patient was treated with valacyclovir 1 gram twice a day for one week and silver sulfadiazine cream twice daily to eroded areas. At one-month follow-up, the patient had dramatic improvement in the lesions, and a prophylactic twice daily dose of valacyclovir 500 mg was initiated.

Page 54 A VESICULOBULLOUS ERUPTION FOLLOWING SOLID ORGAN TRANSPLANTATION pneumonitis or myocarditis.2,3 Widespread assay or polymerase chain reaction.11 cutaneous dissemination is rare, but when it References 5 In organ transplant patients, CMV is a 1. Tan HH, Goh CL. Viral infections affecting the occurs it is associated with high mortality rates. major cause of disease and mortality, with a skin in organ transplant recipients. Epidemiology Diagnosis of HSV can be approached in several symptomatic infection occurring in 20% to 60% and Current Management Strategies. Am J Clin ways. A positive culture of the vesicles or ulcers of all transplant recipients.4 Infection can occur Dermatol. 2006;7(1):13-29. indicates active infection. Furthermore, HSV-1 as a result of reactivation of an existing latent 2. Piaserico S, Sandini E, Peserico A, et and HSV-2 can be distinguished by monoclonal infection in the recipient, from a donor strain of al. Cutaneous viral infections in organ antibody staining. Skin biopsy for histopathology CMV, or as a primary infection in a previously transplant patients. G Ital Dermatol Venereol. may be performed, and common findings include CMV-naïve individual. Cutaneous CMV is 2014;149(4):409-15. keratinocytes with uniform steel-gray nuclei present in 10% to 20% of patients with systemic and margination of chromatin, ballooning infection, and its presentation is often nonspecific 3. Wilck MB, Zuckerman RA. Herpes Simplex degeneration with secondary acantholysis, and varied. Clinical manifestations includes Virus Infections in Solid Organ Transplant multinucleated giant cells and an underlying ulcers, morbilliform rashes, petechiae, purpuric Recipients. Am J Transplant. 2009;9 Suppl mixed inflammatory cell infiltrate. The Tzanck eruptions, necrotic papules, and vesiculobullous 4:S104-7. 1 smear, although underutilized in the clinical eruptions. Systemic manifestations include fever, 4. Smith SR, Butterly DW, Alexander BD, et al. 11 setting, is a rapid, simple, noninvasive method leukopenia, malaise and arthralgias. Chronic Viral infections after renal transplantation. Am J for the diagnosis of infections, autoimmune CMV infections are associated with risk of acute Dis. 2001;37:659-76. disorders, and less commonly for the diagnosis and chronic graft rejection and an increased risk of various neoplasms and granulomatous of subsequent bacterial and fungal infections. 5. Ruocco E, Brunetti G, Del Vicchio M, et diseases.6 A study by Eryilmaz et al. found that Wilck et al. state that when ganciclovir, acyclovir, al. Practical use of cytology for diagnosis in the Tzanck smear was a reliable diagnostic valacyclovir and valganciclovir are given in dermatology. J Eur Acad Dermatol Venereol. test for erosive vesiculobullous disease.7 A standard doses for CMV prevention, they will 2011;25(2):125-9. positive Tzanck smear shows multinucleated also prevent most HSV reactivation. Ganciclovir, 6. Eryilmaz A, Durdu M, Baba M, et al. keratinocytes and acantholysis. However, the valganciclovir, foscarnet, and cidofovir have Diagnostic reliability of the Tzanck smear. Int Tzanck smear and tissue histopathology without all been approved for the treatment of CMV, Jour Dermatol. 2014;53:178-86. immunohistochemistry stains do not distinguish with foscarnet and cidofovir reserved for strains 7. Eyzaguirre E, Haque, AK. Application of between HSV-1, HSV-2 or VZV. exhibiting ganciclovir resistance.10,11 Immunohistochemistry to Infections. Arch According to Wilck et al., in the absence of antiviral Pathol Lab Med. 2008;132:424-31. prophylaxis, HSV-seropositive organ transplant Conclusion 8. Prentice HG. Use of acyclovir for recipients are at risk for clinical reactivation, even We describe a severe but typical presentation of prophylaxis of herpes infections in severely if they had not had prior clinical HSV disease. HSV-1 occurring on the bilateral buttocks in an immunocompromised patients. J Antimicrob The incidence of clinically apparent HSV disease immunosuppressed organ transplant patient. The Chemother. 1983;12 Suppl B:153-9. in seropositive patients not receiving prophylaxis, diagnosis was quickly confirmed at the patient’s Wilck et al. state, ranges from 35% to 68%.3 initial presentation using the underutilized but 9. Mues MB, Cheshenko N, Wilson DW, et HSV prophylaxis using acyclovir, valacyclovir, or reliable Tzanck smear, enabling prompt treatment al. Dynasore disrupts trafficking of herpes famciclovir should be considered for all HSV-1 with valacyclovir 1 gm twice daily. Practitioners simplex virus proteins. J Virol. 2015 Apr 15: and HSV-2 seropositive organ recipients for the should be mindful to send viral cultures in P11:JVI.00636-15. (Epub ahead of print) 8 first month after transplantation. Following the immunosuppressed patients presenting with 10. Schoenfeld J, Cannon S, Cam K, et al. first post-transplant period, treatment should be vesiculobullous lesions to rule out primary or Cutaneous Co-infected Cytomegalovirus and initiated promptly based on clinical diagnosis for concomitant CMV infection. Herpes Simple Virus Perigenital Ulcers in improved clinical outcome. Of interest, a recent Human Immunodeficiency Virus Patients. J Clin study by Mues et al. investigated dynasore, a Aesthet Dermatol. 2013;6(10):41-3. small-molecule inhibitor of dynamin. Dynasore was found to have multiple deleterious effects 11. Jenkins FJ, Rowe DT, Rinaldo CR. Herpesvirus on HSV-1 and HSV-2 infection by impeding Infections in Organ Transplant Recipients. Clin crucial steps in the viral life cycle. This is a new Diagn Lab Immunol. 2003;10:(1)1-7. and promising approach to HSV treatment and prevention that is on the horizon.9 Correspondence: Nadine George, DO; Acyclovir-resistant HSV should be suspected [email protected] if there are very frequent recurrences while on suppressant therapy, which will require treatment with either ganciclovir or valganciclovir.1 Furthermore, if an fails to respond to therapy, HSV infection with concomitant CMV infection must also be considered. Schoenfeld et al. describe two cases of HIV patients who presented with genital ulcers in which both HSV and CMV were proven to be the causative agents. They stress that it is crucial to at least consider CMV as a causative agent when an immunocompromised patient presents with genital lesions, especially in those not responding to the usual treatment, as CMV may be a marker of impending systemic infection.10 Cutaneous infection by CMV is diagnosed by immunohistochemical staining or viral culture, while systemic disease or acute viremia is diagnosed by a CMV antigenemia GEORGE, REED, DON, SKOPIT Page 55 A rare case of verrucous psoriasis in young female: A case report and review of clinicohistologic presentation and variable therapeutic response

John Moesch, BA,* Jessica Mercer, MD,** Jennifer B. Sissom, PA-C,*** Jonathan S. Weiss, MD****

*Medical student, 4th year, Philadelphia College of Osteopathic Medicine, Suwanee, GA **Board-certified dermatopathologist, Gwinnett Dermatology, PC, Snellville, GA ***Physician assistant, Gwinnett Dermatology, PC, Snellville, GA ****Board-certified dermatologist, Gwinnett Dermatology, PC, Snellville, GA

Abstract We present a case of verrucous psoriasis (VP) in a young female. VP is a rare clinicohistologic variant of psoriasis. A PubMed search of VP yielded only 12 relevant articles. Our patient represents the first known case of VP in a child. In this report we discuss salient features of her history, physical exam, and treatment. After presenting her case, we provide a literature review on potential etiologies, clinical presentations, and treatments for verrucous psoriasis.

present and enlarging for more than a month. was taking no medications. Introduction Her primary care physician had prescribed a six- Psoriasis is a common, chronic, immune- Cutaneous exam revealed a hypertrophic plaque week course of griseofulvin for presumed tinea mediated disorder that results in epidermal with verrucous scale located on the right medial capitis. No biopsy or culture was performed, and hyperproliferation. In addition to the most forehead (Figure 1). A 2-cm verruca vulgaris was no improvement ensued. The patient reported typical presentation of erythematous plaques also noted on the right thumb. A shave biopsy no previous dermatologic disease. Review of surmounted by micaceous scale with a predilection of the forehead lesion revealed hyperkeratosis systems and medical and social histories were for the scalp, lower back, and extensor surfaces of with neutrophils within mounds of parakeratosis, unremarkable. On presentation to our office, she the limbs, several distinct clinical variants include digitated and psoriasiform epidermal hyperplasia, erythrodermic, guttate, and pustular psoriasis. mild spongiosis, dilated blood vessels at the tips One particularly rare clinicohistologic variant is of dermal papillae, and superficial perivascular verrucous psoriasis (VP), which has engendered mixed inflammatory-cell infiltrate (Figures 2, 3). far less documentation in the medical literature. Clinical and histopathological observations were A PubMed search of VP yielded only 12 relevant consistent with verrucous psoriasis. articles. The patient was prescribed proprionate VP most commonly presents clinically as a - 0.05% foam twice daily for five days and 1 like lesion. Histopathologic assessments reveal acetonide 0.01% topical solution a combination of verruca and psoriasis, including thereafter until her return appointment. She was localized hyperkeratosis with parakeratosis, also advised to use 3% salicylic acid shampoo. hypogranulosis, Munro’s microabscesses, The patient returned to the office 10 days later papillomatosis, dilated capillaries in dermal 2 with significant improvement (Figure 4). She papillae, and perivascular lymphocytes. While had applied clobetasol proprionate 0.05% foam the case we present describes a usual twice daily for two days and then fluocinolone clinicopathologic representation of this rare acetonide topical solution 0.01% for seven days. form of psoriasis, it is unique because it’s the She had used the shampoo three times the first first documented case of VP in a child. After week and two days during the week she came discussing the case, we will review previous case Figure 2. Digitated and psoriasiform epidermal back to the office. reports of VP focusing on suggested etiologies, hyperplasia (H&E, 4x). unusual presentations, and treatments. Discussion Verrucous psoriasis is an infrequent phenomenon Case report in dermatology. There are a limited number of A 14-year-old Hispanic female presented to the case reports, and this variant of psoriasis does office with the chief complaint of a large, pruritic not appear in the majority of currently published lesion on her right medial forehead that had been general dermatologic textbooks. While the exact

Figure 1. Hypertrophic verrucous plaque with Figure 3. Hyperkeratosis with neutrophils Figure 4. Resolving lesion after 10 days of scale located on the right medial forehead. within mounds of parakeratosis (H&E, 20x). treatment.

Page 56 A RARE CASE OF VERRUCOUS PSORIASIS IN YOUNG FEMALE: A CASE REPORT AND REVIEW OF CLINICOHISTOLOGIC PRESENTATION AND VARIABLE THERAPEUTIC RESPONSE Table 1. VP clinical presentations and treatments

Case Sex Age at Lesion Lesion type Successful treatments Failed treatments diagnosis localization Nakamura, M 60 Trunk, extremities, Erythematous Topical corticosteroids, 2% coal tar None et al.3 fingers papules, plaques ointment, PUVA (ineffective on papules but effective on plaques), cryosurgery (resolved papules) Kawtar, et F 43 Thigh, fingers, Verrucous No treatment reported No treatment reported al.4 perianal area plaques Scavo, et al.5 M 44 Trunk, glans penis, Erythematous- Lesion regression 2 weeks after None external auditory desquamative stopping interferon treatment for canals, scalp, toes, plaques HCV, plus emollients and systemic fingernails antihistamines

Curtis, et al.6 M 46 Trunk, extremities, Verrucous plaques Moderate improvement with Topical , face, scalp, genital manifesting as ustekinumab high-potency topical area erythroderma steroids, acitretin (3 mos), methotrexate (6 mos), etanercept (4 mos), adalimumab (3 mos), infliximab (2 mos)

Emel, et al.7 F 22 Upper and lower Symmetric, Healing of lesions after 15 days of None back annular, 5% crude coal tar, moderate-potency erythematous topical steroid ointment plaques with verrucous, rupial, yellow-gray scaling Monroe, et F 84 Posterior arm, Verrucous papules, Initial resolution of extremity and None al.8 lumbosacral back, plaques chest lesions with topical thigh, distal leg, and agents, urea and chest, abdomen salicylic acid, but flares ultimately continued on extremities and trunk even with topical steroid treatment Munoz, et al.9 M 60 Extremities, trunk Erythematous Resolution of lesions after two months Topical steroids and lesions covered by of oral etretinate topical vitamin D3 with thick, adherent PUVA scales

Hall, et al.10 M 44 Frontal scalp, trunk, Verrucous papule No successful treatment reported Topical salicylic acid extremities

Katayama, et M 55 Trunk, extremities Verrucous scale Marked improvement with Numerous topical al.11 on erythematous adalimumab psoriasis agents plaque

Current case F 14 Right medial Hypertrophic 0.05%, None forehead verrucous plaque 0.01%, 3% with scale salicylic acid shampoo etiology of VP is presently unknown, there are a to the pathogenesis of VP.3-5 Since our patient clinical presentations. For example, one case of handful of theories as to the cause. Khalil et al. had a verruca vulgaris on the right thumb, we histologic VP presented clinically as widespread suggested that repeated trauma in an individual considered the possibility of super-infection of hypertrophic verrucous plaques on a broad, with preexisting psoriasis may result in lesions of the psoriatic plaque with human papillomavirus inflamed erythematous background. Prior to V P. 1 This case report also proposed pulmonary (HPV) as the cause of our patient’s VP. We biopsy, the differential diagnosis included T-cell dysfunction and phlebitis as predisposing subsequently performed immunohistochemical lymphoma, Darier’s disease, verrucous carcinoma, conditions to VP due to the anoxic conditions staining for HPV in our patient’s forehead tissue, and pityriasis rubra pilaris.6 We compiled a in the peripheral tissues and circulation. Based and the results were negative. list of all known published case reports of VP on comorbidities present in their patients, and their documented clinical presentations Most reported cases of VP presented as clinical other authors have postulated diabetes mellitus, and treatments (Table 1). Interestingly, this and histological hybrids of psoriasis and verruca autoimmune hepatitis, and chronic hepatitis C investigation revealed that all patients previously vulgaris. However, there have been several reports treated with interferon as conditions contributing diagnosed with VP were adults. This makes our of histologically confirmed VP with unusual

MOESCH, MERCER, SISSOM, WEISS Page 57 finding in a 14-year-old the first known case of References VP reported in a child. 1. Khalil F, Keehn C, Saeed S, Morgan Treatment of VP has proved challenging in the M. Verrucous Psoriasis: A Distinctive majority of previously reported cases. Attempted Clinicopathologic Variant of Psoriasis. Am J therapies have included both topical and systemic Dermatopathol. 2005 Jun;27(3):204-7. 6 agents used in other variants of psoriasis. After 2. Rapini R. Practical Dermatopathology review, we found that most patients’ VP improved [Internet]. 2nd ed. Philadelphia: Elsevier; with either topical or intralesional steroids, which 7-10 c2012 [cited 2015 Feb 2]. Eczematous and holds true for our patient. Combination Papulosquamous Diseases [about 1 screen]. topical therapies have been successful in some Available from: https://www-clinicalkey- patients. One patient with annular VP responded com.ezproxy.pcom.edu/#!/content/book/3- to a combination of 5% crude coal tar and s2.0-B9780323066587000026. moderately potent steroid ointment.7 Another report showed healing of VP plaques on the chest 3. Nakamura S, Mihara M, Hagari Y, Shimao S. and extremities with a combination of topical Psoriasis Verrucosa Showing Peculiar Histologic fluocinonide, urea, and salicylic acid.8 Systemic Features. J Dermatol.1994;21:102-5. agents, specifically biologics, had variable success 4. Kawtar I, Mariame M, Siham L, Fatimazahra in the treatment of VP. The erythrodermic M, Hassania A, Taqufiq H, Afaf A, Noureddine variant of VP discussed earlier was recalcitrant to A. Verrucous Psoriasis and Verrucous Lichen varying combinations of acritretin (50 mg daily), Associated with an Autoimmune Hepatitis. J high-potency topical steroids, methotrexate (15 Clin Diagn Res [Internet]. 2014 Mar [cited mg weekly), and multiple biologics (etancercept, 2015 Feb 12];2(2). Available from: http:// adalimumab, and infliximab). The patient finally omicsonline.com/open-access/verrucous- showed signs of moderate improvement on 45 mg psoriasis-and-verrucous-lichen-associated-with- ustekinumab every 12 weeks after nine months an-autoimmune-hepatitis-2376-0311.1000107. 6 of treatment. Another case showed remarkable php?aid=30220. improvement of a VP plaque after treatment with adalimumab.11 Similar to the biologics, results 5. Scavo S, Gurrera A, Mazzaglia C, Magro with methotrexate have not been consistent. In G, Pulvirenti D, Gozzo E, Neri S. Verrucous one case report, the addition of methotrexate Psoriasis in a Patient with Chronic C Hepatitis to topical and intralesional steroids caused Treated with Interferon. Clin Drug Investig. significant regression of VP lesions. The only 2004;24(7):427-9. retinoid that produced good treatment results 6. Curtis A, Yosipovitch G. Erythrodermic with VP was oral etretinate, reported in the case of Verrucous Psoriasis. J Dermatolog Treat. a male from Japan. However, this drug is banned 2012;23:215-8. in the United States.9 Other oral retinoids, 7. E Emel, Bozdogan O. Annular Verrucous specifically acitretin, did not produce results in Psoriasis with Exaggerated Papillomatosis. Am J cases we reviewed; however, a report of a case Dermatopathol. 2001;23(2):133-5. that was diagnosed as verrucous carcinoma and treated successfully with acitretin was argued by 8. Monroe H, Hillman J, Chiu M. A Case of others to have been a case of VP.11 This suggests Verrucous Psoriasis. Dermatol Online J [Internet]. that acretin could be a viable treatment for VP in 2011[cited 2015 Feb 6];17(5):10. Available from: some cases. Any therapeutic results reported in http://escholarship.org/uc/item/0cn3d92h. VP need to be interpreted with caution given the 9. Munoz L, Cortes A, De la Calle M, Sanchez small sample size and varying clinical scenarios. D, Beato MJ, Lucas R, Vidaurrazaga C. Psoriasis Verrucosa in an obese Japanese man; a prompt Conclusion clinical response observed with oral Etretinate. J VP is a rare and distinctive variant of psoriasis that Eur Acad Dermatol Venereol. 2006;20:1328-99. presents with overlapping clinical and histological 10. Hall Lawrence, Marks V, Tyler W. Verrucous features. The literature on VP is lacking, and Psoriasis: A clinical and histopathologic mimicker while further research is desirable to delineate the of verrucous vulgaris. J Am Acad Dermatol. 2013 specific etiology, the likelihood of such research Apr;68(4):AB218. is remote given the rarity of the condition. The limited numbers of published case reports have 11. Katayama C, Maejima H, Watarai A, suggested some potential treatments for VP. Our Nishiyama H, Katsuoka K. A case of Psoriasis patient, representing a typical clinicopathologic Verrucosa treated with Adalimumab. J Drugs presentation of localized VP in a child, showed Dermatol. 2012 Nov;11(11):74-5. excellent response to treatment with topical 12. Larson F, Susa J, Cockerell J. Cases of multiple steroids and 3% salicylic acid shampoo. At this verrucous carcinomas responding to treatment point, it is difficult to know whether cases of VP to acretretin more likely to have been a case of represent unique pathophysiologic circumstances verrucous psoriasis. J Am Acad Dermatol. 2007 resulting in common clinical presentations or Sept;57(3):534-535. whether this rare histopathologic variant of psoriasis has unifying etiologic factors among patients in whom it presents. Further case series Correspondence: John Moesch, BA; may help to uncover the answers to this question. [email protected]

Page 58 A RARE CASE OF VERRUCOUS PSORIASIS IN YOUNG FEMALE: A CASE REPORT AND REVIEW OF CLINICOHISTOLOGIC PRESENTATION AND VARIABLE THERAPEUTIC RESPONSE HALOG Cream and Ointment are designed for a difference your patients can truly feel.

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