sign in sign up
<<
Home , Anetoderma, Epidermoid cyst, Hyperkeratosis, Koebner phenomenon, Nevus anemicus, Pallor

JAOCDJournal Of The American Osteopathic College Of

The Osteopathic Principles Incarnate

Also in this issue: Proteus Syndrome in a 14-year-old Male Painful, Pruritic Exacerbated by Heat and Sweating Marijuana: An Unusual Cause of Fixed last modified on April 27, 2015 8:12 AM

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

2014-2015 AOCD OFFICERS

PRESIDENT Rick Lin, DO, FAOCD

PRESIDENT-ELECT Alpesh Desai, DO, FAOCD

FIRST VICE-PRESIDENT Karthik Krishnamurthy, DO, FAOCD

SECOND VICE-PRESIDENT Daniel Ladd, DO, FAOCD

THIRD VICE-PRESIDENT John P. Minni, DO, FAOC

Editor-in-Chief SECRETARY-TREASURER Karthik Krishnamurthy, DO Jere J. Mammino, DO, FAOCD TRUSTEES Danica Alexander, DO, FAOCD (2012-2015) Reagan Anderson, DO, FAOCD (2012-2015) Michael Whitworth, DO, FAOCD (2013-2016) Tracy Favreau, DO, FAOCD (2013-2016) Sponsors: David Cleaver, DO, FAOCD (2014-2017) Amy Spizuoco, DO, FAOCD (2014-2017)

AuroraDx Immediate Past-President Ranbaxy Suzanne Sirota Rozenberg, DO, FAOCD EEC Representatives Valeant James Bernard, DO, FAOCD Michael Scott, DO, FAOCD

Finance Committee Representative Steven K. Grekin, DO, FAOCD

AOBD Representative Stephen Purcell, 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 32

JAOCD Editors...... 4 Letter from the President...... 5 Letter from the Executive Director...... 6 Letter form the Editor-in-Chief...... 7 FEATURE ARTICLE: The scar as a representation of the osteopathic principles...... 11 Sarah Belden, DO, Jenifer Lloyd, DO, Michael Rowane, DO EDITOR’S PICKS: Marijuana: An Unusual Cause of Fixed Drug Eruption...... 16 Christina Steinmetz-Rodriguez, DO, Brent Schillinger, MD Painful, Pruritic Blisters Exacerbated by Heat and Sweating...... 19 Collin M. Blattner, BS, Dustin V. Wilkes, DO, Dongkun Chang, MD Proteus Syndrome: Case Report and Review...... 21 Holly Kanavy, DO, Cindy Hoffman, DO ORIGINAL ARTICLES AND CASE REPORTS: Reactive Responding to Excision and by Secondary Intention...... 24 G. Trey Haunson, DO, Mariana A. Phillips, MD, FAAD, FACMS, Douglas J. Grider, MD, FCAP, Daniel S. Hurd, DO, FAOCD A Case of Cutaneous Rosai-Dorfman ...... 27 Donna Tran, DO, Gabriel Guerrero, DO, Paul Shitabata, MD, Navid Nami, DO Pathogenesis of Pruritic Disorders and Mechanisms of Phototherapy...... 29 Soham Chaudhari, BA, Argentina Leon, MD, Ethan Levin, MD, Om Chaudhari, John Koo, MD The Cutaneous Manifestations of Metastatic Lung : Case Report and Review...... 34 Sarah Ferrer-Bruker, DO in a 2-year-old Female: A Case Report and Review of the Literature...... 37 Mathew Koehler, DO, Anne Nguyen, MS, Navid Nami, DO Secondary to Mid-dermal Elastolysis...... 40 Gabriela A. Maloney, BS, Jane James, MD, PhD, Michael Welsch, MD, Marylee Braniecki, MD Generalized Linear : A Case Report and Discussion...... 42 Stephanie Blackburn, DO, Zaina Rashid, DO, John Moad, MD, Michelle Duff, DO, Jason Barr, DO Permanent Imiquimod-induced ...... 45 Anne Donato, MD, J. Kate Jackson, PA-C, Laura Sandoval, DO, Jonathan S. Crane, DO, FAOCD Macularis Eruptiva Perstans: A Case Presentation and Discussion...... 47 Sergey Petrosian, BS, Shane Meehan, MD, Anna Slobodskya, DO, Peter Saitta, DO Hypomelanosis of Ito in Two Infants: A Case Series with Literature Review...... 49 Mathew Koehler, DO, Nicole Rouse, BS, Tarin Molly Koehler, DO, Navid Nami, DO Phacomatosis Cesioflammea: A Case Report of a Newborn with an Unusual and Port Wine Stain...... 52 Joy Ishii Zarandy, DO, Sara Clark, MD, Katherine Shew, MD PERSPECTIVES: While Serving Abroad, Remembering the “Why” Behind Dermatology...... 56 Leela Athalye, DO Letter to the Editor: Wegener’s Granulomatosis Eponym...... 58 David Thomas, MD, JD, EdD, Jacqueline Thomas, DO

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 Michael Scott, DO Scott Wickless, DO Red Bluff, CA Bozeman, MT Wilmington, NC Seattle, WA Dallas, Texas Editorial Board Sami Abbasi, DO Mohamad Goldust, MD Angela Leo, DO John Perrotto, DO Brownstown, MI Tabriz, Eastern New York, NY West Palm Beach, FL Azerbaijan, Iran

Brett Bender, DO Marcus Goodman, DO Scott Lim, DO Andrew Racette, DO Farmington Hills, MI Roswell, GA Erie, PA Phoenix, AZ

Ryan Carlson, DO Melinda Greenfield, DO Chava Lustig, DO Richard Rudnicki, DO Hilliard, OH Albany. GA Weston, FL Mesquite, TX

Igor Chaplik, DO Denise Guevara, DO Jere Mammino, DO Amara Sayed, DO Aventura, FL Weston, FL Winter Springs, FL San Marcos, TX

Michael P. Conroy, MD Andrew Hanly, MD John Minni, DO Joseph Brant Schneider, DO Columbus, OH Miami, FL Port St. Lucie, FL Shawnee Mission, KS

John Coppola Joel Harris, DO Tony Nakhla, DO Gregg Severs, DO Ormond Beach, FL Madison Heights, MI Orange County, CA Scranton, PA

David Dorton, DO Heather Higgins, DO Navid Nami, DO Sean Stephenson, DO Spring Hill, 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 Ormond Beach, FL

Page 4 JAOCD EDITORS Letter from the President

Rick Lin, DO, MPH, FAOCD President, AOCD Dear Members of the AOCD, Welcome to another issue of our journal! Under the leadership of Dr. Karthik Krishnamurthy and his dedicated board of editors, we are seeing another issue of the Journal of the American Osteopathic College of Dermatology come to fruition. Speaking of issues coming together, this past February, I was invited to represent the AOCD at a meeting hosted by AAD President Dr. Brett Coldiron. The topic of discussion was the proposition to create Board certification for “micrographic and dermatologic oncology.” This proposal was favored by many of the organizations represented there. The discussion focused on the potential outcome of mending the division between “fellowship trained” and “society trained” Mohs surgeons with a new category of “Board certified” Mohs surgeons. It was noted that the new Board certification would bring recognized expertise in cutaneous “surgery” and “oncology” to the house of dermatology. This recognition by other medical specialties within the ABMS would further elevate the status of dermatology within the broader house of medicine. However, this effort to define surgical subspecialization is not without its drawbacks. The further division of dermatology into “medical” and “surgical” dermatology is a potential outcome. This point was emphasized by some of the attendees. Concerns about the increased potential legal risks when a general dermatologist decides to perform an excision or electrodessication and curettage also were raised. In the case of a bad outcome, the decision is more difficult for a general dermatologist to defend legally if a micrographic surgeon/dermatologic oncologist was available. It was proposed that there be a five-year grandfather period during which any provider who practices Mohs surgery at least 20 percent of the time may take the examination. The candidate also will need to be board-certified by the American Board of Dermatology. However, ABD certification will not apply to our members who are board-certified by the AOBD. We will continue to monitor this effort to create a subspecialty board certification and how it will impact osteopathic dermatologists and the field of dermatology as a whole. In the meantime, I look forward to seeing many of you at our spring meeting in Charlotte, North Carolina. Dr. Dan Ladd, the program chair, has put together a highly educational program. The latest dermatological concepts and practice-management pearls will be presented. In addition, we are privileged to have Dr. Nicole Owens, chair of ACGME’s Residency Review Committee for Dermatology, address our membership. On a final note, I would like to say that the future of our College, as with any College, is dependent on its members. To the challenges ahead, I encourage you to reach out to the AOCD Board of Trustees to share your thoughts and volunteer your time. We are looking for members who would like to play significant roles in the leadership of the AOCD. In the years to come, the survival of our College will impact our future recertification process. With the ACGME merger, our future is in a state of flux. Only through the dedication of our members will we be able to chart our future, rather than have it decided for us. Rick Lin, DO, MPH, FAOCD President, American Osteopathic College of Dermatology

LETTER FROM THE PRESIDENT Page 5 Letter from the Executive Director

Marsha Wise Executive Director, AOCD

Hello, Everyone, It seems as though winter has lasted forever, but spring is finally here! We’ve had a busy start to the year. Drs. Suzanne Sirota Rozenberg, Lloyd Cleaver, Rick Lin and I attended the AOA Osteopathic Medical Education Leadership Conference in January. In February, Dr. Lloyd Cleaver and I attended the ACGME’s Annual Educational Conference. Both of these meetings provided valuable updates on the Single Accreditation System, or SAS. The information regarding SAS can be found on the AOA and ACGME websites. We encourage everyone to log on and familiarize themselves with the single accreditation system: http://www.osteopathic.org/inside-aoa/single-gme-accreditation-system/Pages/default.aspx http://www.acgme-i.org/Requirements-and-Process-Overview/What-is-Accreditation Programs may begin to apply for pre-accreditation status in April 2015. In February, the ACGME announced that Dr. Stephen Purcell was appointed to the Dermatology Residency Review Committee. We’re excited to have Dr. Purcell represent the AOCD and the osteopathic profession. Dr. Purcell’s leadership in the AOCD has been invaluable, and he is a true advocate for osteopathic dermatologists. During the General Membership Meeting recently held in Seattle, the membership voted to accept the changes to the bylaws that had been presented last summer. On March 2, we received word that the AOA approved our proposed changes. These changes are now in effect and can be found on our website at: https://aocd.site-ym.com/?page=ByLaws. March and April have been busy with the AAD meeting and our Spring Conference in Charlotte, NC. A panel discussion on “Unified U.S. Dermatology Training Accreditation and the Unification of the Specialty of Dermatology” took place at the AAD Annual Meeting on Sunday, March 22. Be sure to look for highlights of these meetings in upcoming Dermline publications. Exciting changes are in store for our Fall Conference. Our meeting is scheduled for October 16th through 19th, 2015, in Orlando at the Loews Royal Pacific Resort. An information packet with further details will be mailed to our members about the changes happening with this meeting. Please call or email the AOCD office (660-665-2184, [email protected]) if you have questions or need assistance. Sincerely, Marsha Wise Executive Director, American Osteopathic College of Dermatology

Page 6 LETTER FROM THE EXECUTIVE DIRECTOR Letter from the Editor-in-Chief

Karthik Krishnamurthy, DO, FAOCD Editor-in-Chief

Dear Readers, Many of you are familiar with the “Blurred Lines” controversy in which the Marvin Gaye estate won judgment for copyright infringement. Many artists are outraged, fearing this will set a dangerous precedent, claiming that all music is derivative in some way. What is considered “original” versus “copied” can be ill-defined -- which side does “was-influenced-by” sit on? This has made me ponder how we authors face this same issue every time we prepare a manuscript. We all gasp at the word “plagiarism,” look over our as we whisper the word, almost as if we would with “murder.” And yet almost everyone reading this column has infringed on someone else’s work, almost certainly without realizing it. It’s not something we would ever consciously do. It is exceptionally difficult to find ways to incorporate relevant information in an original way when citing a resource, especially since there is a limited and acceptable way in which we are trained to communicate certain data in the medical field. The online resource iThenticate is a service we can use to check for verbatim overlap when preparing our manuscripts, but this only gets us so far. According to our Assistant Editor: Copying another author’s words verbatim is only the most obvious type of plagiarism. Let’s say you change a couple of words in a sentence -- that’s still plagiarism, even if you attribute it to the source. The new sentence is too close to the original. In addition to attribution, it needs quotation marks around all of the words not changed. (If you ask me, it’s easier to just use the original and put quotes around the whole thing.) If you significantly change both sentence structure and words, a.k.a. paraphrase, it’s also plagiarism -- unless you attribute it. Paraphrasing is fine as long as you give credit to the source. Plagiarism isn’t only about another author’s words, though. You can plagiarize yourself. And regardless of the words you use, restating another author’s idea or interpretation without attribution is plagiarism (and a much more complicated subject). I guess imitation is not always the highest form of flattery. If you’d like to explore this more, try “Avoiding plagiarism, self-plagiarism, and other questionable writing practices,” by Miguel Roig, PhD (https://ori.hhs.gov/avoiding-plagiarism-self-plagiarism-and-other-questionable-writing- practices-guide-ethical-writing). It speaks specifically to science writing. Fraternally, Karthik Krishnamurthy, DO, FAOCD Editor-in-Chief, Journal of the American Osteopathic College of Dermatology

LETTER FROM THE EDITOR -IN-CHIEF Page 7 Aurora Diagnostics’ laboratories are focused on providing unsurpassed dermatopathology DISCOVER services to our referring physicians. Our network A NEW LEVEL OF of expertise consists of DERMATOPATHOLOGY SERVICES over forty board-certified dermatopathologists that are based locally throughout the country providing advanced technology and unparalleled customer support.

We believe that the practice of medicine and the delivery of healthcare are both personal EXPERTS IN DERMATOPATHOLOGY and best served locally.

LABORATORY LOCATIONS: BIRMINGHAM, AL Cunningham

TAMPA, FL DermDX Tampa

MIAMI, FL ACCESS TO ADVANCED DIAGNOSTICS DermDX Miami Global Pathology Laboratory

JACKSONVILLE, FL DermDX Jacksonville

BOSTON, MA DermDX New England

MONROE, MI Pinkus Dermatopathology Laboratory

PLYMOUTH, MN Aurora Diagnostics CONVENIENT LOCAL SERVICE Twin Cities Dermatopathology EATONTOWN, NJ Aurora Diagnostics Pathology Solutions

LAS VEGAS, NV LMC Pathology Services

WOODBURY, NY Aurora Diagnostics Laboratory of Dermatopathology

GREENSBORO, NC Aurora Diagnostics A PARTNER FOR YOUR PRACTICE GPA Laboratories RIDGELAND, SC Aurora Diagnostics Biopsy Diagnostics

SAN ANTONIO, TX DISCOVER, CALL 866.420.5512 Aurora Diagnostics South Texas WWW.AURORADX.COM Dermatopathology Laboratory Aurora Diagnostics’ dermatopathology laboratories are focused on providing unsurpassed dermatopathology DISCOVER services to our referring physicians. Our network A NEW LEVEL OF of expertise consists of DERMATOPATHOLOGY SERVICES over forty board-certified dermatopathologists that are based locally throughout the country providing advanced technology and unparalleled customer support.

We believe that the practice of medicine and the delivery of healthcare are both personal EXPERTS IN DERMATOPATHOLOGY and best served locally.

LABORATORY LOCATIONS: BIRMINGHAM, AL Cunningham Pathology

TAMPA, FL DermDX Tampa

MIAMI, FL ACCESS TO ADVANCED DIAGNOSTICS DermDX Miami Global Pathology Laboratory

JACKSONVILLE, FL DermDX Jacksonville

BOSTON, MA DermDX New England

MONROE, MI Pinkus Dermatopathology Laboratory

PLYMOUTH, MN Aurora Diagnostics CONVENIENT LOCAL SERVICE Twin Cities Dermatopathology EATONTOWN, NJ Aurora Diagnostics Pathology Solutions

LAS VEGAS, NV LMC Pathology Services

WOODBURY, NY Aurora Diagnostics Laboratory of Dermatopathology

GREENSBORO, NC Aurora Diagnostics A PARTNER FOR YOUR PRACTICE GPA Laboratories RIDGELAND, SC Aurora Diagnostics Biopsy Diagnostics

SAN ANTONIO, TX DISCOVER, CALL 866.420.5512 Aurora Diagnostics South Texas WWW.AURORADX.COM Dermatopathology Laboratory RETIN-A MICRO® (tretinoin) Gel microsphere,

Exclusively available in a 50g pump

Except as otherwise indicated, all product names, slogans, and other marks are trademarks of the Valeant family of companies. © 2015 Valeant Pharmaceuticals North America LLC. DM/RAM/14/0003(1)a 3 /15 Printed in USA. The Scar as a Representation of the Osteopathic Principles

Sarah Belden, DO,* Jenifer Lloyd, DO,** Michael Rowane, DO***

*Traditional Rotating Intern, University Hospitals Regional Hospitals, Richmond Heights, OH **Program Director, Dermatology Residency Program, University Hospitals Regional Hospitals, Richmond Heights, OH ***Director of Medical Education, University Hospitals Regional Hospitals, Richmond Heights, OH

Abstract A scar is the manifestation of the ’s healing process following an . It can be a cosmetic concern to some individuals while dismissed and disregarded by others. New treatment options continue to be investigated, but no solution currently exists for erasing a problematic scar. By viewing the scar as a source of somatic dysfunction using the four osteopathic principles, the dermatologist is able to employ the use of osteopathic manipulative treatment techniques as an adjunctive tool in scar management. Here we explore the scar through an osteopathic lens and describe treatment strategies that have been shown to be effective in improving the somatic dysfunction caused by the presence of a scar. Introduction the saying “a scar is more than skin deep,” a scar Principle 2. The body is capable of self-regulation, A scar, or cicatrix, is the end result of the may have a deeper value to one person but not to self-healing, and health maintenance. wound repair mechanism in adults and children another. It can serve as a permanent reminder of Upon any introduction of trauma to the skin, the following an injury, either traumatic or surgical, the past, whether it is pleasant or unpleasant, that body elicits an instant repair mechanism that is beyond the . It is the consequence of extends to the body, mind and spirit. designed to restore the natural homeostasis of the . This repair mechanism is divided into a a and is inevitable despite the It is known that the connection between the skin series of stages, each having unique characteristics. surgeon’s best efforts to hide it within the skin’s and the mind is a powerful one. For example, natural contour lines. stress can exacerbate and cause The first stage of is known as It is a common encountered in dermatology, breakouts.7 Stress can also play a role in scar the inflammatory phase, where cytokines and and it is the source of much cosmetic concern. formation. Furtado et al. found that psychological inflammatory cells are recruited and infiltrate the More than 230 million surgical procedures are stress influences the rate of recurrence of site to destroy potential pathogens, remove debris, performed around the world each year, all of when stress is experienced the day before and initiate coagulation through the formation of excision, increasing the chances of keloid an initial .12 The inflammatory pathway which result in cutaneous wounds that heal 8 with .1 A recent survey indicated that 91% recurrence by 34%. The location of the scar of wound healing, a large determinant of the of patients who underwent a routine surgical and the patient’s age or gender are factors that outcome of a scar, has long been the focus of procedure would value any improvement in influence its impact. A scar on the chest of a attack for anti-scarring research, but strategies 2 young female, for example, may cause increased that block alone have so far proved scarring. Scars also affect other body systems 13 including the musculoskeletal system or deep self-consciousness and impact the clothing she suboptimal with significant side effects. 3,4 viscera in the form of adhesions. They are also chooses to wear. The second stage, called proliferation, is 5,6 linked to pain and depression. There is a variety of psychosocial comorbidities characterized by the cell. The cosmetic outcome of a scar and its subsequent associated with scarring. Depression is the are responsible for producing , which implications on a patient’s overall wellbeing is of predominant finding in patients suffering provides the structure to the wound and creates a primary importance in dermatology. Patients are from scars5. A combination of anxiety, new matrix—the groundwork of a scar. often left desperate for treatment options after depression and PTSD-related disorders were Remodeling, the final stage of wound repair, first-line treatments—such as silicone sheeting, seen in 64% of the patients who developed scars begins at about two to three weeks following following ICU admission for severe soft-tissue pressure dressings and intralesional steroids— 6 trauma and can last for years depending on the Other psychosocial 12 fail. Osteopathic manipulative treatment in one study. size of the wound. During this stage, fibroblasts (OMT) is a non-invasive, cost-effective therapy characteristics of patients with scars, particularly are responsible for organizing and cross-linking for scar management that may be employed within the burn population, include avoidance the collagen, increasing the strength of the new 9 loneliness10 and living a by considering the scar as an application of of social interaction, site, and causing contraction of the wound edges solitary lifestyle.11 osteopathic principles and practices. Here, we in the process. apply A.T Still’s four osteopathic principles Thus, the first step in scar management is to The appearance of a scar is influenced by many to the scar and describe the mechanisms consider the whole patient. The stressors and factors: the depth of trauma (injury limited to the responsible for the interaction between the scar history behind the scar are important to address epidermis can heal without scarring), the location and its surrounding skin as a source of somatic prior to subsequent treatment. Approaches such (the chest is an area more susceptible to scar dysfunction. The OMT techniques applicable as suggesting stress-management techniques formation), whether the patient is at risk of keloid to scar management are reviewed and their perioperatively may help improve the chances of or hypertrophic scarring (genetics, ethnicity, etc.), effectiveness explored, revealing the growing a better scar outcome. Counseling or referring 3,12 age, and nutritional and deficiencies. opportunity for further osteopathic research. to psychiatry is important for patients displaying psychological symptoms. Education plays a It is important to appreciate that the dynamics helpful role, such as teaching the patient the between the wound repair process and the scar Discussion do not end immediately. Rather, an interplay Osteopathy and scars importance of keeping the scar covered from the sun and applying sunscreen after the surgery. It between the traumatized tissue, the scar, and Principle 1. The body is a unit; the person is a unit of is important to consider the whole patient when the surrounding non-traumatized tissue results body, mind, and spirit. performing a procedure; the patient’s age, incision in altered tissue arrangement that manifests as This osteopathic principle represents how a scar length and location should be respected in order tissue texture changes contributing to the scar’s 3,14,15 can affect a person’s entire wellbeing. Much like to ensure the best possible scar outcome. appearance.

BELDEN, LLOYD, ROWANE Page 11 This mechanism can best be explained through disorders, female infertility, and chronic lower changes listed in Table 1. The extent of the tissue the osteopathic bioelectric model of as abdominal pain.3,21 texture changes and the restriction and resistance described by Judith O’Connell, DO, FAAO, which Scars can also cause dysfunction of major muscles (pathological barriers) of the deeper tissue may be illustrates the important relationship between the determined by palpation.24 15,16 and . Frozen , for example, is a and its underlying fascia. Fascia is well-known complication of the shoulder found between the deep and superficial adipose following rotator cuff injury where the shoulder Table 1. Tissue texture changes associated with layers and is connected to the dermis through exhibits pain and neurological symptoms from chronic somatic dysfunction of a scar* 17 It perpendicular septa of fibrous extensions. scar accumulation. communicates with the dermis via bioelectric Ropiness: cord-like, fibrotic feeling Muscular dysfunction may be observed in the currents through the , which is (in the scar itself) considered a homeostatic relationship within the dermatological arena following the formation skin.15,18 of facial scars. The SMAS is a structure that Stringiness: fine or string-like ensheaths the facial muscles and neurovasculature The presence of a scar applies extra mechanical myofascial structures and plays an intricate role in coordinating and tension to the tissue, causing a disruption of the 22 exaggerating facial expressions. If a scar extends Firmness, hardening normal homeostatic signaling between the fascia to the level of the SMAS, the thickened and dermis. The collagen within the scar itself Temperature changes may cause stiffness of the fascia, which may lead also releases microelectrical-potential changes Increased/decreased moisture 15,18 to altered range of motion of the facial muscles, into the extracellular fluid. This aberrant 18 affecting normal facial expression. bioelectric current not only alters the local architecture of the dermis and fascia but also Principle 4. Rational treatment is based on an *Adapted from: American Association of Colleges the arrangement of surrounding tissue (neural, understanding of the basic principles of body unity, of Osteopathic Medicine - Educational Council muscular, vascular, and lymphatic), resulting in self-regulation, and the interrelationship of structure on Osteopathic Principles. Glossary of osteopathic and function. terminology. Chevy Chase, MD: American Association changes such as stiffness, altered motion, pain, and of Colleges of Osteopathic Medicine; rev. Nov 2011. that can be restored using OMT.3,15,16,19 Treatment relies on a full understanding of how a scar can affect the entire body while Thus, it is important to acknowledge that the acknowledging the first-line evidence-based Lymphedema is a common finding associated wound repair process and its end product, the treatment strategies and knowing alternatives with the chronic somatic dysfunction of a scar. scar, is not a static process. Rather, there are many for more refractory cases. First-line treatment The term “scar lymphedema” is used to describe dynamic homeostatic elements that are ongoing for scars includes a variety of options such as the localization of lymphatic fluid around the scar following scar formation that contribute to the silicone sheeting, pressure dressings, intralesional site due to the damage of the lymphatic channels overall somatic dysfunction and scar appearance. steroids, 5-FU, bleomycin, and verapamil, as and pathways caused by the surgical incision.25 Principle 3. Structure and function are reciprocally well as laser therapy, localized radiotherapy, The difference between edema and lymphedema interrelated. micro-needling, and intralesional cryotherapy surrounding a scar is based upon location of the 23 This principle stems from Dr. Still’s belief that for the more refractory cases. Osteopathic swelling. With lymphedema, swelling affects abnormal tissue structure is likely to result in manipulative therapy is a cost-effective and non- only the “upstream” side of a healed incision (such disruptions in tissue function and vice versa. A invasive treatment option that may be employed as the circumscribed central area of a U-shaped scar disrupts the normal architecture and function as an adjunct and for those scars resistant to scar), whereas nonspecific edema will surround of surrounding skin. The clinical result is an area the standard therapy. Several techniques may the entire scar.26 of skin tissue whose biomechanical function and be utilized and have been shown to be effective “Active scar” is another term used to describe a normal viscoelastic behavior is compromised; it is in improving the appearance of a scar and its scar that would benefit from OMT; it is “active” an area of somatic dysfunction. surrounding tissue. if it exhibits soft-tissue changes characterized by The skin’s basic protective functions are altered It is important for the osteopathic dermatologist increased skin drag, owing to increased moisture in the presence of a scar. The fibrotic infiltration to gain an understanding of which scar (sweating), impaired skin stretch, and a thickened of a scar alters the complex arrangement characteristics are clinically relevant for OMT skin fold.24 of desmosomes and that is used to and the rationales for treatment based on the The exact timeline of when it is appropriate to provide protection and support, leaving the site models of osteopathic care. treat scars using OMT has not been formally susceptible to mechanical damage. Similarly, established.27 The use of pressure therapy on scars protection against UV radiation is compromised Identifying a scar to be treated The first step in effective OMT is to properly after burn injury showed that earlier treatment as a scar alters the arrangement of 12 identify whether a scar and its surrounding (scars treated <6 months after burn injury) pigments. The processes of hyperkeratinization tissue would benefit from treatment. Its level of resulted in better outcome than those treated and DNA repair are also compromised by 28 20 acuity must be assessed. It is important to not It has been proposed that noninvasive the altered vascularization created by a scar. later. manipulate acute scars, i.e., hot, boggy, tender or Sensation becomes impaired when the scar management, such as manipulation, typically erythematous scars, or those exhibiting venous of the skin’s free nerve endings that normally occur within the early maturation phase of the congestion/edema. Manipulation of an acute extend to the epidermis is altered even by the wound healing process in order to improve scar scar would delay the wound healing process, 29 most superficial of scars. Adnexal structures (e.g. outcome and accelerate time of scar maturity. which would worsen the structure and function More studies are needed to investigate the most follicles, sweat and sebaceous ) as well dynamics of the scar.24 appropriate time to implement OMT. as components of the dermal may fail to regenerate following the formation of The scar should exhibit chronic somatic a scar, resulting in a loss of normal skin function dysfunction. By its standard definition, chronic Treatments and impaired morphology.12 somatic dysfunction is “impairment or altered The biomechanical model and the respiratory- function of related components of the somatic circulatory model of osteopathy help guide the Scars, in the form of adhesions, have the potential (body framework) system characterized by dermatologist to select the most appropriate to disrupt normal visceral function. Intra- tenderness, itching, fibrosis, and tissue OMT therapies. Based on these models, soft- abdominal adhesions are cited to occur after contraction; identified by TART”.25 The forces tissue techniques, myofascial release and a 50% to 100% of the surgical interventions of the 4 exerted by the scar to the surrounding tissue, as lymphatic approach to the scar are considered. abdomen. They can lead to bowel obstruction, described above, may manifest as tissue texture The therapeutic principles of the models in irregular bowel movements, meteorism, digestive

Page 12 THE SCAR AS A REPRESENTATION OF THE OSTEOPATHIC PRINCIPLES respect to the scar are explained below. Biomechanical Model: Techniques and Myofascial Release The goal of the biomechanical model seeks to address problems with the soft tissue, muscle and fascia by removing the restrictive forces of the tissue.30 As previously mentioned, there are many restrictive forces or tissue texture abnormalities that may be palpated surrounding the scar. Soft tissue OMT and scar (myofascial) release are two techniques that address these forces and have been shown to improve scar outcome. Both techniques utilize the concept of pressure restoring balance to the scar. Physical pressure at the site of a scar causes local , which induces the of fibroblasts, suppresses collagen production, and activates collagenase, which overall expedites collagen dismantling.33 The fibroblasts, which play a role in contracting Figure 2: Diaphragm release of the palmar fascia to induce motion patterns in multiple planes of an elbow scar.

collagen lattices, are relaxed through the pressure of manipulation.34,35 This relaxation results in increased microcirculation to the site owing to the restoration of tissue texture abnormalities.36 It has been shown that manipulation encourages collagen fibrils of the dermis to realign.37 The immediate result of these changes can be palpated through the form of a release.30 There is a variety of soft-tissue techniques that may be used for treating scars. The treatment goals include increasing tissue elasticity, enhancing circulation to local fascial structures, improving local tissue nutrition and oxygenation, improving local immune response, and providing a general state of relaxation.38 Scar soft- tissue manipulation is distinguished from scar therapy in that it makes use of the barrier-and-release phenomenon; scar massage does not.24 Soft-tissue techniques used for scars include effleurage, skin rolling, stretching, and petrissage.24,38,39,40 Effleurage is a light stroking soft-tissue technique that is used on more superficial scar tissue. McKay performed a five-week treatment of soft-tissue techniques including effleurage to improve the appearance and function of cleft- scars.39 Based upon patient subjective results, she found soft-tissue manipulation to be an effective means Figure 1: for increased patient satisfaction and improvement of the appearance of the scar. Indirect myofascial scar release of an elbow scar. Skin rolling is another soft-tissue technique. It involves lifting the skin away from the deeper structures and “rolling” the skin fold along the body.38 Pohl examined the changes in the structure of collagen in scars following

BELDEN, LLOYD, ROWANE Page 13 manual treatment using skin rolling with Table 2. Diaphragms to treat based on scar location* ultrasound.36 Prior to therapy, the tension of the scar was appreciated using ultrasound echoes Scar , face, Upper Chest, upper Abdomen, Lower that detected higher densities within the collagen Location neck extremity back lower back, extremity fibers. Following the skin-rolling technique, she buttocks, found a reduction in the densifications of collagen pelvis within the dermis as well as an overall increase Suggested Tentorium Palmar fascia Respiratory Pelvic Plantar fascia of thickness in the dermis. These changes were 32,34,35 Diaphragm thoracic inlet diaphragm diaphragm attributed to the relaxation of fibroblasts.

Soft-tissue stretching along the site of a scar *Adapted from: O’Connell J. Chapter 47. Myofascial release approach. In: Chila AG, Carreiro JE, Dowling DJ, has also been shown to be effective in scar Gamber RG, Glover JC, Habenicht AL, Jerome JA, Patterson MM, Rogers FJ, Seffinger MA, Willard FH. management. Soft-tissue stretch engages the Foundations of Osteopathic Medicine. 3rd ed. Philadelphia, Baltimore: Lippincott Williams & Wilkins. 2001. barrier palpated along the distal ends of the scar while slowly stretching and releasing the fibrin and collagen.42 resume tissue stretch in all directions. surrounding tissue in multiple planes.24 Lewit et al. used soft-tissue skin stretching in combination The proposed application of lymphatic treatments 5. Upon resistance, apply simple pressure in the with heat on “active” scar sites following a variety to scars involves first opening the myofascial direction of the pathological barrier until release of operations including appendectomy, breast pathways to increase microcirculation to the site is felt. (via the soft-tissue techniques and myofascial surgery and gynecologic surgery and found 6. Achieve relaxation of the tissue by lightly release), and then treating the diaphragms.42 marked immediate results with general soft- stroking the scar and surroundings. tissue stretch. 24 The treatment led to decreased By definition, diaphragms occur at important 16 pain and increased tissue mobility in the majority anatomical crossroads in the body where curves Diaphragm release (Figure 2) of cases. The scar ends were found to be the most and cavities change and where passage points for major circulatory and lymphatic vessels Based on the location of the scar and patient active sections of the scar, and treatment was 16 history, choose the most appropriate diaphragm aimed predominately at these sites. occur. Maximizing the motion of diaphragms helps to improve circulatory and lymphatic to treat, as noted in Table 2. Petrissage, which is a deeper kneading and flow, which would be beneficial in the setting of 1. Using compression, distraction or the full squeezing pressure, is considered to be an a scar exhibiting lymphedema in the setting of 41,42 deep respiration cycle, induce motion and note excellent soft-tissue technique for scars. chronic somatic dysfunction.30 In dermatology, the different patterns of interaction between the Morien et al. investigated a combination of the relevant diaphragms are both peripheral and normal and dysfunctional tissue response. effleurage, petrissage, stretching and rolling in central, based on the location of the scar as listed 2. The dysfunctional pattern, whether a barrier a group of post-burn patients, which showed in Table 2. Clinical studies are needed in order or point of ease, should become apparent at the improvement in range of motion at the scar to explore the outcome of diaphragm release and 40 diaphragm, making the primary dysfunction at site and overall patient satisfaction. Field other lymphatic treatments for scars. et al. compared a group of post-burn patients the scar evident, and a release should begin. who received a combination of skin rolling, Examples of Osteopathic Manipulative 3. If treating using respirations, motion in the stretching and stroking to a group who received Treatment Techniques tissue should begin as a release occurs, with a new 43 no manipulation. It was found that those in Indirect myofascial scar release (Figure 1)14 end point of motion manifesting. the manipulation group experienced a relief of pruritus, pain, anxiety and improvement in mood 1. Place fingers parallel to either side of the scar. associated with their scarring. Conclusion 2. Approximate your fingers gently to reduce By viewing the scar through an osteopathic lens, “Scar release” is an indirect form of a myofascial- tension on the scar. the dermatologist is able to gain an understanding release technique that may be used to reduce 3. Move the tissues on either side gently in of how the scar is more than just a fibrosis on asymmetric tension and restore functional balance different directions (cephalic, caudal, left, right) to the skin; it represents how one dermatological to the stresses transmitted through a scar.­ It is determine the tension pattern in the surrounding lesion can affect the entire person. It is an active utilized to engage deeper tissue such as muscle tissues. participant within the homeostatic environment and fascia. Successfully releasing the deep fascial of the skin that can affect both structure and 4. Gently move your fingers on either side of the restriction and correcting the restrictive forces in function of the . Based on available 16 scar in the direction that most reduces tension turn activates surrounding bioenergetic tissue. clinical data, osteopathic manipulative treatment until you perceive a sense of balance. It has been reported to be an effective technique should be considered in the dermatological arena in improving post-mastectomy axillary cord 5. Hold in the balanced position until you perceive as a therapeutic strategy for scar management. anchoring secondary to scar formation, leading a release, that is, a further relaxation of tension. Further clinical studies are needed to establish to improvement of axillary-scar appearance and the most effective OMT modalities and the most 44 6. Have the patient exhale and hold the breath in surrounding lymphedema. step 5 to enhance the balance of tension. appropriate time to initiate and continue therapy. Respiratory-Circulatory Model: 7. Reassess tension of the soft tissue surrounding Diaphragm Release and Lymphatic Pump the wound or scar. References Based upon the respiratory-circulatory model, 1. Weiser TG, Regenbogen SE, Thompson KD, lymphatic techniques are designed to remove Direct myofascial release skin stretch with heat24 Haynes AB, Lipsitz SR, Berry WR, Gawande AA. An estimation of the global volume of surgery: a impediments to lymphatic circulation and 1. Lightly stroke the whole area of the scar and 42 modeling strategy based on available data. Lancet. promote and augment the flow of lymph. area around it for relaxation. As previously noted, lymphedema can be a 2008 Jul;372(9633):139-44. 2. Undergo skin stretching in all directions. prominent feature of the chronic scar; it may 2. Young VL, Hutchison J. Insights into patient even be measured using lymphoscintography.26 3. Apply a hot pack to the site for a short duration and clinician concerns about scar appearance: Mobilizing the tissue surrounding the scar can along with pressure and shifting the soft tissue in semiquantitative structured surveys. Plast Reconstr help improve circulation and the exchange of multiple planes. Surg. 2009 Jul;124(1):256-265. lymphatic fluids and metabolites, which can ultimately encourage the normal distribution of 4. Following the application of the hot pack, 3. Bordoni B, Zanier E. Skin, and scars:

Page 14 THE SCAR AS A REPRESENTATION OF THE OSTEOPATHIC PRINCIPLES symptoms and systemic connections. J Multidiscip and Practice. 1st ed. 2009. Saunders Elsevier. p 33. Son D, Harijan A. Overview of surgical scar Healthc. 2013 Dec;28(7):11-24. 105-112. prevention and management. J Korean Med Sci. 4. DiZerega GS. Contemporary 18. Becker RO, Selden G. The Body Electric: 2014 Jun;29(6):751-7. prevention. Fertil Steril. 1994;61:219–235. Electromagnetism and the foundation of life. New 34. Adams LW, Priestley GC. Contraction of 5. Roh YS, Chung HS, Kwon B, Kim G. Association York: William Morrow and Company. 1985. collagen lattices by skin fibroblasts: drug induced between depression, patient scar assessment and 19. Kottke FJ, Stillwell GK, Lehman JF. changes. Archives of Dermatological Research. burn-specific health in hospitalized burn patients. Krusen’s Handbook of Physical Medicine and 1988;280:114-118. . 2012 Jun;38(4):506-12. Rehabilitation. 3rd ed. Philadelphia: W.B. 35. Coulomb B, Dubertret L, Bell E, Touraine R. 6. Hellgren EM, Lagergren P, Larsson AC, Schandl Saunders Company. 1982. The contractility of fibroblasts in a collagen lattice AR, Sackey PV. Body image and psychological 20. Scheithauer MO, Rettinger G. Operative is reduced by . J Invest Dermatol. outcome after severe skin and soft tissue treatment of functional facial skin disorders. GMS 1984;82:341-344. requiring intensive care. Acta Anaesthesiologica Curr Top Otorhinolaryngol Head Neck Surg. 36. Pohl H. Changes in the structure of collagen Scandinavica. 2013 Feb;57(2):220-8. 2005;4:18. distribution of the skin caused by a manual 7. Bolognia JL, Schaffer JV, Duncan KO, Ko CJ. 21. Brüggmann D, Tchartchian G, Wallwiener technique. J Bodyw Mov Ther. 2010;14: 27-34. Dermatology Essentials. Oxford: Elsevier; 2014. M, Münstedt K, Tinneberg HR, Hackethal A. 37. Stearns ML. Studies of the development of Chapter 7, Psychocutaneous disorders; p. 50-55. Intra-abdominal adhesions: definition, origin, in transparent chambers in the 8. Furtado F, Hochman G, Farber PL, Muller MC, significance in surgical practice, and treatment rabbit ear. Am J Anat. 1940; 67:55-57. options. Dtsch Arztebl Int. 2010;107(44):769– Hayashi LF, Ferreira LM. Psychological stress as 38. Ehrenfeuchter WC. Chapter 50. Soft Tissue/ 775. a risk factor for postoperative keloid recurrence. J Articulatory Approach. In: Chila AG, Carreiro Psychosom Res. 2012 Apr;72(4):282-7. 22. Flowers FP, Breza TS. Chapter 142. Surgical JE, Dowling DJ, Gamber RG, Glover JC, 9. Ye EM. Psychological morbidity in patients with anatomy of the head and neck. In: Bolognia JL, Habenicht AL, Jerome JA, Patterson MM, Rogers facial and neck burns. Burns. 1998 Nov;24:646-8. Jorizzo JL, Schaffer JV, editors. Dermatology. 3rd FJ, Seffinger MA, Willard FH. Foundations ed. Philadelphia: Elsevier Limited; 2012: 2327- of Osteopathic Medicine. 3rd ed. Philadelphia, 10. Taal L, Faber AW. Posttraumatic stress and 2341. Baltimore: Lippincott Williams & Wilkins. 2001. maladjustment among adult burn survivors 1 to 2 years postburn: Part II: the interview data. Burns. 23. Monstrey S, Middelkoop E, Vranckx JJ, Bassetto 39. McKay E. Assessing the effectiveness of 1998 Aug;24(5):399-405. F, Ziegler UE, Meaume S, Teot L. Updated scar massage therapy for bilateral cleft lip reconstruction management practical guidelines: non-invasive scars. Int J Ther Massage Bodywork. Jun 2014; 11. Fauerbach JA, Heinberg LJ, Lawrence JW, and invasive measures. J Plast Reconstr Aesthet 7(2). Munster AM, Palombo DA, Richter D, Spence Surg. Aug 2014;67(8) 1017-1025. RJ, Stevens SS, Ware L, Muehlberger T. Effect 40. Morien A, Garrison D, Smith NK. Range of early body image dissatisfaction on subsequent 24. Lewit K, Olsanka S. Clinical importance of of motion improves after massage in children psychological and physical adjustment after active scars: abnormal scars as a cause of myofascial with burns: a pilot study. J Bodyw Mov Ther. disfiguring injury. Psychosom Med 2000 Jul- pain. J Manipulative Physiol Ther. 2004. 27(6); 2008;12:67–71. 399-402. Aug;62(4):576-82. 41. Steele KM, Li TS, Lemley WW, Kribs JW, 12. Eming SA. Chapter 141. Biology of wound 25. Van Duyn J. Lymphedema in face scars. South Essing-Beatty DR, Garlitz JM, Comeaux ZJ. healing. In: Bolognia JL, Jorizzo JL, Schaffer Med J. 1969;62:1149. Chapter 1. Introduction to osteopathic diagnosis JV, editors. Dermatology. 3rd ed. Philadelphia: 26. Warren AG, Slavin SA. Scar lymphedema: fact and treatment. In: The Pocket Manual of OMT. Elsevier Limited; 2012. p. 2313-2325. or fiction? Ann Plast Surg. 2007 Jul;59(1):41-5. 2nd ed. Philadelphia: Lippincott Williams & Wilkins. 2011. 13. Wong VW, Beasley B, Zepeda J, Dauskardt 27. Shin TM, Bordeaux JS. The role of massage RH, Yock PG, Longaker MT, Gurtner GC. in scar management: a literature review. Dermatol 42. Kuchera ML. Chapter 51. Lymphatics A Mechanomodulatory Device to Minimize Surg. 2012 Mar;38(3):414-23. approach. In: Chila AG, Carreiro JE, Dowling Incisional Scar Formation. Adv Wound Care DJ, Gamber RG, Glover JC, Habenicht AL, 28. Leung PC, Ng M. Pressure treatment for (New Rochelle). May 2013;2(4):185–194. Jerome JA, Patterson MM, Rogers FJ, Seffinger hypertrophic scars resulting from burns. Burns. MA, Willard FH. Foundations of Osteopathic 14. Krettek JM. Chapter 14. Surgical patient. 1908;6:244-50. Medicine. 3rd ed. Philadelphia, Baltimore: In: Somatic Dysfunction in Osteopathic Family 29. Parry I, Sen S, Palmieri T, Greenhalgh D. Lippincott Williams & Wilkins. 2001. Medicine. 1st ed. Nelson KE, Glonek T, editors. Nonsurgical scar management of the face: does Philadelphia, Baltimore: Lippincott Williams & 43. Field T, Peck M, Hernandez-Reif M, Krugman early versus late intervention affect outcome? Wilkins. 2007. p 137. S, et al. Post-burn itching, pain, and psychological Journal of Burn Care and research. 2013;34(5):569- symptoms are reduced with massage therapy. J 15. O’Connell J. Bioelectric responsiveness of 575 2013. Burn Care Rehabil 2000;21:189–93. fascia: a model for understanding the effects 30. American Association of Colleges of of manipulation. Techniques in Orthopaedics. 44. Josenhans E. Physiotherapeutic treatment for Osteopathic Medicine - Educational Council on 2003;18(1):67-73. axillary cord formation following breast cancer Osteopathic Principles. Glossary of osteopathic surgery. Zeitschrift fur Physiotherapeuten. 16. O’Connell J. Chapter 47. Myofascial release terminology. Chevy Chase, MD: American 2007;59(9):868-78. approach. In: Chila AG, Carreiro JE, Dowling DJ, Association of Colleges of Osteopathic Medicine; Gamber RG, Glover JC, Habenicht AL, Jerome JA, rev. Nov 2011. Patterson MM, Rogers FJ, Seffinger MA, Willard 31. DiGiovanna EL. Chapter 4. Somatic Correspondence: Sarah Belden, DO; sebelden@ FH. Foundations of Osteopathic Medicine. 3rd dysfunction. In: DiGiovanna EL, Schiowitz S, gmail.com ed. Philadelphia, Baltimore: Lippincott Williams Dowling DJ, editors. An Osteopathic Approach & Wilkins. 2001. to Diagnosis and Treatment. 3rd ed. Philadelphia, 17. Fang RC, Mustoe TA. Chapter 11. Structure Baltimore: Lippincott Williams & Wilkins. 2005. and function of the skin. In: Guyuron B, Eriksson 32. Randolph RK, Simon M. Dermal fibroblasts E, Persing JA, Chung KC, Disa JJ, Gosain AK, actively metabolize retinoic acid but not retinol. J Kinney BM, Rubin JP. : Indications Invest Dermatol. 1998 Sep;111(3):478-484. BELDEN, LLOYD, ROWANE Page 15 Marijuana: An Unusual Cause of Fixed Drug Eruption

Christina Steinmetz-Rodriguez, DO,* Brent Schillinger, MD**

*First-year dermatology resident, Palm Beach Consortium for Graduate Medical Education, West Palm Hospital, West Palm Beach, FL **Clinical assistant professor of medicine, Nova Southeastern College of Osteopathic Medicine, Ft. Lauderdale, FL; Dermatology Associates PA of the Palm Beaches, Delray Beach, FL

Abstract Fixed drug eruptions (FDE) are a frequently reported mucocutaneous drug eruption. We present a case of multiple mucocutaneous due to marijuana use presenting as FDE. Marijuana use continues to increase worldwide with the growing legalization for both medicinal and recreational use. As a consequence, it is crucial that clinicians be aware of any possible adverse reactions. The most common systemic and cutaneous signs of marijuana use are reviewed here. Dermatologists may be the first provider to encounter such clues, and as such we may be the first to recognize substance abuse and dependence, allowing earlier intervention for treatment.

Introduction States becomes more widespread, it is important Discussion First described by Burns in 1889, subsequently for clinicians to recognize the cutaneous Fixed Drug Eruptions named “eruption erythemato-pigmentee fixe” by manifestations of marijuana use. Because drug Drug eruptions are one of the most Brocq, the “fixed drug eruption” is one of the most abuse carries a negative stigma, patients are not common cutaneous disorders encountered common types of drug eruptions, and its incidence always immediately forthright in reporting their history of illicit drug use. By both recognizing by dermatologists, representing 2% to 3% of continues to increase over the years relative to 3 1-3 all dermatological issues. FDE is a form of other drug eruptions. The most characteristic cutaneous signs and routinely inquiring about drug that presents as single or multiple findings of FDE are “lesions that recur at the illicit drug use, dermatologists can be the first round, sharply demarcated, dusky red lesions same anatomic sites upon repeated exposure to to recognize signs of illicit drug use in patients, 3 several centimeters in diameter that occur at an offending agent,” according to Pai et al. A resulting in earlier treatment. the same sites after each administration of large number of drugs, including barbiturates, 5 penicillin, sulfonamides, tetracycline, bismuth and the inciting drug. Pruritis and burning are 4 Case Presentation often associated symptoms. The average age iodides, have been linked to FDE. Marijuana A 32-year-old man presented to the use, however, remains an underreported cause of dermatology clinic with complaints of recurring of onset is approximately 30 years old, and the most commonly implicated medication is FDE. As legalization of marijuana in the United hyperpigmented patches on his face over the 5,6 past year that were transient. He denied any trimethoprim-sulfamethoxazole. Between the Figure 1 pain, pruritis or discomfort. He noticed that the time when the individual is first exposed to the lesions would erupt in the same location on his medication and development of the first lesion, a variable refractory period can exist, ranging face each time, on a monthly basis, and resolve in 5 six to seven days. He denied any prior medical from a week to months or even years. With history and reported no medication use including subsequent exposure, lesions appear within 30 over-the-counter medications. minutes to eight hours. Typically, the lesions heal with residual . However, revealed a well-defined, other types of FDE have been reported (Table 1). 2 cm, circular hyperpigmented patch over his right zygoma with mild scaling at the periphery (Figure 1). Additionally, two 0.5 cm hyperpigmented macules bilaterally on the lower lip, and a 1 cm macule in the philtral ridge, were seen on examination (Figure 2). Shave biopsy of the zygomatic lesion revealed interface vacuolar changes with dermal melanophages and some eosinophils, as well as near-full-thickness epidermal necrosis (Figures Figure 3 Figure 2 3 and 4). The PAS stain failed to reveal any . However, the PAS did reveal normal thickness of the epidermal basement membrane, consistent with fixed drug eruption. After the biopsy results returned, a careful review of the patient’s medical history revealed that each episode was produced by the same event -- recreational use of marijuana. A short course of topical therapy resulted in complete resolution of the lesions, and the patient was advised to abstain from marijuana use.

Figure 4

Page 16 MARIJUANA: AN UNUSUAL CAUSE OF FIXED DRUG ERUPTION 1 Table 1. Types of Fixed Drug Eruptions (FDE) and Examples of Causes3,5 targeted initially by the viral infection.” Histological examination displays two possible FDE Type Presentation Known Causes scenarios depending on when the biopsy is done. In lesions that are only one to two days Pigmenting Lesions that heal with residual Barbiturates, penicillin, old, examination reveals hydropic degeneration hyperpigmentation NSAIDs sulfonamides, of basal with dyskeratotic cells in tetracyclines, bismuth, iodides 20 the epidermis and exocytosis of mononuclear multiforme-like Lesion with three zones: Mefenamic acid cells.3 Healed hyperpigmented lesions often central, dusky ; demonstrate pigmentary incontinence revealing elevated, edematous, pale ring; dermal melanophages with little perivascular and surrounding erythema infiltration of inflammatory cells, as seen in our Toxic epidermal necrolysis-like Widespread, bullous lesions NSAIDs21 patient.3 To identify the culprit of the FDE, Linear Multiple lesions that are Trimethoprim provocation tests can be done, with the patch distributed linearly; may follow test being the most commonly used method. The Blaschko’s lines or nerve-root is effective as long as it is placed over a distribution previously involved site and the patient is not in the refractory period.3 Challenging a patient with Wandering Involved sites that don’t flare Acetaminophen an oral provocation test has been associated with with each exposure and activity generalized bullous lesions in some cases.5 In our that does not always appear at case, we did not re-challenge the patient with the the same location with each suspected drug due to legal concerns. Treatment recurrence consists of cessation of the suspected drug along Nonpigmenting Lesions that do not leave any Pseudoephedrine with the use of topical steroids and systemic residual hyperpigmentation hydrochloride, .3 Extensive lesions, or those with and appear uniformly red tetrahydrozoline, contrast bullae, may require systemic corticosteroids.3 media, betahistine, etodolac Post-inflammatory hyperpigmentation can be 5 Bullous Subepidermal blisters that heal Aminophenazone, treated with hydroquinone bleaching creams. without scarring antipyrine, barbiturates, Cutaneous manifestations of illicit drug use cotrimoxazole, trimethoprim, According to the Substance Abuse and Mental sulfamethoxazole, Health Administration, in 2013 “an estimated diazepam, mefenamic 24.6 million individuals aged 12 or older were acid, acetaminophen, current illicit drug users,” representing over phenylbutazone, piroxicam, 9% of the population in the United States.8 sulfadiazine, sulfathiazole Dermatologists may be the first to recognize drug abuse in select patients, allowing for earlier Our patient presented with the classic pigmented commonly occur on the glans penis, , palms, intervention and treatment (Table 2). As often 5 FDE, with lesions appearing within six hours of soles and groin area. Overall, the legs are most the vascular and cardiac manifestations are marijuana use. commonly affected in women and the genitalia internal, they cannot be readily seen by clinicians 1 While generally only a solitary lesion appears are most commonly affected in men. outside of dermatology. on first exposure, repeated administration of the As explained by Pai et al., the reaction “is believed Cannabis medication can lead to new lesions or an increase to be a lymphocyte CD8-mediated reaction, Cannabis remains the most commonly used illicit 5 in size of the original lesions. Although they wherein the offending drug may induce local drug, with an estimated 7% of the population in can occur anywhere on the skin, FDE’s most reactivation of memory T cell lymphocytes … the United States using this substance regularly.9 8,10 Since the Neolithic times, cannabis, which is the Table 2: Cutaneous manifestations of illicit drug use Latin name for hemp, has been widely used, with Illicit Drug Percent of Americans Using Cutaneous Manifestations the first account of marijuana in the Western (12+ Years Old) medical literature reported in 1840 by the British physician O’Shaughnessy.9,10 Today, Cannabis Cannabis 7.5% Contact urticaria, cannabis arteritis, skin sativa has a wide variety of uses ranging from aging recreational use for its psychoactive properties Cocaine/Crack 0.6% Nasal septal perforation, “snorter ,” or medicinal properties, to biofuel, insulation, , bullous , animal litter, paper, cosmetics, rope and fabric “crack ,” , Henoch- manufacturing.10 The stem provides the fibers, Schonlein purpura, due to while the resin produced from the flowering levamisole tops is often used recreationally. The seeds are commonly used for birdseed or fishing bait.11 Ecstasy 0.4% hallucinogen use “Ecstasy ,” guttate psoriasis There are four subspecies of Cannabis sativa, (including LSD and ecstasy) varying in geographic location and in application 0.2% “Meth mites,” “meth mouth,” xerosis, (Table 3). “Hashish” refers to the unadulterated premature aging resin that is collected and dried, while marijuana refers to the cut flowers, leaves and stems, which Heroin 0.1% Track marks, , candida , 9 transcutaneous botulism, generally possess a fifth of the potency of hashish. formation, pruritis, fixed drug eruption, Cannabis can be smoked or consumed in “puffy syndrome,” tourniquet foods, infusions or vapor form. Delta- hyperpigmentation 9-tetrahydrocannibol (THC), the main

STEINMETZ-RODRIGUEZ, SCHILLINGER Page 17 10 Table 3: Subspecies of Cannabis sativa References 1. Pai VV, Bhandari P, Kikkeri NN, Athanikar Cannabis sativa Subspecies Use Region SB, Sori T. Fixed drug eruption to fluconazole: a Sativa (cultivated hemp) Recreational (high Worldwide, primarily case report and mini-review of literature. Indian J tetrahydrocannabinol [THC] equatorial regions Pharmacol. 2012;44(5):643-645. content), industrial uses 2. Brocq L. Eruption erythemato-pigmentee Indica (Indian hemp) Recreational use (high THC Himalayas, Middle East, India fixe due a l’antipyrine. Ann Dermatol Venereol. content), seldom used for its 1894;5:308–313. fiber 3. Lee AY. Fixed drug eruptions. Incidence, Spontanea (wild hemp) Industrial use (low THC Eastern Europe, China, Russia recognition and avoidance. Am J Clin Dermatol. content, not commonly used for 2000;1(5):277-285. recreation) Kafiristanica (Afghan hemp) Recreational use (high THC Afghanistan, Pakistan 4. Stritzler C, Kopf AW. Fixed drug eruption content), unfit for manufacturing caused by 8-chlorotheophylline in Dramamine of fibers with clinical and histologic studies. J Invest Dermatol. 1960;34:319-330. 5. Gendernalik SB, Galeckas KJ. Fixed drug psychoactive substance in cannabis, which is eruptions: a case report and review of literature. found in the plant’s resin, is responsible for its Conclusion To our knowledge, this is the first case report Cutis. 2009;84(4):215-219. perception- and mood-altering properties. The describing fixed drug eruption elicited by concentration of THC can vary from 0.1 to 12%, recreational marijuana use. With 19.8 million 6. Ozkaya-Bayazit E, Bayazit H, Ozarmagan depending upon the subspecies and method of G. Drug related clinical pattern in fixed drug 12 current users in the United States and the growing preparation. Onset of activity after smoking rate of use associated with legislature changes, eruption. Eur J Dermatol. 2000;10(4):288-291. marijuana is within 10 to 20 minutes, and the questions regarding a patient’s recreational drug 7. Liu SW, Lien MH, Fenske NA. The effects 9 8 effects usually resolve within three hours. use should be included in the patient’s history. of alcohol and drug abuse on the skin. Clin Cutaneous manifestations of marijuana present as By recognizing the cutaneous findings of illicit Dermatol. 2010;28(4):391-399. conjunctival , contact urticaria, and type drug use, dermatologist can stand on the forefront 1 hypersensitivity, which can include anaphylaxis of early recognition. 8. Substance Abuse and Mental Health Services or cannabis arteritis. Cannabis arteritis, a subtype Administration, Center for Behavioral Health of thromboangiitis obliterans, is seen mainly in Statistics and Quality. The NSDUH Report: long-term users.12 Cannabis arteritis is believed Substance Use and Mental Health Estimates to be caused by the vasoconstrictive side effects from the 2013 National Survey on Drug Use of THC and contaminants such as arsenic and Health: Overview of Findings. SAMHSA: (known to cause thromboangitis obliterans Rockville (MD); 2014. in cigarette smokers) and is one of the major 9. Lieberman CM, Lieberman BW. Current causes of peripheral arterial disease in patients concepts: marihuana—a medical review. N Engl J 10,12 under the age of 50. Manifestations of this Med. 1971;284(2):88-91. atherogenesis include Raynaud’s phenomenon; 10. Tennstedt D, Saint-Remy A. Cannabis and digital necrosis with small, dry necrotic patches skin . Eur J Dermatol. 2011;21(1):5-11. on the extremities; and decreased tibial and pedal pulses. Diagnosis is based upon duplex 11. Williams C, Thompstone J, Wilkinson M. ultrasound in order to differentiate it from Work-related contact urticaria to Cannabis atherosclerosis.12 Treatment includes cessation of Sativa. Contac . 2008;58(1):62-63. marijuana, aspirin (81 mg to 200 mg daily) or, in 12 12. Hennings C, Miller J. Illicit drugs: what severe cases, iloprost. Smoking marijuana is also dermatologists need to know. J Am Acad associated with premature skin aging, resulting Dermatol. 2013;69(1):135-142. in prominent wrinkles.7 A case of erythema multiforme-like recurrent drug eruption was also 13. Ozyurt S, Muderrisoglu F, Ermete M, Afsar reported with marijuana use.13 No reported cases F. Cannabis-induced erythema multiforme- of fixed drug eruption secondary to marijuana use like recurrent drug eruption. Int J Dermatol. were found in a literature search. 2014;53(1):e22-23. In the 1980s, an epidemic of fixed drug eruptions 14. Westerhof W, Wolters EC, Brookbakker JT, occurred in Holland due to heroin being smoked, Boelen RE, Schipper ME. Pigmented lesions of and presented as hyperpigmented lesions of the the in heroin addicts-fixed drug eruption. tongue.14 Despite denial by our patient, one Br J Dermatol. 1983;109(5):605-610. possibility is that heroin may have been mixed in the marijuana cigarette, and thus the FDE may have been due to adulterants and not the Correspondence: Christina Steinmetz- marijuana. Rodriguez, DO; [email protected]

Page 18 MARIJUANA: AN UNUSUAL CAUSE OF FIXED DRUG ERUPTION Painful, Pruritic Blisters Exacerbated by Heat and Sweating

Collin M. Blattner, BS,* Dustin V. Wilkes, DO,** Dongkun Chang, MD***

*Medical Student, 4th year, Des Moines University, Des Moines, IA **Attending Dermatologist, Department of Dermatology, JPS Health Network, Fort Worth, TX ***Attending Pathologist, Department of Pathology, JPS Health Network, Fort Worth, TX

Abstract Bullous congenital ichthyosiform erythroderma is a rare that affects 1 in 200,000 people. Management for adults entails symptomatic relief, but infants may require intensive care if substantial blistering is present. We present a case of bullous congenital ichthyosiform erythroderma in a 48-year-old male and provide a discussion about the disease and treatment options.

Introduction and soles with fissures and cracks (Figure 1). There were also few coarse, irregularly shaped, Bullous congenital ichthyosiform erythroderma Brown, cardboard-like scale with on granules and intracytoplasmic (BCIE) is a rare genodermatosis that was the neck, back, abdomen, and extremities was also , along with involvement of the formerly known as epidermolytic present. The lesions extended to the volar aspect of entire suprabasal layer. This was consistent with (EHK) or epidermolytic (EI). About the wrists, the dorsa of the feet, and the Achilles the diagnosis of BCIE. 50% of cases arise from spontaneous mutation, . Dark-brown hyperkeratosis with mild but autosomal-dominant (AD) and rare scaling, arrayed in a linear fashion, was present in his autosomal-recessive forms also exist.1-3 BCIE axillae, antecubital fossa (Figure 2), and popliteal clinically manifests with erythema, blistering, and erythroderma in infancy, but the severity of disease may decrease over time.1

Case Report A 48-year-old African American male presented for evaluation of blisters and scaling over the entirety of his body since birth. The blisters were painful, pruritic, and made worse by heat and sweating. He had previously used Eucerin lotion without relief. The patient had an otherwise Fig 3. Orthokeratotic hyperkeratosis, unremarkable 12-point review of symptoms , church-spire-like except for mild joint pain, 15 pack-year smoking , and marked vacuolar changes history, and moderate alcohol intake. in the keratinocytes of the upper spinous and granular layers (H&E, 40x) Dermatological examination revealed marked hyperkeratosis, thickened palms with palmoplantar , hyperlinear creases, Discussion BCIE is a rare AD genodermatosis that was first described by Brocq in 1902.4 It is caused by mutations in 1 and keratin 10 that impair intermediate filament formation in the suprabasal keratinocytes, although a case with a novel mutation in the 1A helix initiation motif Fig 2. Antecubital fossa with dark-brown 4 hyperkeratosis and scaling of keratin 1 has been reported. Confirmation of disease can be established by mutation-specific testing for keratin defects using buccal swabs fossa. The hair, teeth, nails, mucosa, and other body or blood.5 Cost constraints prohibited genetic surfaces were spared. The patient’s mother, maternal testing and genetic counseling for our patient, aunt, and two cousins had a similar but these services should be offered to affected with pronounced scaling. Differential diagnosis individuals and families. Patients should also included BCIE, , lamellar be made aware of the possibility of passing the ichthyosis, X-linked ichthyosis, staphylococcal chromosomal defect on to their children. scalded skin syndrome, Stevens-Johnson syndrome, Clinically, BCIE presents in neonates with and toxic epidermal necrolysis. erythema, widespread superficial blistering, and Two 4mm punch biopsies were taken from erythroderma. If the blisters rupture, they may representative lesions on the abdomen and leave raw, denuded areas that can cause secondary left knee. Histopathological findings revealed infections, sepsis, dehydration, electrolyte orthokeratotic hyperkeratosis, hypergranulosis, imbalances, and hypothermia. In light of these church-spire-like papillomatosis, and marked concerns, affected newborns should be handled Fig 1. Thickened palm with palmoplantar vacuolar changes in the keratinocytes of the gently and transferred to the intensive care unit keratoderma and hyperlinear creases upper spinous and granular layers (Figure 3). (ICU) immediately after birth. Although a

BLATTNER, WILKES, CHANG Page 19 delicate scale may be present following delivery, Review. hyperkeratosis is seldom noticeable until the References 1. Frost P, Van Scott EJ. Ichthyosiform 13. Li H, Törmä H. reduce formation of third month of life. Clinical data from 28 dermatoses. Classification based on anatomic and keratin aggregates in heat-stressed immortalized patients with BCIE in Japan found that 96.4% biometric observations. Arch Dermatol. 1966 keratinocytes from an epidermolytic ichthyosis had , 67.9% had erythroderma, and 75% of Aug;94(2):113-26. patient with a KRT10 mutation. Acta Derm patients younger than 20 years had generalized Venereol. 2013 Jan;93(1):44-9. blistering.6 As a person ages, the symptoms 2. Terheyden P, Grimberg G, Hausser I, Rose may wane or even disappear, but the classically C, Korge BP, Krieg T, Arin MJ. Recessive 14. Brecher AR, Orlow SJ. Oral described “corrugated cardboard” scale persists.6 epidermolytic hyperkeratosis caused by a therapy for dermatologic conditions in children Proliferation of scale allows for the overgrowth previously unreported termination codon and adolescents. J Am Acad Dermatol. 2003 of , particularly Staphylococcus aureus, that mutation in the keratin 10 . J Invest Aug;49(2):171-82; quiz 183-6. Review. 6 Dermatol. 2009 Nov;129(11):2721-3. causes malodor. 15. Ruiz-Maldonado R, Tamayo L. Retinoids in In 1994, DiGiovanna and Bale separated the 3. Tsubota A, Akiyama M, Kanitakis J, Sakai K, disorders of keratinization: their use in children. various clinical presentations of BCIE into two Nomura T, Claudy A, Shimizu H. Mild recessive Dermatologica. 1987;175 Suppl 1:125-32. bullous congenital ichthyosiform erythroderma primary types based on the presence or absence 16. Kragballe K, Steijlen PM, Ibsen HH, van de 5 due to a previously unidentified homozygous of palm and sole hyperkeratosis. The two Kerkhof PC, Esmann J, Sorensen LH, Axelsen keratin 10 nonsense mutation. J Invest Dermatol. primary types were further subdivided into three MB. Efficacy, tolerability, and safety of calcipotriol 2008 Jul;128(7):1648-52. subtypes each that described the various clinical ointment in disorders of keratinization. Results of presentations. Some subtypes have generalized 4. Uezato H, Yamamoto Y, Kuwae C, Nonaka 5 a randomized, double-blind, vehicle-controlled, involvement; others are more localized. EHK K, Oshiro M, Kariya K, Nonaka S. A case of right/left comparative study. Arch Dermatol. is still being used as a synonym for BCIE even bullous congenital ichthyosiform erythroderma 1995 May;131(5):556-60. though multiple unusual subtypes of BCIE (BCIE) caused by a mutation in the 1A helix 7-11 17. Kwak J, Maverakis E. Epidermolytic (annular, linear, cyclic) have been described. initiation motif of keratin 1. J Dermatol. 2005 hyperkeratosis. Dermatol Online J. 2006 Sep The histopathological hallmark of BCIE is Oct;32(10):801-8. “epidermolytic hyperkeratosis” (EHK) despite 8;12(5):6. 5. DiGiovanna JJ, Bale SJ. Clinical heterogeneity the identical finding being present in several 18. Achar A, Naskar B, Laha R, Ray S. in epidermolytic hyperkeratosis. Arch Dermatol. conditions including acanthoma, epidermoid , Epidcermolytic hyperkeratosis: a case report. J 1994 Aug;130(8):1026-35. infundibular cyst, epidermal , hidradenoma, Indian Med Assoc. 2009 Mar;107(3):171-2. nevus comedonicus, seborrheic , actinic 6. Kurosawa M, Takagi A, Tamakoshi A, 19. Rothnagel JA, Lin MT, Longley MA, Holder keratosis, , basal cell carcinoma, Kawamura T, Inaba Y, Yokoyama K, Kitajima Y, 12 RA, Hazen PG, Levy ML, Roop DR. Prenatal , and . Aoyama Y, Iwatsuki K, Ikeda S. Epidemiology diagnosis for keratin mutations to exclude and clinical characteristics of bullous congenital Although no cure exists for BCIE, oral retinoids transmission of epidermolytic hyperkeratosis. ichthyosiform erythroderma (keratinolytic such as isotretinoin, acitretin, and etretinate are Prenat Diagn. 1998 Aug;18(8):826-30. the mainstay of therapy.13 Studies of etretinate ichthyosis) in Japan: results from a nationwide for children with BCIE demonstrated a good survey. J Am Acad Dermatol. 2013 Feb;68(2):278- safety profile and remission rates of 70% to 83. Correspondence: Dustin V. Wilkes, DO; 80%.14 Dosing is started at 1 mg/kg/d to 2 mg/ 7. Lacz NL, Schwartz RA, Kihiczak G. [email protected] kg/d, and once remission is achieved, the dose Epidermolytic hyperkeratosis: a keratin 1 or 10 can be adjusted to the minimal amount necessary mutational event. Int J Dermatol. 2005;44(1):1-6. to keep the skin free of lesions.14 Children who 8. Sheth N, Greenblatt D, McGrath JA. New underwent treatment with oral retinoids had KRT10 gene mutation underlying the annular improved quality of life and enhanced social and variant of bullous congenital ichthyosiform psychological development, and a subset showed erythroderma with clinical worsening during improved physical growth.15 Adjunctive therapies . Br J Dermatol. 2007;157:602–4. that provide symptomatic relief include high-dose beta-carotene, topical retinoids, 10% glycerin, 9. Kocaturk E, Zemheri E, Kavala M, Aktas lactic acid, alpha-hydroxy acid, calcipotriol, S, Sarigul S, Sudogan S. Two cases of linear antibacterial soap, and urea.16-18 Proper use of epidermolytic hyperkeratosis: therapeutic emollients and other barrier ointments that challenge with acitretin. Eur J Dermatol. retain moisture are recommended. Gene therapy 2010;20(3):404-5. is a promising new treatment option that is being 10. Chassaing N, Kanitakis J, Sportich S, Cordier- studied at the University of Colorado. Researchers Alex MP, Titeux M, Calvas P, Claudy A, Berbis hope to generate induced pluripotent stem cells P, Hovnanian A. Generalized epidermolytic that allow for genetic correction of the defect in hyperkeratosis in two unrelated children from keratin 1 or keratin 10. parents with localized linear form, and prenatal diagnosis. J Invest Dermatol. 2006;126(12):2715- Conclusion 7. In conclusion, accurate diagnosis of BCIE is 11. Sybert VP, Francis JS, Corden LD, Smith LT, important so that genetic counseling and prenatal 19 Weaver M, Stephens K, McLean WH. Cyclic diagnosis may be offered to affected families. Ichthyosis with Epidermolytic Hyperkeratosis: Management includes oral retinoids for children A Phenotype Conferred by Mutations in the and symptomatic care with proper use of 2B Domain of Keratin K1. Am J Hum Genet. emollients and mild antibacterial cleansers for 1999;64:732–8. adults.14 Infants should be treated in the ICU to prevent secondary infections, sepsis, dehydration, 12. Kumar P, Kumar R, Mandal RK, Hassan S. electrolyte imbalances, or death.14 Systematized linear epidermolytic hyperkeratosis. Dermatol Online J. 2014 Jan15;20(1):21248.

Page 20 PAINFUL, PRURITIC BLISTERS EXACERBATED BY HEAT AND SWEATING Proteus Syndrome: Case Report and Review

Holly Kanavy, DO,* Cindy Hoffman, DO**

*PGY-4, St. Barnabas Hospital, Bronx, NY **Program Director, Dermatology Residency Program, St. Barnabas Hospital, Bronx, NY

Abstract Proteus syndrome (PS) is a rare, progressive hamartomatous disorder characterized by overgrowth and hyperplasia of diverse tissues including connective tissue, , skin, adipose, and central nervous system. Mosaic expression of a post-zygotic somatic mutation in the AKT1 gene results in random distribution of affected tissues and creates significant phenotypic variability among patients. Herein, we describe a case of PS presenting with a cerebriform connective-tissue nevus in a 14-year-old male and review the pathogenesis, clinical presentation and differential diagnosis, management, and prognosis of patients with the disorder.

Introduction of the lesion was performed. revealed mutation results in a greater number of disease Proteus syndrome was first described in 1979 dense connective tissue beneath an acanthotic, manifestations than a late mutation, because the by Cohen and Hayden, and it was named by acantholytic epidermis. Stellate cells and early somatic cell carrying a mutation would give Weidmann et al. in 1983 for the Greek god entrapped were present in the rise to more affected cell lineages. dermis (Figures 2a [2x], 2b [10x]). The patient Proteus, who was capable of assuming many Due to the clinical overlap with other 1,2 was assigned a diagnosis of Proteus syndrome forms. With fewer than 100 confirmed cases hamartomatous disorders, a mutation in the and referred for genetic testing. reported, Proteus syndrome is extremely rare; tumor suppressor gene PTEN was initially its estimated incidence is less than 1:1,000,000 thought to be pathogenic in PS. However, it 3 persons. It is seen twice as frequently in males, is now believed that individuals with PTEN 4 and there is no ethnic predilection. The variable gene mutations and asymmetric overgrowth presentation and rarity of the disease led to do not meet the diagnostic criteria for Proteus frequent misdiagnosis of the disorder until 1999, syndrome. Instead, these individuals are when Biesecker et al. proposed detailed and considered part of a larger group of disorders 3 specific diagnostic criteria. called PTEN hamartoma tumor syndromes. Other entities in this group include Cowden Case Presentation syndrome, Bannayan-Riley-Ruvalcaba syndrome, A 14-year-old Caucasian male presented with and Proteus-like syndrome.7 AKT1 is activated a slowly enlarging growth on the bottom of his by loss-of-function mutations in PTEN, which left foot that was present for about three years. explains why patients with such mutations and The patient reported some discomfort with those with activating mutations in AKT1 display Figure 2a ambulation due to the increasing size of the overlapping clinical features. lesion. His medical history included chronic macrocytosis and reticulocytopenia, which Clinical Manifestations prompted a bone marrow biopsy at the age of The clinical features of PS arise postnatally with 10. No evidence of hematologic irregular, asymmetric, progressive overgrowth was found; however, a non-clonal that can involve many tissues, most commonly 15 deletion: 45 XY del(15)(q11.2) was revealed. bone, connective tissue and . Skeletal changes (Chromosome 15 deletions have been described include gigantism of the hands and/or feet and in association with .) partial or complete hemihypertrophy. Localized The patient also had a history of developmental overgrowths may exert asymmetric forces on the abnormalities and was diagnosed with autism/ spine and result in scoliosis. Connective-tissue Asperger’s disease. An MRI of the brain from abnormalities, such as cerebriform connective- five years prior revealed encephalomalacia and tissue nevi (CCTN), typically present in the periventricular leukomalacia (localized areas of Figure 2b first or second year of life and tend to evolve necrosis attributed to infarction or ). slowly, in some patients continuing to develop One of the patient’s two brothers had spina bifida. Pathogenesis throughout adolescence.8 The lesion is virtually A full skin examination revealed one café au lait pathognomonic for PS and appears as gyriform Proteus syndrome is a progressive, hamartomatous gross thickenings of cutaneous and subcutaneous macule on the back. The plantar aspect of the left disorder that may involve any germ layer. The foot contained several flesh-colored cerebriform tissues, most commonly on the soles and hypothesized pathogenesis involves a post- occasionally on the hands, abdomen, and nose. and nodules (Figure 1). Partial biopsy zygotic somatic mutation in the AKT1 gene (chromosome 14q32.33), which is lethal in the Other dermatological manifestations include non-mosaic state.5 This gene belongs to the AKT linear verrucous epidermal nevi, which tend family of serine/threonine kinases and is involved to develop in the first year of life, and vascular in regulation of multiple cellular processes, malformations that can be either venous, 8 including proliferation and survival, cell size and capillary, lymphatic-type, or mixed. Four types response to nutrient availability, tissue invasion of abnormalities of fat may occur in Proteus and .6 Constitutive activation of syndrome: (1) , (2) lipohypoplasia, (3) the underlies the overgrowth and tumor fatty overgrowth, and (4) localized fat deposits or susceptibility in patients carrying this mutation. partial lipohyperplasia. Lipomas may be single or Mosaic expression of the mutation is what results multiple and occur subcutaneously or internally. in the random distribution of affected tissue and Lipomas of the abdomen and can be very 8 creates significant phenotypic variability among aggressive despite their benign histology. Figure 1 patients. Accordingly, an early post-zygotic Specific facial features have been described in KANAVY, HOFFMAN Page 21 Table 1. Proteus Syndrome Diagnostic Criteria PS is not inherited, so prenatal testing is not indicated. Criteria Category Clinical Characteristics (Diagnosis requires either A, Differential Diagnosis two from B, or three from C) Among the differential diagnoses for Proteus syndrome are those entities described as part of Category A Cerebriform connective tissue nevus PTEN hamartoma tumor syndrome. Bannayan- Riley-Ruvalcaba syndrome is an autosomal- Category B 1. Linear epidermal nevus dominant disorder characterized by macrocephaly, angiomatosis, lipomatosis, polyposis of the colon 2. Asymmetric, disproportionate overgrowth with at least one of and rectum, and pigmented macules of the the following: penis. These patients lack the progressive digital · Affected limbs overgrowth, skull exostoses, epidermal nevi, · Hyperostosis of the skull and palmar or plantar changes seen in Proteus · Hyperostosis of the external auditory canal syndrome. Patients with Cowden syndrome · Megaspondylodysplasia typically present with facial trichilemmomas, · Viscera: spleen or thymus acral keratoses, papillomatous lesions, lipomas, hemangiomas, and epidermal nevi (Cowden 3. Specific tumors before the second decade: nevus), but do not develop cerebriform · Bilateral ovarian cystadenoma connective-tissue nevi. These patients also · Parotid monomorphic adenoma carry an increased risk for breast, thyroid, and endometrial . Patients with Proteus-like Category C 1. Dysregulated adipose tissue with either of the following syndrome have significant clinical features of PS (either of the following): but do not meet the diagnostic criteria for PS. · Lipomatous overgrowth They are distinguished by macrocephaly, marked · Regional lipohypoplasia lipohypertrophy, and lack of progressive bony overgrowth.7 2. Vascular malformations (one of the following): In SOLAMEN (segmental overgrowth, · Capillary malformation lipomatosis, AVMs, epidermal nevus) syndrome, · Venous malformation patients display thickening of the soles and · Lymphatic malformation increased wrinkling instead of the gyri found · Lung bullae in CCTN. There is segmental proportionate overgrowth with soft-tissue and ballooning effect, as well as lymphatic 3. Facial phenotype (all of the following): 12 · Dolichocephaly and shunting arteriovenous malformations. Proteus syndrome may be distinguished from · Long face neurofibromatosis by the absence of multiple café · Down-slanting palpebral fissures au lait macules, Lisch nodules, axillary freckling, · Depressed nasal bridge and multiple . Hemihyperplasia · Wide or anteverted nares and multiple lipomatosis syndrome (HHML) is · Open mouth at rest characterized by subcutaneous lipomatosis and asymmetric overgrowth (hemihyperplasia) that is patients with PS and are most commonly seen in pulmonary insufficiency, persistent atelectasis, not as progressive as in PS.3 individuals with cognitive deficits. These include pneumonia, or even death.3 Syndromes characterized by vascular down-slanting palpebral fissures, flattening of Other manifestations include ophthalmologic malformations may also be considered in the the malar , a relative lengthening of the findings such as strabismus, epibulbar , differential diagnosis of PS. In Maffucci syndrome, face, low nasal bridge with wide nostrils, and a 3 and epibulbar dermoids (42%); otolaryngologic enchondromatosis, most commonly of the hands persistently open mouth. Our patient did not abnormalities (37%); mental deficiency (30%); and feet, with multiple cavernous hemangiomas display any of these characteristics. 3 non-cystic pulmonary disease (20%); dental are seen. This should not be difficult to Central nervous system abnormalities are seen abnormalities (19%); reproductive/genital non- distinguish from Proteus syndrome owing to the 4 in up to 40% of patients with PS. Dietrich et tumor abnormalities (18%); male reproductive lack of enchondromatosis in Proteus syndrome. al. described 12 children with PS whose CNS tumors (11%) and renal/urologic manifestations Klippel-Trenaunay syndrome is characterized by 7 abnormalities included hemimegalencephaly (9%); and hair and abnormalities. the three main features of nevus flammeus (port- (8), hypodense periventricular white matter (4), wine stain), venous and lymphatic malformations, periventricular calcification (3), corpus callosal Diagnosis and soft-tissue hypertrophy of the affected limb. abnormalities (3), atrophic brains (2), and Dandy- The diagnosis of Proteus syndrome is based on There are no CCTN seen, and overgrowth is 9 3 Walker malformation (1). Mental deficiency is clinical findings. Individuals must meet all of the present at birth and more severe than in PS. 3 seen in approximately 30% of cases. general criteria, including mosaic distribution In Parkes Weber, a mutation in the RASA1 of lesions, sporadic occurrence, and progressive While no specific hematologic abnormalities have gene leads to multiple capillary malformations, course, along with certain specific criteria as including AV fistulas that can lead to been described in association with PS, studies 3 outlined in Table 1. failure, as well as overgrowth of one limb, most have demonstrated that AKT1 and AKT2 are 3 critical regulators of long-term hematopoietic Although PS is primarily a clinical diagnosis, commonly the leg. In the differential diagnosis stem-cell function.10 It is feasible that an molecular genetic testing for the somatic of the CCTN is isolated plantar collagenoma, a hamartomatous lesion consisting of proliferation AKT1 gene mutation may underlie the chronic mutation in the AKT1 gene can be helpful to 13 macrocytosis and reticulocytopenia observed in confirm the diagnosis. This can be technically of normal collagen tissue. Collagenomas our patient. challenging because blood is not an appropriate are commonly encountered in other genetic source and tissue may show low-level mosaicism. disorders, such as Buschke-Ollendorff syndrome, Patients with PS are prone to developing several Skin scrapings from epidermal nevi in PS a rare autosomal-dominant condition, resulting types of tumors, most commonly monomorphic patients have been shown to be a good source of from nonsense mutation in the LEMD3 gene, adenomas of the parotid , ovarian mutant cells and may provide an alternate source which encodes for a potent negative regulator cystadenomas, meningiomas, and various types of 11 3 for genetic testing. It is important to note that of bone morphogenic protein and transforming testicular tumors. Cystic lung disease may cause -β signaling pathways. Recently,

Page 22 PROTEUS SYNDROME: CASE REPORT AND REVIEW a mutation in LEMD3 has been reported in with parents and children and refer for counseling Manifestations. Am J Neuroradiol. 1998;19:987– familial cutaneous collagenomas as well.14 and peer-support groups if needed.20 990. 10. Juntilla MM, Patil VD, Calamito M, Joshi Histopathology Prognosis RP, Birnbaum MJ, Koretzky GA. AKT1 and Histopathologically, cerebriform connective- Regarding progression of skin lesions, AKT2 maintain hematopoietic function tissue nevi are characterized by an irregular Beachkofsky et al. evaluated 36 patients with by regulating reactive oxygen species. Blood. 2010 proliferation of highly collagenized fibrous Proteus syndrome with serial photography for an 15 May 20;115(20):4030–4038. tissue. Biopsies of lipomatous overgrowths average of 53 months. Cerebriform connective- reveal nonencapsulated lobules and mature tissue nevi showed progression in 13 children but 11. Wieland I, Tinschert S, Zenker M. High- .16 Vascular malformations are lined by not in 3 adults. Lesions progressed by expansion level somatic mosaicism of AKT1 c.49G>A, flat endothelium, exhibiting a normal, slow rate into previously uninvolved skin, increased mutation in skin scrapings from epidermal of turnover. The flat, organoid type of epidermal thickness, and development of new lesions. nevi enables non-invasive molecular diagnosis nevus in PS shows acanthosis, hyperkeratosis, and Lipomas increased in size and/or number in 8 in patients with Proteus syndrome. Am J Med papillomatosis.16,17 out of 10 children. Epidermal nevi and vascular Genet. 2013;161A:889–891. malformations generally did not spread or 21 12. Caux F. Segmental overgrowth, lipomatosis, Management increase in number. arteriovenous malformation and epidermal The sporadic and unpredictable nature of nevus (SOLAMEN) syndrome is related to Proteus syndrome can pose a challenge for Long-term prognosis varies across patients. mosaic PTEN nullizygosity. Eur J Hum Genet. health care providers. Since PS can affect many Approximately 20% of PS patients suffer 2007;15:767-73. different parts of the body to varying degrees, premature death, most commonly due to venous or pulmonary thromboembolism, pneumonia, or a multidisciplinary approach is important in 8,22 13. Nelson A. Isolated plantar collagenoma not the management and prevention of secondary surgical complications. associated with Proteus syndrome. J Am Acad complications. Serial clinical photography with Dermatol. 2008 Mar;58(3):497-9. an initial skeletal survey and targeted follow-up Conclusion Proteus syndrome is a complex disease that can 14. McCuaig C. Connective tissue nevi in radiographs should be performed to evaluate the involve many areas of the body, especially the children: institutional experience and review. J degree of obstruction or deformation based on 18 skeletal system, connective tissue, fat, and central Am Acad of Dermatol. 2012 Nov;67(5):890-7. the patient’s medical history and physical exam. nervous system. The variable clinical presentation, 15. Cohen MM Jr. Putting a foot in one’s mouth or Other imaging recommendations include rarity of the disorder, and clinical overlap with putting a foot down: nonspecificity v. specificity of intracranial MRI to evaluate for CNS several other diseases has led to significant the connective tissue nevus in Proteus syndrome. malformations that may be associated with confusion and misdiagnosis. Molecular genetic Proc Greenwood Cent. 1995;14:11-13. developmental delay, mental retardation or testing can be performed, with the highest yield seizures. Findings may include multiple from epidermal nevi or tissue specimens. Patients 16. Nguyen D, Turner JT, Olsen C, Biesecker LG, meningiomas, polymicrogyria, and periventricular should be managed with a multidisciplinary Darling TN. Cutaneous manifestations of Proteus heterotopias.3 Abdominal MRI is recommended approach. syndrome. Arch Dermatol. 2004;140:947-953. to exclude intra-abdominal lipomas, regardless of 17. Nazzaro V, Cambiaghi S, Montagnani the presence of symptoms, due to the aggressive References A, Brusasco A, Cerri A, Caputo R. Proteus nature of these lesions. CT of the chest to 1. Cohen Jr MM, Hayden PW. A newly syndrome: ultrastructural study of linear evaluate pulmonary cystic malformations should recognized hamartomatous syndrome. Birth verrucous and depigmented nevi. J Am Acad be carried out if clinically warranted to evaluate Defects Orig Artic Ser. 1979;15:291-296. Dermatol. 1991 Aug;25:377–383. for cystic malformations.3 2. Wiedemann HR, Burgio GR, Aldenhoff P, 18. Biesecker LG. The challenges of Proteus One of the most common causes of death for Kunze J, Kaufmann HJ, Schirg E. The proteus syndrome: diagnosis and management. Eur J patients with PS, including children, is deep syndrome. Partial gigantism of the hands and/ Hum Genet. 2006 Nov;14(11):1151–1157. venous and pulmonary embolism. or feet, nevi, hemihypertrophy, subcutaneous For this reason, perioperative anticoagulant tumors, macrocephaly or other skull anomalies 19. Guidera KJ, Brinker MR, Kousseff BG, Helal is recommended.18 Chronic anticoagulation, and possible accelerated growth and visceral AA, Pugh LI, Ganey TM, Ogden JA. Overgrowth however, is not recommended, particularly since affections. Eur J Pediatr. 1983;140:5-12. management in Klippel-Trenaunay-Weber and many of these patients have underlying vascular Proteus syndromes. J Pediatr Orthop.1993 Jul- 3. Biesecker LG, Happle R, Mulliken JB, Aug;13:459–466. anomalies. Weksberg R, Graham JM Jr, Viljoen DL, Cohen Tumor surveillance is not recommended in PS MM Jr. Proteus syndrome: Diagnostic criteria, 20. Turner J, Biesecker B, Leib J, Biesecker L, patients. These patients appear to be predisposed differential diagnosis, and patient evaluation. Am Peters KF. Parenting children with Proteus to a broad range of , and it has not J Med Genet.1999;84:389–395. syndrome: Experiences with and adaptation to courtesy stigma. Am J Med Genet. been demonstrated that early detection of tumors 4. Turner JT, Cohen MM Jr, Biesecker LG. 18 2007;143A:2089–2097. in PS improves prognosis. Reassessment of the Proteus syndrome Cerebriform connective-tissue nevus (CCTN) literature: application of diagnostic criteria to 21. Beachkofsky TM, Sapp JC, Biesecker LG, is a common dermatologic overgrowth that is published cases. Am J Med Genet A. 2004 Oct Darling TN. Progressive overgrowth of the usually found at the plantar aspect of the foot. 1;130A(2):111-22. cerebriform connective tissue nevus in patients The grooves in CCTN can be difficult to clean, with proteus syndrome. J Am Acad Dermatol. 5. Lindhurst MJ, et al. A mosaic activating 2010;63:799–804. leading to the accumulation of bacteria and mutation in AKT1 associated with the proteus fungus that may cause infection and a malodor. syndrome. N Engl J Med. 2011;365:611–19. 22. Slavotinek AM, Vacha SJ, Peters KF, Biesecker CCTN can progressively increase in size, grow LG. Sudden death caused by pulmonary on previously non-involved areas of the foot and 6. Altomare DA, Testa JR. Perturbations of thromboembolism in Proteus syndrome. Clin coalesce. This can be disfiguring, painful, and the AKT signaling pathway in human cancer. Genet. 2000;58:386–9. interfere with ambulation.3 Surgical removal of Oncogene. 2005;24:7455–7464. CCTN can lead to disappointing results since 19 7. Blumenthal G. PTEN hamartoma recurrence and painful scarring is possible. tumor syndromes. Eur J Hum Genet. 2008 Correspondence: Holly Kanavy, DO; Dermatological follow-ups and the use of custom Nov;16(11):1289-300. [email protected] orthotics to manage pain, pressure ulcerations, and/or skin breakdown are preferred treatments.1,3 8. Cohen, MM. Proteus Syndrome: An Update. Because patients and their families can undergo a Am J Med Genet C Semin Med Genet. 2005 great deal of stress from this disease, clinicians are Aug 15;137C(1):38-52. encouraged to assess psychosocial issues routinely 9. Dietrich, et al. The Proteus Syndrome: CNS

KANAVY, HOFFMAN Page 23 Reactive Keratoacanthoma Responding to Excision and Healing by Secondary Intention

G. Trey Haunson, DO,* Mariana A. Phillips, MD, FAAD, FACMS,** Douglas J. Grider, MD, FCAP,*** Daniel S. Hurd, DO, FAOCD****

*Private Practice Dermatology, MetroDerm, Hiram, GA **Dermatology and Mohs Surgery, Carilion Clinic, Roanoke, VA ***Dermatopathology, Solstas Lab Partners, Roanoke, VA ****Program Director, Dermatology Residency, LewisGale Hospital Montgomery, Blacksburg, VA

Abstract (KA) are rapidly-growing tumors of uncertain etiology. KAs mimic squamous-cell carcinoma (SCC) histologically but have the capacity to regress spontaneously or, rarely, progress to metastatic SCC. KA recurrence has been noted following complete excision and destructive treatment modalities. The term “reactive KA” has been used in this setting. We report three cases of reactive KAs that responded to excision and healing with secondary intention.

Introduction While the pathogenesis of keratoacanthoma (KA) development is debated and likely multifactorial, KA formation at sites of cutaneous trauma are well-documented in the literature.1 The term “reactive KA” has been used in this setting. In reviewing the literature, the time from treatment to appearance of reactive KA ranges from two weeks to six months, with a mean of two months.1-5 Most patients are elderly, with a mean age of 80, and most reactive KAs occur on exposed areas of the extremities.1-5 We report three cases of reactive KA effectively treated with surgical excision utilizing minimal cutaneous trauma. Case 1 A 57-year-old woman with a history of numerous SCCs on the bilateral dorsal forearms presented for evaluation of two hyperkeratotic nodules on the right forearm (Figure 1A). Biopsies confirmed well-differentiated SCCs (Figure 1B). Figure 1. (A) Two hyperkeratotic nodules, right forearm. (B) Exo-endophytic crateriform atypical Both were completely excised, and the defects squamous proliferation with central keratin debris and features suggestive of arising from closed primarily. She returned five weeks later infundibular portion of . Interpreted as SCC extending to biopsy base (H&E, 2x for evaluation of hyperkeratotic plaques involving magnification). (C) Reactive KA within excision scar. (D) Re-excision with crateriform atypical both previous excision scars and a new nodule squamous proliferation with central keratin debris appearing to arise from infundibular portion of on the mid forearm. Biopsy of all three lesions hair follicle. Features typical of classic keratoacanthoma toward periphery (H&E, 2x).

Figure 2. (A) Shave with excoriation and features of with and lobules of atypical keratinocytes extending to biopsy base (H&E, 4x). (B) Lesions treated with IL bleomycin or . (C) No recurrence at follow-up.

Page 24 REACTIVE KERATOACANTHOMA RESPONDING TO EXCISION AND HEALING BY SECONDARY INTENTION Figure 3. (A) Recurrent SCC on left elbow. (B) Reactive KAs within excision scar. (C) Re-excision of squamous proliferation with histologic features suggestive of KA arising in infundibular portion of pilosebaceous unit (H&E, 2x). showed well-differentiated SCC. The largest that leg without complication. Biopsy revealed has been used in this setting. In reviewing the lesion was re-excised and closed primarily. SCC. The lesion was excised with one stage literature, the time from treatment to appearance of MMS and repaired with primary closure. She returned five weeks later for treatment of the of reactive KA ranges from two weeks to six Four months later she returned with a nodule 1-5 remaining SCCs, and a new nodule was noted in months, with a mean of two months. Most developing in the center of the scar (Figure 4A). the recent re-excision scar (Figure 1C). Reactive patients are elderly, with a mean age of 80, and Biopsy showed an invasive, well-differentiated KAs were suspected, and all three lesions on most reactive KAs occur on exposed areas of the SCC (Figure 4B). Reactive KA was suspected, 1-5 the right forearm were excised and left to heal extremities. and the lesion was excised with the defect allowed by secondary intention. Histology confirmed Distinguishing between a recurrent, incompletely to heal by secondary intention. One vein was well-differentiated SCC with clear surgical excised SCC and a reactive KA is a subject of ligated with 4-0 polyglactin 910 suture, and no margins (Figure 1D). The patient returned debate. A true recurrence would be expected electrodessication was used. There has been no four weeks later with three new hyperkeratotic to develop in the most central aspect of a scar. evidence of recurrence after six months of follow- nodules involving the remainder of the scar on Some of the lesions we encountered occurred on up. the right lower forearm. Histology revealed the lateral aspect of excision scars, which suggests excoriated atypical squamous proliferations Discussion the lesions were instead reactive in nature. (Figure 2A). All three nodules were treated Additionally, the rapid timing of recurrence The pathogenesis of KA development is with 0.2 cc intralesional bleomycin (1 unit/ supports this etiology. likely multifactorial. Genetic predisposition, cc). Additional nodules developing in previous immunosuppression, (UV) radiation, The dilemma is further compounded by saucerization scars were biopsied and found to 2,5 chemical carcinogens, and viral infections have indistinct histologic features. It is not possible represent hypertrophic scars, which were injected 1 all been implicated. KA formation at sites to distinguish reactive KAs histologically. A with IL triamcinolone (Figure 2B). The patient of thermal burns, laser resurfacing, chemical well-differentiated SCC with endophytic has shown no evidence of recurrence after four peels, skin graft donor sites, and other forms of or crateriform features mimics KA both in months of follow-up (Figure 2C). 1 cutaneous trauma has been documented. KA architecture and sometimes in cytology with Case 2 recurrence following routine surgical excision the classic description of keratinocytes at An 81-year-old man presented for re-excision occurs at a rate of 4% to 8%, though this does not the periphery exhibiting glassy eosinophilic of a recurrent SCC on the left elbow (Figure appear to denote increased malignant behavior.2,3 cytoplasm.2 However, most reactive KAs seem 3A). The lesion had been previously excised Brisk KA recurrence has been documented to have the helpful feature of being associated three times over an eight-month period. The following histologically confirmed complete with the infundibular portion of one or more SCC was removed with two stages of Mohs excision and MMS.4 The term “reactive KA” hair follicles.2 KAs are thought to arise from micrographic surgery (MMS), and the defect was closed primarily. The patient returned four weeks later with two hyperkeratotic nodules within the excision scar (Figure 3B). Biopsy revealed a squamous proliferation with features of KA (Figure 3C). Reactive KA was suspected, and the nodules were excised utilizing minimal electrocautery and the defect left to heal by secondary intention. There has been no evidence of recurrence after 18 months of follow-up. Case 3 A 76-year-old woman presented with a rapidly- Figure 4. (A) Reactive KA within excision scar. (B) Re-excision with shallow overlying invasive enlarging nodule on the left upper pre-tibia. She SCC associated with fibrosing consistent with prior biopsy site (H&E, 4x). had a history of two previous SCCs excised from

HAUNSON, PHILLIPS, GRIDER, HURD Page 25 follicular infundibula in hair-bearing (most often Correspondence: G. Trey Haunson, DO; exposed) skin.2 It is also possible that although [email protected] the natural history of a KA results in spontaneous involution, a bona fide SCC might arise within a lesion of KA.3 It has been proposed that surgical trauma, including the use of electrodessication and placement of sutures, can contribute to the formation of reactive KAs, possibly representing a form of .5 Minimizing surgical trauma led to resolution of several recrudescent reactive KAs in our case series. Needle puncture sites should also be minimized during anesthesia administration.5 We report one patient who developed several lesions that responded to IL bleomycin. Intralesional 5-FU and methotrexate are other non-surgical treatment modalities that have been reported to be successful for reactive KAs.2 Systemic retinoids such as acitretin have also been effective in maintaining lesion clearance.2,3 Destructive modalities such as electrodessication and curettage (ED&C) and external beam radiation have been associated with worsening of the condition.2 Conclusion Early recognition of the reactive KA phenomenon is important in order to prevent and morbidity to the patient. In our series, the reactive KAs were excised, and particular effort was made to minimize electrodessication and suture placement. This approach was effective for all lesions treated. References 1. Pattee SF, Silvis NG. Keratoacanthoma developing in sites of previous trauma: a report of two cases and review of the literature. J Am Acad Dermatol. 2003;48:S35-8. 2. Hadley JC, Tristani-Firouzi P, Florell SF, Bowen GM, et al. Case series of multiple recurrent reactive keratoacanthomas developing at surgical margins. Dermatol Surg. 2009;35:2019-24. 3. Schwartz RA. Keratoacanthoma: A clinico- pathologic enigma. Dermatol Surg. 2004;30:326- 33. 4. Goldberg LH, Silapunt S, Beyrau KK, et al. Keratoacanthoma as a postoperative complication of excision. J Am Acad Dermatol. 2004;50:753-8. 5. Chesnut GT, Maggio KL, Turiansky GW. RE: Case series of multiple recurrent reactive keratoacanthomas developing at surgical margins. Dermatol Surg. 2011;37:884-5.

Page 26 A CASE OF CUTANEOUS ROSAI-DORFMAN DISEASE A Case of Cutaneous Rosai-Dorfman Disease

Donna Tran, DO,* Gabriel Guerrero, DO,** Paul Shitabata, MD,*** Navid Nami, DO****

*Dermatology Resident, PGY3, Western University of Health Sciences, College Medical Center, Long Beach, CA **Intern, College Medical Center, Long Beach, CA ***Director of Dermatopathology, Western University of Health Sciences, Torrance, CA ****Program Director, Dermatology Residency Program, Western University of Health Sciences, College Medical Center, Long Beach, CA

Abstract Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy (SHML), is a benign, self-limiting disease of histiocytes with unknown etiology. RDD typically presents in the first or second decade of life with massive, painless cervical lymphadenopathy. Cutaneous RDD is a rare, extra-nodal variant that is strictly limited to the skin. In both forms, the histiocytes stain positive for S-100 protein and negative for CD1a. Herein, we describe a rare case of cutaneous RDD presenting on the face and trunk of a 79-year-old man and review the literature on systemic RDD and its rare cutaneous variant.

Introduction Erythrocyte sedimentation rate was slightly groups, in women, and in non-black ethnic Systemic Rosai-Dorfman disease (S-RDD), elevated at 21 mm/hr. groups, in contrast to the systemic form, which affects children and young adults in the first or also known as sinus histiocytosis with massive A of two lesions was performed, and second decade of life.1,2,4-6 lymphadenopathy (SHML), is a non-Langerhans histopathological examination revealed a diffuse, cell histiocytosis first recognized as a distinct predominantly histiocytic dermal infiltrate with The etiology of S-RDD and C-RDD remains clinicopathologic entity by Rosai and Dorfman in a background of small lymphocytes, neutrophils, unclear, and a debate between infection, immune 1 2,4,9 1969. It commonly presents as bilateral, painless and scattered plasma cells (Figure 2). A number dysregulation, and neoplasia remains. To date, cervical lymphadenopathy with fever, leukocytosis, of histiocytes showed emperipolesis (Figure 3). many infectious agents, including Epstein-Barr , elevated erythrocyte sedimentation rate, Immunohistochemical staining was positive for virus, , Brucella, Klebsiella 1,2 and polyclonal hypergammaglobulinemia. S-100 protein (Figure 4) and CD68, and negative rhinoscleroma and many others, have been 2 Although less common, other lymph nodes may for CD1a. Based upon clinicopathological reported in association with RDD. In addition, 2 be involved. Lymphadenopathy with extranodal correlation, a diagnosis of cutaneous Rosai- autoimmune diseases such as systemic disease may occur in up to 43% of patients and erythematosus, rheumatoid arthritis, and thyroid Dorfman disease was made, and the patient 4,5 includes sites on the skin, soft tissues, eyes, was referred to oncology for workup of systemic disease have been associated with RDD. respiratory tract, liver, spleen, testes, skeleton and involvement. Histopathologically, systemic and cutaneous 2,3 nervous system. Purely extranodal cutaneous RDD are indistinguishable. The main microscopic disease without lymph node involvement is rare. Discussion findings include proliferation of large polygonal Herein, we describe a rare case of cutaneous S-RDD, or sinus histiocytosis with massive and palely eosinophilic histiocytes with variable RDD without lymph node involvement in a lymphadenopathy, is a rare disorder characterized amounts of a mixed, but predominantly chronic, 79-year-old man. by a proliferation of non- inflammatory infiltrate. Emperipolesis is often histiocytes in the lymph node. It may have present, which is the intracytoplasmic inclusion extranodal involvement, the skin being the most of inflammatory cells including lymphocytes, Case Report 2,4,6-8 A 79-year-old male with no significant past common site. RDD limited to the skin without plasma cells, and neutrophils within vacuoles. The cells are also characterized by round or oval medical history presented to our dermatology nodal involvement, or cutaneous Rosai-Dorfman 2,4,6-8 clinic with multiple, asymptomatic lesions on his disease (C-RDD), is even rarer, with only 85 vesicular nuclei. The pattern of the infiltrate 4,5 face and trunk of two years’ duration. Physical cases having been described. Contrary to the in cutaneous layers is usually nodular and diffuse but may be patchy or interstitial and correlates examination revealed violaceous papules and systemic form, C-RDD generally has no systemic 6-8 4,5 nodules on his cheek, chest and upper back involvement or laboratory abnormalities. with the clinical presentation. The infiltrate is (Figures 1a - 1c). No other lesions were noted, mostly confined to the dermis but may have some Clinically, the cutaneous lesions are similar in subcutis involvement or be confined to only the and no lymphadenopathy was appreciated. He both S-RDD and C-RDD. The lesions are often subcutis.4,6-8 Epidermal changes are usually absent denied any history of fever, weight loss, night slow-growing, asymptomatic papules and nodules or mild.4,6,8 The histiocytes stain positive for sweats, or malaise. His complete blood cell count, with yellow to red, brown, or violaceous color, S-100 protein and negative for CD1a, unlike the complete metabolic panel, antinuclear antibody, varying in size from less than 1 cm to 30 cm.4-6,8 4,5 Langerhans cells, which statin positive for both serum protein electrophoresis, and urine protein 4,6,8 The lesions may be localized or disseminated. markers. electrophoresis were all within normal limits. C-RDD tends to occur in slightly older age

1a 1b 1c

Figures 1a - 1c: Violaceous papulonodular lesions on the left cheek, chest, and back.

TRAN, GUERRERO, SHITABATA, NAMI Page 27 or indirectly from the disease. Due to S-RDD RF. The cutaneous manifestations of sinus having lesions in any system, complications histiocytosis with massive lymphadenopathy. are more common with S-RDD than C-RDD. Arch of Dermatol. 1978;114:191-97. Treatment of RDD is based on anecdotal reports, and several therapies have been utilized with variable rates of success, including glucocorticoids Correspondence: Donna Tran, DO; and chemotherapy for S-RDD. [email protected] C-RDD is benign and usually self-limited. Documented treatments of C-RDD include surgical excision, glucocorticoids, antibiotics, cryotherapy, radiotherapy, thalidomide, isotretinoin, acitretin, interferon-alpha, dapsone, methotrexate, and pulsed , with surgery yielding the highest success rates.4,5 Conclusion Due to the rarity of C-RDD, insufficient data and Figure 2. Diffuse dermal infiltrate with studies of small sample sizes fail to clarify whether histiocytic predominance; background of small C-RDD is a specific subset of S-RDD, a separate lymphocytes, neutrophils, and scattered plasma entity, or if the two are part of a spectrum. The cells (H&E, 20x). pathogenesis of RDD remains largely unknown. Although studies do not support progression of C-RDD to S-RDD, long-term follow-up is nonetheless recommended to rule out systemic involvement and associated autoimmune and neoplastic diseases 4-7 Our patient had only skin involvement with no adenopathy or systemic involvement. His lesions were controlled with topical mid-potency glucocorticoid. References 1. Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy: a newly recognized benign clinicopathologic entity. Arch Pathol. 1969;87:63-70. 2. Foucar E, Rosai J, Dorfman R. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): review of the entity. Semin Diagn Pathol. 1990;7:19-73. Figure 3. Histiocytes with large cytoplasm 3. Thawerani H, Sanchez RL, Rosai J, Dorfman presenting emperipolesis (H&E, 60x). RF. The cutaneous manifestations of sinus histiocytosis with massive lymphadenopathy. Arch of Dermatol. 1978;114:191-97. 4. Brenn T, Calonje E, Granter S, et al. Cutaneous Rosai-Dorfman disease if a distinct clinical entity. Am J Dermatopathol. 2002;24(5):385-391. 5. Frater JL, Maddox JS, Obadiah JM, Hurley MY. Cutaneous Rosai-Dorfman disease: comprehensive review of cases reported in the medical literature since 1990 and presentation of an illustrative case. J Cutan Med Surg. 2006;10(6):281-90. 6. Wang KH, Chen WY, Liu HN, Huang CC, Lee WR, Hu CH. Cutaneous Rosai-Dorfman disease: clinicopathological profiles, spectrum and evolution of 21 lesions in six patients. Br J Dermatol. 2006 Feb;154(2):277-86. 7. Chu P, LeBoit P. Histologic features of cutaneous Figure 4. Immunohistochemistry staining sinus histiocytosis (Rosai-Dorfman disease): positive for in the histiocytic cell study of cases both with and without systemic (60x). involvement. J Cutan Pathol. 1992;19:201-06. 8. Lu C, Kuo T, Wong W, Hong H. Clinical and Both S-RDD and C-RDD generally have a benign histopathologic spectrum of cutaneous Rosai- course with spontaneous regression over a period Dorfman disease in Taiwan. J Am Acad Dermatol. of months to years, although a small number of 2004;51(6):931-9. patients may have significant morbidity, directly 9. Thawerani H, Sanchez RL, Rosai J, Dorfman Page 28 A CASE OF CUTANEOUS ROSAI-DORFMAN DISEASE Pathogenesis of Pruritic Disorders and Mechanisms of Phototherapy

Soham Chaudhari, BA,* Argentina Leon, MD,** Ethan Levin, MD,** Om Chaudhari,*** John Koo, MD****

*Osteopathic Medical Student, 4th year, Touro University Nevada, Osteopathic College of Medicine, Henderson, NV **Research Fellow, Department of Dermatology, University of California, San Francisco, CA ***University of Nevada Las Vegas, College of Sciences, Honors College, Las Vegas, NV ****Professor and Vice Chairman, Department of Dermatology; Director, Psoriasis Treatment Center, University of California, San Francisco, CA

Abstract Phototherapy is an efficacious method for managing many cutaneous conditions. Although psoriasis is the most commonly treated condition, phototherapy also has a role in the management of pruritic disorders, including (AD), nodularis (PN), and (UP). We have reviewed the pathogenesis of pruritus and the mechanism of action of phototherapy in treating pruritic disorders. AD is an inflammatory skin condition with an induction of pruritus due to cytokines released by CD4-positive-T helper (Th) 2 cells. Langerhans cells, T cells, proinflammatory cytokines, and keratinocytes are decreased in AD patients treated with phototherapy. PN has an increase in mast cells and neuropeptides that mediate pruritus. UV light decreases the release of these neuropeptides and alleviates pruritus in PN. Finally, UP causes a microinflammatory state with changes in cutaneous nociceptive endings. A circulating substance responsible for pruritus in UP is annihilated through the apoptotic actions of phototherapy.

Introduction their entire spectrum. Narrowband UVB (NB- Discussion Pruritus is the number one symptom presented UVB) uses 311-313 nm, and UVA1 uses 340- Pathogenesis of : Localized itch involves to any dermatology practice.1 The physical 400 nm with a peak at 365 nm. UVA1 can be alpha-delta fibers, whereas diffuse, generalized and psychological distress caused by chronic administered at high dose (HD-UVA1) (130 J/ itch is transmitted through dermal unmyelinated cm2), medium dose (MD-UVA1) (50 J/cm2), and pruritus has a significant impact on quality 2 c-fibers. Both of these nociceptive fibers travel of life for patients. Because topical therapy is low dose (LD-UVA1) (20 J/cm ). Monochromic to the dorsal horn of the spinal cord, which is often inadequate in controlling pruritus, other excimer laser (MEL) (308nm) is a more targeted then processed by the cerebral cortex through treatments are needed. Phototherapy can alleviate phototherapy device that delivers 308 nm UVB to the spinothalamic tract.3 They have a slow the constant sensation of itch without many of a localized area and can expand treatment options conduction velocity and innervate large areas the adverse effects of systemic medications. In by sparing unaffected areas. Both cutaneous and of the skin.4 Dry skin and disruption of the addition, it is safe and can be utilized in all age systemic diseases can present with pruritus as skin barrier can induce keratinocytes to release categories.2 UVB (290-320 nm) and UVA (320- the primary symptom. This article summarizes pruritogenic substances.5 Nerve fibers typically 400 nm) are implemented in UV-based therapy. the pathogenesis of pruritic disorders including end at the dermal-epidermal junction, although Broadband UVB (BB-UVB) and broadband AD, PN, and UP and the mechanism of action of some project into the epidermis.6 Itch receptors, UVA (BB-UVA) use a light source covering phototherapy in each of these (Table 1). formed mostly by keratinocytes, respond to

Figure 1. Pruritus

CHAUDHARI, LEON, LEVIN, CHAUDHARI, KOO Page 29 pruritogens such as histamine, proteases, growth of eczematous lesions is a Th2-driven response, interfere with ceramide metabolism, as cytolytic factors, neuropeptides, cytokines, and opioids chronic lesions demonstrate a greater level of Th1 alpha toxin causes damage and (Figure 1).7,8 They are found only in skin, mucus activity.18 Acute and chronic AD lesions contain superantigenic toxin causes release of TNF- membranes, and cornea.9 Substance P (SubP) more mRNA expression for IL-4, IL-5, and alpha and Beta-hemolysin, which interfere with and calcitonin gene-related peptide (CGRP) are IL-13 than normal skin. The mRNA expression ceramide metabolism.34 These toxins also prevent the most studied neurotransmitters and have both of IFN-gamma, however, is similar to that of keratinocytes from producing antimicrobial central and peripheral activity.10,11 Allokinesis, normal skin.20,30 Chronic lesions express more peptides to kill S. aureus.35 the perception of non-pruritic stimuli as pruritic, IL-5, IL-12 and anti-eosinophil cationic protein Mechanism of Action for Phototherapy in AD: is due to central sensitization. This explains the (ECP) antibody eosinophils than acute lesions. Many studies have demonstrated the beneficial intense pruritus AD patients experience in Thus, IL-12 may be important in the transition effects of phototherapy in treating AD.36 The response to sweat or sudden changes in ambient from acute to chronic lesions. The predominance intralesional mRNA expression of IFN-gamma temperature. of Th2 cytokines in the acute phase, such as was successfully downregulated during the course Mast cells produce two proteinases, tryptase and IL-4 and IL-5, stimulates eosinophils, which of UVA1 therapy, whereas IL-4 mRNA expression chymase. Tryptase activates C fibers and thus produce IL-12, thereby activating Th1 cells and remained relatively unchanged even after those stimulates the sensation of itch. It also triggers the undifferentiated T cells to produce IFN-gamma, with chronic AD improved under treatment.37,38 release of SubP, which not only causes pruritus causing a negative feedback on Th2 responses The high efficacy of UVA1 phototherapy in and maintaining the AD lesion over an extended but also evokes further mast-cell activation. 19 the treatment of AD can be attributed to the Increased levels of tryptase have been observed in period (Figure 2). patients with UP.12 The sensations of pain and itch are carried by different C-fibers. Frequency of the stimulus can modulate the magnitude of itch but does not change the quality of itch into pain. Histamine- induced itch activates some motor areas, suggesting a neuronal association between itch and scratching.13 Scratching and vibration are transmitted by larger A-beta fibers that inhibit itch signals on the slower C-fibers.14 While pain causes one to avoid a motor response, itch causes a stimulatory motor response. Painful stimuli can inhibit itch, as observed in pruritic patients who only stop scratching once skin lesions begin and become painful. Itch and pain share the same cortical brain areas but have different patterns of activation: Itch has a weaker activation of somatosensory cortices and a stronger activation of ipsilateral motor areas as compared with pain processing.15,16

ATOPIC DERMATITIS (AD) Pathogenesis of AD: The pathogenesis of AD is a complex interplay between several different cell types and factors. CD-4 positive Th2 cells have been found to play a major role in pruritus induction by producing and releasing cytokines and chemokines.17 Localization Figure 2. Atopic dermatitis to the skin in AD is due to the presence of a skin-homing receptor on memory effector T lymphocytes, called “cutaneous lymphocyte- The is the permeability barrier combination of UV-light induced apoptosis associated antigen,” which interacts with the between the body and the external environment, of T lymphocytes as well as the reduction of vascular endothelial cell-surface antigens to direct and thus when it is impaired, increased Langerhans cells and mast cells in the dermis.39 circulating T lymphocytes to the reactive skin transepidermal water loss causes xerosis and Preventing Langerhans cells and mast cells 18 site. Th1 cells initiated by IL-12 predominantly intense pruritus.31 The barrier is compromised from exiting the epidermis results in a decreased secrete IL-2 and interferon-gamma (IFN- due to an overexpression of an enzyme that number of Ig-E binding cells in the dermis.40 gamma), whereas Th2 cells are activated by IL- hydrolyzes sphingomyelin, producing free fatty Phototherapy induces the immunosuppressive 19- 10 to produce mainly IL-4, IL-5, and IL-13. acid and sphingosylphosphorylcholine, an mechanisms of the body, such as suppressing the 24 Atopic disorders such as eczema have been inducer of keratinocyte proliferation and up- antigen-presenting function of Langerhans cells, associated with a hyper Th2 response, as they regulator of plasminogen activator, resulting in inducing apoptosis in infiltrating T cells, causing signal B lymphocytes to produce IgE, stimulate decreased ceramides.32 Additionally, scratching DNA damage, and halting the rapid accumulation eosinophils and mast cells, and cause type 1 from pruritus induces trauma and further of epidermal keratinocytes.41-43 Colonization by 25-27 hypersensitivity reactions. Environmental insult to an already compromised stratum Staphylococcus aureus and Pityrosporum orbiculare 28 factors may enhance Th2 allergic response. AD corneum, which triggers keratinocytes to release is decreased through the use of UV radiation.44,45 patients commonly have a higher Staphylococcus proinflammatory cytokines. It is also because UV light also increases the thickness of the aureus burden than the general population, and of this defective barrier that microorganisms stratum corneum and therefore results in the Th2 cytokines of AD augment the toxicity such as S. aureus enter and colonize eczematous smaller eczematous reactions due to a decreased 29 of the lytic staphylococcal protein alpha toxin. skin.33 Toxins released by microbes further penetration of antigens.46 Thus, UV light exerts It has been shown that, although the initiation Page 30 PATHOGENESIS OF PRURITIC DISORDERS AND MECHANISMS OF PHOTOTHERAPY Figure 4. Uremic pruritus

UREMIC PRURITUS (UP) Pathogenesis of UP and Mechanism of Action for Phototherapy in UP: Although the pathogenesis of UP is not completely understood, it is known to present with dystrophic neurotrophic changes in cutaneous nociceptor nerve endings, with a “microinflammatory” state Figure 3. of increased Th1 markers, chemokines, and interleukin-6 (IL-6).71,72 It also causes calcium- its beneficial effects through a multitude of release NGF and contribute to neurohyperplasia 53 phosphate imbalance, hyperparathyroidism, mechanisms. Although AD is the primary disease of PN. Dermal Langerhans cells are increased anemia, increased serum histamine levels, and explained above, a similar mechanism of action in PN, suggesting their involvement in the peripheral neuropathy.73,74 for UV-based therapy can be applied to PN and development or persistence of PN.57 In addition, LSC owing to their similar inflammatory nature. the numbers of Merkel cells are increased in PN at the basal cell layer, explaining the abnormal UVB therapy is beneficial for patients with PRURIGO NODULARIS (PN) sensitivity to touch from these slowly adapting UP. Possible mechanisms include reduction in 58 Pathogenesis of PN: A background of atopic sensory touch receptors. skin divalent-ion content, reduction in Vitamin diathesis has been suggested for PN after Mechanism of Action for Phototherapy in A and retinol content, stabilization of or examining the history of AD, allergic rhinitis, PN: UV light hinders rapid epidermal cell reduction in number of mast cells, detoxification and bronchial asthma.47,48 Tanaka et al. found turnover and thereby leads to a reduction in of undetermined pruritogenic substances, PN patients with an atopic background to pseudoepitheliomatous hyperplasia of the photoactivation of antipruritogenic substances, develop the disease at a younger age and display epidermis.59 PN patients have an increase in the and changes in the excitability of epidermal nerve a hypersensitivity reaction pattern similar to that number of nerve fibers in the papillary dermis.60 endings. Mast-cell proliferation, degranulation, and subsequent histamine release plays a role in observed in AD, suggesting a close pathological These nerve fibers demonstrate immunoreactivity 49 uremic pruritus (Figure 4). Histamine secretion link between the two disorders. The typical for SubP and CGRP and thus mediate the 76 PN nodule is secondary to traumatization. cutaneous neurogenic inflammation and pruritus is evoked by an increased release of SubP. NB- Histopathologically, PN has an increased in PN. It is postulated that MEL modulates UVB induces apoptosis of dermal mast cells 61-63 and reduces the release of neuropeptides such as downward projection of the epidermis, suggesting the release of these neuropeptides. The 66,77 pseudoepitheliomatous hyperplasia. Skin biopsies long remission noted for MEL could be due SubP by decreasing epidermal nerve fibers. of PN reveal an increase in the number of mast to inhibition of neuropeptide releases, which Nitric oxide and IL-2 have also been implicated in the pathogenesis of uremic pruritus, both of cells in both the epidermis and the dermis, with cause pruritus and can consequently perpetuate 76,78-80 some invasion into the cutaneous nerve-fiber the rubbing, scratching, and picking cycle. which are decreased by NB-UVB. Schultz bundles.50,51 Mast cells are known to release MEL treatment causes a depletion of T cells et al. suggest the response to UVB indicates a nerve growth factor (NGF) and are seen in and alterations of apoptosis-related molecules, deposition of some substance in the skin that proximity to nerves expressing increased levels along with a decreased proliferation index of is degraded or inactivated by the light. Because of NGF receptor (NGFr) (Figure 3).52,53 Thus, keratinocytes.64 PUVA downregulates CGRP uremic patients respond to cholestyramine, and the overexpression of NGF in PN explains the and Th2 cytokines and depletes epidermal phototherapy serves to clear bilirubin in jaundiced 65-67 premature infants, bile salts were considered to be neurohyperplasia, which subsequently explains the dendritic cells. The longer wavelengths used 81 strong itch secondary to increased axon firing.54 in PUVA penetrate the acanthotic thick epidermis involved in UP pathogenesis. Individuals with The mast cells in PN lesions also demonstrate more fully than classical NB-UVB.63,67-69 UVB advanced CRF had higher levels of serum total morphological changes, such as enlarged cell irradiation inhibits mast-cell granule release.70 bile acids when compared to controls, and those bodies with a dendritic shape as compared to Thus, phototherapy is successful in combating with pruritus had higher levels of bile acids than 52,55,56 those without pruritus. Thus, the intensity of the round shape seen in normal skin. Thus, itch in PN because it reduces the number of 82 neuropeptides and histamine from mast cells epidermal nerve fibers.66 pruritus correlated with bile acid concentration. Certain bile acids also cause cytotoxicity to cooperatively generate neurogenic inflammation 83 to induce and transmit itch. Eosinophils can also mastocytes, thereby releasing histamine.

CHAUDHARI, LEON, LEVIN, CHAUDHARI, KOO Page 31 Table 1: Comparison of Mechanism of Action of Phototherapy in Pruritic Disorders 2006;10(5):473-8. 16. Drzezga A, Darsow U, Treede RD, Siebner Disease Type of Phototherapy Mechanism of Action H, Frisch M, Munz F, et al. Central activation by Atopic Dermatitis UVA1 ↓IFN – gamma histamine-induced itch: analogies to pain processing: ↓T cells a correlational analysis of O-15 H2O positron emission tomography studies. Pain. 2001;92(1- ↓Langerhans cells 2):295-305. ↓Mast cells 17. Homey B, Steinhoff M, Ruzicka T, Leung DY. ↓IgE binding Cytokines and chemokines orchestrate atopic skin inflammation. J Allergy Clin Immunol. ↓colonization by Staphylococcus aureus 2006;118(1):178-89. and Pityrosporum orbiculare 18. Leung DY. Atopic dermatitis: new insights and ↑Stratum corneum thickness opportunities for therapeutic intervention. J Allergy Clin Immunol. 2000;105(5):860-76. ↓epidermal cell turnover Prurigo Nodularis MEL 19. Grewe M, Bruijnzeel-Koomen CA, Schopf ↓neuropeptide release E, Thepen T, Langeveld-Wildschut AG, Ruzicka ↓T cells T, et al. A role for Th1 and Th2 cells in the immunopathogenesis of atopic dermatitis. Immunol PUVA ↓CGRP Today. 1998;19(8):359-61. ↓Th2 cytokines 20. Hamid Q, Naseer T, Minshall EM, Song YL, ↓Dendritic cells Boguniewicz M, Leung DY. In vivo expression of IL-12 and IL-13 in atopic dermatitis. J Allergy Clin UVB ↓Mast-cell granule release Immunol. 1996;98(1):225-31. Uremic Pruritus UVB ↓Skin-divalent ions 21. Sonkoly E, Muller A, Lauerma AI, Pivarcsi A, Soto H, Kemeny L, et al. IL-31: a new link between ↓Vitamin A and Retinols T cells and pruritus in atopic skin inflammation. J ↓Mast cells Allergy Clin Immunol. 2006;117(2):411-7. ↓SubP 22. Neis MM, Peters B, Dreuw A, Wenzel J, Bieber T, Mauch C, et al. Enhanced expression levels of ↓Nitric oxide IL-31 correlate with IL-4 and IL-13 in atopic and ↓IL-2 allergic . J Allergy Clin Immunol. 2006;118(4):930-7. ↑Antipruritogenic substances 23. Nomura I, Goleva E, Howell MD, Hamid QA, Ong PY, Hall CF, et al. Cytokine milieu of atopic in pruritus research: scratching the brain for more dermatitis, as compared to psoriasis, skin prevents Conclusion effective itch therapy. J Clin Invest. 2006;116(5):1174- induction of innate immune response . J The mechanisms of action for phototherapy 86. Immunol. 2003;171(6):3262-9. in each of the discussed pruritic disorders are unique and dependent on the pathophysiology 7. Inoue K, Koizumi S, Fuziwara S, Denda S, Inoue K, 24. Jeong CW, Ahn KS, Rho NK, Park YD, Lee DY, Lee JH, et al. Differential in vivo cytokine mRNA of the disease. Phototherapy decreases pruritus in Denda M. Functional vanilloid receptors in cultured expression in lesional skin of intrinsic vs. extrinsic AD, PN, and UP through its apoptotic and anti- normal human epidermal keratinocytes. Biochem Biophys Res Commun. 2002;291(1):124-9. atopic dermatitis patients using semiquantitative RT- inflammatory actions and is therefore a useful PCR. Clin Exp Allergy. 2003;33(12):1717-24. therapeutic modality for these disorders. Due to 8. Heymann WR. Itch. J Am Acad Dermatol. the similarity in mechanisms of these diseases, 2006;54(4):705-6. 25. Knoell KA, Greer KE. Atopic dermatitis. Pediatr Rev. 1999;20(2):46-51; quiz 2. there is sufficient evidence to support the use of 9. Denman ST. A review of pruritus. J Am Acad various forms of UV-based treatment for reducing Dermatol. 1986;14(3):375-92. 26. Friedmann PS. The pathogenesis of atopic eczema. Hosp Med. 2002;63(11):653-6. pruritus and its associated manifestations. 10. Steinhoff M, Stander S, Seeliger S, Ansel JC, Schmelz M, Luger T. Modern aspects of cutaneous 27. Jelinek DF. Regulation of B lymphocyte References neurogenic inflammation. Arch Dermatol.differentiation. Ann Allergy Asthma Immunol. 1. Charlesworth EN, Beltrani VS. Pruritic 2003;139(11):1479-88. 2000;84(4):375-85; quiz 85-7. dermatoses: overview of etiology and therapy. Am J 11. Steinhoff M, Vergnolle N, Young SH, Tognetto M, 28. Leung DY, Bieber T. Atopic dermatitis. Lancet. Med. 2002;113 Suppl 9A:25S-33S. Amadesi S, Ennes HS, et al. Agonists of proteinase- 2003;361(9352):151-60. 2. Veith W, Deleo V, Silverberg N. Medical activated receptor 2 induce inflammation by a 29. Travers JB. Toxic interaction between Th2 phototherapy in childhood skin diseases. Minerva neurogenic mechanism. Nat Med. 2000;6(2):151-8. cytokines and Staphylococcus aureus in atopic Pediatr. 2011;63(4):327-33. 12. Dugas-Breit S, Schopf P, Dugas M, Schiffl H, dermatitis. J Invest Dermatol. 2014;134(8):2069-71. 3. Andrew D, Craig AD. Spinothalamic lamina I Rueff F, Przybilla B. Baseline serum levels of mast 30. Hamid Q, Boguniewicz M, Leung DY. neurons selectively sensitive to histamine: a central cell tryptase are raised in hemodialysis patients and Differential in situ cytokine gene expression in neural pathway for itch. Nat Neurosci. 2001;4(1):72- associated with severity of pruritus. J Dtsch Dermatol acute versus chronic atopic dermatitis. J Clin Invest. 7. Ges. 2005;3(5):343-7. 1994;94(2):870-6. 4. Schmelz M, Schmidt R, Bickel A, Handwerker 13. Valet M, Pfab F, Sprenger T, Woller A, Zimmer 31. Werner Y. The water content of the stratum HO, Torebjork HE. Specific C-receptors for itch in C, Behrendt H, et al. Cerebral processing of corneum in patients with atopic dermatitis. . J Neurosci. 1997;17(20):8003-8. histamine-induced itch using short-term alternating Measurement with the Corneometer CM 420. Acta temperature modulation--an FMRI study. J Invest Derm Venereol. 1986;66(4):281-4. 5. Denda M, Nakatani M, Ikeyama K, Tsutsumi M, Dermatol. 2008;128(2):426-33. Denda S. Epidermal keratinocytes as the forefront of 32. Hara J, Higuchi K, Okamoto R, Kawashima the sensory system. Exp Dermatol. 2007;16(3):157- 14. Melzack R, Schecter B. Itch and Vibration. M, Imokawa G. High-expression of sphingomyelin 61. Science. 1965;147(3661):1047-8. deacylase is an important determinant of ceramide 6. Paus R, Schmelz M, Biro T, Steinhoff M. Frontiers 15. Stander S, Schmelz M. Chronic itch and deficiency leading to barrier disruption in atopic pain--similarities and differences. Eur J Pain. dermatitis. J Invest Dermatol. 2000;115(3):406-13.

Page 32 PATHOGENESIS OF PRURITIC DISORDERS AND MECHANISMS OF PHOTOTHERAPY 33. Cho SH, Strickland I, Tomkinson A, Fehringer invasion of peripheral nerve in skin lesions of atopic 69. Tamagawa-Mineoka R, Katoh N, Ueda AP, Gelfand EW, Leung DY. Preferential binding of dermatitis. Acta Derm Venereol Suppl (Stockh). E, Kishimoto S. Narrow-band ultraviolet B Staphylococcus aureus to skin sites of Th2-mediated 1992;176:74-6. phototherapy in patients with recalcitrant nodular inflammation in a murine model. J Invest Dermatol. prurigo. J Dermatol. 2007;34(10):691-5. 52. Liang Y, Marcusson JA, Jacobi HH, Haak- 2001;116(5):658-63. Frendscho M, Johansson O. Histamine-containing 70. Danno K, Toda K, Horio T. Ultraviolet-B 34. Esche C, de Benedetto A, Beck LA. Keratinocytes mast cells and their relationship to NGFr- radiation suppresses degranulation in atopic dermatitis: inflammatory signals. Curr immunoreactive nerves in prurigo nodularis: a induced by compound 48/80. J Invest Dermatol. Allergy Asthma Rep. 2004;4(4):276-84. reappraisal. J Cutan Pathol. 1998;25(4):189-98. 1986;87(6):775-8. 35. Ong PY, Ohtake T, Brandt C, Strickland 53. Johansson O, Liang Y, Emtestam L. Increased 71. Fantini F, Baraldi A, Sevignani C, Spattini I, Boguniewicz M, Ganz T, et al. Endogenous nerve growth factor- and tyrosine kinase A-like A, Pincelli C, Giannetti A. Cutaneous antimicrobial peptides and skin infections in atopic immunoreactivities in prurigo nodularis skin -- an innervation in chronic renal failure patients. An dermatitis. N Engl J Med. 2002;347(15):1151-60. exploration of the cause of neurohyperplasia. Arch immunohistochemical study. Acta Derm Venereol. Dermatol Res. 2002;293(12):614-9. 1992;72(2):102-5. 36. Gambichler T. Management of atopic dermatitis using photo(chemo)therapy. Arch Dermatol Res. 54. Liang Y, Marcusson JA, Johansson O. Light 72. Kimmel M, Alscher DM, Dunst R, Braun 2009;301(3):197-203. and electron microscopic immunohistochemical N, Machleidt C, Kiefer T, et al. The role of micro- observations of p75 nerve growth factor receptor- inflammation in the pathogenesis of uraemic pruritus 37. Grewe M, Gyufko K, Schopf E, Krutmann J. immunoreactive dermal nerves in prurigo nodularis. in haemodialysis patients. Nephrol Dial Transplant. Lesional expression of interferon-gamma in atopic Arch Dermatol Res. 1999;291(1):14-21. 2006;21(3):749-55. eczema. Lancet. 1994;343(8888):25-6. 55. Perez GL, Peters MS, Reda AM, Butterfield JH, 73. Narita I, Iguchi S, Omori K, Gejyo F. Uremic 38. Krutmann J. Ultraviolet A-1 irradiation as a Peterson EA, Leiferman KM. Mast cells, neutrophils, pruritus in chronic hemodialysis patients. J Nephrol. tool to study the pathogenesis of atopic dermatitis. and eosinophils in prurigo nodularis. Arch Dermatol. 2008;21(2):161-5. Methods Enzymol. 2000;319:296-302. 1993;129(7):861-5. 74. Patel TS, Freedman BI, Yosipovitch G. An update 39. Dawe RS. Ultraviolet A1 phototherapy. Br J 56. Liang Y, Jacobi HH, Marcusson JA, Haak- on pruritus associated with CKD. Am J Kidney Dis. Dermatol. 2003;148(4):626-37. Frendscho M, Johansson O. Dendritic mast 2007;50(1):11-20. 40. Grabbe J, Welker P, Humke S, Grewe M, Schopf cells in prurigo nodularis skin. Eur J Dermatol. 75. Szepietowski JC, Schwartz RA. Uremic pruritus. E, Henz BM, et al. High-dose ultraviolet A1 (UVA1), 1999;9(4):297-9. Int J Dermatol. 1998;37(4):247-53. but not UVA/UVB therapy, decreases IgE-binding 57. Johansson O, Liang Y, Heilborn JD, Marcusson cells in lesional skin of patients with atopic eczema. 76. Urbonas A, Schwartz RA, Szepietowski JC. JA. Langerhans cells in prurigo nodularis investigated J Invest Dermatol. 1996;107(3):419-22. Uremic pruritus--an update. Am J Nephrol. by HLA-DR and S-100 immunofluorescence double 2001;21(5):343-50. 41. Majoie IM, Oldhoff JM, van Weelden H, staining. J Dermatol Sci. 1998;17(1):24-32. Laaper-Ertmann M, Bousema MT, Sigurdsson V, 77. Szepietowski JC, Morita A, Tsuji T. Ultraviolet B 58. Nahass GT, Penneys NS. Merkel cells and prurigo et al. Narrowband ultraviolet B and medium-dose induces mast cell apoptosis: a hypothetical mechanism nodularis. J Am Acad Dermatol. 1994;31(1):86-8. ultraviolet A1 are equally effective in the treatment of ultraviolet B treatment for uraemic pruritus. Med of moderate to severe atopic dermatitis. J Am Acad 59. Vaatainen N, Hannuksela M, Karvonen J. Local Hypotheses. 2002;58(2):167-70. Dermatol. 2009;60(1):77-84. photochemotherapy in nodular prurigo. Acta Derm 78. Mettang T, Pauli-Magnus C. The Venereol. 1979;59(6):544-7. 42. Caricchio R, Reap EA, Cohen PL. Fas/Fas pathophysiological puzzle of uremic pruritus- ligand interactions are involved in ultraviolet-B- 60. Weedon D. Tumors of the epidermis. 2nd ed. -insights and speculations from therapeutic induced human lymphocyte apoptosis. J Immunol. London: Churchill Livingstone; 2002. and epidemiological studies. Perit Dial Int. 1998;161(1):241-51. 2000;20(5):493-4. 61. Vaalasti A, Suomalainen H, Rechardt L. Calcitonin 43. Duthie MS, Kimber I, Norval M. The effects of gene-related peptide immunoreactivity in prurigo 79. Yamaoka J, Sasaki M, Miyachi Y. Ultraviolet ultraviolet radiation on the human immune system. nodularis: a comparative study with neurodermatitis B radiation downregulates inducible nitric oxide Br J Dermatol. 1999;140(6):995-1009. circumscripta. Br J Dermatol. 1989;120(5):619-23. synthase expression induced by interferon-gamma or tumor necrosis factor-alpha in murine keratinocyte 44. Faergemann J, Larko O. The effect of UV-light on 62. Abadia Molina F, Burrows NP, Jones RR, Terenghi Pam 212 cells. Arch Dermatol Res. 2000;292(6):312- human skin microorganisms. Acta Derm Venereol. G, Polak JM. Increased sensory neuropeptides in 9. 1987;67(1):69-72. nodular prurigo: a quantitative immunohistochemical analysis. Br J Dermatol. 1992;127(4):344-51. 80. Walters IB, Ozawa M, Cardinale I, Gilleaudeau P, 45. Ring J, Alomar A, Bieber T, Deleuran M, Fink- Trepicchio WL, Bliss J, et al. Narrowband (312-nm) Wagner A, Gelmetti C, et al. Guidelines for treatment 63. Lee MR, Shumack S. Prurigo nodularis: a review. UV-B suppresses interferon gamma and interleukin of atopic eczema (atopic dermatitis) Part II. J Eur Australas J Dermatol. 2005;46(4):211-18; quiz 9-20. (IL) 12 and increases IL-4 transcripts: differential Acad Dermatol Venereol. 2012;26(9):1176-93. 64. Bianchi B, Campolmi P, Mavilia L, Danesi A, Rossi regulation of cytokines at the single-cell level. Arch 46. Jekler J, Larko O. Combined UVA-UVB R, Cappugi P. Monochromatic excimer light (308 Dermatol. 2003;139(2):155-61. versus UVB phototherapy for atopic dermatitis: a nm): an immunohistochemical study of cutaneous 81. Silverberg DS, Iaina A, Reisin E, Rotzak R, paired-comparison study. J Am Acad Dermatol. T cells and apoptosis-related molecules in psoriasis. Eliahou HE. Cholestyramine in uraemic pruritus. Br 1990;22(1):49-53. J Eur Acad Dermatol Venereol. 2003;17(4):408-13. Med J. 1977;1(6063):752-3. 47. Rowland Payne CM, Wilkinson JD, McKee 65. Rombold S, Lobisch K, Katzer K, Grazziotin TC, 82. Borgeat A, Stirnemann HR. Ondansetron is PH, Jurecka W, Black MM. Nodular prurigo- Ring J, Eberlein B. Efficacy of UVA1 phototherapy in effective to treat spinal or epidural morphine-induced -a clinicopathological study of 46 patients. Br J 230 patients with various skin diseases. Photodermatol pruritus. Anesthesiology. 1999;90(2):432-6. Dermatol. 1985;113(4):431-9. Photoimmunol Photomed. 2008;24(1):19-23. 83. Quist RG, Ton-Nu HT, Lillienau J, Hofmann 48. Miyachi Y, Okamoto H, Furukawa F, Imamura S. 66. Wallengren J, Sundler F. Phototherapy reduces AF, Barrett KE. Activation of mast cells by bile acids. Prurigo nodularis. A possible relationship to atopy. J the number of epidermal and CGRP-positive dermal Gastroenterology. 1991;101(2):446-56. Dermatol. 1980;7(4):281-3. nerve fibres. Acta Derm Venereol. 2004;84(2):111-5. 49. Tanaka M, Aiba S, Matsumura N, Aoyama H, 67. Gambichler T, Hyun J, Sommer A, Stucker M, Tagami H. Prurigo nodularis consists of two distinct Altmeyer P, Kreuter A. A randomised controlled trial Correspondence: Soham Chaudhari, BA; forms: early-onset atopic and late-onset non-atopic. on photo(chemo)therapy of subacute prurigo. Clin [email protected] Dermatology. 1995;190(4):269-76. Exp Dermatol. 2006;31(3):348-53. 50. Green R, Cordero A, Winkelmann RK. Epidermal 68. Clark AR, Jorizzo JL, Fleischer AB. Papular mast cells. Arch Dermatol. 1977;113(2):166-9. dermatitis (subacute prurigo, “itchy red bump” disease): pilot study of phototherapy. J Am Acad 51. Sugiura H, Maeda T, Uehara M. Mast cell Dermatol. 1998;38(6 Pt 1):929-33.

CHAUDHARI, LEON, LEVIN, CHAUDHARI, KOO Page 33 The Cutaneous Manifestations of Metastatic Lung Cancer: Case Report and Review

Sarah Ferrer-Bruker, DO*

*Third-year Dermatology Resident PGY-6, Palm Beach Consortium for Graduate Medical Education, West Palm Hospital, West Palm Beach, FL; West Palm Beach VA Medical Center, West Palm Beach, FL

Abstract Cutaneous metastasis comprises a tiny minority of skin tumors, estimated at 2%, and its timely diagnosis is extremely important to the clinical course of patients. Cutaneous metastasis of all primary systemic cancers usually indicates a poor prognosis with only a few months of survival time. Lung cancer remains the leading cause of cancer-related death among men and women in the United States. This article highlights an atypical presentation of lung metastasis to the skin and provides an overview of other uncommon and common cutaneous effects of lung cancer in general.

Introduction intestinal resection for colon cancer resulting in Figure 2 Although uncommon in clinical practice, the use of an ostomy bag for more than 18 years. cutaneous metastasis is important to keep on a He also had a history of lung cancer for which clinical provider’s list of differential diagnoses. he underwent partial lobectomy of the right Lung cancer continues to earn listings as the lower lobe along with radiation two years prior “most common cause of cancer-related deaths for a T2aN0M0 lung tumor non-small-cell type in both men and women,” “cancer most likely (adenocarcinoma). He had regular follow-ups to metastasize in general,” and, affecting with all of his subspecialists and primary care dermatologists particularly, “most common tumor providers, and was negative. to metastasize to the skin in males,” particularly in On exam, his left lower abdomen was significant 1-3 men over 40. The data reinforce the importance for an intact ostomy bag, with superior of having a low threshold for biopsy, especially if and bilateral lower abdominal quadrants patient history directs. demonstrating large, indurated, erythematous and violaceous blanchable plaques oriented Figure 3 Case Presentation horizontally, not extending below his pannus fold. An 83-year-old male presented to our The left aspect of the rash had a “peau d’orange,” dermatology clinic with a complaint of a rash palpable nodularity (Figure 1). on his lower abdomen for approximately two Two 4.0 mm punch biopsies were performed at months. The patient’s rash was asymptomatic. initial consultation, with an initial differential He had cataract surgery planned, which was put diagnosis inclusive of infection; ; on hold due to this rash, which he attributed to erysipeloid and/or carcinoma en cuirasse-like a reaction from EKG leads placed in the area of presentation of underlying carcinoma; atypical the rash upon his pre-op clearance studies. He angiosarcoma, due to patient history of radiation was sent to the ER for a suspected cellulitis-type to the area; and interstitial granulomatous infection, and subsequently we were consulted. dermatitis. His past medical history was notable for Figure 4

Figure 1

Figure 5

Page 34 THE CUTANEOUS MANIFESTATIONS OF METASTATIC LUNG CANCER: CASE REPORT AND REVIEW Pathology revealed findings consistent with When approached broadly, one retrospective within a fibrotic stroma. metastatic carcinoma, lymphangitic-type spread study of 4,020 patients showed that breast, The most common type of lung cancers reported (Figure 2, H&E). The immunostain pattern melanoma, and lung, in that order, top the list for to metastasize to the skin are adenocarcinoma of CK-7 positive (Figure 3), TTF-1 positive most common cancers to spread to the skin.6 For and large-cell carcinoma, followed by squamous- (Figure 4), and CK-20 negative (Figure 5) older men who present with skin metastases, lung 10 cell. A couple of studies from Japan have favored primary lung carcinoma. cancer is the most common primary, at about demonstrated that large-cell carcinoma has the 24%, followed by colorectal cancer, melanoma, 4 The patient was then referred to / highest incidence of metastasis to the skin. and carcinoma of the oral cavity. In women, lung oncology. On close review of past records cancer ranks fourth after primary breast cancer, On histology, metastatic adenocarcinoma of the and considering findings on new imaging colon cancer, and melanoma.5-6 Overall, if a lung may display glandular, well-differentiated demonstrating two new masses at an area adjacent patient has lung cancer, their chance of cutaneous structures with mucin, in which case GI, ovarian, to his previous partial lobectomy, this was metastasis varies, ranging 1% to 12%. Although breast and kidney metastases must be ruled thought to be a recurrence of a previous diagnosis the skin is not the first organ it usually spreads to, out. CK 20 paranuclear dot positivity helps of non-small-cell cancer. He was quickly started when it does it does so quickly, with mean time of differentiate from Merkel-cell carcinoma. Other on a chemotherapy regimen of gemcitabine and less than six months.6 types of lung cancer that rarely metastasize to followed regularly in dermatology clinic to track the skin include mesothelioma and bronchial his metastatic lesions. Although initially given an carcinoid, which usually show more of a ominous prognosis, the patient is doing very well. Clinical Presentation trabecular pattern and sometimes present with In most cases, skin metastases present after the 10,11 His abdominal lesions are fading, which correlate . to his overall response to treatment (Figure 6, diagnosis of a known primary. Occasionally, these almost one year after initial biopsy). lesions may be the inciting event that eventually Immunohistochemistry (IHC) has evolved into leads to diagnosis of underlying disease. In one a reliable tool in diagnosis. An IHC battery of study, 11 out of 21 patients with metastatic lung an unknown cutaneous metastasis helps narrow Discussion down the differential diagnosis. Although not Although usually detected in a patient with known cancer had their metastatic skin lesions present as 6 originally studied in the skin, useful markers and widespread disease, on occasion cutaneous the first sign of extranodal disease. include CK 7 and CK 20 and anti-thyroid metastasis may be the presenting sign of clinically Skin metastasis from lung cancer does not have transcription factor (TTF). CK 7 is very silent lung cancer. Early detection of cutaneous a typical presentation. Anatomically, the chest, sensitive and is positive in virtually all cases of metastasis, then, affects how fast a patient may be abdomen, and head and neck are common sites. primary lung adenocarcinoma; however, it has diagnosed and placed on appropriate therapy by Morphologically, lesions are usually nodular, lower specificity since it is also positive in may hematology/oncology. Further, depending on the painless, and may be either single or multiple. The other types of lung carcinoma (70% of large- morphologic presentation, cutaneous metastasis scalp, head and neck are the most common sites, 3,6 cell neuroendocrine, 40% of large-cell, and 23% may not only help with diagnosis of otherwise along with anterior chest and abdomen. Several 12 of squamous-cell). Anti-TTF is a sensitive asymptomatic disease, as with the case presented atypical presentations of metastatic lung cancer and specific marker that identifies pulmonary in this article, but may also serve as a marker in have been described including spread to both origin of an adenocarcinoma, bronchoalveolar monitoring response to chemotherapy. upper and lower limbs, gingiva, genitalia, and 7-8 carcinoma, and small-cell carcinoma if a thyroid incision sites. Although nodules are the most 12 Reviewing statistics involving cancers most likely origin is excluded. common presentation, different patterns have to metastasize to the skin may be confusing. The been reported including zosteriform, ulcerative, Overall, IHC panels are not substitutes for the proportion of patients with metastatic disease fungating, and erysipeloid-like presentations.6-9 big-picture approach to diagnosis, incorporating with cutaneous involvement depends upon the a thorough review of systems and history, exam, particular malignancy. When looking at the and screening tools such as appropriate bloodwork percentage of all patients with metastatic disease Diagnosis and radiologic studies. Communication of the who have developed metastasis particularly to Diagnosis is made on biopsy. Patterns on H&E above to pathology and consulting specialists may the skin, melanoma dominates.6 Differences also are generally either nodules of tumor cells within prove to be invaluable. occur when factoring in age and sex of patients. the dermis or cords of atypical tumor cells mixed

Figure 6 Treatment and Prognosis Treatment approach for any cutaneous metastasis is multidisciplinary. If the cutaneous metastases are localized and discrete, surgery alone or combined with chemotherapy and/or radiation may be possible for functional or even cosmetic reasons. Some studies have shown that treatment of localized disease with surgery or combination modalities may increase survival.13 If disease is more disseminated, chemotherapy remains the best option. Sometimes during chemotherapy, cutaneous lesions may be thought of as a marker for response to therapy. Patients without cutaneous metastasis tend to live longer than those who present with them. Mean survival is short, usually five to six months after diagnosis of cutaneous metastasis. Living past a year, as with our patient, is unusual but has been reported.4-5

Conclusion Although uncommon, cutaneous metastasis may occasionally be the presenting sign of an internal

FERRER-BRUKER Page 35 malignancy. Since lung cancer is so prevalent, 13. Garrido M, Ponce C, Martinez J, Martinez it is an important differential diagnosis of any C, Sevilla J. Cutaneous metastases of lung cancer. unexplained, fresh lesion in someone with risk Clin Transl Oncol. 2005 May;8:330-3. factors. These lesions are usually on the trunk, head and neck, but could present practically anywhere and with many morphologies, like the Correspondence: Sarah Ferrer-Bruker, DO; erysipeloid and peau d’orange presentation in [email protected] this case. Despite an ominous prognosis, early recognition and timely diagnosis usually confers a better survival time, as with our patient. Biopsy is essential, with immunohistochemical panels proving to be helpful and guiding tools. Likely these panels will become more sophisticated and expand their utility in terms of determining prognosis and targets for therapy.

References 1. Helm T, Lee T, Elston D. Dermatologic Manifestations of Metastatic Carcinomas. Medscape. [Internet]. 2014 Aug 11 [Cited Jan 2015 1]. Available from: http://emedicine. medscape.com/article/1101058-overview 2. Alcaraz I, Cerroni L, Rutten A, Kutzner H, Requena L. Cutaneous metastasis from internal malignancies: a clinicopathologic and immunohistochemical review. Am J Dermatopathol. 2012 Jun;34(4):347-93. 3. Rammurti Kamble, Lalit Kumar, Vinod Kochupillai, Atul Sharma, MS Sanhoo, BK Mohanti. Cutaneous metastasis of lung cancer. Postgrad Med J. 1995;71 741-743. 4. Terashima T, Kanazawa M. Lung Cancer with Skin Metastasis. Chest. 1994 Nov; 106(5): 1448- 1450. 5. Mollet, TW, Garcia CA, Koester, G. Skin metastases from lung cancer. Dermatol Online J. [Internet]. 2009;15(5). [Cited 2015 Jan 1]. Available from: http://escholarship.org/uc/ item/9r83m6wj 6. Lookingbill DP, Spangler N, Helm KF. Cutaneous metastases in patients with metastatic carcinoma: a retrospective study of 4020 patients. J Am Acad Dermatol. 1993 Aug;29:228-36. 7. Marcoval J, Moreno A, Peyrí J. Cutaneous infiltration by cancer. J Am Acad Dermatol. 2007 Oct;57:577-80. Epub 2007 Mar 26. 8. Rosen T. Cutaneous Metastasis. Med Clin North Am. 1980 Sep; 65:885-900. 9. Wen-Hao L, Chih-Yen T, Te-Chun H, Po- Yuan W. Zosteriform Skin Metastasis of Lung Cancer. Chest. 2012;142(6);1652-1654. 10. Dreizen S, Dhingra H, Chiuten DF, Umawasdt T, Valdivieso M. Cutaneous and subcutaneous metastasis of lung cancer. Postgrad Med. 1986;80:111-116. 11. Brownstein MH, Helwig EB. Metastatic tumors of skin. Cancer. 1972 May;29:1298-1307. 12. Jerome Marson V, Mazieres J, Gourssard O, Garcia O, Berjaud J, Dahan M, Carles P, Daste G. Expression of TTF-1 and cytokeratins in primary and secondary epithelial lung tumours: correlation with histological type and grade. Histopathology. 2004 Aug;45:125-34.

Page 36 THE CUTANEOUS MANIFESTATIONS OF METASTATIC LUNG CANCER: CASE REPORT AND REVIEW Loose Anagen Syndrome in a 2-year-old Female: A Case Report and Review of the Literature

Mathew Koehler, DO,* Anne Nguyen, MS,** Navid Nami, DO***

* Dermatology Resident, 2nd year, Opti-West/College Medical Center, Long Beach, CA ** Medical Student, 4th Year, Western University of Health Sciences, College of Osteopathic Medicine, Pomona, CA *** Dermatology Residency Program Director, Opti-West/College Medical Center, Long Beach, CA

Abstract Loose anagen syndrome is a rare condition of abnormal hair cornification leading to excessive and painless loss of anagen from the scalp. The condition most commonly affects young females with blonde hair, but males and those with darker hair colors can be affected. Patients are known to have short, sparse hair that does not need cutting, and hairs are easily and painlessly plucked from the scalp. No known treatment exists for this rare disorder, but many patients improve with age. Case Report neck line. The patient had no notable medical Discussion We present the case of a 27-month-old female history and took no daily medicines. An older Loose anagen syndrome is an uncommon presenting to the clinic with a chief complaint brother and sister had no similar findings. She condition characterized by loosely attached hairs of diffuse for the last five months. The was growing well and meeting all developmental of the scalp leading to diffuse thinning with poor mother stated that she began finding large clumps milestones. The mother denied any major growth, thus requiring few haircuts. It was first of hair throughout the house, most notably in the traumas, psychologically stressful periods or any described in 1984 by Zaun, who called it “syndrome child’s play area. She stated that the condition major illnesses that the patient or the family of loosely attached hair in childhood.”1 A few had progressed to where she is afraid to wash experienced in the last year. The mother denied years later, Price and Gummer along with Hamm or comb her hair and is exceptionally careful any hair manipulation or hair-pulling behaviors and Traupe began describing similar cases in the changing her clothes, as even minor pulling on and stated that the daughter is so concerned about American literature and coined the current term the hair will result in additional loss. The mother her hair being pulled out she is now refusing to “loose anagen hair syndrome,” or LAHS.2,3 The reports that her once long, curly locks are now play in close proximity to her siblings or friends. annual incidence has been estimated at 2.5 cases short and straight, and no hair will grow past her On physical examination, we found a shy white per million, with 6:37 cases in boys as compared 4 female with sparse blond hair. Her hair reached to girls. However, it has been suggested that the Figure 1 only to the neck, and the mother stated that she condition may be underestimated in boys due to 5 does not need haircuts (Figures 1 and 2). She differences in hairstyle. Cases described within appeared generally healthy and eventually began families occurring in an autosomal-dominant playing in the examination room. She had no pattern further suggest a ratio that is probably 6-8 other skin, dental or nail findings. Her eyebrows, closer to 1. body hair and eye lashes were unaffected. The classical clinical picture is that of a young girl Laboratory evaluation done by her pediatrician, with blonde hair that can be easily and painlessly including complete blood count, renal panels, plucked. Even so, cases do occur frequently in liver panel, anti-nuclear antibody and thyroid boys and adults, as well as in individuals with studies, were all within normal limits. dark hair. Recent formal reports document cases from Egypt and India.8,9 Three phenotypes, types A hair-pull test was done, with more than 10 hairs A, B, and C, have been described. In Type A, hair being pulled without pain. The mom and patient is sparse and does not grow long. In Type B, the were very upset when this test was done, as it was individual has unruly hair that is either diffuse or not fully explained, and refused further hair pulls. patchy. In Type C, the hair appears normal but They did allow me to pull lightly on individual 10 has excessive shedding and loose anagen hairs. hairs, which repeatedly were easily pulled from 7,11 The eyebrows and eyelashes are not affected. the child’s head without pain. A trichogram was done, which showed a distorted anagen bulb with A diagnosis relies on the presence of loose anagen a “rumpled sock” appearance (Figure 3). Figure 3 Based on the history and physical examination, a diagnosis of loose anagen syndrome (LAS) was made. The mother and child were advised on the natural history of this condition and were offered a trial of minoxidil 5% hair solution to be applied to her scalp daily. We encouraged her to continue being mindful of and avoid activities that would result in further hair loss such as combing, shampooing and pulling narrow-necked clothing over her head. The patient will continue to follow with us, and although not happy with her condition, they were relieved to have received a diagnosis.

Figure 2

KOEHLER, NGUYEN, NAMI Page 37 Table 1. Differential Diagnosis of Pediatric Alopecia examination, the hair bulb is long, tapered, and twisted along the long axis. The cuticle appears as Condition Clinical Findings Pathology Hair-pull Test a “rumpled sock.”2,12,15 Loose Anagen Diffusely thin hair that “Rumpled sock” look >10 hairs painlessly Abnormalities in keratinization have prompted Syndrome tends to not grow beyond to anagen bulb on pulled. Individual molecular analysis studies. Particular attention the shoulders. Bald patches trichogram. hairs easily pulled. has been devoted to identifying the may be present. Hair may be within the inner , outer root sheath, dull, unruly, or matted. and companion layer. Of significance, Chaplain Lupus Erythematous papules and Follicular red dots Normal et al. identified a G-to-A substitution mutation plaques with scale. Lesions on trichoscopy. On in the cytokeratin K6hf of the companion layer expand centrifugally. histology, vacuolar leading to replacement of glutamic acid by . Follicular plugging with interface change with It is hypothesized that this mutation may lead to , scarring, and chronic inflammation of instability of the intermediate filament network telangiectasia. Dark- eccrine sweat glands and and thus poor anchoring of the hair shaft to the 7 skinned individuals arrector pili. Increased sheath. It was not until recently that keratins of 16,17 may have peripheral dermal mucin. IgG and the , K25-28, were described. hyperpigmentation with C3 deposition at D-E Molecular analysis for possible mutation in these central . junction. genes has yet to be done. Non-scarring, round-to- Yellow dots, exclamation May be positive in Although the majority of cases have been sporadic, oval patch of hair loss. mark appearance, and the diffuse variant. as previously mentioned, there is some evidence Totalis, universalis, dystrophic hairs on of autosomal-dominant inheritance with variable and reticular variants. Nail trichoscopy. penetrance.6,7 There have been associations with changes may be present. certain conditions such as Noonan’s syndrome,13,18 May be chronic and coloboma,19 hypohidrotic ,20 relapsing. and woolly hair.21 Trichotillomania Patchy or full alopecia of On histology, Normal There is no agreed upon or universally effective hair-bearing areas, most incomplete, disrupted treatment for LAS. In some individuals, the commonly the scalp. Patches follicular anatomy, condition improves with age, most notably have bizarre and irregularly trichomalacia, pigment around puberty. However, in some individuals the shaped borders with hairs casts. condition persists into adulthood. A recent case of varying lengths. Occiput report showed good results using daily therapy sparing. with minoxidil without any side effects in a 2-year- 22 Most commonly presents Comma hair on Normal old patient. While minoxidil is generally safe as alopecia with or without trichoscopy. Infection and inexpensive, there are some considerations scale. Presentation can range with T. tonsurans (>90% when prescribing to pediatric patients. Rare cases from a non-inflammatory of cases in the U.S.) of reversible generalized have been scaling resembling results in the classic reported in children using excessive amounts of minoxidil for alopecia areata, so caution should seborrheic dermatitis to black dot appearance. 23 severe pustulosis also known be used. Another consideration in pediatric as a kerion. patients is excessive systemic absorption, which could potentially cause cardiovascular symptoms Thinning involving the Mixture of normal Positive for two such as tachycardia, and dizziness, so entire scalp and other hair- anagen and telogen hairs or more normal patients and their caregivers should be advised to bearing regions. with >20% telogen hairs. telogen hairs. monitor for side effects.24 Loose anagen syndrome is an uncommon hairs that when examined under the microscope precise pathogenesis of this syndrome has yet condition that can cause a significant psychosocial display derangements involving the inner and to be elucidated. The reigning theory is that of impact in patients and families. More research possibly the outer root sheaths.12 A hair-pull inner-root-sheath derangement leading to poor is needed to fully understand the cause of this test or trichogram can be performed in order to adhesion between the cuticle of the inner root condition and to improve the limited treatment support the diagnosis, although there are several sheath and that of the hair shaft, causing poor options available. Patients should be advised that drawbacks. Few controlled studies have been anchoring. Normal anagen hair is a complex this condition is thought to be benign in nature, done in order to properly define the parameters structure requiring orderly development and and many patients’ hair normalizes with age. We for a positive test. Authors have suggested using maturation in order to achieve the proper hair have chosen to recommend minoxidil to our greater than 10 loose anagen hairs, compared to follicle. Deranged anagen follicles of LAS exhibit patient while warning the mother of the potential the usual one or two hairs in normal subjects, characteristic features under both light and of cardiovascular side effects and hypertrichosis. as the cutoff for constituting a positive pull electron microscopy.7,12,13 The keratinized cell We will continue to follow her progress. test.10 On trichogram, greater than 70% loose sheath portion of the Henle layer is abnormally anagen hairs compared to the normal 10% is thickened and tortuous. Cells are irregularly considered positive. To avoid overdiagnosis, one shaped and contain nuclear debris. In addition, References 1. Zaun H Differential diagnosis of alopecia must keep in mind that anagen hairs can be there is premature keratinization and in children. In: Happle R, Grosshans E, eds. found on normal scalp; their presence is neither with pyknotic nuclei, sparse filaments, and Pediatric dermatology. Berlin: Springer; 1987. pathognomonic nor specific.13 The differential for trichohyalin granules, in an edematous cytoplasm. 157-166 p. LAS should include alopecia areata, tinea capitis, The Huxley layer also exhibits premature trichotillomania, , and secondary keratinization with edema. Lastly, the cuticle cells 2. Price VH, Gummer CL. Loose anagen .14 See Table 1 for differential. of the hair shaft and Henle layer contain vacuoles syndrome. J Am Acad Dermatol. 1989;20(2 Pt 12 1):249-56. Much research has been done, although the with irregularly arranged cells. On gross

Page 38 LOOSE ANAGEN SYNDROME IN A 2-YEAR-OLD FEMALE: A CASE REPORT AND REVIEW OF THE LITERATURE. 3. Hamm H, Traupe H. Loose anagen hair of familial association between ocular coloboma childhood: the phenomenon of easily pluckable and loose anagen syndrome. Clin Genet. hair. J Am Acad Dermatol. 1989;20(2 Pt 1):242- 1995;47(4):214-6. 8. 20. Azon-masoliver A, Ferrando J. Loose anagen 4. Sinclair R, Cargnello J, Chow CW. Loose hair in hypohidrotic ectodermal dysplasia. Pediatr anagen syndrome. Exp Dermatol. 1999;8(4):297- Dermatol. 1996;13(1):29-32. 8. 21. García-hernández MJ, Price VH, Camacho 5. Pham CM, Krejci-manwaring J. Loose anagen FM. Woolly hair associated with loose anagen hair syndrome: an underdiagnosed condition in hair. Acta Derm Venereol. 2000;80(5):388-9. males. Pediatr Dermatol. 2010;27(4):408-9. 22. Chandran NS, Oranje AP. Minoxidil 5% 6. Baden HP, Kvedar JC, Magro CM. Loose solution for topical treatment of loose anagen hair anagen hair as a cause of hereditary hair loss in syndrome. Pediatr Dermatol. 2014;31(3):389-90. children. Arch Dermatol. 1992;128(10):1349-53. 23. Herskovitz I, Freedman J, Tosti A. Minoxidil 7. Chapalain V, Winter H, Langbein L, et al. induced hypertrichosis in a 2 year-old child. Is the loose anagen hair syndrome a keratin F1000Res. 2013;2:226. disorder? A clinical and molecular study. Arch 24. Georgala S, Befon A, Maniatopoulou Dermatol. 2002;138(4):501-6. E, Georgala C. Topical use of minoxidil in 8. Dey V, Thawani M. Loose anagen hair children and systemic side effects. Dermatology. syndrome in black-haired Indian children. 2007;214(1):101-2. Pediatr Dermatol. 2013;30(5):579-83. 9. Abdel-raouf H, El-din WH, Awad SS, et al. Loose anagen hair syndrome in children of Upper Correspondence: Matthew Michael Koehler, Egypt. J Cosmet Dermatol. 2009;8(2):103-7. DO; [email protected] 10. Olsen EA, Bettencourt MS, Coté NL. The presence of loose anagen hairs obtained by hair pull in the normal population. J Investig Dermatol Symp Proc. 1999;4(3):258-60. 11. Chapman DM, Miller RA. An objective measurement of the anchoring strength of anagen hair in an adult with the loose anagen hair syndrome. J Cutan Pathol. 1996;23(3):288-92. 12. Mirmirani P, Uno H, Price VH. Abnormal inner root sheath of the hair follicle in the loose anagen hair syndrome: an ultrastructural study. J Am Acad Dermatol. 2011;64(1):129-34. 13. Tosti A, Piraccini BM. Loose anagen hair syndrome and loose anagen hair. Arch Dermatol. 2002;138(4):521-2. 14. Bolognia J, Jorizzo JL, Schaffer JV. Dermatology. 3rd edition. Philadelphia (PA): Saunders; 2012. 1093p. 15. Dicle O, Velipasaoglu S, Ozenci CC, Akkoyunlu G, Demir N. Report of a new case with loose anagen hair syndrome and scanning electron microscopy findings. Int J Dermatol. 2008;47(9):936-8. 16. Porter RM, Corden LD, Lunny DP, Smith FJ, Lane EB, Mclean WH. Keratin K6irs is specific to the inner root sheath of hair follicles in mice and humans. Br J Dermatol. 2001;145(4):558-68. 17. Langbein L, Rogers MA, Praetzel S, Winter H, Schweizer J. K6irs1, K6irs2, K6irs3, and K6irs4 represent the inner-root-sheath-specific type II epithelial keratins of the human hair follicle. J Invest Dermatol. 2003;120(4):512-22. 18. Mazzanti L, Cacciari E, Cicognani A, Bergamaschi R, Scarano E, Forabosco A. Noonan-like syndrome with loose anagen hair: a new syndrome?. Am J Med Genet A. 2003;118A(3):279-86. 19. Murphy MF, Mcginnity FG, Allen GE. New

KOEHLER, NGUYEN, NAMI Page 39 Anetoderma Secondary to Mid-dermal Elastolysis

Gabriela A. Maloney, BS,* Jane James, MD, PhD,** Michael Welsch, MD,** Marylee Braniecki, MD**

*Midwestern University, Downers Grove, IL **Pathology Department, University of Illinois Hospital & Health Sciences System, Chicago, IL

Abstract Anetoderma usually presents as circumscribed, 1 cm to 2 cm patches and plaques of flaccid skin secondary to loss of dermal elastic tissue. Lesions often occur in the neck, upper extremities, chest, and back. On histopathology, one sees complete loss of dermal elastin involving the papillary and reticular dermis, with infiltration of plasma cells and histiocytes. A 40-year-old female with no significant medical history presented with multiple round, 1 cm to 2 cm lesions scattered on her upper back and chest. Skin biopsy demonstrated elastic-fiber loss localized to the mid-dermis along with a lymphohistiocytic infiltrate with elastophagocytosis and active inflammatory phase in the papillary and mid-reticular dermis. The histopathological findings were consistent with mid-dermal elastolysis with advancing inflammation, and the clinical features were consistent with anetoderma. The microscopic examination revealed an active inflammatory phase of mid-dermal elastolysis, supporting the postulated theory that MDE may be part of a continuous spectrum with anetoderma. Case Report by lax, wrinkled skin with underlying palpable biopsy and elastic-fiber staining demonstrated A 40-year-old female with no significant medical depression (Figure 1). They were often preceded elastic-fiber loss in the mid-dermis along with history presented with multiple round, 1 cm to by two to six months of local erythema and had a lymphohistiocytic infiltrate with evidence 2 cm lesions scattered throughout the upper increased in number over the past two years. No of elastic-fiber phagocytosis and an active back and chest. The lesions were characterized response was seen after topical steroids. Skin inflammatory background in the papillary and reticular dermis (Figures 2, 3 and 4). This is a case demonstrating the development of anetoderma as seen by the progressive inflammation and elastophagocytosis in the papillary and reticular dermis that developed in the setting of mid- dermal elastolysis (MDE).

Figure 1: Multiple round-to-ovoid, wrinkled skin lesions with overlying palpable depressions and surrounding erythema. Figure 2: H&E (10x): Active inflammatory phase with mid-dermal stromal histiocytes with scattered plasma cells. Discussion Mid-dermal elastolysis (MDE) is a rare acquired disorder of elastic-tissue degradation limited to the mid-dermis. It consists of a clear band of mid-dermal elastic-tissue loss as a result of inflammatory destruction of dermal elastotic fibers.1 The elastic-tissue loss occurs as a result of inflammatory destruction of dermal elastic fibers. Remnants of abnormal elastic tissue and granuloma formation may be present, along with evidence of elastophagocytosis.2 Elastic tissue is Figure 3: H&E (20x): Multinucleated Figure 4: Elastic stain (20x): Elastic fibers usually preserved around hair follicles, resulting histiocytes with elastophagocytosis. engulfed by histiocytes. in perifollicular papules on the affected skin.

Page 40 ANETODERMA SECONDARY TO MID-DERMAL ELASTOLYSIS The condition was first described in 1977 by anetoderma. Emer et al. described a case of of anetoderma as seen by progressive Shelley and Wood, and since then, there have anetoderma that was instigated by penicillin G to inflammation and elastophagocytosis in the been approximately 80 cases reported in the treat syphilis in an HIV-positive patient without papillary and reticular dermis that developed in literature.3 It has a female predominance and any previous skin complaints.9 the setting of mid-dermal elastolysis (MDE). The presents clinically as diffuse, fine wrinkling on Mid-dermal elastolysis and anetoderma, both histopathological findings were consistent with the neck, arms, and trunk in patients between the mid-dermal elastolysis with active inflammation, 2 disease entities resulting from elastic-fiber ages of 30 and 50 years. degradation, are differentiated histopathologically and the clinical features were consistent with It is classified into three types: type I, or classic by the extent and location of elastic-fiber loss. The anetoderma. The microscopic examination type, with well-demarcated patches with former consists of elastic-tissue loss localized to revealed loss localized to the mid- wrinkling; type II, with perifollicular papular the mid-dermis, and the latter is characterized by dermis along with a lymphohistiocytic infiltrate protrusions; and type III, with reticular/annular elastic-fiber loss in the entire dermis.1 with elastophagocytosis and active inflammatory patches with wrinkling. phase in the papillary and mid-reticular dermis. It has been speculated that MDE and anetoderma Such areas of active inflammation indicate the Mid-dermal elastolysis has been reported to are within the same spectrum of disorders, as they development of anetoderma in the pre-existing originate from involuting sites of granuloma present similar histopathological configurations MDE background as elastic-fiber degradation annulare that started as a patchy, slightly indurated to different extents, suggesting MDE may evolve spread beyond the mid-dermis to involve the and violaceous eruption involving the neck and into anetoderma secondary to long-standing papillary and reticular dermis. trunk and eventually became atrophic, pale and inflammation.4,10,11 Our patient demonstrated a wrinkled. Urticaria, atopic dermatitis, Sweet’s classic histopathology of MDE with secondary Anetoderma often occurs from existing inflammatory processes that lead to elastic-fiber syndrome, phototoxic dermatitis, and pityriasis anetoderma resulting from an active inflammation 4 thus the overall findings in this case rosea have also been described to precede MDE. and elastophagocytosis, lymphocytes, plasma cells destruction, may support the theory that MDE is part of a Mid-dermal elastolysis can also occur in areas of and histiocytes extending to the papillary and continuous spectrum with anetoderma. preceding erythema, which is consistent with our reticular dermis. patient’s clinical presentation.5 Mid-dermal elastolysis and anetoderma need to References Anetoderma, also known as dermatitis maculosa be differentiated from other connective-tissue 1. Bolognia JL, Jorizzo JL, Schaffer JV, eds. atrophicans, is an elastic-tissue disorder that diseases affecting elastic fibers, including cutis Dermatology. 3rd ed. Philadelphia: Elsevier shows focal loss of elastic fibers in the dermis. laxa, (PXE), and Saunders; 2012. 1631-35 p. The term “anetoderma” is derived from the PXE-like papillary dermal elastolysis. Post- 2. Gambichler T. Mid-dermal elastolysis revisited. Greek words “anetos,” meaning slack, and traumatic scars, perifollicular elastolysis, papular 1 Arch Dermatol Res. 2010;302:85-93. “derma,” meaning skin. Sac-like tumors that elastorrhexis, pseudoxanthoma elasticum, focal herniate upon palpation were first described dermal hypoplasia (Goltz syndrome), and nevus 3. Shelley WB, Wood MD. Wrinkles due to by Schweninger and Buzzi in 1891, but lipomatosus are other entities that may be included idiopathic loss of mid-dermal elastic tissue. Br J anetoderma was first officially described in 1892 in the differential diagnosis of anetoderma.1 Dermatol. 1977;97:441-5. 7,8 by Jadassohn. It usually presents as multiple, is an entity with redundant and loose 4. Lai JHC, Murray SJ, Walsh NM. Evolution of circumscribed, 5 mm to 25 mm areas of flaccid skin seen on the eyelids, cheeks, shoulder girdle, to mid-dermal elastolysis: skin with fine wrinkling that can occur in the abdomen and neck. It presents clinically with report of a case and review of the literature. J neck, upper extremities, chest, and back. The premature aging secondary to loose skin folds Cutan Pathol. 2014;41:462-8. lesions are skin color but can present with a blue- 6 with or without internal organ involvement. In Affected areas of skin can 5. Gambichler T. Mid-dermal elastolysis revisited. white discoloration. this condition, the whole dermis is affected with herniate after palpation (“buttonhole” sign) and Arch Dermatol Res. 2010;302:85-93. 1 diminished and fragmented elastic fibers, and it can show central depressions. 1 can occur in an acquired or hereditary form. 6. Venecie PY, Winkelmann RK, Moore BA. Anetoderma: clinical findings, associations, and Anetoderma is classified as either primary Pseudoxanthoma elasticum (PXE) and PXE- (idiopathic) or secondary. Primary anetoderma long-term follow-up evaluations. Arch Dermatol. like papillary dermal elastolysis present as 1984;120:1032-9. is divided in two types: Jadassohn-Pellizzari type, cobblestoning yellow papules and redundant folds which has preceding inflammatory lesions, and in flexor areas. The former can be associated with 7. Schweninger E, Buzzi F. Multiple benign Schweninger-Buzzi type, which has no preceding ocular and cardiovascular involvement.1 It occurs tumor-like new growths of the skin. International inflammation. It is seen more commonly in in sites of previous scars, , groin, and lateral Atlas Seltener Hautkrankheiten, plate 15. women than men and mostly occurs in individuals 9 neck and consists of clumped and calcified elastic Leipzig: L Voss, 1891. Secondary between 15 and 25 years of age. fibers in the mid-dermis. The latter is seen in anetoderma may be associated with tumors, 8. Jadassohn J. Uber eine eigenartige form inframammary folds, lower abdomen, axilla, and depositions, autoimmune disorders, infections, von’atrophica maculosa cutis. Arch Dermatol neck, and has a band-like pattern of clumping drugs and inflammatory cutaneous disorders. Syphilol. 1892;24:342-58. and fragmentation of elastic tissue in the papillary The loss of elastic tissue is usually localized to 9 dermis. 9. Emer J, Roberts D, Sidhu H, et al. Generalized those sites of previous skin lesions caused by the 1 Anetoderma after Intravenous Penicillin Therapy primary disease. Intralesional triamcinolone injections and for Secondary Syphilis in an HIV patient. J Clin systemic administrations of dapsone, aspirin, On histopathology, there is focal loss of elastic Aesthet Dermatol. 2013;6(8):23-28. penicillin G, , and inositol niacinate fibers in the dermis with infiltration of plasma have been used to treat existing anetodermal 10. Gambichler T, Breuckmann F, Kreuter A, cells and histiocytes. The elastic fibers can have 1 lesions without success. Administration of et al. Immunohistochemical investigation of an irregular shape and may be fragmented or hydroxychloroquine, colchicine, and aminocaproic mid-dermal elastolysis. Clin Exp Dermatol. engulfed by . Remnants of abnormal acid, as well as surgical excision, have resulted 2004;29:192-5. elastic tissue and granuloma formation may be 1 in some improvement. Cho et al. reported present. 11. Verhagen AR, Woederman MJ. Post- anetoderma presenting after Stevens-Johnson inflammatory elastolysis and cutis laxa. Br J Activated macrophages and fibroblasts from syndrome successfully treated with ablative Dermatol. 1975;92:183-90. existing inflammatory processes can destroy carbon dioxide fractional laser.12 Lasers destroy dermal stromal elements by releasing proteolytic the hydrogen bonds in the collagen triple helix, 12. Cho S, Jung JY, Lee JI. Treatment of enzymes. UV light exposure and autoimmunity instigating an inflammatory cascade that is anetoderma occurring after resolution of Stevens- against elastic fibers are thought to contribute to believed to be responsible for rebuilding stable Johnson Syndrome using ablative 10,600nm the condition. Defects in the synthesis of elastin and more native-like collagen and elastic fibers, carbon dioxide fractional laser. Dermatol Surg. and dysregulation of elastic-fiber digestion by thereby reverting the pathological process.9 2012;38(4):677-79. metalloproteinases (MMPs) also seem to play Correspondence: Gabriela Maloney BS; 5 a role. Giant cells and elastophagocytosis may Conclusion [email protected] be present in both mid-dermal elastolysis and We report a case demonstrating the development

MALONEY, JAMES, WELSCH, BRANIECKI Page 41 Generalized Linear Porokeratosis: A Case Report and Discussion

Stephanie Blackburn, DO,* Zaina Rashid, DO,** John Moad, MD,*** Michelle Duff, DO,**** Jason Barr, DO*****

*Dermatology Resident, 1st year, Affiliated Dermatology/MWU, Scottsdale, AZ **Assistant Professor, Midwestern University, Phoenix, AZ *** Medical Director, Dermatopathologist Laboratory, Dayton, OH ****Dermatology Resident, 2nd year, Affiliated Dermatology/MWU, Scottsdale, AZ *****Program Director, Affiliated Dermatology/MWU Residency Program, Scottsdale, AZ

Abstract Linear porokeratosis is a clinical variant of porokeratosis that usually arises in infancy or childhood, but may present in adulthood. There are two presentations, the first being more common and localized. It is unilateral and confined to one extremity. In the rarer version, the lesions affect multiple extremities and the trunk, appearing in a zosteriform pattern.1 Of all the variants of porokeratosis, linear porokeratosis has the greatest chance of malignant transformation, with squamous cell carcinoma and basal cell carcinoma being the most common. We present a case of a 57-year-old man with reddish-brown skin lesions showing central atrophy with surrounding scale, hyperpigmentation and erythema present on the right posterior back, right arm, right lateral leg and right buttock. Within the lesion on his leg there was noted actinic damage. There are numerous treatment options for porokeratosis, with varying benefits and risks. It is important to take into consideration the age of the patient and the morphology of the lesions being treated in order to leave the patient with the most cosmetically pleasing outcome. For our patient, we elected to treat with topical imiquimod 5% and fluorouracil 5% because of the large areas of involvement. Introduction Figure 1 Figure 3 The porokeratoses are a group of acquired or genetic disorders of epidermal keratinization characterized by singular or multiple, annular, atrophic lesions surrounded by a keratotic border.16 The peripheral keratinization of the demarcated lesions corresponds to a typical histopathologic feature, namely, the cornoid lamella. Various forms of porokeratosis have been established based on the clinical course of the disease, the morphology and the distribution of the lesions.1 Linear porokeratosis is a clinical variant of porokeratosis. It consists of one or more plaques that are similar in appearance to classic porokeratosis; however, the plaques follow the lines of Blaschko and are most commonly on the extremities. When linear porokeratotic lesions have a typical clinical appearance, it is easy to diagnose. However, in lesions that are smaller and have less elevation of borders, it may be confused with other linearly arranged lesions. Differential diagnosis includes inflammatory linear verrucous epidermal nevus, linear lichen Figure 2 Figure 4 planus, (stage II), linear psoriasis, linear Darier’s disease, and lichen striatus. We present a case of linear porokeratosis with arising SCC in situ in a 57-year-old male.

Case Report A 57-year-old Caucasian male presented for evaluation of a lesion on the left lateral arm and was found to have extensive skin lesions showing central atrophy with surrounding scale, hyperpigmentation and erythema. The lesions were confined to the right side of his body and followed the lines of Blaschko. They were present on the right posterior back in a curved/whorled fashion, the right arm, and the right lateral leg and buttock (Figures 1-4). Extending down the lateral leg, it was evident that the inferior portion had actinic activity present (Figure 5). A shave biopsy was taken during his first visit, showing SCC in situ. Two punch biopsies taken

Page 42 GENERALIZED LINEAR POROKERATOSIS: A CASE REPORT AND DISCUSSION Figure 5 during the 1980s, he visited a dermatologist with of the underlying dermis shows mild perivascular the Navy in Hawaii. He had a second biopsy mononuclear cell infiltrate.1 Fibroblasts also taken performed and remembers being treated with a from the underling dermis of a lesion have shown 5% “fading” cream that was applied to his right instability of the short arm of chromosome 3.5 arm only and wrapped with cellophane. In The nuclei of keratinocytes beneath the cornoid approximately 2005, he was evaluated at an Air lamella in the epidermal basal layer have shown Force Base, where he saw a dermatologist. A over-expression of p53.6 It has been noted that biopsy was performed. He was told that it was this may explain the malignant potential of not cancerous, and no further action was taken. porokeratosis.3

Pathogenesis Treatment Porokeratosis is a premalignant disease of There are numerous modalities used for epidermal keratinization characterized by the treatment of porokeratosis. In general, atrophic macules and patches with a surrounding treatment of linear porokeratosis is disappointing border of hyperkeratinization. The cornoid and contradictory.21 Treatment modalities lamella is the hyperkeratotic border of vertical include topical creams such as fluorouracil mounds of parakeratotic that lies 5%, corticosteroids, retinoids, keratolytics, and in the periphery around the lesions.16 Clonal calcipotriol; surgical treatments such as curettage, proliferation of atypical keratinocytes from excision, cryotherapy, and electrodessication; the stratum corneum and superior epidermis, laser treatment with ; and demonstrating abnormal terminal keratinocyte . Systemic retinoids can also be differentiation, leads to the formation of the utilized as a method of clearance and prophylaxis. Figure 6 cornoid lamella. The pathway that leads to the For our patient, fluorouracil 5% and imiquimod clonal proliferation of abnormal keratinocytes 5% were selected as treatment options due to the is not known; it has been thought that genetic large areas of the lesions and extensive actinic susceptibility, UV-radiation exposure, viral damage within each lesion. Fluorouracil 5% is infection, and immune status may be contributing 4 a topical antineoplastic, anti-metabolite cream factors. Immunodeficiency may be due to organ containing pyrimidine fluorouracil, used in the transplant, chemotherapy, chronic kidney disease, treatment of and superficial HIV, , or repeated trauma as well as 13 basal cell carcinoma. It works by inhibiting DNA other pathological processes. Mosaicism is and RNA synthesis. Anti-metabolites block the a proposed genetic mechanism for two types replication of DNA by preventing the building of porokeratosis, porokeratosis of Mibelli and of the lower extremity showed definitive cornoid blocks of DNA (the purines and pyrimidines) linear porokeratosis. Mosaicism occurs when lamellae with thin and flattened epidermis. Subtle from being incorporated into DNA, which halts cells within an individual have different genetic interface change with few necrotic keratinocytes 8 normal development and division. Imiquimod is makeup. There is conflicting evidence as to was also noted. There was mild superficial an immune-response modifier that acts as a toll- the association between ultraviolet radiation perivascular lymphocytic inflammation with like receptor 7 agonist. Like fluorouracil 5%, it is and porokeratosis. Support for the relationship melanophages. Focal with few used to treat actinic keratoses and superficial basal is due to the observation that disseminated superficial epidermal dyskeratotic keratinocytes cell carcinoma. Field therapy with imiquimod superficial actinic porokeratosis (DSAP) occurs was noted. (Figure 6) Past medical history, 5% is a treatment of choice on areas where in individuals with extensive sun exposure, medications, , social history, and family surgery or other treatments may be complicated, occurs on areas of sun-exposed skin, and occurs history were noncontributory. difficult or otherwise undesirable. This is why it in experimental settings with the use of artificial was selected for our patient, who had very large The patient reported that he developed the ultraviolet radiation. However, the relative areas of skin involvement that would not have lesions in 1967 when he was 12 years old. At sparing of the face weakens the relationship been surgically operable without skin grafts or this time he suffered from an episode of severe between UV radiation and the development of other measures. Imiquimod’s mechanism of sun exposure with peeling and blistering on his porokeratosis. Also, treatment of DSAP with action is via stimulation of innate and acquired chest, arms and back. Shortly after, he noticed psoralen plus ultraviolet A (PUVA) has shown immune responses, leading to inflammatory-cell the development of vesicles that started on his 9 to improve lesions. Immunosuppression or infiltration within the field of drug application right arm, no bigger than the size of a pustule. immunodeficiency has been shown to increase followed by apoptosis of diseased tissue. Our The vesicles then spread to his right leg and back. the risk of porokeratosis. The evidence is due patient, after being treated with fluorouracil 5% He reported that his lower extremities were not to reports of remission of porokeratosis after and imiquimod 5%, was clear of actinic keratosis exposed and did not get sunburned. After a few 10,11 cessation of immunosuppressive therapy. within the plaques. He did not follow up, so years, he presented to his primary care physician, Also, porokeratosis has developed in areas of definitive clearance is unable to be determined. who referred him to a skin specialist who thought long-term topical corticosteroid use.12 the lesions were due to “shooting up” drugs. No biopsy was performed at that visit. Discussion Biopsy Since its first description by Mibelli and Respighi At 18 years of age, the patient entered the Biopsy of porokeratosis shows stacked, tightly in 1893, many new variants of porokeratosis have Navy. The lesions had remained constant packed parakeratotic cells that are well- 1 been described. A patient may develop more since appearing years before. He noticed that differentiated from the rest of the corneocytes. than one type of porokeratosis simultaneously they would bleed and become erythematous The is either absent or or consecutively. Each variant consists of its own during hot weather. Due to these symptoms, decreased, and the may possess 3 properties regarding morphology, distribution vacuolated or dyskeratotic cells. 1 in approximately 1976 he saw a dermatologist The defective and clinical course. The initial lesions present desquamation of the corneocytes may be due to a 1 in Hawaii at an Army hospital. A biopsy was in a centrifugal manner as keratotic papules. decrease in the keratohyalin granules and lamellar taken; however, the diagnosis was never relayed These lesions then progress, showing central to him and no treatment was performed. Again bodies underneath the cornoid lamella.1 Biopsy

BLACKBURN, RASHID, MOAD, DUFF, BARR Page 43 atrophy with a collar of keratin. A biopsy of the squamous cell carcinoma, including Bowen’s 1993;28:651. 21 lesion’s border shows parakeratotic cells stacked disease, and basal cell carcinoma. A few 12. Yazkan F, Turk BG, Dereli T, Kazandi AC. tightly, sticking out from the rest of the stratum risk factors have been established, including Porokeratosis of Mibelli induced by topical corneum. This cornoid lamella is the hallmark excessive sun exposure, , corticosteroid. J Cutan Pathol 2006;33:516. of porokeratosis. Further manifestations include internal malignancies, and a family history of thinning of the stratum granulosum, dyskeratotic porokeratosis.2 It has been hypothesized that 13. Taking urchin RH, White KP, White CR cells in the stratum spinosum and subsequent the increased malignant potential for linear Jr., Simpson EL. Verrucous porokeratosis of the thinning of the . Abnormalities in porokeratosis may be due to allelic loss in addition gluteal cleft (porokeratosis ptychotropica): a rare the maturation of keratinocyte clones has been to overexpression of the tumor suppressor disorder easily misdiagnosed. J Cutan Pathol. implicated in the pathogenesis of porokeratosis. gene p53 within linear porokeratosis lesions.22 2010 July;37(7):802-7. The most common forms of porokeratosis are: Monitoring for suspicious lesions is key in the 14. McGuigan K, Shurman D, Campanelli C, care of patients with porokeratosis. Lee JB. Porokeratosis ptychotropica: a clinically • Classic porokeratosis of Mibelli (PM) distinct variant of porokeratosis. J Am Acad • Disseminated superficial actinic Dermatol 2009;60:501-3. porokeratosis (DSAP) and its non- Conclusion Linear porokeratosis is a rare variant of 15. Corradin MT, Giulioni E, Forcione M, actinic variant, disseminated superficial porokeratosis that has an increased risk of Fiorentino R, Faggion D, Alaibac M, Belloni- porokeratosis (DSP) malignant transformation. Individuals with this Fortina A. Porokeratosis ptychotropica. Eur J • Linear porokeratosis type should have regular follow-up visits and Dermatol. 2011 May-Jun;21(3):416-7. • Porokeratosis palmaris et plantaris yearly skin exams. There are multiple treatment disseminata (PPPD) 16. Kanitakis J, Rival-Tringali AL, Chouvet B, options, and each patient case is different. • Punctate porokeratosis, which might Vignot E, Claudy A, Faure M. Porokeratoma represent a variant of PPPD (porokeratotic acanthoma): immunohistological study of a new case. J Cutan Pathol. 2009 Besides these, there are a few rare, atypical References 1. Sertznig P, von Felbert V, Megahed M. Jul;36(7):804-7. morphological forms such as facial porokeratosis, Porokeratosis: present concepts. J Eur Acad 17. Goddard DS, Rogers M, Frieden IJ, Krol giant porokeratosis, punched-out porokeratosis, Dermatol Venereol. 2012;26:404-412. hypertrophic verrucous porokeratosis and AL, White CR Jr, Jayaraman AG, Robinson- reticulate porokeratosis.7 Porokeratosis 2. Maubec E, Duvillard P, Margulis A, Bachollet Bostom L, Bruckner AL, Ruben BS. Widespread ptychotropica is a recently described subtype B, Degois G, Avril MF. Common skin cancers porokeratotic adnexal ostial nevus: clinical of inflammatory perianal disease showing in porokeratosis. Br J Dermatol. 2005;152:1360- features and proposal of a new name unifying symmetrically distributed, reddish-brown 1398. porokeratotic eccrine ostial and dermal duct nevus papules and plaques involving the gluteal cleft 3. Chow KY. Linear Porokeratosis. Hong Kong and porokeratotic eccrine and hair follicle nevus. and genital areas.13-15 Porokeratoma, otherwise Dermatol Venereol Bull. 2000;8:21-23. J Am Acad Dermatol. 2009 Dec;61(6):1060. known as porokeratotic acanthoma, is a tumor- 4. Murase J, Gilliam AC. Disseminated superficial 18. Choi KH, Kim TY. A case of inflammatory like acanthoma showing cornoid lamellation disseminated superficial porokeratosis in a colon 16 actinic porokeratosis co-existing with linear and characteristic of porokeratosis. These lesions verrucous porokeratosis in an elderly woman: cancer patient. Ann Dermatol 2009;21:150-3. have a keratotic or verrucous appearance and are Update on the genetics and clinical expression of 19. Tee SI, Chong WS. Eruptive pruritic papular commonly found on the limbs. Histologically, porokeratosis. J Am Acad Dermatol. 2010;63:886. porokeratosis. Indian J Dermatol Venereol they have multiple and confluent cornoid Leprol. 2012 Nov-Dec;78(6):758-60. lamellae. A rare congenital disorder of 5. Imakado S, Ostuka F, Ishibashi Y, et al. keratinization characterized by eccrine and hair- Abnormal DNA ploidy in cells of the epidermis 20. Levitt JO, Keeley BR, Phelps RG. Treatment follicle involvement is known as porokeratotic a case of porokeratosis. Arch Dermatol. of porokeratosis of Mibelli with cantharidin. J adnexal ostial nevus (POAN). This name was 1988;124:331-2 Am Acad Dermatol. 2013 Nov;69(5):e254-5. proposed to incorporate porokeratotic eccrine 6. Magee, JW, McCalmont, TH, LeBoit PE. 21. Curkova AK, Hegyi J, Kozub P, Szep Z, ostial and dermal duct nevus (PEODDN) and Over-expression of p53 tumor suppressor protein D’Erme AM, Simaljakova M. A case of linear porokeratotic eccrine and hair-follicle nevus in porokeratosis. Arch Dermatol 1988;124:331-2 porokeratosis treated with photodynamic therapy (PEHFN).17 Pruritic popular porokeratosis is 7. Palleschi GM, Torchia D. Porokeratosis with confocal microscopy surveillance Dermatol a variant described in only about 10 previous of Mibelli and Superficial disseminated Ther. 2014 May-Jun;27(3):144-7. reports in the English literature.18,19 This form porokeratosis. J Cutan Pathol. 2008;35:253-5 22. Dervis E, Demirkesen C. Generalized of porokeratosis represents lesions that arise fairly linear porokeratosis. Int J Dermatol. 2006 abruptly in a patient with or without preexisting 8. Stankiewicz P, Lupski JR. Gene, Genomic, Sep;45(9):1077-9. disseminated superficial porokeratosis and tend and Chromosomal Disorders. IN: Goldman to resolve over months.19 L, Schaffer AL, eds. Cecil Medicine. 24th ed. 23. Malhotra SK, Puri KJ, Goyal T, Chahal KS. Philadelphia, PA: Saunders Elsevier; 2011: chap Linear porokeratosis. Dermatol Online J. 2007 Less-commonly reported clinical entities that 40. Oct 13;13(4):15. share the histopathologic characteristic of cornoid lamellation include viral warts, some ichthyoses, 9. Schwarz T, Seiser A, Gschnait F. Disseminated 24. Garg T, Ramchander, Varghese B, Barara M, naevoid hyperkeratosis, , superficial “actinic” porokeratosis. J Am Acad Nangia A. Generalized linear porokeratosis: a squamous cell carcinoma, basal cell carcinoma, Dermatol. 1984;11:724. rare entity with excellent response to acitretin. verruca vulgaris, scars, milia, and solar keratosis.3 10. Gilead L, Guberman D, Zlotogorski A, et Dermatol Online J. 2011 May 15;17(5):3. A differential diagnosis includes psoriasis, actinic al. Immunosuppression-induced porokeratosis keratoses, Darier’s disease, and lichen striatus, of Mibelli: Complete regression of lesions upon Correspondence: Stephanie Blackburn, DO; along with others. cessation of immunosuppressive therapy. J Eur [email protected] Acad Dermatol Venereol. 1995;5:170. Malignant transformation occurs in all of the five major forms of porokeratosis, with variable 11. Tsambaos D, Spiliopoulos T. Disseminated rates of transformation depending on the clinical superficial porokeratosis: complete variant. Lesions of linear porokeratosis have an remission subsequent to discontinuation of increased risk of malignant transformation into immunosuppression. J Am Acad Dermatol. Page 44 GENERALIZED LINEAR POROKERATOSIS: A CASE REPORT AND DISCUSSION Permanent Imiquimod-induced Depigmentation

Anne Donato, MD,* J. Kate Jackson, PA-C,** Laura Sandoval, DO,*** Jonathan S. Crane, DO, FAOCD****

*Internal Medicine Resident, 1st year, New Hanover Regional Medical Center, Wilmington, NC **Dermatology Physician Assistant, Dermone, Wilmington, NC ***Dermatology Resident, 1st year, Campbell University School of Osteopathic Medicine, Buies Creek, NC; Sampson Regional Medical Center, Clinton, NC ****Dermatologist, Dermone, Wilmington, NC; Campbell University School of Osteopathic Medicine, Buies Creek, NC; Dermatology Residency Program Director, Sampson Regional Medical Center, Clinton, NC

Abstract Imiquimod may be used as a topical therapy for actinic keratosis.1 We report on a patient treated with imiquimod for actinic keratoses who developed an inflammatory reaction, which subsequently resulted in depigmentation of the skin at the sites of imiquimod application. At nine-year follow-up, the patient still had skin depigmentation. We hope to increase awareness amongst dermatologists of this rare but potentially permanent of imiquimod and discuss the possible mechanisms by which depigmentation may occur. Introduction Imiquimod is a topical immune-response modifier commonly used in dermatology. It is approved by the U.S. Food and Drug Administration (FDA) for the treatment of condyloma acuminata; non-hyperkeratotic, non-hypertrophic actinic keratosis; and superficial basal-cell carcinomas less than 2 cm in diameter located on the trunk (excluding anogenital area), neck, or extremities (excluding hands and feet).1 The most frequently reported dermatologic adverse reactions include localized erythema, , and crusted skin.1 Pigmentary changes secondary to imiquimod use have been previously reported and are therefore mentioned as a possible side effect on the package.2 However, there are relatively few clinical cases available in the literature, and there is a lack of multi- year follow-up to determine the duration of depigmentation. The FDA lists 68 reports of pigmentary changes out of a total of 1,257 reports related to imiquimod from 1997 to 2003.3 In this case, we report an unusual presentation of imiquimod-induced depigmentation with nine years of follow-up, supporting the possibility that this adverse effect may be permanent. depigmentation on the chest from the imiquimod. (interferon-alpha, interferon-gamma, and Nine years after use of imiquimod cream, the interleukin-12), thereby leading to cell-mediated Case Report patient continues to have areas of depigmentation immunity including anti-viral and anti-tumor A 57-year-old woman presented with multiple 16,17 actinic keratoses at various locations including on her chest (Figure 1). activity. This creates an inflammatory the nose, right upper lip, and chest. She was reaction, such as the erythema that our patient prescribed imiquimod 5% cream to apply to Discussion initially experienced where she applied the the lesions Monday, Wednesday, and Friday Imiquimod-induced depigmentation is a imiquimod cream. Thus, the depigmentation nights. After one month, this was increased to rare side effect. In our case, depigmentation may be analogous to post-inflammatory application every night for three weeks. Five days continued at nine years post imiquimod therapy, hypopigmentation. after starting the nightly application, the patient providing valuable insight suggesting that the Additional mechanisms may also play a role. called complaining of swelling and blistering depigmentation can be permanent. A literature Imiquimod may further cause depigmentation around her lips, swelling around her eyes, and review revealed the development of imiquimod- via a mechanism similar to the pathogenesis of erythema where she had applied the imiquimod. induced depigmentation in a limited number of . Imiquimod promotes cytokine release, She was instructed to stop the imiquimod and previously published case reports.3-15 The nine- which results in the activation of cytotoxic T cells return to office for evaluation. On evaluation, the year follow-up in our case supports that this effect and antigen presentation by Langerhans cells.17 patient was noted to have erythema, edema, and may be long-lasting and of cosmetic significance Depigmentation in vitiligo occurs with the crusting on facial and chest application sites. The to patients. presentation of autoantigens by Langerhans cells patient was instructed to use petroleum jelly three The possible mechanism of the pigmentary leading to activation of cytotoxic T cells to destroy times a day and continue the discontinuation changes secondary to imiquimod use relates to . Melanocytes also have increased of topical imiquimod. At the follow-up two its properties as an immune-response modifier. sensitivity to the oxidative stress that may be months later, the patient had developed areas of 18 Imiquimod stimulates cytokine production mediated by imiquimod. Depigmentation may

DONATO, JACKSON, SANDOVAL, CRANE Page 45 be a result of direct effects on melanocytes. One imiquimod cream. Clin Exp Dermatol. 2006 study demonstrated that imiquimod induces Sep;31(5):721-2. apoptosis of melanocytes.19 Therefore, the 9. Senel E, Seckin D. Imiquimod-induced desirable therapeutic anti-viral and anti-tumor vitiligo-like depigmentation. Indian J Dermatol effects of imiquimod, through a mechanism Venereol Leprol. 2007 Nov-Dec;73(6):423. involving inflammation and Langerhans cells antigen presentation, may also lead to the 10. Serrao VV, Paris FR, Feio AB. Genital undesirable side effect of depigmentation. vitiligo-like depigmentation following use of imiquimod 5% cream. Eur J Dermatol. 2008 Imiquimod may also lead to depigmentation via May-Jun;18(3):342-3. its signaling of the innate immune system through toll-like receptor 7 (TLR7).20 Melanocytes treated 11. Stefanaki C, Nicolaidou E, Hadjivassiliou M, with imiquimod led to reduced pigmentation, Antoniou C, Katsambas A. Imiquimod-induced suggesting TLRs in melanocytes play a role in vitiligo in a patient with genital warts. J Eur Acad inflammation-related pigmentary changes. Dermatol. 2006 Jul;20(6):755-6. 12. Urbina F. Giant basal cell carcinoma. Conclusion Improvement and vitiligo-like hypopigmentation Given that imiquimod is a commonly used after intermittent treatment with 5% imiquimod. therapy, dermatologists should be aware of the Acta Dermatol Croatica. 2012 Dec;20(4):275-8. potential side effect of depigmentation that may 13. Sriprakah K, Godbolt A. Vitiligo-like be permanent. Patients should be educated about depigmentation induced by imiquimod treatment their treatment options and informed about of superficial basal cell carcinoma. Aust J this possible side effect before deciding whether Dermatol. 2009 Aug;50(3):211-13. or not to use imiquimod therapy. Alternative treatments such as cryosurgery may also result 14. Li W, Xin H, Ge L, Song H, Cao W. in depigmentation; in fact, in a small study Induction of vitiligo after imiquimod treatment comparing cryotherapy to imiquimod therapy of condylomata acuminata. BMC Infectious for actinic keratosis, the cosmetic outcome was Diseases. 2014 Jun; 14: 329. better with imiquimod, with significantly fewer 15. Kwon HH, Cho KH. Induction of Vitiligo- 21 patients experiencing hypopigmentation. The Like Hypopigmentation after Imiquimod mechanism leading to imiquimod-induced Treatment of Extramammary Paget’s Disease. depigmentation likely involves post-inflammatory Ann Dermatol. 2012 Nov; 24(4):482-84. hypopigmentation as well as immune-mediated 16. Sauder DN. Immunomodulatory and effects on melanocytes. pharmacologic properties of imiquimod. J Am Acad Dermatol. 2000 Jul;43(1 Pt 2):S6-11. References 17. Suzuki H, Wang B, Shivji GM, Toto P, 1. Imiquimod: Drug Information [Internet]. Amerio P, Tomai MA, et al. Imiquimod, a topical Waltham, MA: UpToDate. [Cited 2014 Aug immune response modifier, induces migration 24]. Available from http://www.uptodate.com/ of Langerhans cells. J Invest Dermatol. 2000 contents/imiquimod-drug-information. Jan;114(1):135-41. 2. ALDARATM (imiquimod) cream, 5% 18. Mashiah J, Brenner S. Possible mechanisms in [Internet]. FDA. [Cited 2014 Aug 24]. Available the induction of vitiligo-like hypopigmentation from http://www.accessdata.fda.gov/drugsatfda_ by topical imiquimod. Clin Exp Dermatol. 2008 docs/label/2002/20723s11s12lbl.pdf. Jan;33(1):74-6. 3. Brown T, Zirvi M, Cotsarelis G, Gelfand JM. 19. Kim CH, Ahn JH, Kang SU, Hwang HS, Vitiligo-like hypopigmentation associated with Lee MH, Pyun JH, et al. Imiquimod induces imiquimod treatment of genital warts. J Am Acad apoptosis of human melanocytes. Arch Dermatol Dermatol. 2005 Apr;52(4):715-6. Res. 2010 May;302(4):301-6. 4. Al-Dujaili Z, Hsu S. Imiquimod-induced 20. Jin SH, Kang HY. Activation of toll-like vitiligo. Dermatol Online J. 2007;13(2):10. receptors 1, 2, 4, 5, and 7 on human melanocytes 5. Burnett CT, Kouba DJ. Imiquimod-induced modulate pigmentation. Ann Dermatol. 2010 depigmentation: report of two cases and Nov;22(4):486-9. review of the literature. Dermatol Surg. 2012 21. Foley P, Merlin K, Cumming S, Campbell Nov;38(11):1872-5. J, Crouch R, Harrison S, et al. A comparison 6. Gowda S, Tillman DK, Fitzpatrick JE, Gaspari of cryotherapy and imiquimod for treatment AA, Goldenberg G. Imiquimod-induced vitiligo of actinic keratosis: lesion clearance, safety, and after treatment of nodular basal cell carcinoma. J skin quality outcomes. J Drugs Dermatol. 2011 Cutan Pathol. 2009 Aug;36(8):878-81. Dec;10(12):1432-8. 7. Jacob SE, Blyumin M. Vitiligo-like hypopigmentation with following Correspondence: Jonathan S. Crane, DO, treatment of superficial basal cell carcinoma with FAOCD; [email protected] imiquimod. Dermatol Surg. 2008 Jun;34(6):844- 5. 8. Mendonca CO, Yates VM. Permanent facial hypopigmentation following treatment with

Page 46 PERMANENT IMIQUIMOD-INDUCED DEPIGMENTATION Telangiectasia Macularis Eruptiva Perstans: A Case Presentation and Discussion

Sergey Petrosian, BS,* Shane Meehan, MD,** Anna Slobodskya, DO,*** Peter Saitta, DO****

*Medical Student, 3rd year, New York Institute of Technology College of Osteopathic Medicine, Old Westbury, NY **Director of Dermatopathology, Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY ***Dermatology Resident, 1st year, St. John Episcopal Hospital, Far Rockaway, NY ****Dermatologist and Clinical Instructor, Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY

Abstract Telangiectasia macularis eruptiva perstans (TMEP) is a rare subtype of cutaneous that tends to appear during adulthood. Cutaneous mastocytosis is a proliferation of mast cells limited to the skin that spares other organs. of the lesions show red-to-brown, telangiectatic macules diffusely spread over the trunk and upper extremities. We present a case of a 32-year-old male with TMEP who lacked systemic symptoms and discuss the clinical presentation, histopathology, and treatments. Another 3 mm punch biopsy was taken from the patient’s lower back on the right side. The pathology report described occasional small lymphocytes and scattered mast cells (Figure 5). Leder stain highlighted approximately 18 mast cells per high power field in the papillary and superficial dermis (Figure 6). The patient was sent for genetic testing. No abnormalities were reported. The constellation of physical and histological features pointed toward a diagnosis of telangiectasia macularis eruptiva perstans. Discussion Mastocytosis is a collection of rare disorders, all caused by the pathologic proliferation of mast cells. The disorders are typically categorized into two major subtypes based on whether or Figure 1. Multiple brown-to-red, telangiectatic macules of varying sizes, diffusely distributed on not the proliferation is localized. When limited the patient’s back. to the skin, the term “cutaneous mastocytosis” is used. If the proliferation of cells is widespread preceding illness, dyspnea, epistaxis, abdominal throughout the organs of the body, it is termed pain and . Past medical and surgical “systemic mastocytosis.”1 Mast cells play a role in history was insignificant. Family history included inflammatory and allergic responses by releasing a first cousin on the maternal side with vitiligo cytokines, histamines, tryptases, interleukins and and epistaxis and a mother who died of breast other chemical mediators upon degranulation. cancer. The patient had no known drug allergies. The downstream effects of these mediators on their receptors cause the clinical manifestations Physical examination revealed no visible oral seen in mastocytosis. mucosal or lesions. Cutaneous findings included multiple brown-to-red, Systemic mastocytosis is marked by , telangiectatic macules of varying sizes diffusely tachycardia, pruritus, dyspnea, abdominal pain, diarrhea or .1 Cutaneous mastocytosis, on Figure 2. Erythematous, telangiectatic macules placed on the body, with the majority of the the other hand, does not manifest with systemic of varying sizes on the patient’s chest. lesions present on the scapula (Figures 1 and 2). The remainder of the exam was essentially symptoms. It is subdivided into four categories: normal. , mastocytoma, diffuse Case Report and erythrodermic cutaneous mastocytosis, A total tryptase level, CBC with differential, A 32-year-old Caucasian male presented and telangiectasia macularis eruptiva perstans CMP, BMP, and thyroid-hormone level were complaining of new-onset skin lesions on his (TMEP).1,2 TMEP was initially described obtained, and all were within normal limits. chest, back and left eye. He reported that the by Parkes Weber in 1930 and is found in less lesions began to appear about three months A 6 mm biopsy was taken from the patient’s skin than 1% of patients diagnosed with cutaneous prior and since then had increased in number. overlying the right scapula. The pathology report mastocytosis.2,3 The patient complained that the lesions felt described dilated small blood vessels within the TMEP, unlike the other types of cutaneous pruritic, burning and very uncomfortable. He also superficial dermis (Figure 3). A Leder stain mastocytosis, often presents in adulthood.3 reported that he had sudden onset of flushing highlighted a slightly increased number of mast Clinically, it is characterized by red-to-brown, and sweating with stress. A review of systems was cells within the dermis (Figure 4). negative for weight loss, constitutional symptoms, telangiectatic macules. The lesions are usually PETROSIAN, MEEHAN, SLOBODSKYA, SAITTA Page 47 between 2 mm and 4 mm in diameter and are G, Krishnaswamy G. Telangiectasia macularis commonly found on the trunk and proximal eruptiva perstans: more than skin deep. extremities, symetrically.3 The palms, soles and Dermatology Reports [serial online]. January face are classically spared.3 There may be variable 2011;3(1):23-30. amounts of pruritus associated with the lesions. 4. Ragi J, Lazzara DR, Harvell JD, Milgraum Darier’s sign (urticaria after friction accompanied SS. Telangiectasia Macularis Eruptiva Persians with erythema, pruritus and swelling) is Presenting as Island Sparing. Journal Clin commonly absent in this form of cutaneous Aesthet Dermatol. 2013;6(4):41-42. mastocytosis, but is found in other types. 5. Crawhall JC, Wilkinson RD. Systemic TMEP has been found in the setting of systemic mastocytosis: management of an unusual case mastocytosis.2,3 Suspicion of systemic involvement with histamine (H1 and H2) antagonists and should arise if patients have simultaneous cyclooxygenase inhibition. Clin Invest Med. Figure 3. Scapula lesion, H&E stain: Increased symptoms of anaphylaxis, dyspnea, diarrhea, 1987;10:1-4. perivascular and interstitial mast cells syncope, tachycardia, pruritus, abdominal pain, surrounding dilated telangiectatic blood and flushing.1 Tryptase is a large component of 6. Johnson GJ, Silvis SE, Roitman B, et al. vessels. the granules contained within mast cells, and Long-term treatment of systemic mastocytosis therefore measuring the total serum tryptase level with histamine H2 receptor antagonists. Am J is a good test to decipher if patients have systemic Gastroenterol. 1980;74:485-9. involvement. 7. Murali MR, Castells MC, Song JY, et al. Case Histopathologic studies of skin biopsies are used records of the Massachusetts General Hospital. to confirm the diagnosis of TMEP. Histologically, Case 9-2011. A 37-year- old man with flushing TMEP demonstrates increased perivascular and and hypotension. N Engl J Med; 2011;364:1155- interstitial mast-cell collections surrounding 65. 4 dilated telangiectatic blood vessels. The mast 8. Alto WA, Clarcq L. Cutaneous and systemic cells are usually located in the upper portion manifestations of mastocytosis. Am Fam of the dermis, surrounding the dilated blood Physician. 1999;59:3047-60. vessels.4 The number of mast cells is only slightly 9. Sotiriou E, Apalla Z, Ioannides D. increased, and there may also be associated 3 Telangiectasia macularis eruptive perstans Figure 4. Scapula lesion, Leder stain: Mast findings of epidermal hyperpigmentation. cells surrounding dilated, thin-walled successfully treated with PUVA therapy. There is no gold standard therapy for TMEP, and blood vessels in the dermis. Photodermatol Photoimmunol Photomed. the goal is to alleviate symptoms. H1 2010;26:46-7. antagonists can be used to treat the pruritus and 10. Prignano F, Troiano M, Lotti T. Cutaneous flushing symptoms, while H2 antagonists can be 3,5,6 mastocytosis: successful treatment with used in treating the gastric hypersecretion. It is narrowband ultraviolet B phototherapy. Clin Exp important for patients to avoid triggers that can Dermatol. 2010;35:914-5. stimulate mast-cell degranulation. Triggers can include, but are not limited to: alcohol, bacterial 11. Czarnetzki BM, Rosenbach T, Kolde G, et toxins, stress, exercise, food, sunlight, temperature al. Phototherapy of urticaria pigmentosa: clinical extremes, narcotics and anesthesia.3,7,8 Psoralen response and changes of cutaneous reactivity, (oral), UVA photochemotherapy, high-dose histamine and chemotactic leukotrienes. Arch UVA-1 and narrow-band UVB phototherapy Dermatol Res. 1985;277:105-13. have all been shown to improve symptoms 3,9-11 12. Monahan TP, Petropolis AA. Treatment and cosmetic appearance. Surgery via a of telangiectasia macularis eruptiva perstans Figure 5. Lower-back lesion, H&E stain: 585 nm flashlamp-pumped dye laser has also with total skin electron beam radiation. Cutis. Increased perivascular and interstitial mast shown cosmetic improvement in the cutaneous 3,12,13 2003;71:357-9. cells surrounding dilated telangiectatic blood lesions. The replacement of antihistamine 13. Ellis DL. Treatment of telangiectasia vessels. therapy with montelukast therapy was shown to be effective in the treatment of TMEP.14 Most of macularis eruptiva perstans with the 585-nm the results from treatment are temporary unless flashlamp-pumped dye laser. Dermatol Surg. therapy is continued indefinitely. A recent study 1996;22:33. used cabozantinib, a signal transduction inhibitor 14. Cengizlier R, et al. Treatment of telangiectasia that blocked growth of mast cells with the D816V macularis eruptive perstans with montelukast. 15 codon mutation. Allergol Immunopathol (Madr). 2009;37:334 References 15. Shah K, Dunn A, Amato C, et al. 1. Izikson L, English JC, Zirwas MJ. The flushing Carbozantinib may be an effective treatment patient: differential diagnosis, workup, and of TMEP with D816V mutation in KIT. J Am treatment. J Am Acad Dermatol. 2006;55:193– Acad Dermatol. 2014;70(5)(suppl1):AB132 208. 2. Soter NA. Mastocytosis and the skin. Hematol Figure 6. Lower-back lesion, Leder stain: Correspondence: Sergey Petrosian, BS; Oncol Clin North Am. 2000;14: 537-55. Mast cells surrounding dilated, thin-walled [email protected] blood vessels in the dermis. 3. Watkins C, Bokor W, Leicht S, Youngberg

Page 48 TELANGIECTASIA MACULARIS ERUPTIVA PERSTANS: A CASE PRESENTATION AND DISCUSSION Hypomelanosis of Ito in Two Infants: A Case Series with Literature Review

Mathew Koehler, DO,* Nicole Rouse, BS,** Tarin Molly Koehler, DO,*** Navid Nami, DO****

*Dermatology Resident, 2nd year, Opti-West/College Medical Center, Long Beach, CA **Medical Student, 4th Year, Western University of Health Sciences, College of Osteopathic Medicine, Pomona, CA ***Family Medicine Physician, Venice Family Clinic, Venice, CA ****Dermatology Residency Program Director, Opti-West/College Medical Center, Long Beach, CA

Abstract Hypomelanosis of Ito is an uncommon condition representing pigmentary and chromosomal mosaicism. Characteristic findings include whorls and streaks of hypopigmentation involving some or all of the skin surface and generally following the lines of Blaschko. Associated systemic findings include orthopedic, neurologic, ocular and dental anomalies, but the severity of extracutaneous involvement varies greatly from cases to case. We report two cases of hypomelanosis of Ito: a 4-month-old male infant with extensive cutaneous involvement, associated joint contractures and presumed neurologic developmental delay; and a 3-month-old male with limited skin involvement and no apparent systemic involvement. Introduction Case 2 Pigmentary disorders are common in infants A 3-month-old male Indian infant presented and children, often causing emotional distress to our clinic for concerns of pigmentation to parents and providers. Hypomelanosis of changes. The parents stated that at birth it was Ito is an uncommon condition representing undetectable, but the pigmentation became somatic mosaicism, with hypopigmented patches pronounced by about six weeks of age. They had and streaks following the lines of Blaschko. tried hydrocortisone lotion as well as emollients Associated systemic findings range from none to without improvement. Beyond his skin findings, severe systemic effects. The diagnosis is clinical, the child has been eating well and meeting all based on history and physical examination, milestones. Family history was reviewed and and subsequent workup is based on associated found to be non-contributory. findings. Currently, there is no treatment for Physical examination showed the ventral aspect cutaneous manifestations. of the child’s trunk, the proximal legs and the left forearm to have hypopigmented patches following a blaschkolinear pattern (Figure 3). Case Reports The remaining body surfaces had no noticeable Case 1 pigmentation changes. The child did not A 4-month-old male Hispanic infant presented have teeth at the time of exam. There were no to our clinic with a primary concern of unusual noticeable musculoskeletal abnormalities, and eye pigmentation covering the child’s entire body. examination showed matching irises. The child’s Figure 2 The mother stated that when the infant was case was discussed with the pediatrician and the born, she noticed mild pigmentation changes, parents, and no referrals were made. Instead, but by two weeks of age the pigmentation was we decided to continue to monitor the child’s very noticeable. The child had been diagnosed development and make further evaluations based with bilateral sensorineural hearing loss, plantar on potential findings as they arise. flexion contractures of the feet bilaterally, ankle contractures and flexion contractures of the fingers. His pediatrician was concerned for developmental delay based on poor head control and delayed motor skills. The gestational period was uneventful, with the patient being born at term with a normal vaginal delivery. Family history was reviewed and not contributory. On examination, the patient had whorls and streaks of hypopigmented patches involving the majority of his skin surface in a blaschkolinear pattern (Figures 1 and 2). The patient had no teeth at the time of examination. Examination of the eyes revealed matching eye color and no strabismus. Head control was indeed poor, and he had stiff joints of the hands and feet bilaterally. No laboratory work or biopsies were done. Based Figure 3 on the child’s history and physical examination, a diagnosis of hypomelanosis of Ito was made. No Discussion specific treatments were rendered, but referrals Hypomelanosis of Ito (HI) is an uncommon were made to a geneticist, neurologist and syndrome presenting as hypopigmented orthopedic surgeon for evaluation and possible whorls or streaks that generally follow the treatment. Since initial evaluation, the patient has Figure 1 lines of Blaschko. This striking physical been lost to follow-up. KOEHLER, ROUSE, KOEHLER, NAMI Page 49 Table 1. Diagnostic Criteria Proposed by Ruiz-Maldonado, et al.1 and many mild cases likely go unreported, it is difficult to know the true number of HI cases that Criteria 1 Congenital or acquired nonhereditary cutaneous hypopigmentation in have associated systemic anomalies. Nehal et al. (must have) linear streaks or patches involving more than two body segments found that extracutaneous manifestations were only present in 33% of cases, and that the severity Major 1+ nervous system anomalies of these symptoms was directly correlated with 1+ MSK anomalies 7 the level of mosaicism, as with our two patients. Minor 2+ congenital malformations other than neuro or MSK Associated findings include neurologic, Chromosomal anomalies musculoskeletal (MSK), dental and ocular 5 Definitive dx Criteria 1 and 1+ Majors, or abnormalities. Neurologic symptoms are most Criteria 1 and 2+ Minors common, ranging from seizures to severe mental retardation. Musculoskeletal symptoms are Presumptive dx Criteria 1 alone, or also common and include abnormalities of the Criteria 1 with 1 minor phalanges, limbs, spine, skull and sternum.2,8-10 Dental abnormalities include anodontia and pattern represents chromosomal mosaicism in described as incontinentia pigmenti achromians, dysplasia. Strabismus and hypertelorism have pigment production of the skin.1 The majority as it appeared to be a negative image of been reported. Recently, an infant was diagnosed of cases follow the blaschkolinear pattern, but incontinentia pigmenti, but this term has fallen with HI and associated pulmonary hypoplasia.11 occasionally checkerboard, dermatomal, phylloid out of favor because the two conditions are not 2-4 Diagnosis is clinical, based on the cutaneous and plaque-like patterns can be found. The related. findings, but associated symptoms may help extent of involvement varies from segmental to 5 Associated systemic abnormalities are common, identify HI. Some authors, however, only apply the total cutaneous involvement. It presents within but hypopigmentation is the only constant feature term HI when there are extracutaneous symptoms the first year of life in 75% of patients, with 12 and has wide phenotypic variability based on associated with the hypopigmentation. lighter-skinned children sometimes presenting when gene defects occurred during embryologic Alternative terms to use for patients with only as late as childhood. There is a slight female 5 6 migration. As this condition is uncommon, cutaneous findings could be “linear nevoid predominance. Historically, HI had been

Table 2. Differential Diagnosis of Blaschkolinear Pigment Alteration Condition Presentation Associated Findings Hypomelanosis - Numerous genetic defects associated - Central nervous system involvement (seizures, mental retardation) of Ito - Somatic mosaicism - Dental anomalies - Hypopigmented macules and papules that follow the - Musculoskeletal abnormalities lines of Blaschko - Abnormal neural migration1 - Covers more than two dermatomes - Often bilateral, but not symmetrical Incontinentia - X-linked dominant, and deadly in males - Scarring alopecia Pigmenti - NEMO gene mutation - Dystrophic nail changes - Four stages: - Anodontia or conical deformities of the teeth Newborns: linear papules and vesicles; eosinophilia - Ophthalmologic problems Lesions progress to verrucous streaks that usually - Central nervous system manifestations resolve 3-6 months: hyperpigmented whorls and swirls along Blaschko lines 2nd-3rd decade: hyperpigmented whorls become hypopigmented Lichen Striatus - Sudden eruption of erythematous or skin-toned linear - Nail involvement possible. papules - No known associated systemic findings - Usually asymptomatic, but can be pruritic - Active eruption lasts approximately 6-12 months - Post-inflammatory pigment alteration common for years - Unilateral Linear and - Also represents somatic mosaicism - Variable, may have no findings Whorled Nevoid - Hyperpigmented and hypopigmented macules that - Central nervous system involvement Hypermelanosis follow lines of Blaschko - Musculoskeletal abnormalities (LWNH) - Present at birth or in infancy and continues to grow - Heart abnormalities for 1-2 years, then stabilizes McCune-Albright - GNAS1 mutation - Multiple endocrine abnormalities Syndrome - Café-au-lait macules that follow the lines of Blaschko - Precocious puberty and present in infancy - Polyostotic fibrous dysplasia - Often unilateral - Oral mucosal lentigines may present later in life - “Coast of Maine” border of café-au-lait macule Focal Dermal - X-linked dominant - Ectrodactyly (lobster-claw deformity) Hypoplasia (Goltz - Mutation in PORCN gene - “Raspberry-like” papillomas favoring perioral and perianal area Syndrome) - Hypopigmented or hyperpigmented blaschkolinear - Ocular and dental abnormalities common lesions with associated dermal atrophy and telangiectasias

Page 50 HYPOMELANOSIS OF ITO IN TWO INFANTS: A CASE SERIES WITH LITERATURE REVIEW hypopigmentation” or “pigmentary mosaicism.” dental and ocular symptoms. Identification of 10. Ruiz-Maldonado R, Toussaint S, Tamayo L, This naming system seems ill-conceived, though, hypopigmentation can be made with histology, Laterza A, del Castillo V. Hypomelanosis of Ito: since the true effects of subtle neurologic and genetic testing and Wood’s light. Once HI is diagnostic criteria and report of 41 cases. Pediatr extracutaneous defects may not be evident until suspected, optional testing includes radiography Dermatol. 1992;9(1):1-10. years later, as developmental milestones and for skeletal abnormalities, electromyelography speech progress, and the eventual recognition (EMG) for muscle function, head CT or MRI, 11. Bhat RY, Patra S, Varma PV, Prakashini K. of those defects would require a renaming of ophthalmologic exam, and electroencephalography Hypomelanosis of Ito with an unusual pulmonary the child’s condition. We prefer to consider this (EEG) if seizures are present. Magnetic resonance abnormality in an infant. Indian Dermatol Online a spectrum of disease and use HI to describe all imaging appears to be the most sensitive test to J. 2014;5(2):196-7. 24,25 patients with this phenotypic pattern. visualize neural migration abnormalities. It 12. Hall BD. Of mice, persons, and pigment. Am J In 1992, Ruiz-Maldonado et al. proposed criteria is prudent to involve primary care, orthopedic or Hum Genet. 1989;45(2):191-2. 10 physical medicine specialists, and neurologists (as to diagnose HI, found in Table 1. They based needed) early in the patient’s life. A referral to a 13. Donnai D, Read AP, McKeown C, Andrews T. the criteria on clinical experience and previous geneticist is also likely warranted. Hypomelanosis of Ito: a manifestation of mosaicism reports, though they admit the criteria may not or chimerism. Am J Med Genet. 1988;25(12):809- be accurate in diagnosing HI until its etiology 18. has been found. They categorized the presence of Conclusion 14. Ritter CL, Steele MW, Wenger SL, Cohen BA. chromosomal anomalies as a minor criterion, and There are no specific treatments for Chromosome mosaicism in hypomelanosis of Ito. present HI as a neurocutaneous syndrome. While hypomelanosis of Ito, but prompt identification Am J Med Genet. 1990;35(1):14-7. significant advances have been made since this of associated findings may improve prognosis classification was introduced, it may still provide in patients. Once identified, early involvement 15. Sybert VP, Pagon RA, Donlan M, Bradley useful guidance for practitioners. of a multidisciplinary team is warranted based CM. Pigmentary abnormalities and mosaicism for Mosaicism is the presence of two genetically on the extracutaneous findings. The striking chromosomal aberration: association with clinical distinct cell lines in a single person derived from features similar to hypomelanosis of Ito. J Pediatr. 13-15 physical findings are a result of pigmentary and a homogeneous zygote. In embryogenesis, chromosomal mosaicism, but there is still much 1990;116(4):581-6. are randomly distributed and to be learned about the genetic mutations leading 16. Moss C, Larkins S, Stacey M, Blight A, Farndon migrate dorsoventrally along lines of Blaschko, to these findings. With improved knowledge, PA, Davison EV. Epidermal mosaicism and resulting in two populations of epidermal skin Blaschko’s lines. J Med Genet. 1993;30(9):752-5. with different pigment-producing potential. more focused workups and treatments may be Phenotype varies greatly depending on the available in the future. 17. Happle R. Incontinentia pigmenti versus timing of the mutation and the cell lines affected. hypomelanosis of Ito: the whys and wherefores of a As would be expected, a mutation presenting References confusing issue. Am J Med Genet. 1998;79(1):64-5. earlier in embryologic development will have 1. Hamosh A. Hypomelanosis of Ito. HMI 18. Koiffmann CP, de Souza DH, Diament A, more widespread pigmentary mosaicism and be Johns Hopkins University. 2001 [updated 2011; Ventura HB, Alves RS, Kihara S, et al. Incontinentia associated with more severe systemic findings.7 cited 2014]. Available from: http://www.omim. pigmenti achromians (hypomelanosis of ITO, MIM Mutations occurring late in development are org/entry/300337?search=hypomelanosis of 146150): further evidence of localization at Xp11. likely more segmental and associated with absent ito&highlight=hypomelanosi of ito. Am J Med Genet. 1993;46(5):529-33. or mild systemic findings. Our two cases seem to support this. 2. Kuster W, Konig A. Hypomelanosis of Ito: no 19. Hatchwell E, Robinson D, Crolla JA, Cockwell entity, but a cutaneous sign of mosaicism. Am J Med AE. X inactivation analysis in a female with Multiple genetic defects have been found in Genet. 1999;85(4):346-50. patients with HI. Thomas et al. found mosaicism hypomelanosis of Ito associated with a balanced in lymphocytes and skin fibroblasts along with 3. Metzker A, Morag C, Weitz R. Segmental X;17 translocation: evidence for functional disomy autosomal or sex chromosomes.4 Moss et al., . Acta Derm Venereol. of Xp. J Med Genet. 1996;33(3):216-20. however, found no dermal abnormalities but did 1983;63(2):167-9. 20. Grosshans EM, Stoebner P, Bergoend H, 16 find mosaicism within involved keratinocytes 4. Thomas IT, Frias JL, Cantu ES, Lafer CZ, Stoll C. [Incontinentia pigmenti achromians Pascual-Castroviejo et al. recorded autosomal- Flannery DB, Graham JG, Jr. Association of (ITO). Clinical and histopathological study]. dominant inheritance in some patients, but Dermatologica. 1971;142(2):65-78. 9 pigmentary anomalies with chromosomal and most cases appear to be sporadic. Happle et al. genetic mosaicism and chimerism. Am J Hum published a case report of sporadic inheritance in 21. Happle R, Krenz J, Pfeiffer R. [Ito’s syndrome 17 Genet. 1989;45(2):193-205. a 26-year old male. Despite the variation, four (incontinentia pigmenti achromians)]. Hautarzt. common genetic defects have been found: short 5. Ponti G, Pellacani G, Tomasi A, Percesepe A, 1976;27(6):286-90. arm of X-chromosome (XP11), short arm of Guarneri C, Guerra A, et al. Hypomelanosis of Ito 22. Nordlund JJ, Klaus SN, Gino J. Hypomelanosis chromosome 12, trisomy of chromosome 18, and with a trisomy 2 mosaicism: a case report. J Med of Ito. Acta Derm Venereol. 1977;57(3):261-4. triploides.1,18 In addition, failure of X-inactivation Case Rep. 2014;8:333. (lyonization) may be responsible for sporadic 23. Saxena U, Ramesh V, Iyengar B, Misra 19 6. Sharma S, Gupt R, Saxena GN, Raghu MS, cases of HI. RS. Hypomelanosis of ito: histochemical and Patodi A. Hypomelanosis of Ito. J Assoc Phys India. ultrastructural observations. Australas J Dermatol. Histopathologic examination could be useful if the 2014;62(1):47-8. 1989;30(1):45-7. diagnosis is in doubt, but it is not required in the evaluation of HI. Histology can show only subtle 7. Nehal KS, PeBenito R, Orlow SJ. Analysis of 54 24. Ardinger HH, Bell WE. Hypomelanosis of Ito. changes of fewer melanocytes and fewer, smaller cases of hypopigmentation and hyperpigmentation Wood’s light and magnetic resonance imaging as melanosomes that do not produce sufficient along the lines of Blaschko. Arch Dermatol. diagnostic measures. Arch Neurol. 1986;43(8):848- pigment.2,6 Cytogenetic analysis may reveal 1996;132(10):1167-70. 50. chromosomal mosaicism in the keratinocytes, but 8. Jelinek JE, Bart RS, Schiff SM. Hypomelanosis of 25. Lungarotti MS, Martello C, Calabro A, Baldari this test may not be available in all areas. Electron 20-23 Ito (“incontinentia pigmenti achromians”). Report F, Mariotti G. Hypomelanosis of Ito associated with microscopy reveals fewer dendrites. None of of three cases and review of the literature. Arch chromosomal translocation involving Xp11. Am the histological, genetic or electron-microscopy Dermatol. 1973;107(4):596-601. Journal Med Genet. 1991;40(4):447-8. findings are adequate to diagnose HI. Differentials for hypopigmentation that follow Blaschko lines 9. Pascual-Castroviejo I, Lopez-Rodriguez L, de can be found in Table 2. la Cruz Medina M, Salamanca-Maesso C, Roche Herrero C. Hypomelanosis of Ito. Neurological Correspondence: Mathew Koehler, DO; Presentations of HI may vary, and it is important complications in 34 cases. Can J Neurol Sci. [email protected] to perform a thorough examination to identify 1988;15(2):124-9. any concurrent musculoskeletal, neurologic,

KOEHLER, ROUSE, KOEHLER, NAMI Page 51 Phacomatosis Cesioflammea: A Case Report of a Newborn with an Unusual Mongolian Spot and Port Wine Stain

Joy Ishii Zarandy, DO,* Sara Clark, MD,** Katherine Shew, MD***

* Family Medicine Resident, 2nd year, AnMed Health, Anderson, SC **Pediatric Hospitalist, Greenville Health Hospital System, Greenville, SC ***Dermatologist, Anderson Dermatology and Skin Surgery Center, Anderson, SC

Abstract Phacomatosis cesioflammea is a rare congenital cutaneous disorder that presents with aberrant Mongolian spot and port-wine stain in a newborn. About half of reported cases develop extracutaneous symptoms, especially involving the central nervous system, so early diagnosis is key in managing these patients so that appropriate referral to a specialist is promptly initiated.1 This case report documents the process of evaluating a newborn with an unusual Mongolian spot and port-wine stain. A thorough list of differential diagnoses, including nevus simplex, arteriovenous malformations, , Klippel- Trenaunay syndrome and Sturge-Weber Syndrome, was ruled out before ultimately diagnosing the patient with phacomatosis cesioflammea. After a year of close neurodevelopmental monitoring, the patient has not manifested any systemic complications, and his prognosis remains good.

Introduction condition with similar presentation. This case patient’s vascular markings, nevus-simplex Phacomatosis cesioflammea is the most report documents the process of diagnosing a patches have indistinct borders, favor the common subtype of a group of rare newborn with phacomatosis cesioflammea and midline such as the nape of the neck or eyelids, congenital cutaneous abnormalities known subsequent management considerations. and resolve spontaneously. Arteriovenous as phacomatosis pigmentovascularis (PPV). malformation, another vascular cutaneous The Latin translation of phacomatosis Case Report finding, may present as macular-vascular A healthy term African-American male, born cesioflammea, meaning “bluish gray” and patches that generally possess a thrill and grow vaginally after an uncomplicated pregnancy to 5 “flame,” appropriately describes the classic over time. Infantile hemangiomas, the most a 23-year-old G1P1, presented with unusual appearance of congenital dermal melanocytosis frequently encountered type of , skin findings on initial newborn exam (Figure (Mongolian spots) and nevus flammeus (port- often appear at birth as telangiectasia with 1). An extensive Mongolian spot covered his 4 wine stain). Cutaneous lesions alone are surrounding due to vasoconstriction. right flank, buttock, and thigh (Figure 2), and largely asymptomatic, but approximately 50% These lesions may resemble port-wine stains in a large port-wine stain extended from his chest of cases have systemic involvement, which early stages and then enlarge in the first few to the fingertips of the right extremity (Figure 6 usually presents within the first months of life.1 years of life before spontaneously resolving. 3). A 6 mm x 20 mm café-au-lait spot was For this reason, a complete physical, including also noted on the right lower back. Limbs were The prominence and unilaterality of the a dilated ocular exam by an ophthalmologist, symmetric, without leg-length or limb-girth patient’s port-wine stain, preferentially and close neurodevelopmental monitoring discrepancies. History and clinical exam were distributed to the right upper extremity, raised are imperative parts of management.1,2 otherwise unremarkable. Family history was concern for presence of an associated syndrome Furthermore, keeping in mind a broad significant only for eczema in his mother. such as Klippel-Trenaunay syndrome (KTS) differential is prudent when diagnosing any rare or Sturge-Weber syndrome (SWS). KTS is disorder so as not to overlook a more common The first task at hand was to formulate a list a congenital malformation of the capillary, of differential diagnoses. Vascular venous, and lymphatic systems in the such as port-wine stains are common findings extremities. Cutaneous findings classically in a newborn, either in the absence of or present with unilateral extremity enlargement in association with congenital cutaneous from underlying musculoskeletal hypertrophy, 3 syndromes. Port-wine stains are low-flow visceral hemangiomas, and venous varicosities.7 capillary malformations that present as SWS presents with facial port-wine stain, blanchable, red or pink patches in 0.1% to leptomeningeal capillary malformations, and 4 2% of newborns. Nevus simplex, also known central nervous system (CNS) abnormalities as “salmon patch” or “stork bite,” is evident including seizures, mental retardation, in 80% of newborns and may be similar in glaucoma or neurologic deficits. Cutaneous 4 appearance to a port-wine stain. Unlike this manifestations are often progressive and Figure 2 Figure 3

Figure1

Page 52 PHACOMATOSIS CESIOFLAMMEA: A CASE REPORT OF A NEWBORN WITH AN UNUSUAL MONGOLIAN SPOT AND PORT WINE STAIN bilateral.8 After further evaluation, KTS and (pigmentation along the first or second warranted in patients with cutaneous findings SWS were placed low on the list of differential branches of the trigeminal nerve), café-au- only, but for cosmetic purposes a pulsed dye diagnoses given that the patient had no note lait macules, CNS involvement or ocular laser can be used for nevus flammeus and a of leg- or arm-size abnormalities and no symptoms. Prognosis of the disorder largely Q-switched laser for pigmented nevi.16 These facial , and these diagnoses would not depends on the presence of systemic disease.8 procedures should be performed in childhood adequately explain the patient’s extensive before school age for the best results.18 Roughly 250 total cases of PPV have been Mongolian spot. reported worldwide, with phacomatosis Evidence of extracutaneous involvement may Mongolian spots are the most common type cesioflammea accounting for 77% of these require further evaluation with early referral 2 and prompt treatment to optimize patient of hyperpigmented lesions in a newborn, cases. Studies reveal a slight female 16 8 outcome. especially in Asian, African American, and predominance as well as an increased Hispanic populations.9 These lesions are incidence in Argentinian, Hispanic, and benign and present as blue-to-gray macules Japanese populations.13 Conclusion Limited literature Mongolian spots and port-wine stains can be due to delayed disappearance of dermal of twin studies in PPV strongly suggest twin common findings on initial newborn exams. melanocytes deep in the dermis. Pigment is discordance, in which monozygotic twins of Special attention should be paid when dealing usually located near the sacral and buttock 14 PPV patients are unaffected. with atypical presentations of these otherwise- area and fades within the first two years of The pathogenesis of PPV is largely unknown. benign pigmented and vascular birthmarks, life.10 Lesions located in extrasacral areas are The most promising hypothesis involves “twin or if the two present simultaneously such known as “aberrant” and may raise concern for spotting” or didymosis, a phenomenon well- as in phacomatosis cesioflammea. Upon underlying disorders. For example, perioral 15 studied in plants and animals. Didymosis diagnosis, a thorough physical exam should Mongolian spots have been reported in 20% to represents a specific form of somatic be performed, including a dilated eye exam by 50% of patients with cleft lip.11 There have also recombination whereby two neighboring an ophthalmologist and close monitoring for been cases of persistent ventrally and dorsally but genetically different mutant clonal cells signs of neurodevelopmental delay, to assess distributed Mongolian spots associated with 2 12 sporadically cross over to form distinctive for extracutaneous manifestations. In patients certain lysosomal-storage disorders. 1 homozygous cell lines. In the case of PPV, this with cutaneous findings alone, prognosis is The patient was eventually given a working process likely occurs in genes coding for vessel good, and treatments such as pulsed dye laser diagnosis of phacomatosis cesioflammea, and development, thus resulting or Q-switched laser are optional for cosmetic which was later confirmed by dermatology in the mosaic appearance of both vascular and purposes.16 Patients with extracutaneous consultation. This cutaneous disorder pigmented nevi.14 findings, which mainly involve the central adequately explained the patient’s unusual nervous system, may require referral to a Skin lesions alone are largely asymptomatic presentation of Mongolian spot and port-wine 16 specialist for further management as indicated. and may lighten over time. However, stain. The overall anticipated prognosis for While phacomatosis cesioflammea is a rarely approximately 50% of PPV cases have this particular patient is good. The absence of reported disorder, physicians should keep it systemic involvement, usually appearing systemic involvement is especially encouraging. 1 in mind when evaluating any newborn with within the first months of life. Research Close contact has been maintained with the prominent and unusual birthmarks. suggests a correlation between the amount of patient’s mother and pediatrician, who report cutaneous involvement and an increased risk he is happy and developing appropriately. He 8 Acknowledgments for multi-systemic complications. The central had a dilated ocular exam per ophthalmology, Special thanks the patient’s mother for her close nervous system is most commonly affected, which was normal, and is to follow up annually communication and cooperation throughout presenting with seizures, cerebral atrophy, with dermatology to monitor cutaneous lesions. the writing of this article. Thanks as well to neurodevelopmental delay, psychomotor AnMed Health Women’s and Children’s retardation, external hydrocephalus, stroke, Hospital, Dr. Lorraine Bruce, Dr. Matthew Discussion and intracerebral hemorrhage.8,13,16 Phacomatosis pigmentovascularis, or PPV, Common Cline, Greenwood Genetics, Melanie LaVoie, is a group of rare congenital cutaneous ocular findings include glaucoma, episcleral Dr. Theresa Knoepp, Dr. David Malpass, and abnormalities diagnosed clinically by the vascular malformations, conjunctival Dr. Mary K. Spraker for their contributions in coexistence of pigmented nevi and vascular melanocytosis, primary acquired , providing medical care for this patient. 2 epiretinal membrane, vitreous hemorrhage, malformations. The first case of PPV pigmented cataracts, amblyopia, and related was described in 1947 by Ota et al., who References choroidal melanoma.1,2 categorized the disorder into types I through Other complications 1. Brittain P, Walsh E, Smidt A. Blotchy Baby: V, with subtype “a” for cutaneous involvement include atrial septal defect, renal agenesis, A case of Phakomatosis Pigmentovascularis. J only and “b” for presence of extracutaneous umbilical , idiopathic facial paralysis, Pediatr. 2013;162:1293. 2 , vitiligo, hyper IgE, IgA findings. In 2005, a simpler classification 2. Shields CL, Kligman BE, Suriano M, deficiency, pyogenic granuloma, cavernous system was established by Happle involving et al. Phacomatosis Pigmentovascularis of hemangioma, scoliosis, premature tooth four main groups: phacomatosis cesioflammea, Cesioflammea Type in 7 Patients: combination eruption, macrocephaly, Arnold-Chiari type phacomatosis spilorosea, phacomatosis of ocular pigmentation (melanocytosis or 2 I, syndactyly, bilateral deafness, and eczema. cesiomarmorata, and unclassifiable PPV. melanosis) and nevus flammeus with risk Some reports note an association with KTS Phacomatosis cesioflammea, or PPV type for melanoma. Arch Ophthalmol. 2011 and SWS.17 II, is diagnosed by the presence of aberrant June;129(6):746-750. Mongolian spots and port-wine stain. Initial workup should include a complete 3. Jacobs AH, Walton RG. The incidence of Additional cutaneous findings may include physical exam, close neurodevelopmental birthmarks in the neonate. Pediatrics. 1976; (hypopigmentation due to monitoring, and a thorough dilated ocular exam 58:218. permanent vasoconstriction), nevus of Ota by an ophthalmologist.2 No treatment may be ZARANDY, CLARK, SHEW Page 53 4. Kanada KN, Merin MR, Munden A, J Am Acad Dermatol. 2008;58(1):88-93. Friedlander SF. A prospective study of cutaneous findings in newborns in the United 18. Segatto MM, Scmitt EU, Hagemann LN, States: correlation with race, ethnicity, and da Silva RC, Cattani CAS. Phacomatosis gestational status using updated classification Pigmentovascularis Type IIa - Case Report. and nomenclature. J Pediatr. 2012;161:240. An Bras Dermatol. 2013;88(6 Suppl 1):S85-8.

5. Requena L, Sangueza OP. Cutaneous vascular anomalies. Part I. Hamartomas, Correspondence: Joy Zarandy, DO; joy. malformations, and dilation of preexisting [email protected] vessels. J Am Acad Dermatol. 1997;37:523.

6. Vidaurri-de la Cruz H, Tamayo-Sanchez L, Duran-McKinster C, de la Luz Orozco- Covarrubias M, Ruiz-Maldonado R. Phakomatosis Pigmentovascularis IIA and IIB: Clinical findings in 24 patients. J Dermatol. 2003;30:381-388. 7. Jacob AG, Driscoll DJ, Shaughnessy WJ, et al. Klippel-Trénaunay syndrome: spectrum and management. Mayo Clin Proc. 1998;73:28.

8. Okunola P, Ofovwe G, Abiodun M, Isah A, Ikubor J. Phakomatosis pigmentovascularis type IIB in association with external hydrocephalus. BMJ Case Rep. 2012 June 25;2012. 9. Cordova A. The Mongolian spot: a study of ethnic differences and a literature review. Clin Pediatr (Phila). 1981;20:714. 10. Gupta A, Thappa DM. Mongolian spots- -a prospective study. Pediatr Dermatol. 2013; 30:683. 11. Kurata S, Ohara Y, Itami S, et al. Mongolian spots associated with cleft lip. Br J Plast Surg. 1989;42:625. 12. Hackbart BA, Arita JH, Pinho RS, et al. Mongolian spots are not always a benign sign. J Pediatr. 2013;162:1070. 13. Rasi A, Tabaie M, Hassannejad H. Phakomatosis pigmentovascularis type IIa. Iranian J Dermatol. 2012;15:62-65. 14. Castori M, Sarazani S, Binni F, Pezzella FR, Cruciani G, Grammatico P. Monozygotic twin discordance for phacomatosis cesioflammea further supports the post-zygotic mutation hypothesis. Am J Med Genet. 2011;155:2253- 2256. 15. Bolognia JL, Jorizzo J, Schaffer JV. Dermatology. 3rd Edition. China: Elsevier; 2012. Chapter 55, Twin Spotting; Vol 1, Section 9. 16. Wobser M, Goebeler M, Hamm H. Extensive Red and Blue Patches in a Young Girl. Klin Padiatr. 2013;225:46-47. 17. Fernandez-Guarino M, Boixeda P, de las Heras E, Aboin S, Garcia-Millan G, Olasolo PJ. Phakomatosis Pigmentovascularis: Clinical findings in 15 patients and review of literature.

Page 54 PHACOMATOSIS CESIOFLAMMEA: A CASE REPORT OF A NEWBORN WITH AN UNUSUAL MONGOLIAN SPOT AND PORT WINE STAIN last modified on April 27, 2015 8:12 AM

Perspectives Views from the JAOCD Readership

ATHALYE Page 55 While Serving Abroad, Remembering the “Why” Behind Dermatology

Leela Athalye, DO; Chief Resident, Western University/College Medical Center, Long Beach, CA

Most of us started the long, often arduous journey Addis Ababa, Ethiopia. Here, we created our to become dermatologists for one reason: to help own clinic using an elementary school and saw people. However, with the various complicated over 1,100 patients within a week’s time. Every steps we take on a daily basis, like learning the day, we would walk into a chaotic scene where billing, dealing with insurance companies, and people were lined up for hours just to see us. It memorizing the board fodder, we often forget the was an extremely rewarding experience to end simple, true motivation behind what we do. I feel each day knowing we had served each person who fortunate that my dermatology program through had waited to the best of our abilities. Along the Western University/College Medical Center way, we picked up some of the local language, continues to instill the spirit of altruism by Amharic, which to this day we try to use with the providing us the opportunity to serve underserved occasional Ethiopian patient we may encounter. people in the global community. We also spent time volunteering at an HIV- Our dermatology program is the only dermatology clinic, as well as a osteopathic dermatology program in the state clinic. Here we saw HIV-related dermopathy of California. Historically it has been led by Dr. that we had only read about and were able David Horowitz, and now is being continued to learn about the various stages of leprosy by Dr. Navid Nami. From day one of our first-hand, as well as see the local approach dermatology residency, Dr. Horowitz reminded Lines of people waiting to be seen after lunch to diagnosis. We saw interesting pathology, us of why we are doing this. He gave us a list in Addis Ababa. including a hemangiopericytoma on an infant’s of tips that successful people use on a daily basis hand, X-linked ichthyosis and Madura foot. It to not only be successful in our dermatology encourages his residents to partake in at least one was an amazing experience for all of us because it residencies but also in every aspect of our lives so medical mission per year to not only better their was the first time any of us residents had been to that hopefully, we can represent our osteopathic dermatologic knowledge of rarer conditions but Africa and we were awarded the chance to meet communities well. also to serve some of the most underprivileged so many interesting local people. One of the major lessons Dr. David taught all our regions of the world. My second year of residency, we went to the residents is the importance of caring for people, While I was applying to dermatology residency, Dominican Republic, where we served a small not only in our local communities but also in our Dr. David took his team to the Philippines, where community in San Francisco de Marcos. Here, world at large. Fifteen years ago, Dr. Horowitz they performed hundreds of . They were we traveled with the Global Health Organization was approached by an Ethiopian pastor who also able to experience the local culture, e.g., and saw mainly dermatology but also primary described the great need for dermatologic care trying various exotic seafood dishes. My first year care patients with the help of our multispecialty in some of the underserved and impoverished of residency, we returned to one of Dr. David’s team. We treated a range of conditions, from areas of Ethiopia. Dr. Horowitz was inspired to fondest and most well-traveled destinations of mundane conditions like verruca, acne, address this growing dilemma by bringing a team of physicians with him to volunteer in Africa. In addition to Ethiopia, Dr. Horowitz has dedicated his time and money to a dozen medical missions, including ones in Mexico, the Philippines, Guatemala, Ecuador, Dominican Republic, and Kenya. Through his amazing clinical and philanthropic experiences, Dr. Horowitz

Our Dominican team working together to take care of patients of all ages. (Residents Michael Our team of providers and student translators in the Dominican Republic: The many people needed Kassardjian, Donna Tran, Leela Athalye) to make a successful mission.

Page 56 WHILE SERVING ABROAD, REMEMBERING THE “WHY” BEHIND DERMATOLOGY and to less-common entities like . We also performed house calls in the local community, where we treated severe decubitus ulcers and performed hospice care. One of the best parts of our experience was that we were able to further develop our Spanish- speaking skills by talking to patients, as well as with the help of the volunteer Dominican students who translated. Through our interaction with these Dominican students, we were able to not only have a better cultural experience but also give back further to the community as mentors, which is a role we treasure to date. Our international dermatology experiences are one of the most cherished memories that I will take away as I graduate from residency in the next few months. We were able to not only travel to new and exotic locations but also reach many people and provide them with the medical aid they have needed for years. Dr. Horowitz’s ambition to treat patients internationally has only grown stronger as he has retired as program director; with his direction, we continue to be excited about serving abroad. We are currently planning our next Our dermatology team in the Dominican Republic, led by our fearless leader in altruism, Dr. David medical mission to Guatemala and look forward Horowitz. to again embracing the philanthropic reason why we all joined this profession in the first place.

THOMAS, THOMAS Page 57 Letter to the Editor: Wegener’s Granulomatosis Eponym

David Thomas, MD, JD, EdD,* Jacqueline Thomas, DO**

*Professor and Chair of Surgery, 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

To the JAOCD Editor, While there is no evidence of war crimes or criminal activity, the record clearly reflects Dr. References Thank you very much for the latest illuminating 1. Wegener F. Ueber generalisierte septische Friedrich Wegener’s intimate association with Gefäßerkrankungen [About generalized septic issue of The Journal of the American Osteopathic and membership in the Nazi regime. As such, his College of Dermatology. While all of the articles vascular diseases]. Verh Deut Pathol Ges. character must come into question, and therefore 1936;29:202-10. were truly worthwhile, there is some controversy it seems inappropriate to give him the honor of concerning the eponym in the title of one of attaching his name to a disease entity. The Chest 2. Godman GC, Churg J. Wegener’s the articles, “Herpes Zoster Ophthalmicus in Society took the first step by removing its Master granulomatosis: pathology and review of the a Patient with Wegener’s Granulomatosis,” in Clinician designation. literature. AMA Arch Pathol. 1954;58:533-53. Volume 31, page 24. In 2008, there was a move to 3. Rosen M. Dr. Friendrich Wegener: the ACCP remove this eponym from this disease and refer to Generally speaking, we feel the practice of and history. Chest. 2007;132:739-741. it in a more explicative form as “granulomatosis medicine would be well-served, and the teaching and polyarteritis.” of medicine to our students enhanced, if we 4. Allam SR. Controversy over eponym refrained from the use of eponyms completely “Wegener’s granulomatosis.” Nephrology World In 1936, Dr. Friedrich Wegener described and used only scientific, descriptive terminology [Internet]. May 4, 2010 (Accessed January 29, several cases of small vessel vasculitis with 1 for disease entities. While it might be awkward to 2015). Available from: http://nephrologyworld. granulomatous inflammation. In 1954, Goldman refer to Starling’s Law as “End Diastolic Filling blogspot.com/2010/05/controversy-over- and Churg described seven cases of their own and 2 and Stroke Volume,” the descriptor, as opposed eponym-wegeners.html reviewed another 22 previously reported cases. to the eponym, would not only be a far more 5. Woywodt A, Matterson L. Wegener’s Subsequently, the disease became known as understandable path but would also remove any granulomatosis—probing the untold past of Wegener’s granulomatosis, and that eponym has potential for embarrassing ethical disclosures that the man behind the eponym. remained a fixture of the entity. might be associated with an investigator. [Internet]. 2006;45(10):1303-1306 (Accessed In 1989, just prior to his death in 1990, Wegener Yours truly, January 29, 2015). Available from: from was awarded the Master Clinician award by the David L. Thomas, MD, JD, EdD http://rheumatology.oxfordjournals.org/ American College of Chest Surgeons; however, Jacqueline Thomas, DO content/45/10/1303.full in 2007, the American College of Chest Surgeons rescinded this award predicated on Wegener’s 3 known affiliation with the Nazi Party. Correspondence: Jacqueline A. Thomas, DO; Several authors specializing in diseases of the [email protected] chest, rheumatology, and nephrology have stated that in view of that affiliation, the eponym should no longer be used.3-5 Separately, Woywodt and Matterson conducted an extensive six-year probe into the life of Dr. Wegener.5 They found that as early as 1933, he joined the Nazi Party, rising to the rank of Lieutenant Colonel and serving as the pathologist in Lodz in 1939. His office was adjacent to a Polish ghetto. They found no indication of criminal conduct on the part of Wegener, but they did uncover a letter concerning Wegener’s reviewing an article on pulmonary air embolism. Air embolism was seen in septic abortions and was a notorious finding in Nazi altitude experiments done on prisoners.

Page 58 LETTER TO THE EDITOR: WEGENER’S GRANULOMATOSIS EPONYM

Save the Dates for Upcoming AOCD Meetings 2015 Fall Meeting Loews Royal Pacific Resort at Universal Orlando Orlando, FL October 15-18

Thursday, October 15, 2015 8:00 a.m. - 12:00 p.m. AOCD BOT Meeting Saturday, October 17, 2015 12:00 p.m. - 1:00 p.m. Leaders Luncheon 7:00 a.m. - 10:00 a.m. Lectures 1:00 p.m. - 5:00 p.m. AOCD Program Director Meeting 10:00 a.m. - 10:30 a.m. Break with Exhibitors 8:00 a.m. - 5:00 p.m. Exhibitor Set Up 10:30 a.m. - 11:30 a.m. Lectures 4:00 p.m. - 8:00 p.m. Resident In Training Exam 11:30 a.m. - 1:00 p.m. Lunch Lecture 1:00 p.m. - 1:30 p.m. Break with Exhibitors Friday, October 16, 2015 1:30 p.m. - 5:30 p.m. Lectures 7:00 a.m. - 7:30 a.m. CLIA Proficiency 7:30 a.m. - 11:30 a.m. Lectures Sunday, October 18, 2015 11:30 a.m. - 12:00 p.m. Break with Exhibitors 9:30 a.m. - 12:00 p.m. Lectures 12:00 p.m. - 1:30 p.m. Lunch Lecture 12:00 p.m. - 1:30 p.m. Lunch on your own 1:30 p.m. - 4:30 p.m. Lectures 1:30 p.m. - 5:00 p.m. Lectures 4:30 p.m. - 5:30 p.m. Business Meeting 5:00 p.m. End of Conference 7:00 p.m. Presidential Reception *Schedule Subject to Change

2017 Spring Meeting Ritz Carlton | Atlanta, GA March 29 - April 2

2016 Spring Meeting Ritz Carlton Battery Park | New York, NY March 30 - April 3

Continuing Medical Education Division CERTIFICATION OF HOME STUDY FORM (Category 2-B credit)

This to certify that I, ______, have read the following journals from Jan. 1, 2013-Dec. 31, 2015

Total Credits Earned for Journal Name 3-Year CME Cycle Credits Earned

The D.O. 18 credits ______J.A.O.A 18 credits ______J.A.M.A. 78 credits ______N.E.J.M. 78 credits ______Cancer 18 credits ______Chest 18 credits ______Geriatrics 18 credits ______Lancet 18 credits ______Medicine 18 credits ______Obstetrics and Gynecology 18 credits ______Orthopedics 18 credits ______Osteopathic Medicine 18 credits ______Other Journals Not Listed: ______J.A.O.C.D. !! ! 6 credits ! ______(Journal of the American Osteopathic of Dermatology) ! ______

Medical Text Books: Five (5) credit hours may be granted for the reading of medical books. Please list the titles of any medical books you have read but not yet reported.

Total Credits Earned for Journal Reading and Medical Text Books: Total

Physician’s Signature AOA#

Email Address Phone No. AOA Division of CME 142 E. Ontario St., Chicago, IL 60611 Phone: (312) 202-8262 Fax: (312) 202-8202 Email: [email protected] or