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July/August 2015 • Volume 13 • Issue 4 July/August 2015 • Volume 13 • Issue 4

EDITORIAL Continuing Medical Education III: MOC, CME, ABD, ABMS, ACGME, CMS, FSMB, IOM, MOL, PQRS, SMB, Etcetera et Ad Nauseum, Revisited Lambert and Parish

COMMENTARIES Tungiasis: A Neglected Disease Related to Poverty Rios-Yuil

Annular Elastolytic Giant Cell Granuloma and Temporal Arteritis Following Herpes Zoster

Ruocco, Schiavo, Gambardella, and Ruocco

On Zosteriform Distribution Wolf, Ruocco, and Ruocco

CORE CURRICULUM Oral Mucosal Lesions: Oral Cavity Biology––Part I Sehgal, Syed, Aggarwal, and Sehgal

DEPARTMENTS PERILS OF DERMATOPATHOLOGY What Lies Beneath: The Importance of Proper Diagnosis of Cutaneous Horn Peiris, Mathew, and Lambert

NEW THERAPY UPDATE COSENTYX (Secukinumab) Gupta, Foley, and Abramovits

THE HEYMANN FILE Dermatofibromas: From “Ho-Hum” to “OMG!” Heymann

ORIGINAL CONTRIBUTIONS Zosteriform Staphylococcus aureus Cutaneous Infection: Report of Two Patients With Dermatomal Bacterial Infection

HISTORY OF DERMATOLOGY SOCIETY NEWSLETTER Suppuration Following Hair Implantation

Treatment of Scabies: Comparison of Lindane 1% vs Permethrin 5%

case studies Twenty-Nail Dystrophy and Darier’s (Darier-White) Disease

Schepp and Cohen

Rezaee, Goldust, and Alipour

REVIEW Actinic Prurigo

Rodríguez-Carreón, Rodríguez-Lobato, Rodríguez-Gutiérrez, Cuevas-González, Mancheno-Valencia, Solís-Arias, Vega-Memije, Hojyo-Tomoka, and Domínguez-Soto

Self-Assessment Examination Lambert

Basal Cell Carcinoma in a Patient With Brooke–Spiegler Syndrome Vega-Memije, Boeta-Ángeles, and Cuevas-González

Cutaneous Necrotic Papule as Invasive Aspergillosis in a Heart Transplant Patient

Kaminska, Pei, Kenkare, Petronic-Rosic, and Tsoukas

Benign Eccrine Tumors Presenting on the Penis: Common Tumors at an Uncommon Site Tan, Koh, and Ng

SKINart Time Frozen in a Silver Box Goldsmith

INDUSTRY UPDATE Galderma Product Line Expands as Promised by President Todd Zavodnick Kalaka-Adams

Bernhardt

Sehgal, Chatterjee, Chaudhuri, Verma, and Sharma

Chlorambucil-Induced Radiation Recall Dermatitis Clark, Boffa, Magri, and Muscat

Annular Elastolytic Giant Cell Granuloma and Temporal Arteritis Following Herpes Zoster Panzarelli and Fernández

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TABLE OF CONTENTS July/August 2015 • Volume 13 • Issue 4

EDITORIAL

Continuing Medical Education III: MOC, CME, ABD, ABMS, ACGME, CMS, FSMB, IOM, MOL, PQRS, SMB, Etcetera et Ad Nauseum, Revisited ....................................................................................... 262

W. Clark Lambert, MD, PhD; Lawrence Charles Parish, MD, MD(Hon)

COMMENTARIES

Tungiasis: A Neglected Disease Related to Poverty ................................................................................... 264

Jose Manuel Rios-Yuil, MD, MSc, PhD

Annular Elastolytic Giant Cell Granuloma and Temporal Arteritis Following Herpes Zoster ....................... 267

Eleonora Ruocco, MD, PhD; Ada Lo Schiavo, MD; Alessio Gambardella, MD; Vincenzo Ruocco, MD

On Zosteriform Distribution ...................................................................................................................... 271

Ronni Wolf, MD; Eleonora Ruocco, MD, PhD; Vincenzo Ruocco, MD

ORIGINAL CONTRIBUTIONS Zosteriform Staphylococcus aureus Cutaneous Infection: Report of Two Patients With Dermatomal Bacterial Infection ................................................................................................................ 275

Elizabeth D. Schepp, MD; Philip R. Cohen, MD

T:10.5”

Elham Rezaee, PhD; Mohamad Goldust, MD; Houman Alipour, MD

B:11.25”

Treatment of Scabies: Comparison of Lindane 1% vs Permethrin 5% ....................................................... 283

S:9.75”

REVIEW

Actinic Prurigo .......................................................................................................................................... 287

Alma Angélica Rodríguez-Carreón, DDS, MSc; Erika Rodríguez-Lobato, MD; Georgina Rodríguez-Gutiérrez, MD; Juan Carlos Cuevas-González, DDS; Alexandra Mancheno-Valencia, MD; Martha Patricia Solís-Arias, MD; María Elisa Vega-Memije, MD; María Teresa Hojyo-Tomoka, MD; Luciano Domínguez-Soto, MD

SELF ASSESSMENT EXAMINATION ........................................................................................................... 296

W. Clark Lambert, MD, PhD

CORE CURRICULUM

Virendra N. Sehgal, MD, Section Editor

Oral Mucosal Lesions: Oral Cavity Biology––Part I .................................................................................... 297

Virendra N. Sehgal, MD; Nazim Hussain Syed, MD; Ashok Aggarwal, MD; Shruti Sehgal, MDS

Departments Perils of Dermatopathology

W. Clark Lambert, MD, PhD, Section Editor

What Lies Beneath: The Importance of Proper Diagnosis of Cutaneous Horn ............................................ 301

Timothy Peiris, BS; Laju M. Mathew, MD; W. Clark Lambert, MD, PhD

New Therapy Update

William Abramovits, MD; Aditya K Gupta, MD, PhD, FRCPC, Section Editors

COSENTYX (Secukinumab) ....................................................................................................................... 303

Aditya K. Gupta, MD, PhD, FRCPC; Kelly A. Foley, PhD; William Abramovits, MD

257


TABLE OF CONTENTS July/August 2015 2015 •• Volume Volume 13 13 •• Issue Issue 44 July/August

The Heymann File

Warren R. Heymann, MD, Section Editor

Dermatofibromas: From “Ho-Hum” to “OMG!” ......................................................................................... 308

Warren R. Heymann, MD

COLORS

Eve Lowenstein, MD, PhD, Section Editor

C M Y K

History of Dermatology Newsletter

Suppuration Following Hair Implantation................................................................................................... 311

Mark Bernhardt, MD

case studies

Twenty-Nail Dystrophy and Darier’s (Darier-White) Disease ...................................................................... 313

Virendra N. Sehgal, MD; Kingshuk Chatterjee, DNB; Anita Chaudhuri, MD; Prashant Verma, MD; Sonal Sharma, MD

Chlorambucil-Induced Radiation Recall Dermatitis.................................................................................... 317

Eileen Clark, MD; Michael Boffa, MD; Claude Magri, MD; Victor Muscat, MD

Annular Elastolytic Giant Cell Granuloma and Temporal Arteritis Following Herpes Zoster........................ 321

Amalia Panzarelli, MD; Katrina Fernández, MD

Basal Cell Carcinoma in a Patient With Brooke–Spiegler Syndrome........................................................... 325

María Elisa Vega-Memije, MD; Leticia Boeta-Ángeles, MD; Juan Carlos Cuevas-González, PhD

Cutaneous Necrotic Papule as Invasive Aspergillosis in a Heart Transplant Patient................................... 329

Edidiong C.N. Kaminska, MD; Susan Pei, BA; Sonya Kenkare, MD; Vesna Petronic-Rosic, MD, MSc; Maria M. Tsoukas, MD, PhD

Benign Eccrine Tumors Presenting on the Penis: Common Tumors at an Uncommon Site.......................... 331

Aaron Wei Min Tan, MBBS; Mark Jean Ann Koh, MBBS, MRCPCH, FAMS (Dermatology); See Ket Ng, MBBS, MMed (Int Med)

SKINart

Mark Bernhardt, MD, Section Editor

Time Frozen in a Silver Box........................................................................................................................ 333

Lowell A. Goldsmith, MD

DISK DISK

INDUSTRY UPDATE

Jo-Ann Kalaka-Adams, Section Editor

Galderma Product Line Expands as Promised by President Todd Zavodnick.............................................. 335

Jo-Ann Kalaka-Adams

Erratum .................................................................................................................................................... 336

258

DISK: vv 6/16/15 FILE DESCRIPTION:

CONCENTRICHX FILE NAME: 15ENST0359_Coming Soon Ad_Skin Med 8.25″w x 11″h Print Scale: NONE BLEED: 8″w x 10.75″h TRIM: CLIENT: LEO 7.5″w x 10.25″h RELEASE MECH: vv 4/21/15 SAFETY:

Vesna Petronic-Rosic, MD, MSc, Section Editor


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刀䔀䜀䤀匀吀䔀刀 一伀圀 戀礀 瘀椀猀椀椀渀最 䄀䴀䐀猀礀洀⸀挀漀洀 


July/August 2015

Volume 13 • Issue 4

EDITOR IN CHIEF

Lawrence Charles Parish, MD, MD (Hon) Philadelphia, PA

DEPUTY EDITORS William Abramovits, MD

W. Clark Lambert, MD, PhD

Larry E. Millikan, MD

Jennifer L. Parish, MD

Dallas, TX

Newark, NJ Vesna Petronic-Rosic, MD, MSc

Meridian, MS Marcia Ramos-e-Silva, MD, PhD

Philadelphia, PA

Chicago, IL

Rio de Janeiro, Brazil

EDITORIAL BOARD Mohamed Amer, MD Cairo, Egypt

Howard A. Epstein, PhD Philadelphia, PA

Andrew P. Lazar, MD Washington, DC

Virendra N. Sehgal, MD Delhi, India

Robert L. Baran, MD Cannes, France

Ibrahim Hassan Galadari, MD, PhD, FRCP Dubai, United Arab Emirates

Jasna Lipozencic, MD, PhD Zagreb, Croatia

Riccarda Serri, MD Milan, Italy

Eve J. Lowenstein, MD, PhD New York, NY

Charles Steffen, MD Oceanside, CA

George M. Martin, MD Kihei, HI

Alexander J. Stratigos, MD Athens, Greece

Marc S. Micozzi, MD, PhD Rockport, MA

James S. Studdiford III, MD Philadelphia, PA

Venkataram Mysore, MD, FRCP (Hon, Glasgow) Bangalore, India

Robert J. Thomsen, MD Los Alamos, NM

Anthony V. Benedetto, DO Philadelphia, PA Brian Berman, MD, PhD Miami, FL

Anthony A. Gaspari, MD Baltimore, MD Michael Geiges, MD Zurich, Switzerland

Mark Bernhardt, MD Ft. Lauderdale, FL Jack M. Bernstein, MD Dayton, OH Sarah Brenner, MD Tel Aviv, Israel Henry H.L. Chan, MB, MD, PhD, FRCP Hong Kong, China Joel I. Cohen, MD Engelwood, CO Noah Craft, MD, PhD, DTMH Torrance, CA Natalie M. Curcio, MD, MPH Nashville, TN Ncoza C. Dlova, MBChB, FCDerm Durban, South Africa Richard L. Dobson, MD Mt Pleasant, SC William H. Eaglstein, MD Menlo Park, CA Charles N. Ellis, MD Ann Arbor, MI

Michael H. Gold, MD Nashville, TN Orin M. Goldblum, MD Indianapolis, IN

Julian Trevino, MD Dayton, OH

Oumeish Youssef Oumeish, MD, FRCP Amman, Jordan

Graham Turner, PhD, CBiol, FSB Port Sunlight, UK

Joseph L. Pace, MD, FRCP Naxxar, Malta

Snejina Vassileva, MD, PhD Sofia, Bulgaria

Roderick J. Hay, BCh, DM, FRCP, FRCPath London, UK

Art Papier, MD Rochester, NY

Daniel Wallach, MD Paris, France

Johannes Ring, MD, DPhil Munich, Germany

Michael A. Waugh, MB, FRCP Leeds, UK

María Daniela Hermida, MD Buenos Aires, Argentina

Roy S. Rogers III, MD Rochester, MN

Wm. Philip Werschler, MD Spokane, WA

Warren R. Heymann, MD Camden, NJ

Donald Rudikoff, MD New York, NY

Joseph A. Witkowski, MD Philadelphia, PA

Tanya R. Humphreys, MD Bala-Cynwyd, PA

Robert I. Rudolph, MD Wyomissing, PA

Ronni Wolf, MD Rechovot, Israel

Camila K. Janniger, MD Englewood, NJ

Vincenzo Ruocco, MD Naples, Italy

Matthew J. Zirwas, MD Columbus, Ohio

Abdul-Ghani Kibbi, MD Beirut, Lebanon

Noah Scheinfeld, MD, JD New York, NY

Lowell A. Goldsmith, MD, MPH Chapel Hill, NC Aditya K. Gupta, MD, PhD, FRCPC London, Ontario, Canada Seung-Kyung Hann, MD, PhD Seoul, Korea

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Volume 13 • Issue 4

Editorial

Continuing Medical Education III: MOC, CME, ABD, ABMS, ACGME, CMS, FSMB, IOM, MOL, PQRS, SMB, Etcetera et Ad Nauseum, Revisited W. Clark Lambert, MD, PhD;1 Lawrence Charles Parish, MD, MD(Hon)2 “The left hand does not even seem to know what the left hand is doing.”––Ogden Nash

T

he misplaced zeal of physicians and others to regulate physicians continues unabated.1 In the process, the alphabet soup associated with this ill-advised progression becomes yet more obfuscatory, and much more expensive, even as it becomes cataclysmically more irrelevant and obtrusively more obstructionist.2,3 At the time of this writing, a PubMed search revealed 787 contributions on the subject.4

marks.) We have recently received a very well-written, and certainly well-intended, letter from the current president of the American Academy of Dermatology (AAD), urging us to participate in a survey from the American Board of Dermatology (ABD) and to indicate our preferences regarding these two subjects. There are, however, some issues with the survey:

CME In the above laundry list, we failed to include the ACCME, the “Accreditation Council for Continuing Medical Education,” under the aegis of which a stimulating and courageously organized upcoming international meeting, in which we are both privileged to participate, operating on a paper-thin financial margin with which to begin, could be forced to shell out several tens of thousands of dollars so that it could offer Continuing Medical Education (CME) credit to its participants. Even if the ACCME does not further obstruct the meeting, it stands to take almost all of the proceeds, while assuming none of the risk and doing virtually none of the work. Such CME stamp of approval does nothing to further educational pursuits. The absurdity is not continuing; it is snowballing. MOC Perhaps, the most outrageous (and it was no easy task to achieve this status) aspect of all this is the current hubbub surrounding recertification and “maintenance of certification” (MOC4). (No two parties seem to quite agree just what the latter term really means, thus the quotation

1. We did not receive a copy, nor did most members of the AAD. It turns out that this was no accident––we were not sent a copy, nor were most AAD members, a fact of which the AAD president seemed to have been unaware. We are thankful that the US Postal Service and the Internet are not to blame. 2. We were curious as to what the furor was about and so obtained a copy of the survey. It turns out that the questions are so worded that even if an AAD member/ABD diplomate wished to submit a response, most would be disqualified, if answered truthfully. Although the AAD and the ABD both state that the survey was given to ABD diplomates, neither states to which diplomates. It appears that the stated survey was submitted only to a small, carefully selected subset of diplomates. Again, no one seems to have shared this information with the president of the AAD. 3. Even if one wished to respond to the survey and to state an opinion regarding either recertification or maintenance of certification, the survey is so worded that this is essentially impossible.

From the Departments of Dermatology and of Pathology and Laboratory Medicine, Rutgers University – New Jersey Medical School, Newark, NJ;1 and the Department of Dermatology and Cutaneous Biology and Jefferson Center for International Dermatology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA2 Address for Correspondence: W. Clark Lambert, MD, PhD, Rutgers University – New Jersey Medical School, Departments of Dermatology and of Pathology and Laboratory Medicine, Room C576 Medical Science Building, 185 South Orange Avenue, Newark, NJ 07103 • E-mail: lamberwc@njms.rutgers.edu

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In essence, it is virtually impossible to communicate an opinion, regarding either of these subjects via this survey to the ABD, the AAD, or anyone else. Our Suggestion The sad thing about all of this is the polarization it has created. We feel that this is unnecessary and inappropriate. As we have noted previously, recertification, if at all, could be done easily, painlessly, cheaply, and effectively, provided the rank and file were in agreement. A proctored examination would be acceptable, were it to be conducted as follows: 1. One part (the “anti-senility” part) should be on basic dermatology to be sure that the participant can recall basics; ie, macules, papules, Koebner phenomenon, pruritus, etc. This should not be challenging for anyone who is not, in fact, memory challenged. 2. The second part should be time interval specific, for example, 2005–2010. A participant could take as many modules as necessary for the time interval for which recertification were desired. To illustrate this, a physician wishing to be recertified for 2003 to 2015 might take modules 2000–2005, 2005–2010, and 2010–2015. Most importantly, each module must be based entirely on a short, clearly written, inexpensive, and legible synopsis of what was newly published in the interval in question.

One problem with such examinations is that they tend to be open-ended, thus a participant may study incessantly for a year or more. This would be unnecessary and inappropriate in our proposal. The above arrangement should eliminate this issue, as well as most examination anxiety. Conclusions As we have previously noted, the concerns surrounding these types of examinations have not been about aiding or improving the quality of medical care, but rather about money and power. This must change. It is also necessary that the officers of professional societies, such as the AAD, exercise leadership, especially over the hired staff of such organizations. Recertification must be converted from a cash cow into a process that genuinely serves dermatology, its members, and their patients, not self-appointed bureaucracies. References

3. The examination should be cost-effective, not burdensome, and convenient; for example, linked to the annual meeting of the AAD. It should also not be excessively long or arduous. 4. There should be no quotas. A pass rate of 100% is acceptable, and, in fact, probably expected.

1 Stratman E, Kirsner RS, Horn TD. Maintenance of Certification in dermatology: requirements for diplomates. J Am Acad Dermatol. 2013;69:13.e1–13.e4; quiz 17–18. 2 Lambert WC, Parish LC. Contemporary American dermatology: continuing medical education I. Skinmed. 2010;8:134–135. 3 Lambert WC, Parish LC. Continuing Medical Education II: MOC, CME, ABD, ABMS, ACGME, CMS, FSMB, IOM, MOL, PQRS, SMB, etcetera et ad nauseum. Skinmed. 2013;11:262–263. 4 PubMed search for Maintenance of Certification. http:// www.ncbi.nlm.nih.gov/pubmed/?term=Maintenance+of +Certification. Accessed July 12, 2015.

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July/August 2015

Volume 13 • Issue 4

COMMENTARY

Tungiasis: A Neglected Disease Related to Poverty Jose Manuel Rios-Yuil, MD, MSc, PhD

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ungiasis is a cutaneous parasitic disease caused by hematophagous fleas. Tunga penetrans is the main causative agent, but there have been cases caused by Tunga trimamillata in Ecuador and Peru.1–7 These fleas belong to the phylum Arthropoda, class Insecta, order Siphonaptera, family Tungidae, and genus Tunga.1,5,8

The parasite is native to the Americas, and it was transported to the Eastern hemisphere through transatlantic journeys in the nineteenth century.1 Currently, this parasitosis is endemic in Latin America (from Mexico to Northern Chile and Argentina), the Caribbean, sub-Saharan Africa (from Sierra Leone, Ivory Coast, Nigeria, and Ethiopia to the southern countries), Madagascar, Zanzibar, Seychelles Islands, and some countries in Asia (west coast of India and Pakistan) and Oceania.1–13 The cases from North America, Europe, and Australia have been reported in immigrants or in persons who have traveled to endemic areas.1,5,8–11,14 As it has been noticed, tungiasis is a disease of developing countries and it is undoubtedly related to poverty.5–9,13–15 The prevalence in endemic areas ranges from 15% to 55%.5,6,11,13 The main risk factors for transmission can be divided into environmental and behavioral. The presence of infested soil and the close coexistence with infested animals are among the environmental factors.4–7,9-11,13,14 The most important behavioral factors include the habit of walking barefoot or with sandals, of sleeping on the floor, and the lack of proper hygiene.4–7,9,14 The Parasite and its Relationship With the Host T penetrans is the smallest known flea (less than 1 mm in length). It is laterally flattened and reddish brown or yellow-brown in color.2,4-6,8-11 Its head is triangular with a small pair of eyes and short antennae.8 The mouth pieces are specially adapted to perforate the skin and suck blood.4 The thorax is compact and has

3 segments.4,8 The abdomen has 7 segments, and its shape is pointed in the male and oval in the female.8 It has 3 pairs of legs and the last pair is specially adapted for jumping.4,8 T penetrans is a free-living flea that prefers dry, sandy, and shady soil, especially those rich in organic materials, such as decaying leaves or garbage.7 It spreads mainly during the dry season and it parasitizes homoeothermic hosts such as humans, dogs, cats, pigs, rats, mice, cattle, sheep, goats, horses, monkeys, among others.6,8,9 The male and female fleas are hematophagous and they can jump up to 20 cm vertically and crawl or run up to 1 cm/s. The male does not burrow into the host and dies after copulation.9 The gravid female burrows into the epidermis of the host, leaving exposed its anal-genital opening through which it breathes and expels feces and eggs.2,3,6,8,11,14 Once in the epidermis, the female undergoes a process of hypertrophy where it can grow as large as 1 cm in a period of 2 to 3 weeks. During this period, the female generates 150 to 200 eggs and then dies. These eggs are expelled to the environment and most of them fall into the ground where the larvae hatch within 3 or 4 days. The larvae develop into pupae in 10 to 15 days, and the pupae reach adulthood after 5 to 14 days.6,8,9 Clinical Presentation The feet are the most frequently affected anatomic site, because the flea cannot jump very high and patients usually walk barefoot; however, any part of the body surface can be affected.2–4,6 The lesions can be pruritic, painful, or asymptomatic, but the penetration of the flea into the skin is completely asymptomatic.4,6,9,14,15 In the first 24 hours, an erythematous pruritic macule or papule appears at the site of penetration. This lesion evolves into a nodule with a central black opening corresponding to the posterior part of the flea’s abdomen (Figure 1).2,4,6,8–10,12,14 The presence of eggs attached to the skin surrounding the lesion is

From the Department of Dermatology at the University of Panama, the Latina University of Panama and Interamerican University of Panama, Transístmica, Panama National Researcher II of the National Research System (SNI) of the SENACYT of Panama, Panama Address for Correspondence: Jose Manuel Rios-Yuil, MD, MSc, PhD, Panamanian Social Security, San Fernando Norte Clinic, Department of Dermatology at the University of Panama, the Latina University of Panama and at Interamerican University of Panama, Transístmica, Panama • E-mail: jmriosyuil@hotmail.com

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Figure 2. Skin biopsy with multiple transversal cuts of the Tunga penetrans body parts (hematoxylin and eosin stain). (Courtesy of Ricardo Perez Alfonzo, Caracas, Venezuela.)

Figure 1. Infestation of the left toe by the flea Tunga penetrans. (Courtesy of Ricardo Perez Alfonzo, Caracas, Venezuela.)

a pathognomonic finding of the infestation. After the flea dies, the lesion is covered by a black crust formed by clotted blood and debris, which then involutes, leaving just an epidermal scar.2 Tungiasis is a self-limited disease, and in most cases it spontaneously resolves in 4 to 6 weeks; however, reinfestation is a frequent event.2–5,7–14 Occasionally, the host can be infested by hundreds of parasites at the same time, giving the lesions the aspect of a honeycomb and limiting the patient’s capacity to walk. T penetrans is not a vector for systemic diseases, but secondary infections such as cellulitis, abscess formation, osteomyelitis, thrombophlebitis, or lymphangitis are frequent findings. The disease can also be related to severe complications such as digit loss, tetanus, and potentially fatal bacterial infections.2–5,7–10,12–15 The endosymbiont Wolbachia spp. has been found in the ovaries of T penetrans. This bacterium has been related to abnormal immunologic responses in other parasitic diseases such as onchocerciasis. This could explain, at least in part, why some cases of tungiasis are accompanied by severe inflammation.4,8,11 SKINmed. 2015;13:264–266

Figure 3. Skin biopsy with multiple transversal cuts of the Tunga penetrans body parts (hematoxylin and eosin stain).

Diagnosis The diagnosis is made by the clinical aspect of the lesions (topography and morphology) in residents of endemic areas or tourists who have traveled to these places.2,3,8,10,12,14 Dermatoscopy can aid in the diagnosis, because it allows the visualization of the insect’s dark exoskeleton and of multiple eggs inside the hyperkeratotic nodule.3,4,8,14 A biopsy is not typically performed on a regular basis.8 The pathologic alterations of the epidermis include hyperkeratosis, parakeratosis, marked acanthosis, and spongiosis.5,10 Occasionally, the morphology of the flea or its body parts can be observed inside an epidermal crater (Figure

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COMMENTARY economic status of the communities at risk.2,11,13–15 It is important to encourage the use of closed footwear and repellents (N,N-diethyl-meta-toluamide, Zanzarin, among others) and the immediate extraction of the embedded fleas in order to reduce the potential of transmission.5,8,13–15 References 1 Maco V, Tantaleán M, Gotuzzo E. Evidence of tungiasis in pre-hispanic America. Emerg Infect Dis. 2011;17:855– 862. 2 Heukelbach J, de Oliveira FA, Hesse G, Feldmeier H. Tungiasis: a neglected health problem of poor communities. Trop Med Int Health. 2001;6:267–272. 3 Hager J, Jacobs A, Orengo IF, Rosen T. Tungiasis in the United States: a travel souvenir. Dermatol Online J. 2008;14:3. 4 Zúñiga IR, Caro J. Tungiasis: una ectoparasitosis desconocida en México. Rev Enfer Infec Pediatr. 2011;24:114– 117.

Figure 4. Extraction of the flea with a sterile needle. (Courtesy of Ricardo Perez Alfonzo, Caracas, Venezuela.)

5 Damazio OR, Silva MV. Tungiasis in schoolchildren in Criciúma, Santa Catarina State, South Brazil. Rev Inst Med Trop Sao Paulo. 2009;51:103–108.

2 and Figure 3). The presence of a chitin cuticle (exoskeleton), an hypodermal layer, a digestive tract, and developing eggs are the most useful histologic findings in making a definitive diagnosis of tungiasis.4,8,12 A dense inflammatory infiltrate, rich in lymphocytes, plasma cells, and eosinophils, is usually found in the dermis.4 Treatment and Prevention The best strategy for disease control is to prevent the infestation; however, if the disease is established, the best treatment option is the surgical extraction of the flea under aseptic conditions, followed by the application of a topical antibiotic (Figure 4).2,3,5,6,8– 12,14,15 During the extraction process, care should be taken to prevent tearing of the flea and to avoid parts of the flea being left behind with the ensuing risk of severe inflammation.2,14 Conclusions Prevention can only be effectively achieved through a comprehensive approach that combines health education, control of animal reservoirs, improvement of housing and environmental conditions (street paving, proper garbage disposal), and socio-

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6 Leung AK, Woo T, Robson WL, Trotter MJ. A tourist with tungiasis. CMAJ. 2007;177:343–344. 7 Vallarelli AF, Souza EM. Disseminated tungiasis. An Bras Dermatol. 2011;86:1027–1028. 8 Vergara MC, Barthel ME, Labarca ME, Neira OP, Espinoza ER. Tungiasis afecta a un turista chileno. Rev Chilena Infectol. 2009;26:265–269. 9 Scalvenzi M, Francia MG, Costa C, et al. Tungiasis: case report of a traveller to Kenya. Case Rep Dermatol. 2009;1:29–34. 10 Ramírez A, Ginarte M, Peteiro C, Toribio J. Tungiasis: ectoparasitosis importada. Piel. 2008;23:45–47. 11 Miller H, Rodríguez G. Tungiasis en población indígena del Departamento de Vaupés. Biomédica. 2010;30:215– 237. 12 van Buskirk C, Burd EM, Lee M. A painful, draining black lesion on the right heel. Clin Infect Dis. 2006;43:65–66. 13 Pilger D, Schwalfenberg S, Heukelbach J, et al. Controlling tungiasis in an impoverished community: an intervention study. PLoS Negl Trop Dis. 2008;2:e324. 14 Rosmaninho A, Vilaça S, Costa V, et al. Tunga penetrans: painful lesions on the feet—the first imported case from Guinea-Bissau. Case Report Med. 2010;2010:681302. 15 Ariza L, Seidenschwang M, Buckendahl J, et al. Tungíase: doença negligenciada causando patologia grave em uma favela de Fortaleza, Ceará. Rev Soc Bras Med Trop. 2007;40:63–67.

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Volume 13 • Issue 4

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Annular Elastolytic Giant Cell Granuloma and Temporal Arteritis Following Herpes Zoster Eleonora Ruocco, MD, PhD; Ada Lo Schiavo, MD; Alessio Gambardella, MD; Vincenzo Ruocco, MD

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he case report by Panzarelli and Fernández published in SkinMed1 describes the occurrence of annular elastolytic giant cell granuloma (AEGCG) and temporal arteritis (TA) following an episode of herpes zoster (HZ). It is strange to note that pain and functional limitation of the shoulder (a possible heralding sign of TA) occurred on the right side, while the HZ eruption appeared 48 hours later on the left side. A granulomatous reaction (AEGCG) was observed over the HZ scar, ie, on the left side, 1 month later; subsequently, it extended to the contralateral arm and legs. After 2 weeks, neurologic and ocular symptoms of bilateral TA developed: the vasculitis, shown by magnetic resonance imaging, affected the trajectory of both temporal arteries, but primarily the right one.

granulomatous reactions.6 Despite the apparently large number of cases, the real frequency of the phenomenon is probably still underestimated. The involved pathomechanism is presumably linked to the damage that herpetic infections cause to peripheral nerve fibers. This damage, in addition to causing sensitive troubles, such as pain (HZ) or itching (herpes simplex), can locally alter the release and functions of neuromediators that run through the same sensory route, thus altering the neuroimmune control in the affected dermatome(s) (HZ) or areas (herpes simplex). This immune dysregulation makes these body districts more vulnerable to the subsequent onset of immunity-related disorders (infections, dysimmune granulomatous reactions, malignancies).7

Wolf’s Post-Herpetic Isotopic Response

Recently, an investigation has been carried out in patients with documented nickel sensitivity who had HZ in the prior years. By using nickel patch tests bilaterally (ie, on the involved dermatomes and on the uninvolved contralateral ones), it was shown that the immune response of an HZ-involved dermatome can be different, either enhanced or reduced, from that of the corresponding contralateral dermatome. These findings indicate a variable immune destabilization in dermatomes previously affected by HZ6 and also explain why these districts can subsequently harbor skin disorders that depend on a dysregulated immune response, either exaggerated (eg, granulomatous reactions and psoriasis) or impaired (eg, opportunistic infections and tumors).6,7

The aforementioned case study reports the occurrence of AEGCG on a site previously affected by HZ. This is a well-known phenomenon named Wolf ’s post-herpetic isotopic response.2 The term was coined by Wolf in 1995 to describe the occurrence of a new skin disorder at the site of another unrelated and already healed skin disease, usually a herpetic infection.3 Original observations on the topic date back to 1955, when Wyburn-Mason reported a series of 26 patients in whom malignant tumors developed at the site of a previous HZ or herpes simplex eruption.4 In subsequent years, additional cases of malignancies (leukemic infiltration, angiosarcoma), infections (fungal, bacterial, viral), and granulomatous reactions (sarcoid granuloma, granuloma annulare) were reported to occur at the sites of previous herpetic infections (usually HZ infections), the most emblematic being that of a patient with an angiosarcoma of the head whose topography traced precisely the trigeminal areas (first and second divisions) that had been affected by HZ 10 years previously.5 Presently, we are aware of 189 patients with Wolf ’s post-herpetic isotopic response, 48 of whom had granuloma annulare or ill-defined

Isomorphic Response (Köbner phenomenon) and Isotopic Response (Wolf’s Phenomenon) Panzarelli and Fernández considered the onset of AEGCG over the HZ scars as reminiscent of the Köbner phenomenon. This is incorrect and results from some confusion associated with this

See also pages 321–324. From the Department of Dermatology, Second University of Naples, Naples , Italy Address for Correspondence: Vincenzo Ruocco, MD, Second University of Naples, Department of Dermatology, via Sergio Pansini, 5, 80131 Napoli, Italy • E-mail: vincenzo.ruocco@unina2.it

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terminology. In fact, by definition, the Köbner phenomenon, otherwise known as the Köbner isomorphic response, denotes the appearance of a new lesion of a pre-existing skin disorder at the site of injuries of any kind, including HZ episodes. In the aforementioned case study, no lesions of AEGCG appeared on any body site before the onset of those subsequent to the HZ attack. On the contrary, Wolf ’s isotopic response (or simply Wolf ’s phenomenon) describes the appearance of a new disease at the same place of a previous and different one, in most cases a herpetic infection. This event occurred in the case reported by Panzarelli and Fernández.1 In essence, the isomorphic response (Köbner) denotes the appearance of the same disease at another location, while the isotopic response (Wolf ) denotes the appearance of a new disease at the same location.8 Noninfectious Granulomatous Disorders In the case study,1 AEGCG first appeared on a site previously affected by HZ and subsequently spread to other body areas, which has often been reported in Wolf ’s post-herpetic isotopic response. The assumption that varicella zoster virus could have acted as a triggering factor by altering the antigenicity of elastic fibers, thus inducing the immunocellular reaction that led to AEGCG formation, is convincing. In favor of that theory are both the diffusion of the lesions to sites distant from HZaffected dermatomes and the close appearance of neurological and ocular symptoms related to TA, another granulomatous reaction, which is frequently associated with polymyalgia rheumatica.9 This syndrome is characterized by pain or stiffness, usually in the neck and shoulders, which were precisely

the symptoms presented by the patient described by Panzanelli and Fernández.1 In the literature, the coexistence of AEGCG and TA in the same patient has been reported several times and the two conditions are reported as related to each other. Both diseases represent a typical example of noninfectious granulomatous disorders (as are sarcoidosis, granuloma annulare, and granulomatous vasculitidis) that form a large group of dysimmune reactions affecting the skin and a wide range of organ systems in the body.10 Granulomatous disorders have similar histopathologic characteristics, such as elastic tissue damage, granulomatous infiltration, and T-cell predominance in the infiltrate. As the causal agent or antigenic insult remains unrecognized in many granulomatous disorders, they are clumsily lumped together as a disease group where an ill-defined immunologic upset plays a major role. It is important to acknowledge that several of the “noninfectious” granulomatous disorders can be the result of a post-infectious immunologic response, a slow-growing infection, or presentation of granulomatous disease in the setting of infection. Locus minoris resistentiae: An Old But Still Valid Way of Thinking in Medicine The ancient concept of locus minoris resistentiae (LMR), which denotes a body site that offers lesser resistance than the rest of the body to pathogenic agents or events, has become more and more widespread in several fields of medicine and offers starting points for the comprehension of the peculiar vulnerability of certain body sites. Instances are the appearance of hepatocarcinoma on a cirrhotic liver, the onset of lung carcinoma in a tuberculosis scar, cases of osteosarcoma arising in chronic osteomyelitis, and carcinoma complicating cholelithiasis, just to name a few. In dermatology, there are countless reports of privileged localization of cutaneous lesions on injured skin, which represents a typical condition of LMR.11,12 Both the isomorphic response (Köbner phenomenon) and the isotopic response (Wolf ’s phenomenon) feature demonstrative examples of LMR in dermatology. The Immunocompromised Cutaneous District: An Overarching Concept

Figure. Annular granulomatous giant cell granuloma (AEGCG) lesions appeared on the hand and foot dorsum of the hemiplegic side of the body in a patient with contralateral brain stroke. SKINmed. 2015;13:267–269

In recent years, a novel concept has been emerging that gathers multifarious clinical conditions that can render a given cutaneous site prone to harbor subsequent skin disorders, which are apparently unrelated to the primary injuring event. This innovative concept, labelled immunocompromised cutaneous district (ICD), is an umbrella term for extremely different situations, both congenital (eg, skin mosaicism) and acquired (eg, chronic lymph stasis, herpetic infections, radiation dermatitis, burns,

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mechanical trauma, and central or peripheral nervous system troubles), that have in common the capacity of selectively damaging a skin area, thus making it a dysregulated immune district, where several immunity-linked disorders can in time appear.12–14 The report by Panzarelli and Fernández is a complex case of Wolf ’s post-herpetic isotopic response, which perfectly fits the overarching concept of ICD. This concept has several facets and the isotopic response is probably the best known (the cases we are aware of at the moment amount to 189).6 Recently, some of us reported a case of AEGCG that appeared on the hemiplegic extremities in a patient with contralateral brain stroke (Figure). A histamine skin prick test showed absence of axonal flare response at the affected hemibody in comparison to a normal response at the healthy hemibody.15 These results confirmed the selective immune dysregulation in the involved body segments. The case also illustrates how ample the concept of ICD can be. In fact, in this patient, the destabilization of the neuroimmune control, which presumably favored the outbreak of granulomatous lesions on the two hemiplegic limbs, involved the entire half of the body damaged by the central nervous system injury.14,15 References 1 Panzarelli A, Fernández K. Annular elastolytic giant cell granuloma and temporal arteritis following herpes zoster. Skinmed. 2015;13:321–324. 2 Ruocco V, Ruocco E, Ghersetich I, Bianchi B, Lotti T. Isotopic response after herpesvirus infection: an update. J Am Acad Dermatol. 2002;46:90–94. 3 Wolf R, Brenner S, Ruocco V, Grimaldi Filioli F. Isotopic response. Int J Dermatol. 1995;34:341–348. 4 Wyburn-Mason R. Malignant change arising in tissues affected by herpes. Br Med J. 1955;2:1106–1109.

5 Hudson CP, Hanno R, Callen JP. Cutaneous angiosarcoma in a site of healed herpes zoster. Int J Dermatol. 1984;23:404–407. 6 Ruocco V, Ruocco E, Brunetti G, et al. Wolf’s post-herpetic isotopic response: infections, tumors, and immune disorders arising on the site of healed herpetic infection. Clin Dermatol. 2014;32:561–568 7 Ruocco V, Sangiuliano S, Brunetti G, Ruocco E. Beyond zoster: sensory and immune changes in zosteraffected dermatomes: a review. Acta Derm Venereol. 2012;92:378–382. 8 Wolf R, Lotti T, Ruocco V. Isomorphic versus isotopic response: data and hypotheses. J Eur Acad Dermatol Venereol. 2003;17:123–125. 9 Caylor TL, Perkins A. Recognition and management of polymyalgia rheumatica and giant cell arteritis. Am Fam Physician. 2013;88:676–684. 10 Lo Schiavo A, Ruocco E, Gambardella A, O’ Leary R, Gee S. Granulomatous dysimmune reactions (sarcoidosis, granuloma annulare, and others) on differently injured skin areas. Clin Dermatol. 2014;32:646–653. 11 Lo Schiavo A, Ruocco E, Russo T, et al. Locus minoris resistentiae: an old but still valid way of thinking in Medicine. Clin Dermatol. 2014;32:553–556. 12 Ruocco V, Ruocco E, Brunetti G, Sangiuliano S, Wolf R. Opportunistic localization of skin lesions on vulnerable areas. Clin Dermatol. 2011;29:483–488. 13 Ruocco V, Brunetti G, Puca RV, Ruocco E. The immunocompromised district: a unifying concept for lymphoedematous, herpes-infected and otherwise damaged sites. J Eur Acad Dermatol Venereol. 2009;23:1364–1373. 14 Ruocco V, Ruocco E, Piccolo V, et al. The immunocompromised district in dermatology: a unifying pathogenic view of the regional immune dysregulation. Clin Dermatol. 2014;32:569–576. 15 Lo Schiavo A, Romano F, Alfano R, Ruocco E. Unilateral annular elastolytic giant cell granuloma in a hemiplegic stroke patient. Am J Dermatopathol. 2014;36:928–930.

Chancre of the eyelid from the collection of George C. Andrews, MD. Submitted by Douglas D. Altchek, MD, New York, NY. SKINmed. 2015;13:267–269

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July/August 2015

Volume 13 • Issue 4

COMMENTARY

On Zosteriform Distribution Ronni Wolf, MD;1 Eleonora Ruocco, MD, PhD;2 Vincenzo Ruocco, MD2

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he most important diagnostic instrument in dermatology has always been and continues to be the naked eye. Morphology is the essence of dermatology, and despite the availability of sophisticated methods and cutting-edge tools, the key to a correct diagnosis will always remain the clinical examination of the skin. A description of the localization, distribution, and arrangement of the lesion in question is an essential part of a skin examination and serves as a guide to arriving at the correct diagnosis. This commentary deals with one specific aspect of localization and arrangement of skin lesions, namely, the zosteriform arrangement, apropos an intriguing report that appears in this issue.1 Zosteriform: Definition

It should be emphasized from the onset that the term refers solely to the clinical appearance of an eruption and in no case does it have any relation to its etiology. “Zoster” is the Greek word for a belt or girdle worn by men in ancient Greece. The suffix “-form” comes from the Latin forma (shape, model), thus “zosteriform” means resembling herpes zoster (HZ) or having the shape of HZ (ie, a band-like unilateral distribution along an area of the skin innervated by sensory fibers from a spinal [trigeminal nerve or dermatomal] distribution. It is important to differentiate between zosteriform and herpetiform. While zosteriform defines the distribution of the lesions, herpetiform defines the serpiginous arrangement of the individual lesions (from the Greek verb “herpein” meaning to slither or to crawl). In the specific case at hand, this means a lesion that resembles herpes by virtue of the lesions being clustered together in a serpentine arrangement. A large variety of skin diseases can have a zosteriform distribution. Some, but not all, of these lesions may appear at a site of a previously healed HZ eruption and fit the definition of Wolf ’s post-herpetic isotopic response.

Disease Groups

Zosteriform cutaneous infections Bacterial, fungal, spirochetal (syphilis), and in particular viral infections have all been reported to appear in a zosteriform distribution. These are reviewed and discussed in depth by Schepp and Cohen in the current issue.1 Of particular interest is the authors’ discussion of the pathogenesis of zosteriform herpes simplex. It is very similar to that of HZ and involves retrograde axonal transport from neural ganglia with latent viral infection.

Zosteriform cutaneous metastases Cutaneous metastases occur in approximately 5%2 to 10%3 of patients with metastatic disease. Breast cancer, melanoma, and lung cancer are the most common malignancies that metastasize to the skin, and they do so most commonly on the chest. Cutaneous metastases have no definitive appearance, and they are often described as being either cutaneous or subcutaneous nodules that are flesh-colored to pink or violaceous, appear as solitary or multiple lesions, and often cause no symptoms. Zosteriform metastases are a rare variety of skin metastasis. All the publications on zosteriform metastases that appeared between 1970 and 2009 were collected in a meta-analysis of the literature.4 Of the 56 relevant cases, the most frequently implicated histotypes were melanoma (18%); lymphoma (14%); breast cancer (12%); squamous cell carcinoma (12%); tumors of the digestive (10.7%), respiratory (10.7%), and urinary (7%) systems; and others (14%). Melanoma is the most frequent tumor associated with zosteriform metastases. Of 63 reported cases of zosteriform skin metastasis from cutaneous melanoma published since 1970, 12 (19.05%) were secondary to melanoma.5

See also pages 275–281. From the Dermatology Unit, Kaplan Medical Center, Rehovot, Israel, and Affiliated with the School of Medicine, Hebrew University and Hadassah Medical Center, Jerusalem;1 and the Department of Dermatology, Second University of Naples, Naples, Italy2 Address for Correspondence: Ronni Wolf, MD, Kaplan Medical Center, Dermatology Unit, 76100 Rehovot, Israel • E-mail: wolf_r@netvision.net.il

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Pathomechanism of zosteriform metastases Several theories have been proposed to explain the mechanism of the zosteriform distribution of metastases.4,5 Some of the lesions described in the literature appeared at the sites of healed HZ and can thus be considered as fulfilling the criteria for Wolf ’s postherpetic isotopic response.6 Impaired local immunity or immune dysregulation was suggested as playing a possible role in the zosteriform distribution in those cases.7 Other possible explanations for the nature of tumor cell spread with a zosteriform pattern include direct invasion from underlying structures (in the case of internal cancer), surgical implantation of neoplastic cells into the skin, and invasion of perineural lymphatic vessels or the fenestrated vasculature of the dorsal root ganglion. Progressive cribriform and zosteriform hyperpigmentation We believe this entity should be included in the current context if only due to its including the word “zosteriform.” Progressive cribriform and zosteriform hyperpigmentation was first described in 1978 by Rower and colleagues,8 who also proposed five criteria for the diagnosis: (1) uniformly tan cribriform macular pigmentation in a zosteriform distribution; (2) a histologic pattern consisting of a mild increase in melanin pigment in the basal cell layer and complete absence of nevus cells; (3) no history of dermatitis, injury, or inflammation to suggest postinflammatory hyperpigmentation; (4) onset well after birth with gradual extension; and (5) lack of other associated cutaneous or internal abnormalities. Miscellaneous diseases There is a large variety of dermatologic diseases that manifest with a zosteriform distribution. Among the diseases that have been more frequently mentioned are lichen planus,9 segmental eccrine spiradenom,10 and zosteriform connective tissue nevus.11 Role of Varicella-Zoster Virus An important and yet unanswered question is whether varicella-zoster virus (VZV) has an etiologic role in the development of a zosteriform eruption, or if an HZ infection precedes cases of zosteriform eruption even without a clinically overt and evident disease. The main problem in resolving this issue is that VZV DNA can be detected by polymerase chain reaction only when the lesions appear very shortly (usually 4 to 8 weeks) after an HZ infection.12 To overcome this obstacle, one Japanese group9 used a special immunohistochemical method that involved a murine monoclonal antibody against the enveSKINmed. 2015;13:271–273

lope glycoprotein E of VZV. This antigen was detected in the cytoplasm of eccrine glands and duct epithelium in three of five cases of zosteriform lichen planus lesions that had not been preceded by signs of HZ, thus supporting the etiologic role of HZ infection even in cases without previous disease. Interestingly, those researchers did not detect VZV antigens in cases of linear lichen planus, when they used the same method, thus further strengthening their results. Another interesting case report that supports the assumption that HZ had preceded cases of zosteriform eruption was reported in 2008.13 The investigators described a 48-year-old Caucasian man with lichen planus confined to the right dermatomes L2 and L3 and no history of HZ. The VZV IgA and IgG antibody concentration in serum was elevated, in contrast to the VZV IgM level, which was low. The authors concluded that their “case of lichen planus arranged in a unilateral dermatomal way may be best explained by an isotopic response following HZ sine herpete.” To summarize, we provide some evidence to support the role of a previous HZ infection in cases of zosteriform eruption without clinically manifested signs of the disease. More research and validating data are needed before this issue can be considered settled. Conclusions However important the search for the etiology and pathomechanism of this unusual distribution might be, it is not less important to be knowledgeable about its clinical appearance. Such familiarity is essential in order to differentiate it from HZ and thus avoid unnecessary and inappropriate treatment and, more importantly, to be able to choose the treatment suitable for the accurate diagnosis, particularly in cases of metastases, infections, and others. Reports such as those of Schepp and Cohen in this issue will bring us closer to this goal. We believe that there is still no better way to alert the medical community to new diseases, variants, phenomena, etiologies, mechanisms, therapies, and side effects than a case report. This contribution is testimony to the Journal’s commitment to illustrative case reports. By steadfastly following this policy, the Journal fulfills the mission and achieves the real goal of a scholarly medical journal––that of guiding healers and educating them on how to best “read and understand” clinical signs, as well as being updated about the best and most effective ways to cure or at least alleviate their patients’ suffering, even though it costs the Journal “points” in the race for a high impact factor.

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References 1 Schepp ED, Cohen PR. Zosteriform Staphylococcus aureus cutaneous infection: report of two patients with dermatomal bacterial infection. SkinMed. 2015;13:275–281. 2 Krathen RA, Orengo IF, Rosen T. Cutaneous metastasis: a meta-analysis of data. South Med J. 2003;96:164–167. 3 Lookingbill DP, Spangler N, Helm KF. Cutaneous metastases in patients with metastatic carcinoma: a retrospective study of 4020 patients. J Am Acad Dermatol. 1993;29:228–236. 4 Savoia P, Fava P, Deboli T, Quaglino P, Bernengo MG. Zosteriform cutaneous metastases: a literature metaanalysis and a clinical report of three melanoma cases. Dermatol Surg. 2009;35:1355–1363. 5 Chaudhary S, Bansal C, Husain A. Literature meta-analysis of zosteriform cutaneous metastases from melanoma and a clinico-histopathological report from India. Ecancermedicalscience. 2013;7:324. 6 Wolf R, Brenner S, Ruocco V, Grimaldi-Filioli FG. Isotopic response. Int J Dermatol. 1995;34:341–348. 7 Ruocco V, Sangiuliano S, Brunetti G, Ruocco E. Beyond zoster: sensory and immune changes in zoster-

affected dermatomes: a review. Acta Derm Venereol. 2012;92:378–382. 8 Rower JM, Carr RD, Lowney ED. Progressive cribriform and zosteriform hyperpigmentation. Arch Dermatol. 1978;114:98–99. 9 Mizukawa Y, Horie C, Yamazaki Y, Shiohara T. Detection of varicella-zoster virus antigens in lesional skin of zosteriform lichen planus but not in that of linear lichen planus. Dermatology. 2012;225:22–26. 10 Gordon S, Styron BT, Haggstrom A. Pediatric segmental eccrine spiradenomas: a case report and review of the literature. Pediatr Dermatol. 2013;30:e285–e286. 11 Castellanos-Gonzalez M, Petiti-Martin G, Postigo C, Rodriguez-Peralto JL. Zosteriform connective tissue nevus: a new case report. Actas Dermosifiliogr. 2012;103:640– 642. 12 Requena L, Kutzner H, Escalonilla P, et al. Cutaneous reactions at sites of herpes zoster scars: an expanded spectrum. Br J Dermatol. 1998;138:161–168. 13 Mohrenschlager M, Engst R, Hein R, Ring J. Primary manifestation of a zosteriform lichen planus: isotopic response following herpes zoster sine herpete? Br J Dermatol. 2008;158:1145–1146.

Anthrax: Wax model created by Alfons Kroner. Courtesy of Foundation Deutsches HygieneMuseum in Dresden, Germany Submitted by Uwe Wollina, MD SKINmed. 2015;13:271–273

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July/August 2015

Volume 13 • Issue 4

Original contribution

Zosteriform Staphylococcus aureus Cutaneous Infection: Report of Two Patients With Dermatomal Bacterial Infection Elizabeth D. Schepp, MD;1 Philip R. Cohen, MD2 Abstract The aim of this study was to describe cutaneous infections, which are zosteriform in distribution, including two patients with dermatomal Staphylococcus aureus infection. Herpes zoster infectious lesions usually occur in a dermatomal distribution. Other viruses, such as herpes simplex virus, can also appear with zosteriform lesions and closely mimic the clinical presentation of herpes zoster. Additionally, other skin infections, less commonly, are zosteriform. Two patients who developed zosteriform S aureus skin infection are described. A medical literature search for zosteriform dermatomal infections yielded other cutaneous infections with a zosteriform presentation. Two patients had S aureus and methicillin-resistant S aureus infection with skin lesions occupying the T11-T12 dermatomes and the T4 dermatome, respectively. They responded to antibacterial agents and adjuvant therapy. Patients with viral, fungal, and spirochete zosteriform infections are summarized. In addition to varicella-zoster virus infection, zosteriform skin infection can occur with viral (varicella-zoster virus, herpes simplex virus, and Epstein-Barr virus), superficial (dermatophyte), and deep (phaeohyphomycosis and zygomycosis) fungal, and bacterial (S aureus and methicillin-resistant S aureus) infections. These infections should be considered in the differential diagnosis of a zosteriform infection that does not present with the classic clinical picture for herpes zoster or that does not respond to standard treatments for varicellazoster virus. (SKINmed. 2015;13:275–281)

H

erpes zoster is a viral infection caused by reactivation of latent varicella-zoster virus and is most commonly characterized by cutaneous lesions in a dermatomal distribution. Several conditions, including infections, have skin lesions that mimic the distribution of herpes zoster lesions. We describe two patients with Staphylococcus aureus infection and summarize other patients whose cutaneous infections are zosteriform in appearance. Case 1 A 63-year-old Caucasian man with a history of recent excision of squamous cell carcinoma of the left temple with flap placement presented with a 2-day history of painful erythematous lesions on the right lower abdomen and crusting around flap margins on the left temple. Two months earlier, the patient had a resection of an extensive squamous cell carcinoma on the left of the face that involved the left temporal branch of the facial nerve

(Figure 1a). Surgery included a wide local resection, parotidectomy, modified radical left neck dissection, left auriculectomy, and placement of a flap from the anterolateral right thigh. The patient also received postoperative radiation therapy to the regions of the preoperative tumor and operative bed. Cutaneous examination of the flap located on the left of the face appeared well-healed with crusting at the periphery of the graft and erythema at the sites of radiation therapy (Figure 1b). There were also three tender erythematous nodules on the right side of the abdomen, distributed in the T11 dermatome (Figure 2a and 2b). The nodules measured 10×10 mm, 10×10 mm, and 40×10 mm, respectively. The center of the largest lesion was ulcerated and the middle lesion was pustular. Twice-daily empiric trimethoprim-sulfamethoxazole double strength was begun while awaiting culture results. Adjuvant topical therapy with chlorhexidine 4% topical solution once daily

See also pages 271–273. From the Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX;1 and the Department of Dermatology, University of California San Diego School of Medicine, San Diego, CA2 Address for Correspondence: Philip R. Cohen, MD, 10991 Twinleaf Court, San Diego, CA 92131 • E-mail: mitehead@gmail.com

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a

b

Figure 1. Preoperative (a) and postoperative (b) views of the left side of the face of a 63-year-old man. A large ulcerated squamous cell carcinoma of the left temporal area involved the facial nerve (a). Two months after tumor excision and flap placement (b). There is yellow crusting at the margins of the thigh flap and erythema within the radiation therapy port.

a

b

Figure 2. Distant (a) and closer (b) views of Staphylococcus aureus erythematous nodules located in the T11 dermatome on the right side of the abdomen in a 63-year-old man, following excision of a squamous cell carcinoma and flap placement. The 3 abdominal lesions (from medial to lateral) are ulcerated, pustular, and nodular, respectively (b). SKINmed. 2015;13:275–281

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and mupirocin 2% ointment three times daily to the lesions and the nostrils was also given. Bacterial cultures of the lesions were performed, and S aureus was isolated. Susceptibility testing revealed sensitivity to trimethoprim-sulfamethoxazole. Viral culture did not demonstrate varicella-zoster virus. The patient received 4 weeks of systemic antimicrobial treatment with complete resolution of abdominal nodules and graft crusting. Case 2 A 17-year-old Caucasian woman with a medical history of multiple endocrine neoplasia type 2B and metastatic medullary thyroid carcinoma presented with multiple erythematous pustular and papular lesions on the chest and arm. Three years earlier, the patient had undergone a total thyroidectomy for metastatic medullary thyroid carcinoma and was started on vandetanib therapy. One year prior to presentation, she developed palpable lymphadenopathy and with a rise in calcitonin and carcinoembryonic antigen levels and had undergone a bilateral neck dissection. The patient was on cycle 23 of vandetanib 200 mg daily at the time of examination. The patient also had a history of several episodes of cultureproven methicillin-resistant S aureus nasal colonization and cutaneous infections first diagnosed 15 months earlier. She had received intermittent treatment with mupirocin intranasally and to her skin lesions, as well as occasional bleach baths. Cutaneous examination showed multiple erythematous pustules, papules, and nodules in the T4 dermatome on the right

upper flank, breast, and back (Figure 3a and 3b). Empiric trimethoprim-sulfamethoxazole double-strength twice daily was initiated for 15 days. Adjuvant topical therapy with povidone iodine (Betadine) 10% topical cleanser once daily for 4 weeks and mupirocin 2% ointment three times daily to lesions, umbilicus, and nostrils was also used. Culture of a right flank lesion isolated methicillin-resistant S aureus, which was susceptible to trimethoprim-sulfamethoxazole. Her skin lesions completely resolved. Viral culture did not demonstrate varicella-zoster virus. One month later, the patient developed crusting around her nostrils at the same time that her sister had been diagnosed with impetigo. The patient was treated with an additional 15day course of trimethoprim-sulfamethoxazole with complete resolution of her bacterial skin lesions. Subsequent nasal swab cultures for methicillin-resistant S aureus were negative at 2- and 5-month follow-up appointments. Discussion

Varicella-zoster virus infection The hallmark clinical presentation of localized varicella-zoster virus is lesions in a dermatomal distribution. Varicella-zoster virus is a herpes virus with two classic clinical manifestations: primary infection with varicella-zoster virus causing fever, malaise, and a diffuse maculopapular dermatitis known as varicella, or commonly referred to as chickenpox. During the primary infection, the varicella-zoster virus enters the sensory endings of neurons

a

b

Figure 3. Distant (a) and closer views (b) of methicillin-resistant Staphylococcus aureus pustular and erythematous nodules in the T4 dermatome of a 17-year-old woman with multiple endocrine neoplasia type 2B and metastatic medullary thyroid carcinoma on cycle 23 of vandetanib treatment. SKINmed. 2015;13:275–281

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ORIGINAL CONTRIBUTION ously.5 The phenomenon is known as Wolf ’s post-herpetic isotopic response6–8 and refers to dermatomes or cutaneous districts that, once infected by the herpes virus (often in a clinically latent way), become vulnerable and therefore permissive for a subsequent development of heterogeneous and immunity-related skin disorders, such as opportunistic infections, tumors, and dysimmune reactions that remain confined to the involved dermatome or district. Simply, herpes-infected areas become in time “immunocompromised districts.”9

Table. Infections With Zosteriform Cutaneous Lesions Bacterial Staphylococcus aureus Methicillin-resistant (current report) Methicillin-susceptible (current report) Fungal Superficial Tinea corporis (Microsporum canis)12 Deep Phaeohyphomycosis (Exserohilum rostratum)13 Zygomycosis (Rhizopus arrhizus)14 Spirochetal Syphilide (Treponema pallidum)15 Viral Epstein-Barr virus16 Herpes simplex virus17–24 Varicella-zoster virus1,2

and travels to dorsal root ganglia where it remains dormant. At least 90% of US adults are believed to have had prior varicellazoster virus infection and are thus at risk for reactivation of latent infection in the form of herpes zoster.1,2 Herpes zoster occurs when reactivation within a neuron allows the virus to multiply and spread to other neurons within the ganglia. With anterograde spread down to the sensory nerve endings at the skin, varicella-zoster virus causes a cutaneous eruption.2 Herpes zoster occurs most commonly in the elderly and immunosuppressed patients. Herpes zoster is characterized by a prodromal period of headache, malaise, and pain within the dermatomal distribution of the involved nerve. Cutaneous lesions then develop, which begin as erythematous macules and papules along the involved dermatome; subsequently, the lesions evolve into intraepithelial vesicles on an erythematous base.2,3 Varicella-zoster virus reactivation can also cause disseminated vesicles. The vesicles later rupture and may become crusted, ulcerated, or secondarily infected.

Conditions with zosteriform cutaneous lesions Several conditions may also be characterized in which the skin lesions mimic the distribution of herpes zoster, including cornification disorders, hamartomas and nevi, granuloma annulare and sarcoidosis, paulosquamous disorders, pigmentary disorders, tumors, and vascular disorders.3,4 The most emblematic case is that of a patient with an angiosarcoma of the head whose topography traced precisely the trigeminal areas (first and second branches) that had been affected by herpes zoster 10 years previSKINmed. 2015;13:275–281

Developmental defects of the embryo, linked with the progression of Blaschko lines, can explain the segmental distribution of certain skin diseases, especially keratinization disorders and vascular and melanocytic nevi, a phenomenon known as skin mosaicism.10 Blaschko linear arrangement caused by skin mosaicism is often indistinguishable from a dermatomal (ie, zosteriform) arrangement. This makes it difficult to state whether the vulnerability of a given cutaneous district depends on congenital (skin mosaicism) or acquired (herpetic infection) causes, especially when a clinical history of a previous episode of shingles is lacking.11 Several primary infections involving the skin may also mimic the distribution of herpes zoster (Table).1,2,12–24 These infections not only include other viruses but also bacteria and fungi. Occasionally, the appearance of the lesions may be altered from their classic clinical presentations and thereby confound the diagnosis. Even when the morphology of these infectious lesions is distinctive from varicella-zoster virus, culture or biopsy of the lesions may be necessary to establish the correct diagnosis.

Herpes simplex virus infection Herpes simplex in a dermatomal distribution is the most common infection observed to mimic varicella-zoster. It may present in immunocompetent hosts, but immunocompromised patients experience more frequent and severe recurrences.20,24 Herpes simplex infection classically presents as grouped vesicles on an erythematous base. Lesions are morphologically identical between varicella-zoster virus and herpes simplex virus, and biopsy of lesions for routine stains is identical. Tzanck smear of both viruses shows multinucleated giant cells.20,24 Culture or polymerase chain reaction is necessary to definitively differentiate varicellazoster virus from herpes simplex virus.23,24 During both primary and recurrent infection with herpes simplex virus type 1, the virus may infect the trigeminal ganglion and produce vesicular lesions in the dermatomal distribution of the ophthalmic branch of the trigeminal nerve.17,18 Herpes simplex virus type 2 can also cause dermatomal eruptions and commonly occurs as a result of reactivation from the sacral ganglia.19

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Earlier studies using mouse models have demonstrated that the ability of the herpes simplex virus to produce zosteriform lesions correlates with: (1) the neuroinvasive potential, (2) the ability to enter neurons, and (3) the facility to travel retrograde up the axon to the sensory nerve ganglia.21,22 Subsequent anterograde spread, during either the primary infection or a reactivation of the virus, to the sensory endings results in cutaneous eruption in the area innervated by that nerve.21,22 The diagnosis of herpes simplex may be suspected in patients with recurrent presumed herpes zoster in the same dermatomes. In contrast to herpes simplex, herpes zoster rarely causes a second infection in the same patient. Immunity to varicella-zoster virus declines with age and is primarily related to decreased efficacy of cell-mediated immunity in older patients.2 The varicella-zoster vaccine has proved effective in reducing the rate of zoster in patients older than 60 years by providing a boost to cell-mediated immunity.2 Theoretically, a patient’s first case of herpes zoster should effectively enhance the patient’s immunity and thereby make subsequent infection unlikely.2 Differentiating the varicella-zoster virus from the herpes simplex virus is important. Treatment guidelines and potential complications vary depending on the viral species. Varicella-zoster virus requires higher doses of antivirals and may be associated with post-herpetic neuralgia.1,19,20 Also, treatment of ocular infection varies depending on whether varicella-zoster virus or herpes simplex virus is isolated; intraocular or systemic corticosteroids may be used in the former and are contraindicated in the latter.18,20

Epstein-Barr virus infection Epstein-Barr virus infection in a dermatomal distribution has been described in an 86-year-old Japanese man.16 The patient had a 1-month history of scaly erythematous papules, and on presentation they were noted to be in a zosteriform distribution on the right abdomen.16 Biopsy demonstrated T-cell–rich B-cell lymphoma, and polymerase chain reaction amplification identified Epstein-Barr virus DNA within the lymphoma lesions; hence, both infectious and neoplastic processes were involved in the zosteriform cutaneous eruption in this unique patient.16

Superficial and deep fungal infections Superficial and deep fungal infections have been described with lesions in a dermatomal distribution. These include tinea coporis secondary to Microsporum canis, which presented as erythematous vesicles in the T10–T12 dermatomes of the lower lateral aspect of the back of a 4-year-old boy.12 The child’s parents had initially treated the isolated erythematous scaling papules with hydrocortisone cream, and the boy subsequently developed an SKINmed. 2015;13:275–281

increased number of lesions. The patient was successfully treated with terbinafine 62.5 mg/d and topical sertaconazole twice daily for 5 weeks. The investigators emphasized that application of topical steroids could result in localized cutaneous immune depression that allowed the M canis infection to spread. The investigators also noted that dermatophyte infections may present with an atypical clinical picture—secondary to previous misdiagnosis and improper treatment resulting in pathomorphosis of the primary lesions with loss of the characteristic features of tinea corporis, such as scaling erythema and central clearing—that may mimic multiple other disease. In such patients, the infection has been called tinea incognito.12 Other researchers describe patients with deep fungal infections from zygomycosis and phaeohyphomycosis that mimic varicella zoster. One report describes a 37-year-old woman who had a liver transplant and subsequently developed a primary cutaneous zygomycosis in a zosteriform distribution on the lower part of the abdomen.14 Primary cutaneous zygomycosis is a rare form of infection with this organism. Of the 28 patients reported between 1985 and 1995, only 25% of these individuals were immunocompromised.14 The zosteriform fungal lesions were described as “broad, erythemtous plaques studded with pustules, necrotic areas, and ulceration.”14 The woman’s primary cutaneous zygomycosis lesions were initially diagnosed as herpes zoster; however, they did not respond to intravenous acyclovir treatment. Potassium hydroxide preparation of skin scrapings revealed nonseptate hyphae, and hemotoxin and eosin staining of a lesional biopsy specimen demonstrated the fungal organism. Subsequent tissue culture identified Rhizopus arrhizus, and treatment was started with intravenous amphotericin B and topical amphotericin B. Following poor treatment response, susceptibility testing was performed and oral fluconazole was added to the regimen. Treatment was continued for another 6 months until persistent fungal granulomas were identified on repeat biopsy and excised. The patient had no recurrences in the next 12 months of follow-up. Identification of this cutaneous zygomycosis, which may have an atypical clinical presentation, is important because of the possible complications of systemic dissemination and death.14 A second report of a deep fungal infection presenting in a dermatomal distribution occurred in a patient with phaeohyphomycosis caused by Exserohilum rostratum.13 Subcutaneous phaeohyphomycosis typically occurs in immunocompromised patients at sites of trauma, which allow entry of the organism. This patient, a 74-year-old man with steroid-dependent chronic obstructive pulmonary disease, developed multiple hemorrhagic vesicles along a dermatome involving the forearm and elbow.13

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The vesicles initially developed at the site of an intravenous line infiltration. Full resolution of the infection was achieved after 6 weeks of daily treatment with 200 mg of orally administered ketoconazole and topically applied clotrimazole 1% cream.13

Spirochete infection Syphilis is a spirochete infection caused by Treponema pallidum. It has classical cutaneous manifestations of a primary painless chancre, secondary lesions such as macules and plaques of the palms and soles, alopecia, and condyloma lata, and tertiary findings including gummas. Although these are some of the classic cutaneous manifestations, syphilis has been referred to as “the great imitator” because infection-associated lesions can have many atypical presentations. For example, an earlier author described syphilides occurring in a dermatomal distribution.15 The patient was a 36-year-old man with a 6- to 7-month history of multiple atrophic scars and indurated ulcers in the distribution of the T7 and T9 dermatomes on the left side of the abdomen. He also had similar lesions in the distribution of the ophthalmic (V1) branch of the trigeminal nerve on the scalp and left temple. Although the individual lesions contained no spirochetes on dark field microscopy, the patient was found to be VDRL reactive with a titer of 1:16. The lesions resolved with successful treatment of syphilis with a 2-mL intramuscular injection of procaine penicillin daily for 10 days; thus, the patient was considered to have a spirochete infection with associated zosteriform lesions.15 The author of this manuscript references a previous report of another patient who had a syphilide with a zosteriform presentation.15

such as Epstein-Barr virus and other infectious organisms, can present with lesions distributed within dermatomes (Table).1,2,12–24 The mechanism of dermatomal spread of infections other than herpes simplex and varicella-zoster is not as clearly understood but may represent either a post-herpetic isotopic response in an immunocompromised district or a variable immune responsiveness along developmental lines of Blaschko secondary to skin mosaicism. In patients with suspected recurrent localized varicella-zoster infection or whose presumed herpes zoster does not respond to antiviral treatment, other infectious etiologies, such as bacteria or fungi, should be considered. Culture or biopsy or both may be helpful in establishing the correct diagnosis. References

Bacterial infection To the best of our knowledge, bacterial infections with primary S aureus lesions in a dermatomal distribution have not yet been described. The infection in our patients had a unique distribution; however, the individual lesions had an appearance of erythematous pustules and papules consistent with the common clinical presentation of S aureus infection, and they responded to treatment in a manner similar to that observed in S aureus lesions without this dermatomal pattern. Conclusions Herpes zoster is a viral infection in which the cutaneous lesions present in a dermatomal distribution. Many other cutaneous processes occur in a zosteriform distribution, particularly infections.3,4 The pathogenesis of zosteriform herpes simplex infection is very similar to herpes zoster and involves retrograde axonal transport from neural ganglia with latent viral infection. In addition to herpes simplex virus, additional viral pathogens, SKINmed. 2015;13:275–281

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1 Weaver BA. Herpes zoster overview: natural history and incidence. J Am Osteopath Assoc. 2009;109:S2–S6. 2 Oxman MN. Herpes zoster pathogenesis and cell-mediated immunity and immunosenessence. J Am Osteopath Assoc. 2009;109:S13–S17. 3 Cohen PR. Tests for detecting herpes simplex virus and varicella zoster virus infections. Dermatol Clin. 1994;12:51–68. 4 Cohen PR. Dermatomal lichen striatus. Can J Dermatol. 1991;3:93–97. 5 Hudson CP, Hanno R, Callen JP: Cutaneous angiosarcoma in a site of healed herpes zoster. Int J Dermatol. 1984;23:404–407. 6 Wolf R, Brenner S, Ruocco V, Grimaldi F. Isotopic response. Int J Dermatol. 1995;34:341–348. 7 Ruocco V, Ruocco E, Ghersetich I, et al. Isotopic response after herpesvirus infection: an update. J Am Acad Dermatol. 2002;46:90–94. 8 Ruocco V, Sangiuliano S, Brunetti G, Ruocco E. Beyond zoster: sensory and immune changes in zosteraffected dermatomes: a review. Acta Dermatol Venereol. 2012;92:378–382. 9 Ruocco V, Brunetti G, Puca RV, Ruocco E. The immunocompromised district: a unifying concept for lymphoedematous, herpes-infected and otherwise damaged sites. J Eur Acad Dermatol Venereol. 2009;23:1364–1373. 10 Happle R. Superimposed segmental manifestation of polygenic skin disorders. J Am Acad Dermatol. 2007;57:690–699. 11 Ruocco V, Ruocco E, Brunetti G, Sangiuliano S, Wolf R. Opportunistic localization of skin lesions on vulnerable areas. Clin Dermatol. 2011;29:483–488. 12 Aste N, Pau M, Aste N, Aztzori L. Tinea corporis mimicking herpes zoster. Mycoses. 2011;54:463–465. 13 Tieman JM, Furner BB. Phaeohyphomycosis caused by Exserohilum rostratum mimicking hemorrhagic herpes zoster. J Am Acad Dermatol. 1991;25:852–854. 14 Woods SG, Boni EE. Zosteriform zygomycosis. J Am Acad Dermatol. 1995;32:357–361.

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15 Kodandapani C. Zosteriform late cutaneous syphilide. Br Med J. 1968;1:685.

20 Koh MJ, Seah PP, Teo RYL. Zosteriform herpes simplex. Singapore Med J. 2008;49:e59–e60.

16 Watabe H, Kawakami T, Soma Y, Baba T, Mizoguchi M. Primary cutaneous T-cell-rich B-cell lymphoma in a zosteriform distribution associated with Epstein-Barr virus infection. J Dermatol. 2002;29:748–753.

21 Goel N, Mao H, Rong Q, et al. The ability of an HSV strain to initiate zosteriform spread correlates with its neuroinvasive disease potential. Arch Virol. 2002;147:763– 773.

17 Saito K, Hatano Y, Sakai T, et al. Primary ocular herpes simplex virus infection with zosteriform spreading, accompanied with meningism. J Dermatol. 2012;39:489– 490.

22 Summers BC, Margolis TP, Leib DA. Herpes simplex virus type 1 corneal infection results in periocular disease by zosteriform spread. J Virol. 2001;75:5069–5075.

18 Yamamoto S, Shimomura Y, Kinoshita S, Tano Y. Differentiating zosteriform herpes simplex from ophthalmic zoster. Arch Ophthalmol. 1994;112:1515–1516.

23 Takayama N, Takayama M, Takita J. Herpes simplex mimicking herpes zoster in a child immunized with varicella vaccine. Pediatr Infect Dis J. 2001;20:226–228.

19 Groisser D, Taylor S, Grossman ME. Postsurgical zosteriform herpes simplex 2 in noncontiguous dermatomes. J Am Acad Dermatol. 1990;23:928–930.

24 Kalman CM, Laskin OL. Herpes zoster and zosteriform herpes simplex virus infections in immunocompetent adults. Am J Med. 1986;81:775–778.

Historical Diagnosis and treatment Diagnosis and treatments have advanced over the past century. This feature depicts conditions from a collection of stereoscopic cards published in 1910 by The Stereoscopic Skin Clinic by, Dr S. I. Rainforth.

(Continued on page 300)

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Volume 13 • Issue 4

Original contribution

Treatment of Scabies: Comparison of Lindane 1% vs Permethrin 5% Elham Rezaee, PhD;1 Mohamad Goldust, MD;2 Houman Alipour, MD2 Abstract Scabies, whose etiologic agent is Sarcoptes scabiei, is a neglected parasitic disease that is a major public health problem in many resourcepoor regions. Its current therapies include benzyl benzoate, lindane, permethrin, sulfur, crotamiton, monosulfiram, and oral ivermectin. The aim of this study was to compare the efficacy and safety of lindane 1% lotion vs permethrin 5% in the treatment of scabies. A total of 120 patients with scabies attending a dermatology outpatient department were included. Patients were randomly divided into two groups. Sixty patients and their family contacts received 5% permethrin cream and the other 60 received 1% lindane lotion. Treatment was evaluated at intervals of 2 and 4 weeks. Permethrin provided improvement in 48 patients (80%) after 2 weeks, whereas lindane was effective in only 28 patients (46.6%). Permethrin (5%) cream was found to be significantly more effective in the treatment of scabies compared with lindane in this study. Adverse effects were rare in both the permethrin and lindane groups. (SKINmed. 2015;13:283–286)

S

cabies has been a scourge among human beings for thousands of years. Its worldwide occurrence with epidemics during war, famine, and overcrowding is responsible for an estimated 300 million people currently affected.1,2 Scabies refers to the various skin lesions produced by female mites and their eggs and scybala that are deposited in the epidermis, leading to delayed-type hypersensitivity reactions.3,4 Typical and atypical clinical presentations with pruritus as a hallmark of scabies occur in young, pregnant, immune-compromised, and elderly patients and include bullous and crusted manifestations, as well as those masked by steroid use.5,6 It is transmitted by direct contact, especially under crowded living conditions. The ideal treatment would be an inexpensive and safe drug involving a single administration. Topical applications may require skilled nursing in an institution; furthermore, in some parts of the world, the water supply is poor, justifying the search for an easily administered treatment involving a single dose with minimal adverse effects.7,8 A number of agents are available for use as scabicides and pediculicides. Its current therapies include benzyl benzoate, lin-

dane, permethrin, sulfur, crotamiton, monosulfiram, and oral ivermectin.9,10 Its current therapies in Iran are lindane 1% lotion for adults (two applications with 1-week interval) and sulfur for pregnant women and children. Crotamiton is used as adjuvant therapy.11 Lindane, γ-benzene hexachloride, is an organochloride insecticide that causes neurotransmitter inhibition and respiratory and muscular paralysis in the insect. It is contraindicated in pregnant and lactating women and children younger than 2 years because of central nervous system toxicity. Resistance to lindane is increasing throughout the world, and it has been prohibited in California, as a result of environmental pollution since 2002. Because of potent toxicity, low efficacy, increased resistance, and environment contamination, lindane is now considered to be inferior to permethrin or ivermectin in the treatment of scabies. Currently, 5% topical permethrin cream is considered by many as the drug of choice in the treatment of scabies.12 Permethrin is a synthetic pyrethroid and is one of the first thermostable and photostable insecticides, developed following the elucidation of the chemical structures of natural pyrethrins in 1947.13,14 Permethrin demonstrates extremely low mammalian toxicity, combined with insecticidal activity even higher than natural pyre-

From the Department of Medicinal Chemistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran;1 and the Department of Dermatology, Tabriz University of Medical Sciences, Tabriz, Iran2 Address for Correspondence: Houman Alipour, MD, Tabriz University of Medical Sciences, Tabriz, Iran • E-mail: alipour_homan@yahoo.com

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thrins. These properties, backed by an extensive safety profile of more than 20 years in the veterinary and agricultural industry, makes this compound an ideal candidate for use as a treatment for ectoparasites in humans.15,16 Due to of the relatively high prevalence of scabies in Iran and owing to the lack of information about the efficacy of permethrin in the treatment of scabies, the aim of this study was to compare the efficacy and safety of lindane 1% lotion vs permethrin 5% in the treatment of scabies. Methods From March 2007 to March 2010, 120 patients with scabies who were older than 2 years were seen in the dermatology outpatient department of Sina Hospital, Tabriz University of Medical Sciences. Participation was voluntary, and appropriate informed consent was obtained from patients or parents. All patients younger than 2 years, pregnant and lactating women, patients with a history of seizures, severe systemic disorders, immunosuppressant, and crusted scabies were excluded. Patients had not received any topical or systemic acaricide therapy for 1 month prior to the study. Information about infestation, its natural history, treatment modalities, and preventative measures were given. The permethrin dermal cream and lindane lotion were packaged in identical-appearing boxes, the contents of which were unknown to the evaluation team. This blinding was maintained throughout the study. Similarly, the treatment team members who applied medications took no part in pretreatment scoring of the severity and extent of the infestations and played no role in subsequent evaluations. Prior to entry into the study, patients were given a physical examination, and their history of infestations, antibiotic therapy, and other pertinent information was recorded. Age, sex, height, and weight were recorded for demographic comparison. None of the patients had been treated with pediculicides, scabicides, or other topical agents in the 1 month preceding the trial. The diagnosis of scabies was made by the demonstration of eggs, larvae, mites, or fecal material by light microscopy or by the presence of the following three criteria: demonstration of a burrow and/or typical scabietic lesions at the classical sites, nocturnal pruritus, and history of similar findings in their families and/ or close contacts. Patients who satisfied the above criteria were randomly divided into two groups. The first group and their family contacts received 5% permethrin cream (group A), and the other received SKINmed. 2015;13:283–286

1% lindane lotion (group B) in a double-blind manner. Patients were treated with the scabicides and then followed up at intervals of 2 and 4 weeks. Pretreatment clinical photographs were taken of the body site most affected, and additional photographs were taken at the 1-month evaluation. Clinical evaluations after treatment were made by experienced investigators without knowledge of the treatments. At all evaluation times, they recorded the sites of lesions on body diagram sheets. The notations of their appearance and whether they were new or residuals of original lesions were determined by comparison with the pretreatment photograph. New lesions were also scraped for microscopic examination. Cure was defined as the absence of new lesions, and all old lesions healed. Residual, dry, noninflammatory papules were not counted as active and were always negative on scraping. Treatment failure was defined as a patient with microscopically confirmed new lesions at 1 month and who was not considered cured at 2 weeks. The term reinfestation was applied to patients who were completely clear at 2 weeks and developed new lesions with positive microscopic findings at 1 month. In case of treatment failure, the patient was crossed over to the other group. At the end of the fourth week, another evaluation was performed. The results of the study were statistically analyzed using SPSS, version 16 (SPSS Inc, IBM, Armonk, NY). To account for statistical differences in the two groups, chi-square test or Fisher exact test was used, as appropriate. A P value <.05 was considered significant. Results A total of 134 patients were studied, and 14 patients (6 from group A and 8 from group B) were not able to return after the first follow-up examination and were therefore excluded from the study. The remaining 120 patients continued the study. The demography of the two treatment groups showed no major differences (Table I). The mean age±standard deviation of those treated with permethrin was 40.34±24.36 years and those in the lindane group had a mean age of 42.38±22.12 years. A total of 46.6% of those in the permethrin group were women, as were 40% of those treated with lindane. On entry into the study, the number of patients in each treatment group who were graded as having mild, moderate, or severe infestation was not significantly different (Table II). At 2 weeks post-treatment, treatment was effective in 48 (80%) patients in the permethrin group and 28 patients (46.6%) in the

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Table I. Demographic Characteristics of the Study Population Permethrin (n=60)

Lindane (n=60)

Age, y

40.34±24.36

42.38±22.12

Men

32

36

Women

28

24

Height, cm

182±28

178 ±30

Weight, kg

74±16

70±16

Table II. Severity of Infestation Pretreatment in all Patients Lesions

Permethrin (n=60)

Lindane (n=60)

Total Patients (n=120)

Mild (<50)

8

10

18

Moderate (50–100)

14

8

22

Severe (>100)

38

42

80

Group A n=60

Group B n=60

P Value

48 (80)

28 (46.6)

.002

Table III. Response to Treatment After 2 Weeks Effectively treated at week 2

lindane group (Table III). This difference was significant (P<.05). The 44 patients (26 men and 18 women) who had not improved were crossed over to the other group. At the next follow-up, 4-week post-treatment, two patients in the permethrin group who showed no response at the first follow-up and were subsequently treated with lindane still had severe itching. In contrast, all 32 patients not responding to lindane who were then treated with permethrin showed improvement in itching and skin lesions. Only five patients (three in the permethrin group and two in the lindane group) experienced irritation after application of the drug, but none had allergic reactions. Discussion For the past 60 plus years, lindane has been the preferred therapy for scabies. This product has become the most widely used antiscabietic drug in many countries, including Iran. Lindane (1%) in shampoo and lotion formulations became available in Iran more than 20 years ago. This agent was used on successive nights in Iran to ensure that the eggs and live mites are adequately exposed to treatment. Seizures secondary SKINmed. 2015;13:283–286

to this medication have been reported, particularly when it was applied to wet skin or to skin altered by inflammatory changes that may permit easy absorption. The absorption rate may be ≥40 times that of permethrin, leading to a significant potential for toxicity.17 Bathing prior to application should be avoided. Hair should be washed with plain shampoo and dried thoroughly before applying lindane, as in the treatment of head lice infestation. Children should not apply lindane without adult supervision. In recent years, resistance to lindane seems to be rising, and there are reports of several clusters of patients with lindane-resistant scabies worldwide.18,19 As far as resistance is concerned, it seems reasonable to conclude that potential for adverse reactions from application of lindane preparations therapeutically does exist if the preparations are not used properly. The risk of adverse reactions in their use, however, appears minimal when the preparations are used properly and according to directions. Permethrin cream (5%) was introduced in 1989 for the treatment of scabies and seems to be a good substitute for lindane. It is considered to be the drug of choice in many countries.19 Permethrin is a synthetic compound based on the insecticidal components of naturally occurring permethrins.20 The 5% per-

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methrin preparation kills the organisms and eggs, and has an extremely low rate of absorption, making the toxicity potentially nonexistent. Weekly applications have been extremely successful in preventing reinfection. It is probably the most reliable topical scabicide. Resistance to permethrin in developed countries was reported in 1999.21,22 Our study, however, compared the use of permethrin with that of conventional topical 1% lindane treatment of scabies. Permethrin treatment yielded higher healing rates than the topical treatment 15 days after the initial treatment. Although the persistence of pruritus in scabies for several weeks after cure is not uncommon and is not necessarily predictive of treatment failure, since it is the primary symptom of scabies, a drug with a more rapid effect on relieving pruritus is much more acceptable to patients. There are some reports that complete clearance of lesions occurs earlier in permethrin-treated patients,23 and we think the better response to permethrin in our study is partially related to its effects in reducing pruritus. Adverse effects were very rare with either permethrin or lindane. Previous comparative studies have showed that permethrin is also superior to ivermectin in the treatment of scabies.24 Conclusions We found permethrin to be more effective than lindane for the treatment of human scabies, allowing a fast and safe cure of this condition through simple administration. The treatment of scabies with permethrin becomes an effective resource to control infestation in confined populations and, more generally, for medical plans to eradicate human scabies. References 1 Galvany Rossell L, Salleras Redonnet M, Umbert Millet P. Bullous responding to ivermectin therapy. Actas Dermosifiliogr. 2010;101:81–84. 2 Andrews RM, McCarthy J, Carapetis JR, Currie BC. Skin disorders, including pyoderma, scabies, and tinea infections. Pediatr Clin North Am. 2009;56:1421–1440. 3 Bignell C. Lice and scabies. Medicine. 2010;38:306– 308. 4 Mortazavi H, Abedini R, Sadri F, Soori T, Vasheghani-Farahani A. Crusted scabies in a patient with brain astrocytoma: report of a case. Int J Infect Dis. 2010;6:e526– e527. 5 Mazzatenta C, Fimiani M, Flori L, Andreassi L. Leucocytoclastic vasculitis following nodular Scabies. J Eur Acad Dermatol Venereol. 1996;7:179–181.

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6 Fuchs K, Deutz A, Gressmann G. Detection of spacetime clusters and epidemiological examinations of scabies in chamois. Vet Parasitol. 2000;92:63–73. 7 Heyndrickx G, Brioen P, Van Puyvelde L. Study of Rwandese medicinal plants used in the treatment of Scabies. J Ethnopharmacol. 1992;35:259–262. 8 Bockarie MJ, Alexander ND, Kazura JW, et al. Treatment with ivermectin reduces the high prevalence of scabies in a village in Papua New Guinea. Acta Tropica. 2000;75:127–130. 9 Hengge UR, Currie BJ, Jäger G, Lupi O, Schwartz RA. Scabies: a ubiquitous neglected skin disease. Lancet Infect Dis. 2006;6:769–779. 10 Cestari TF, Martignago BF. Scabies, pediculosis, bedbugs, and stinkbugs: uncommon presentations. Clin Dermatol. 2005;23:545–554. 11 Buffet M, Dupin N. Current treatment for scabies. Fundam Clin Pharmacol. 2003;17:217–225. 12 Orkin M, Maibach HI. Scabies therapy—1993. Semin Dermatol. 1993;12:22–25. 13 Zhang SY, Ueyama J, Ito Y, et al. Permethrin may induce adult male mouse reproductive toxicity due to cis isomer not trans isomer. Toxicology. 2008;248:136–141. 14 Lee SI, Clark JM, Ahn YJ, et al. Molecular mechanisms and monitoring of permethrin resistance in human head lice. Pestic Biochem Physiol. 2010;97:109–114. 15 González-Doncel M, de la Peña E, Barrueco C, Hinton DE. Stage sensitivity of medaka (Oryzias latipes) eggs and embryos to permethrin. Aquat Toxicol. 2003;62:255– 268. 16 Baser S, Erkoç F, Selvi M, Koçak O. Investigation of acute toxicity of permethrin on guppies Poecilia reticulata. Chemosphere. 2003;51:469–474. 17 Franz TJ, Lehman PA, Franz SF, Guin JD. Comparative percutaneous absorption of lindane and permethrin. Arch Dermatol. 1996;132:901–905. 18 Taplin D, Meinking TL, Porcelain SL, Castillero PM, Chen JA. Permethrin 5% dermal cream: a new treatment for scabies. J Am Acad Dermatol. 1986;15:995–1001. 19 Elgart ML. A risk-benefit assessment of agents used in the treatment of scabies. Drug Saf. 1996;14:386–393. 20 Malathion for treatment of head lice. Med Lett Drugs Ther. 1999;41:73–74. 21 Maunder JW. Clinical and laboratory trials employing carbaryl against the human head louse, Pediculus humanus capitis (de Geer). Clin Exp Dermatol. 1981;6:605– 612. 22 Hernandez-Perez E. Resistance to antiscabietic drugs. J Am Acad Dermatol. 1983;8:121–122. 23 Davies JE, Dedhia HV, Morgade C, et al. Lindane poisoning. Arch Dermatol. 1983;119:142–144. 24 Usha V, Gopalakrishnan Nair TV. A comparative study of oral ivermectin and topical permethrin cream in the treatment of scabies. J Am Acad Dermatol. 2000;42:236– 240.

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Actinic Prurigo Alma Angélica Rodríguez-Carreón, DDS, MSc; Erika Rodríguez-Lobato, MD; Georgina Rodríguez-Gutiérrez, MD; Juan Carlos Cuevas-González, DDS; Alexandra Mancheno-Valencia, MD; Martha Patricia Solís-Arias, MD; María Elisa Vega-Memije, MD; María Teresa Hojyo-Tomoka, MD; Luciano Domínguez-Soto, MD Abstract Actinic prurigo is an idiopathic photodermatosis that affects the skin, as well as the labial and conjunctival mucosa in indigenous and mestizo populations of Latin America. It starts predominantly in childhood, has a chronic course, and is exacerbated with solar exposure. Little is known of its pathophysiology, including the known mechanisms of the participation of HLA-DR4 and an abnormal immunologic response with increase of T CD4+ lymphocytes. The presence of IgE, eosinophils, and mast cells suggests that it is a hypersensitivity reaction (likely type IVa or b). The diagnosis is clinical, and the presence of lymphoid follicles in the mucosal histopathologic study of mucosa is pathognomonic. The best available treatment to date is thalidomide, despite its secondary effects. (SKINmed. 2015;13:287–295)

A

ctinic prurigo (AP) is an idiopathic, chronic, inflammatory photodermatosis that affects photoexposed areas, as well as labial and conjunctival mucosa; however, it can also affect nonexposed areas. It is present in darker-skinned populations with a strong Amerindian component. It was first described by López González in Argentina.1,2 In Mexico, it was described by Escalona and colleagues in 1954 under the name of solar dermatitis.3 This disease has received several names throughout the years (eg, solar dermatitis, cutaneous syndrome of Guatemala, solar prurigo, actinic familiar prurigo, polymorphous light eruption of the prurigo type, solar prurigo of the high plateau, and Hutchinson solar prurigo),1,4–6 but “actinic prurigo” is currently the accepted term (Fabio Londoño, Colombia 1968).1,5,7 Epidemiology The condition presents mostly between the ages of 6 and 8 years4,8 but can appear at any age.8 It is more common in women than in men (2:1 ratio),4,8,9 mainly affecting people of dark phototypes (IV and V in Fitzpatrick’s classification)4,8,10 and those who live in a dry, sunny climate at an altitude higher than 1000 meters above sea level, although there are reported cases at lower altitudes.4,8

With regard to racial factors, miscegenation is especially present in countries such as Mexico, Guatemala, Colombia, Honduras, Ecuador, Peru, and Bolivia, where the Amerindian component is significant.5 In Mexico, AP affects 3.9% of dermatologic patients,7 and there are isolated cases in Costa Rica, Venezuela, Argentina, Uruguay, Chile, the north of the United States, the Inuit population in Canada,1,4,9 Australia, United Kingdom, and Thailand (Figure 1).1 Etiology and Physiopathology Little is known as to the causes of AP. Up to 68% of cases have a family member with the condition7; however, data are not consistent, as there has been a rate reported as low as 4.3%.6 Other possible factors implied are low socioeconomic status, residence in rural areas, and constant contact with farm animals and woodsmoke. Regarding genetic susceptibility, a strong link has been reported with leukocyte human antigen (HLA), particularly HLADR4,11 which is highly polymorphic and varies from population to population. In Mexico, 90% to 92.8% of patients with AP have this allele,6,12,13 with HLA-DRB1*04071,7,9 the most frequent (60%–80%),6,13 and HLA-DR4 has also been reported in

From the Dermatology Department, Hospital General Dr. Manuel Gea González, México DF, Mexico Address for Correspondence: Alma Angélica Rodríguez-Carreón, MD, Calzada de Tlalpan 4800, col. Sección XVI, Tlalpan, CP 14080, México D.F • E-mail: drardzcarreon@gmail.com

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Figure 1. Principal countries with actinic prurigo.

Europe.1,7 Other related alleles are HLA-A28 and HLA-B39 in Mexico;1,9 HLA-A24, HLA-Cw4, and HLA-DR14 in Canada;7,9 HLA-B40 and HLA-Cw3 in Bogota;1,7,9 and HLA-Cw4 in Chimila Indians from Colombia. Among all of these alleles, HLAB40 and HLA-Cw3 are the most common in populations with a strong Amerindian component in their ancestry.1,14 In 1984, researchers15 reported patients whose skin had an abnormal immunological response with increase in T lymphocytes in peripheral blood, especially T cooperative lymphocytes (CD4+), and an increase in la+ cells in the dermal inflammatory infiltrate.4,16 This response is induced by solar radiation, particularly UV-A and UV-B radiation, although visible light plays also an important role.1,4,17 UV-B radiation stimulates the production of tumor necrosis factor α (TNF-α) in keratinocytes, mainly in the suprabasal layer.1,8 This radiation is capable of stimulating inmunoreactivity and the expression of adhesion molecules to keratinocytes, which fosters the migration of inflammatory cells that cause tissue and epidermis necrosis.8,18 TNF-α also acts in the activation of the transcription factor nuclear factor-κβ and programmed cellular death (apoptosis); therefore, it likely occurs in the physiopathology of AP.19 SKINmed. 2015;13:287–295

Immunohistochemistry studies have demonstrated a predominance of T lymphocytes CD45RO+ (T memory cells) and interleukin (IL) 2 in the inflammatory infiltrate.1,8,20 Lymphoid follicles observed in mucosa have T lymphocytes (CD45+, IL-2) in the periphery and B lymphocytes (CD20+) in the center, with abundant eosinophils and extracellular deposits of IgM, IgG. and C3 in the papillary dermis.8,9 In lymphoid follicles, many active B cells, instead of differentiating into plasma cells, begins to form lymphoid follicles after the interaction between CD40 of B cells and CD154 of T cells. In addition, this B cell acquires the capacity to attach any type of immunoglobulin and expresses CD80, which interacts with CD28 on T cells to activate IL-2 and the Th2 response (Figure 2). Th2 cells induce the release of IL-5 (which activates eosinophils), IL-4 (which stimulates the production of IgE21 and the activation of mast cells), and finally the characteristic formation of ectopic germinal centers, similar to other hypersensitivity, autoimmunity, and infective diseases.22 T CD4+ lymphocytes induce and amplify IL-2 synthesis, Th2 response, natural killer cells (NK cells) activation, and IgE antibodies production1,23 (Figure 3). Mast cells play an important role in both inflammatory and allergic reactions. They induce secretion of proinflammatory me-

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Figure 2. Costimulatory signals between B and T cells.

diators and cytokine by T lymphocytes when the IgE-antigen complex binds to the high affinity receptor for IgE24,25 (Figure 3). A recent Mexican study demonstrated increased density of mast cells in oral mucosa of patients with AP, compared with patients with healthy mucosa or with other inflammatory diseases; therefore, the presence of IgE, eosinophils, and mast cells suggest a hypersensitivity reaction into the physiopathology of AP.22 In general terms, hypersensitivity reactions are produced by effector cells after an antigen exposition. There are 4 types of hypersensitivity reactions included in the Gell and Coombs classification,26,27 and type IV has 4 subtypes (IVa–IVd) (Figure 4)28 because T cells can trigger different forms of inflammation with different patterns of cytokines and preferential activation of different immune cells.29–32 Considering the different types of hypersensitivity reactions, AP can fit into type IVa, IVb, or I: type IVa15,33,34 after sun exposure, keratinocytes produce TNF-α;1,8 type SKINmed. 2015;13:287–295

IVb due to the presence of IgE, eosinophils, and mast cells;30,31,35 or type I because there is a Th2 response15,36 with a predominant presence of IgE, eosinophils, and mast cells; however, the latter is less probable because the reaction is immediate and severe after exposure, and cutaneous manifestations of this type of reaction include wheals and angioedema, which are not present in AP.27,30,31,36 Clinical Features AP is a polymorphous, bilateral, and symmetric photodermatosis that predominantly affects photoexposed areas of the face, neck, trunk, and extremities, especially in prominent zones of the face (nose, zygomatic and superciliary arches, lower lip, and conjunctivae), where sun rays react with stronger intensity,4,6 although lesions may also be seen in covered areas.5,13 There are erythematous macules and papules that converge to form pruritic plaques (Figure 5), with excoriations, serosangui-

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Figure 3. Biologic actions of IL-2, and effector functions of Th1 and Th2 in pathogenesis of actinic prurigo.

nous crusts, lichenification, scars, and residual hypopigmentation or hyperpigmentation4–6,8,9 (Figure 6). In the vermilion border of the lower lip, there can be edema, cracks, fissures, and serosanguinous crusting, as well as erythema of the labial mucosa, which together comprise AP cheilitis. Some patients have anterior gingival hypertrophy, possibly associated with mouth breathing caused by affliction of the lips6 (Figure 7A and 7B). AP cheilitis is a frequent clinical manifestation that usually affects the lower lip. It occurs in 65% of patients with AP1 and in 27.6% of all cases, it is the only manifestation of the disease.6 At the conjunctival level, AP initially manifests itself with hyperemia, photophobia, and teary eyes; later, papilla hypertrophy and pseudopterygium can be seen, which sometimes produce diminishing of the visual field (Figure 8). AP conjunctivitis is present in approximately 45% of cases. Although not studied in detail, the conjunctival involvement does not occur in an isoSKINmed. 2015;13:287–295

lated manner, possibly because it is a late manifestation of the disease.4–6 The clinical course is chronic with exacerbations after sun exposure. In countries where seasonal transitions are marked, exacerbations occur in spring and remissions in autumn;5,13 while in areas with a tropical climate, where seasonal changes are not marked (such as in Mexico), there are exacerbations year-round and are related to sun exposure.4 Histopathology At a cutaneous level, there are hyperkeratosis (89%), parakeratoses (49%), acanthosis (92%), engrossment of the basal layer (73%), and a superficial inflammatory perivascular infiltrate by lymphocytes. Sometimes, histologic study shows only a chronic picture, but the presence of a nodular inflammatory infiltrate with eosinophils and mast cells suggests the diagnosis.37 Unlike

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Figure 4. Subclassification of type IV hypersensitivity reaction remarking IVa and IVb as possible bases of actinic prurigo pathogenesis.

Figure 6. Sun exposed forearm with excoriations, lichenification, and hematic crusts revealing chronic scratching.

Figure 5. Plaques with erythema, papules, excoriations, and lichenification on prominent parts of the face. SKINmed. 2015;13:287â&#x20AC;&#x201C;295

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Figure 7. (A) Acute cheilitis of actinic prurigo with erythema, edema, cracks, small ulcers with meliceric crusts on bermillion of lower lip, and gingival hypertrophy. (B) Chronic cheilitis of actinic prurigo with erosions, small ulcers, sero-hematic crusts, and hyperpigmentation.

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Figure 9. Histopathology of skin with orthokeratotic hyperkeratosis, irregular acanthosis and a dense perivascular and nodular inflammatory infiltrate by lymphocites (H&E 10x).

other photodermatoses, it is not common to have adnexal affection or solar elastosis6 (Figure 9). The vermillion border of the lip shows hyperkeratosis (87%), serohematic crusts (63.8%) on ulcerated areas, (40.5%) regular acanthosis (96.5%), spongiosis (79.3%), vacuolization of the basal layer (83.6%), eosinophils (74.1%), and melanophages (69.8%) in the epithelial interface. In the lamina propria, there are vasodilatation (60%), edema (80.1%), and a diffuse, inband or nodular lymphocytic infiltrate (75.8%) that forms well-defined lymphoid follicles (follicular cheilitis) characteristic of AP cheilitis6 (Figure 10).

Figure 8. Conjunctivitis of AP with pseudopterigion. SKINmed. 2015;13:287â&#x20AC;&#x201C;295

In the conjunctiva, epithelial hyperplasia alternates with atrophy areas, and there are vacuolization of the basal layer (60%), capillary dilation, and an inflammatory infiltrate with eosinophils, lymphocytes, and melanophages on the lamina propria. Lymphocytes can also have a follicular disposition as observed in the lip4,9 (Figure 11).

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Figure 10. Histopathology of lip with a thin stratified squamous epithelium nonkeratinized, and a nodular inflammatory infiltrate in corion forming the characteristic image of a lymphoid follicle (H&E 10x). Figure 11. Histopathology of conjunctival mucosa with spongiosis, pigment fall and melanophages, dilated small vessels and a diffuse inflammatory infiltrate with lymphocytes, eosinophils and several plasma cells and mastocytes (H&E 20x).

These lymphoid follicles are observed in as many as 80% of the samples of labial or conjunctiva mucosa of AP.1,4,6 With immunohistochemistry, the small and hyperchromatic lymphocytes in the periphery correspond to T cells, and those larger in the center to B lymphocytes.4,9 Diagnosis and Differential Diagnosis The clinical diagnosis should be confirmed by histopathologic study,38 preferably of the oral mucosa, where it is possible to observe lymphoid follicles.37 The main clinical differential diagnoses are atopic dermatitis with photosensitivity, chronic photocontact dermatitis, chronic actinic dermatitis, and polymorphous light eruption.5,9 The main challenge is atopic dermatitis with photosensitivity, as it also starts in childhood and patients often are not aware of their atopic condition.39 AP conjunctivitis should be differentiated from spring conjunctivitis, which is bilateral, highly pruritic, recurrent, and predominates in adolescents with atopy.40 The most important SKINmed. 2015;13:287â&#x20AC;&#x201C;295

clinical differential diagnosis of AP cheilitis is traumatic cheilitis secondary to lip biting, where erythema, atrophy, erosion, melanic hyperpigmentation, burning, and tendency to chronicity are observed.41 It is important not to confuse cheilitis of AP with actinic cheilitis, as they are different entities.42 Treatment It is fundamental to avoid sun exposure and to use sun protection. Pharmacologic treatment depends on the extension and severity of the disease.6,9,43 Therapeutic options include topical or systemic corticosteroids, vitamin E, β-carotenes, tetracycline, antimalarial drugs, antihistamines, cyclosporine A, calcineurin inhibitor, thalidomide, and low dosages of UV-A or UV-B phototherapy, although the response is better with thalidomide.4,6,44

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Thalidomide or alpha N-ftalilmido-glutarimide is a derivative of glutamic acid45 introduced in 1973 by Londoño,46 who showed excellent results in treating patients with AP. These findings were confirmed in 197547,48 and in 1993.14 This is the most efficient current treatment, as it is an immunomodulator that inhibits TNF-α8 and increases the number of T CD3+ cells and interferon γ.49 The most effective dose reported in children aged 9 to 16 years is 0.5 to 2.5 mg/kg/d orally,50 and in adults the initial dose is 100 to 200 mg daily. This dose should be maintained until clinical improvement,6,9,49 which usually occurs between 2 and 4 weeks of treatment6 and diminishes until reaching the minimal effective dose, which is generally 25 mg per week.6,9

9 Hojyo-Tomoka T, Vega-Memije ME, Cortes-Franco R, et al. Diagnosis and treatment of actinic prurigo. Dermatol Ther. 2003;16:40–44.

The main problem with thalidomide is teratogenicity, so it is necessary to use an effective contraception method in women of reproductive age,6,9 but other adverse effects are sleepiness, loss of appetite,9 headaches, nausea, constipation, cutaneous hypersensitivity,1 and sensitive neuropathy.9 The latter can be asymptomatic and is confirmed by nervous conduction studies in up to 90.9% of patients.

14 Vega-Memije ME, Hojyo-Tomoka MT, Dominguez-Soto L. Tratamiento del prurigo actínico con talidomida: Estudio de 30 pacientes. Dermatol Rev Mex. 1993;37:342–343.

Conclusions AP is a typical photodermatosis of Mestizo populations with dark skin types. The pathognomonic histologic data are lymphoid follicles. Thalidomide is currently the most effective treatment, despite its important adverse effects. References 1 Salazar-Mesa AM. Prurigo actínico en la niñez. Dermatol Pediatr Lat. 2005;3:193–200. 2 López González G. Prurigo solar. Arch Argent Dermatol. 1961;11:301–313. 3 Escalona E, Magaña M. Dermatologia. Lo esencial para el estudiante. México: Impresiones Modernas SA; 1964;194. 4 Hojyo-Tomoka MT, Vega-Memije ME, Cortes-Franco R, et al. Actinic prurigo: an update. Int J Dermatol. 1995;34:380–384. 5 Saeb-Lima M, Cortés-Franco R, Vega-Memije ME, et al. Principales fotodermatosis en Latinoamérica. Revisión y actualización. Derm Venez. 1999;37:15–21. 6 Vega-Memije ME, Mosqueda-Taylor A, Irigoyen-Camacho ME, et al. Actinic prurigo cheilitis: clinicopathologic analysis and therapeutic results in 116 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2002;94:83–91. 7 Wiseman MC, Orr PH, Macdonald SM, et al. Actinic prurigo: clinical features and HLA associations in a Canadian Inuit population. J Am Acad Dermatol. 2001;44:952–956. 8 Arrese JE, Domínguez-Soto L, Hojyo-Tomoka MT, et al. Effectors of inflammation in actinic prurigo. J Am Acad Dermatol. 2001;44:957–961.

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10 Sachdeva S. Fitzpatrick skin typing: applications in dermatology. Indian J Dermatol Venereol Leprol. 2009;75:93–96. 11 Granados-Arriola J, Domínguez-Soto L. Inmunogenética del prurigo actinico en Mexicanos. Dermatol Rev Mex. 1993;37(suppl 1):314–315. 12 Hojyo-Tomoka T, Granados J, Vargas-Alarcón G, et al. Further evidence of the role of HLA-DR4 in the genetic susceptibility to actinic prurigo. J Am Acad Dermatol. 1997;36(6 pt 1):935–937. 13 Grabczynska SA, McGregor JM, Kondeatis E, et al. Actinic prurigo and polymorphic light eruption: common pathogenesis and the importance of HLA-DR4/ DRB1*0407. Br J Dermatol. 1999;140:232–236.

15 Moncada B, González-Amaro R, Baranda ML, et al. Immunopathology of polymorphous light eruption. T lymphocytes in blood and skin. J Am Acad Dermatol. 1984;10:970–973. 16 González-Rodríguez G, Ocádiz-Delgado R. Poblaciones clonales de células T y B en prúrigo actínico, una fotodermatosis. Gac Méd Méx. 2001;137:15–20. 17 Hojyo-Tomoka MT. Pruebas fotobiológicas en prurigo actínico. Dermatol Rev Mex. 1993;37(suppl 1):328. 18 Hansen CH, Leitenberger JJ, Jacobe HT, et al. Photoimmunology. In: Gaspari AA, Tyring SK, eds. Clinical and Basic Immunodermatology. London: Springer; 2008:147–155. 19 Van Antwerp DJ, Martin SJ, Kafri T, Green DR, Verma IM. Suppression of TNF-alpha–induced apoptosis by NFkappa B. Science. 1996;274:787–789. 20 Umaña A, Gómez A, Durán MM, et al. Lymphocyte subtypes and adhesion molecules in actinic prurigo: observations with cyclosporin A. Int J Dermatol. 2002;41:139–145. 21 Nairn R, Helbert M. Immunology for medical students. Philadelphia, PA: Mosby Elsevier; 2007:122–123. 22 Chvatchko Y, Kosco-Vilbois MH, Herren S, et al. Germinal center formation and local immunoglobulin E (IgE) production in the lung after an airway antigenic challenge. J Exp Med. 1996;184:2353–2360. 23 Pizzi N. Aspectos menos conocidos del Prurigo actínico. Dermatol Rev Mex. 1993;37(suppl 1):298. 24 Miyazaki D, Nakamura T, Toda M, et al. Macrophage inflammatory protein-1alpha as a costimulatory signal for mast cell-mediated immediate hypersensitivity reactions. J Clin Invest. 2005;115:434–442. 25 Fischer M, Harvima IT, Carvalho RF, et al. Mast cell CD30 ligand is upregulated in cutaneous inflammation and mediates degranulation-independent chemokine secretion. J Clin Invest. 2006;116:2748–2756. 26 Coombs PR, Gell PG. Classification of allergic reactions responsible for clinical hypersensitivity and disease. Gell RR, ed. In: Clinical Aspects of Immnunology. Oxford: Oxford University Press; 1968;575–596.

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27 Warrington R, Silviu-Dan F. Drug allergy. Allergy Asthma Clin Immunol. 2011;7(suppl 1):S10. 28 Schlessinger L. Drug allergy I: epidemiology and pathophysiology. Medwave. 2009;9:e3918. 29 Torres MJ, Mayorga C, Blanca M. Nonimmediate allergic reactions induced by drugs: pathogenesis and diagnostic tests. J Investig Allergol Clin Immunol. 2009;19:80– 90. 30 Pichler WJ. Delayed drug hypersensitivity reactions. Ann Intern Med. 2003;139:683–693. 31 Adam J, Pichler WJ, Yerly D. Delayed drug hypersensitivity: models of T-cell stimulation. Br J Clin Pharmacol. 2011;71:701–707.

40 Magaña M, Mendez Y, Rodriguez A, et al. The conjunctivitis of solar (actinic) prurigo. Pediatr Dermatol. 2000;17:432–435. 41 Boletín de Información Clínica Terapéutica. Queilitis en la Práctica Médica. Academia Nacional de Medicina de México. México; 2008. XVII (4):3–5. Available at: http:// www.anmm.org.mx/2012/publicaciones/boletin_clinico_terapeutico/2008/2008-04.pdf 42 Vega-Memije ME, Ortega-Estrada S, Hojyo-Tomoka MT, et al. Queilitis: correlación clínico-patológica. Dermatol Rev Mex. 1991;XXXV:212–217. 43 Fusaro R, Jonson J. Prevención y tratamiento del Prurigo actínico. Dermatol Rev Mex. 1993;37(suppl 1):339–340.

32 Lerch M, Keller M, Britschgi M, et al. Cross-reactivity patterns of T cells specific for iodinated contrast media. J Allergy Clin Immunol. 2007;119:1529–1536.

44 Crouch R, Foley P, Baker C. Actinic prurigo: a retrospective analysis of 21 cases referred to an Australian photobiology clinic. Australas J Dermatol. 2002;43:128–132.

33 Scheen SR, Connolly SM, Dicken CH. Actinic prurigo. J Am Acad Dermatol. 1980;5:183–190.

45 Cejudo-Rodríguez C. Desórdenes inmunológicos y el resurgimiento de la talidomida. Nuevas aplicaciones clínicas. Alergia, asma e inmunología pediátricas. 1999;8:49–56.

34 Herrera-Esparza R, Vega-Memije ME, Hojyo-Tomoka MT, et al. En búsqueda de autoanticuerpos en pacientes con prurigo actínico. III Comunicación preliminar. Dermatología Rev Mex. 1993;37:312–313.

46 Londoño F. Thalidomide in the treatment of actinic prurigo. Int J Dermatol. 1973;12:326–328.

35 Hari Y, Urwyler A, Hurni M, et al. Distinct serum cytokine levels in drug- and measles-induced exanthema. Int Arch Allergy Immunol. 1999;120:225–229.

47 Flores O. Prurigo solar de altiplanicie. Resultados preliminares del tratamiento con talidomida en 25 casos. Dermatol Rev Mex. 1975;19:26–39.

36 Ávalos E, Ramírez R, Presno M, et al. Subpoblaciones de linfocitos T en pacientes con Prurigo actínico. Dermatol Rev Mex. 1993;37(suppl 1):305–307.

48 Saul A, Flores O, Novales J. Polymorphous light eruption: treatment with thalidomide. Australas J Dermatol. 1976;17:17–21.

37 Vega ME. Características histopatológicas del prurigo actínico. Dermatol Rev Mex. 1993;37(suppl 1):295–297.

49 Estrada GI, Garibay-Escobar A, Nunez-Vazquez A, et al. Evidence that thalidomide modifies the immune response of patients suffering from actinic prurigo. Int J Dermatol. 2004;43:893–897.

38 Lestarini D, Khoo LS, Goh CL. The clinical features and management of actinic prurigo: a retrospective study. Photodermatol Photoimmunol Photomed. 1999;15:183–187. 39 Hojyo-Tomoka MT. Prurigo actínico: diagnóstico diferencial. Dermatol Rev Mex. 1993;37(suppl 1):303.

50 Cazarín J, Román D, Messina M, Magaña M. Talidomida en niños con prurigo solar refractario. Actas Dermatol. 2002;2:11–15.

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SELF ASSESSMENT EXAMINATION W. Clark Lambert, MD, PhD For each of the following numbered questions, select the single most appropriate lettered response unless directed otherwise. 1. Actinic prurigo (AP) is an idiopathic photodermatitis that affects the skin and the: (Answer as many as apply; all, some, or none of the answers may be correct.) a. Conjunctivae. b. Fingernail beds. c. Glans penis. d. Labial (lip) mucosa. e. Labial (vulvar) mucosae. f. Toenail beds.

AP is most strongly linked to: HLA A24. HLA A28. HLA B39. HLA Cw4. HLA DR4. HLA DR14.

5. Factors implicated in the etiopathogenesis of AP include: (Answer as many as apply; all, some, or none of the answers may be correct.) a. CD4+ T lymphocytes. b. Immunoglobulin E (IgE). c. Interleukin 2 (IL 2). d. Mast cells. e. Natural killer (NK) lymphocytes. ANSWERS TO EXAMINATION: 2. e

3. b

4. e

5. a, b, c, d, e

3. AP is most common among: a. African blacks whose ancestors emigrated to South and Central America. b. Amerindians. c. Caucasians of Northern European descent.

4. a. b. c. d. e. f.

1. a, d

2. The pathognomic histopathologic finding in AP is: a. Hyperkeratosis with intermittant parakeratosis of sun exposed skin. b. Orthokeratotic hyperkeratosis of sun exposed skin. c. Pitting of the fingertips with hyperkeratotic plugs. d. Suprabasalar clefting of sun exposed skin. e. Well defined lymphoid follicles in sun exposed mucosae.

d. Caucasians of Mediterranian descent. e. Pacific islanders whose ancestors emigrated to South and Central America.

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From the Departments of Pathology and Dermatology, Rutgers University – New Jersey Medical School, Newark, NJ Address for Correspondence: W. Clark Lambert, MD, PhD, Room H576 Medical Science Building, Rutgers University – New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103 • E-mail: lamberwc@njms.rutgers.edu

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Volume 13 • Issue 4

Core curriculum Virendra N. Sehgal, MD, Section Editor

Oral Mucosal Lesions: Oral Cavity Biology––Part I Virendra N. Sehgal, MD;1 Nazim Hussain Syed, MD;1 Ashok Aggarwal, MD;1 Shruti Sehgal, MDS2

It is important to evaluate the background of oral cavity biology to define morphologic abrasions in oral mucosa following a host of local and/ or systemic disorders. The oral cavity is not only the beginning of the digestive system, but it also plays a significant role in communication; the voice (although the voice is produced in the throat), tongue, lips, and jaw are its essential components to produce the range of sounds. The vestibule and the oral cavity are its major parts, and are usually moist. The lips and the teeth are in approximation, marking its start up. The anatomy of the oral cavity in brief has been reviewed in right prospective for disease related changed morphology, thus facilitating interpretation. (SKINmed. 2015;13:297–300)

T

he oral cavity and pharynx are anatomic spaces formed by hard and soft tissue structures. Their shape changes with the normal physiologic function of the surrounding structures during speech, swallowing, and respiration (Figure).1

Anteriorly, the oral cavity is formed by the upper and lower lips, laterally by the cheeks, superiorly by the hard palate, and inferiorly by the mucosa covering the superior surface of the tongue and the sheet of muscles attached to the inner side of the mandible, including geniohyoid, mylohyoid, and digastric. Although primarily a space through which food and air travel, several structures are found, including upper and lower dentition, the tongue, salivary glands, mucosal glands, and the mucosal tissue covering the hard palate, which bear the rugae (a fold/wrinkle or crease).1 The cavity of the mouth is placed at the start of the digestive tube. It is an oval-shaped/elliptical cavity that consists of two parts, namely an outer, smaller portion (the vestibule), and an inner, larger part (the mouth cavity proper).1

Vestibule/vestibulum oris The vestibule/vestibulum oris is a slit-like space bounded externally by the lips and cheeks and internally by the gums and teeth. It communicates with the surface of the body by the rima/ orifice of the mouth. It is limited above and below by the reflection of the mucous membrane from the lips and cheeks to the gum, covering the upper and lower alveolar arches, respectively. It receives the secretion from the parotid salivary glands and communicates, when the jaws are closed, with the mouth cavity proper by an aperture/gap on either side behind the wisdom teeth and by narrow clefts between opposing teeth.1 Mouth cavity proper Also known as the cavum oris proprium, the mouth cavity proper is bounded laterally and in front by the alveolar arches with their contained teeth; behind, it communicates with the pharynx by a constricted aperture, the isthmus faucium. It is roofed by the hard and soft palates while the greater part of the floor is formed by the tongue, and the remainder by the reflection of the mucous membrane from the sides and under surface of

From the Dermato-Venereology (Skin/VD) Center, Sehgal Nursing Home, Panchwati, Delhi, India, Skin Institute, and School of Dermatology, Greater Kailash, New Delhi,1 and the Department of Conservative Dentistry and Endodontics, Government Dental College, Raipur, India2 Address for Correspondence: Virendra N. Sehgal, MD, FNASc, FAMS, FRAS (Lond), Dermato Venerology (Skin/VD) Center, Sehgal Nursing Home, A/6 Panchwati, Delhi-110 033, India • E-mail: drsehgal@ndf.vsnl.net.in

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Core Curriculum

Figure. Oral cavity biology, depicting display of oral mucosa on anatomical constituents; pharynx, hard palate, superior surface of the tongue, cheeks and lips.

the tongue to the gum lining the inner aspect of the mandible. It receives the secretion from the submaxillary and sublingual salivary glands.1 Oral mucosa The oral epithelium consists of a functional compartment, the progenitor basal and parabasal cells, the site of cell division. This is a maturation compartment comprised of spinous and granular cells where the cells become more terminally differentiated, and a superficial cornified compartment of squames and areas of keratinization, either orthokeratotic or parakeratotic. In the nonkeratinized regions such as the buccal/cheek and floor-ofmouth mucosa, overt keratinization and granular cells are absent and the surface cells are flattened, with elongated nuclei.2 The mucosa is divided into (1) masticatory, (2) lining mucosa, and (3) specialized mucosa. Masticatory mucosa/hard palate and gingiva

On the dorsum of the tongue, specialized mucosa, adapted for taste and mastication, is keratinized, with numerous ret ridges and connective tissue papillae, abundant elastic and collagen fibers in the lamina propria, and no submucosa. The tongue is divided by a V-shaped groove, the sulcus terminalis, into an anterior two thirds and a posterior one third. Various papillae on the dorsum include the filiform papillae, which cover the entire anterior surface and form an abrasive surface to control the food bolus as it is pressed against the palate, and the fungiform papillae. The latter are mushroom-shaped red structures covered by nonkeratinized epithelium. They are scattered between the filiform papillae and have taste buds on their surface. Adjacent and anterior to the sulcus terminalis are 8 to 12 larger circumvallate papillae, each surrounded by a deep groove into which open the ducts of serous minor salivary glands. The lateral walls of these papillae contain taste buds.3,4 Lips

Masticatory mucosa/hard palate and gingiva adapts to the forces of pressure and friction and keratinized with numerous tall rete ridges and connective tissue papillae and little submucosa.3 Lining/buccal, labial, and alveolar mucosa The lining of buccal, labial, and alveolar mucosa make up the floor of the mouth, ventral surface of the tongue, soft palate, and lips and is nonkeratinized with broad rete ridges and connective tissue papillae and abundant elastic fibers in the lamina propria.3,4 SKINmed. 2015;13:297â&#x20AC;&#x201C;300

Specialized mucosa

The lips extend from the lower end of the nose to the upper end of the chin. They consist of the orbicularis oris muscle. The vermilion zone is the transition between the glabrous skin and the mucous membrane, which has a profusion of minor salivary glands. This vermilion zone has no hair or sweat glands, but contains sebaceous glands, the Fordyce sports. Its epithelium has a prominent stratum lucidum and a very thin stratum corneum. The dermal papillae are numerous with a rich capillary supply producing reddish pink lips in white individuals. Melanocytes are abundant in the basal layer of the vermilion of pigmented skin; they are infrequent in white skin.5

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Tongue In the floor of the mouth is the tongue. Its upper surface is convex and is marked along the middle line by a shallow sulcus. The anterior two thirds are rough and studded with papilla and the posterior one third is smooth and tuberculated. The division between the anterior two thirds and the posterior one third is marked by a V-shaped furrow, the sulcus terminalis, which is situated immediately behind the line of the vallate papilla.6 The tongue is a muscular hydrostat, but has no skeletal support capable of movement. It consists of four extrinsic muscles: genioglossus (12th), hyoglossus (12th), styloglossus (12th), and palatoglossus (10th or 12th)—and three groups of intrinsic fibers: vertical, transverse, and longitudinal, all supplied by the hypoglossal nerve (12th).6 The tongue is the primary organ of taste (gustation), as much of the upper surface of the tongue is covered in papillae and taste buds. It is sensitive and kept moist by saliva, and is richly supplied with nerves and blood vessels. In humans, a secondary function of the tongue is phonetic articulation. The tongue also serves as a natural means of cleaning one’s teeth.7 The ability to perceive different tastes is not localized in different parts of the tongue, as is widely believed.8 Teeth The other significant hard tissue structures in the oral cavity are the teeth. The human dentition, rooted in the maxilla and mandible, consists of 32 teeth in four quadrants: left, right, upper, and lower. Humans are born edentulous, and the first deciduous/milk teeth erupt approximately 6 to 8 months after birth. There are five deciduous teeth per quadrant: a medial and a lateral incisor, a canine, and the first and second molars. These teeth are replaced by permanent/adult teeth, with two premolars and a third molar erupting as part of the adult dentition. All but the third molar are in place by approximately 12 years of age. The third molar, in modern humans, either erupts much later or often fails to erupt.9

the three branches of the trigeminal nerve, and the 5th cranial nerve. It comprises the principal functions of sensation from the V2. Blood supply The blood supply to the oral cavity and the pharynx is from branches of the external carotid artery. The branches of the external carotid that supply oral and pharyngeal structures are the ascending pharyngeal artery, lingual artery, facial artery, posterior auricular artery, superficial temporal artery, and numerous branches of the maxillary artery. The venous drainage is through many tributaries, including facial, lingual, and pharyngeal veins.10 Immunity Much of the foreign material is swallowed during speech and swallowing. The need for a cleaning mechanism is clearly apparent in patients with facial paralysis or in those with xerostomia, in whom there is accumulation of oral debris and subsequent infection. Saliva is inhibitory to various microbial agents. Salivary tissue derives its B cells from the gut-associated lymphoid tissue. Salivary acinar cells produce a secretory component needed for transport of IgA into the saliva and its stability in the presence of salivary or gastric proteolytic enzymes. Although the exact contribution to oral defense made by salivary IgA antibodies is difficult to assess, some patients who have IgA deficiency experience oral infections, perhaps because neutrophils and other leukocytes are particularly essential for oral health.10

Innervations and Blood Supply The sensory nerve supply to the pharynx is primarily from the glossopharyngeal the 9th and vagus 10th nerves. Branches of these nerves, including the pharyngeal branch of the glossopharyngeus (9th), small branches from the external and superior laryngeal nerves, and the pharyngeal branches, both from the vagus (10th), form the pharyngeal plexus that lies on the pharyngeal wall. The exception is portions of the nasopharynx, which receive branches of the maxillary nerve (CN V2), one of SKINmed. 2015;13:297–300

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Table. Lymphatic Drainage of the Oral Cavity Draining lymph node

Area

Submandibular

Cheek Upper lip Lower lip, lateral part Mandibular gingivae Floor of the mouth

Deep cervical

Tongue, posterior third Tongue, ventrum Maxillary gingival Hard palate

Submental; remainder drains to submandibular nodes

Tongue tip

Submandibular; some midline crossover of lymphatic drainage

Tongue, anterior two thirds

Submental

Lower lip

Retropharyngeal and deep cervical

Soft palate

Jugulodigastric

Tonsil

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Lymphatic drainage Lymphatic drainage is an intricate issue that varies according to the area of the oral cavity, to different groups of lymphnodes, and to their respective lymph channels/lymphatics (Table). Conclusions The anatomy of oral cavity comprising pharynx, hard palate, superior surface of the tongue, cheeks, and lips have been briefly reviewed to create awareness and to interpret any mucous membrane abrasions. References 1 Scott JH, Symons NBB. Introduction to Dental Anatomy. 8th ed, Edinburgh, Scotland: Churchill Livingstone; 1977. 2 Meyer J, Squier CA, Gerson SJ. The Structure and Function of Oral Mucosa. Oxford, England: Pergamon Press; 1984. 3 Prime SS. Development, structure and function of oral mucosa. In: Scully C, ed. The Mouth in Health and Dis-

ease. Oxford, England: Heinemann Medical; 1989:124– 144. 4 Zugerman C. The lips: anatomy and differential diagnosis. Cutis. 1986;38:116–120. 5 Keir WM, Smith KK. Tongues, tentacles, and trunks: the biomechanics of movement in muscular hydrostats. Zool J Linnean Soc. 1985;83:307–324. 6 Maton A, Hopkins J, McLaughlin CW, et al. Human Biology and Health. Englewood Cliffs, NJ: Prentice Hall; 1993. 7 Smith DV, Margolskee RF. Making sense of Taste. The taste map: all wrong. Sci Am. 2006;16:84–92. 8 Berkovitz BK, Holland GR, Moxham BJ. A Colour Atlas and Textbook of Oral Anatomy. London, England: Wolfe; 1978. 9 Lamey PJ, Scully C. Salivary gland development, anatomy and physiology. In: Scully C, ed. The Mouth in Health and Disease. Oxford, England: Heinemann Medical; 1989:283–288. 10 Saraswathi TR, Ranganathan K, Shanmugam S, et al. Prevalence of oral lesions in relation to habits: Crosssectional study in South India. Indian J Dent Res. 2006;17:121–125.

Historical Diagnosis and treatment: ECZEMA

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Volume 13 • Issue 4

Perils of Dermatopathology W. Clark Lambert, MD, PhD, Section Editor

What Lies Beneath: The Importance of Proper Diagnosis of Cutaneous Horn Timothy Peiris, BS;1 Laju M. Mathew, MD;2 W. Clark Lambert, MD, PhD2,3 “If a lesion receives a pathologic diagnosis of ‘cutaneous horn’ then either the clinician or the pathologist should be fired.”––Wallace Clark, MD

T

he earliest recorded case of cutaneous horn was in an elderly Welsh woman, Margaret Gryffith, in 1588.1 The cause of much speculation and intrigue among the scientific community and laypeople alike at the time, we have since advanced our knowledge by leaps and bounds regarding this dermatologic entity. The cutaneous horn is a conical, hyperkeratotic, projecting nodule distinguished from traditional animal horns by the absence of a central bone. It is generally white or yellow and can have a variety of morphologic forms, such as cylindrical, corrugated, or curved. Thirty percent of these lesions are found in the commonly sun-exposed areas of the face and scalp2; however, what is most concerning to the pathologist is not what rises above the skin but rather what lurks below. The cutaneous horn is a clinical, not a histopathologic, diagnosis. Actinic keratosis, seborrheic keratosis, verruca vulgaris, squamous cell carcinoma, and a variety of other benign, premalignant, or malignant conditions occur in conjunction with and give rise to the cutaneous horn (Figure).2 It is the duty of the pathologist to investigate the origin of the horn to prevent morbidity and mortality. Similarly, it is the duty of the clinician to provide a quality biopsy of the base, as the horn itself is often not of diagnostic value. Benign Lesions Seborrheic keratoses are common benign cutaneous tumors most frequently seen in older populations. Measuring from miniscule to approximately 2.5 centimeters across, these dark growths often have a characteristic “pasted-on” appearance. In one study, 92.7% of 66- to 70-year-old men were found to have at least one seborrheic keratosis.3 The cause of the condition remains

unclear, and treatment is often unnecessary. Irritated seborrheic keratoses can result in the development of a cutaneous horn and may resemble squamous cell carcinoma clinically, requiring further investigation.4 Verruca vulgaris, also known as a wart, characteristically presents as sharply demarcated papules, most often seen on the hands, fingers, or knees. Histologically, this lesion displays papillomatosis, marked hyperkeratosis, acanthosis, and parakeratosis. Human papillomavirus (HPV) type 2 is chiefly responsible for verruca vulgaris, although other HPV subtypes are also commonly seen.5,6 They are commonly found in handlers of meat, poultry, or fish, and in immunosuppressed individuals. HPV infection, skin trauma, and chronic inflammation are prominent risk factors for their development.7 Treatment options fall into four categories: cryodestructive methods, chemotherapy, antiviral therapy, and immunotherapy.5 Efficacy of one treatment category vs another remains hotly debated. Premalignant Lesions Studies have shown that 23% of cutaneous horns are derived from premalignant lesions.9 Actinic keratoses are caused by UV exposure and are estimated to affect 39.5 million people in the United States.2 Characterized by scaly cutaneous lesions, actinic keratoses are more common in persons with red hair, light complexion, and heavy freckling. Incidence increases with age; an elderly, fair-skinned individual with a cutaneous horn most likely has hypertrophic actinic keratosis.7 Failing preventative measures to avoid UV rays, aggressive lesion-directed therapy is indicated to lessen the risk of developing a squamous cell carcinoma.2

From Rutgers – New Jersey Medical School1 and the Departments of Dermatology2 and Pathology,3 Rutgers–New Jersey Medical School, Newark, NJ Address for Correspondence: W. Clark Lambert, MD, PhD, Room H576 Medical Science Building, Rutgers University – New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103 • E-mail: lamberwc@njms.rutgers.edu

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perils of dermatopathology Conclusions Cutaneous horns can arise from a variety of benign, premalignant, and malignant lesions. Benign etiologies are most common, with 61% of cases of cutaneous horn arising from benign lesions9; however, the possibility of an underlying malignancy mandates appropriate histopathologic examination of the base. Appropriate management of the patient necessitates that the clinician and pathologist work in tandem to provide an accurate diagnosis. References 1 Bondeson J. Everard Home, John Hunter, and cutaneous horns. Am J Dermatopathol. 2001;23:362–369. 2 Fernandes NF, Sinha S, Lambert WC, Schwartz RA. Cutaneous horn: a potentially malignant entity. Acta Dermatovenerol Alp Pannonica Adriat. 2009;18:189–193.

Figure. Keratoacanthoma (squamous cell carcinoma, keratoacanthoma type) at the base of a cutaneous horn. (Hematoxylin and eosin, original magnification ×58.)

3 Kyriakis KP, Alexoudi I, Askoxylaki K, Vrani F, Kosma E. Epidemiologic aspects of seborrheic keratoses. Int J Dermatol. 2012;51:233–234. 4 Aydogan K, Ozbek S, Balaban Adim S, Tokgoz N. Irritated seborrhoeic keratosis presenting as a cutaneous horn. J Eur Acad Dermatol Venereol. 2006;20:626–628. 5 Ergun SS, Su O, Buyukbabany N. Giant verruca vulgaris. Dermatol Surg. 2004:30:459–462.

Malignant Lesions Clues that a cutaneous horn may overlay a malignancy include large size of the base, large height-to-base ratio, tenderness, and inflammation. Advanced age, male sex, history of actinic keratosis or skin cancer, and location of the lesion in a sun-exposed area are additional risk factors. It is primarily the possibility of squamous cell cancer that provides the impetus to examine the base of the horn. Basal cell carcinoma, metastatic renal cell carcinoma, granular cell tumor, sebaceous carcinoma, and Kaposi’s sarcoma are also possibilities. Surgical excision of the malignancy is the treatment of choice.2,8

6 Leppard W, Loungani R, Saylors B, Delaney K. Mythology to reality: case report on a giant cutaneous horn of the scalp in an African American female. J Plast Reconstr Aesthet Surg. 2013;67:e22–e24. 7 Barbosa P. Plantar verrucae and HIV infection. Clin Podiatr Med Surg. 1998:15:317–327. 8 Copcu E, Siviroglu N, Culhaci N. Cutaneous horns: are these lesions as innocent as they seem to be? World J Surg Oncol. 2004;2:18. 9 Yu RC, Pryce DW, Macfarlane AW, Stewart TW. A histopathological study of 643 cutaneous horns. Br J Dermatol. 1991;124:449–452.

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NEW THERAPY UPDATE William Abramovits, MD; Aditya K Gupta, MD, PhD, FRCPC, Section Editors

COSENTYX (Secukinumab) Aditya K. Gupta, MD, PhD, FRCPC;1,2 Kelly A. Foley, PhD;2 William Abramovits, MD3,4,5

M

anagement of psoriasis can be difficult for patients, because individual response to treatment varies or treatment is discontinued due to side effects. An understanding of the immunologic underpinnings of psoriasis has led to development of a number of biologics that specifically act on various immune modulators implicated in the pathogenesis of the disease.1 These developments have resulted in targeted therapies for patients who have not responded to other treatments. Secukinumab, a fully human IgG1κ monoclonal antibody and interleukin (IL) 17A antagonist, is one of the newest biologics to become available, with efficacy that is similar, or better, than existing biologics.2–4 The US Food and Drug Administration (FDA) approved secukinumab (Cosentyx) for the treatment of psoriasis in January 2015.2 Phase III Clinical Trials

Two phase III multicenter, randomized, double-blind, placebocontrolled clinical trials assessed the efficacy of subcutaneous (SC) 150 mg and 300 mg secukinumab.3,5 Both the Efficacy of Response and Safety of Two Fixed Secukinumab Regimens in Psoriasis (ERASURE) and the Full Year Investigative Examination of Secukinumab vs. Etanercept Using Two Dosing Regimens to Determine Efficacy in Psoriasis (FIXTURE) trials were 52 weeks long, with an induction period of 12 weeks and a maintenance period of 40 weeks. Secukinumab was administered weekly for weeks 0 to 4, followed by monthly administration until week 48 (Table I).3 Given the success of an open-label period in an earlier phase II trial, monthly secukinumab was selected as the regimen to be investigated as maintenance therapy.6 The FIXTURE trial additionally compared secukinumab with etanercept (Table I) and all treatment groups were matched with corresponding placebo injection

regimens.3 Adult patients were diagnosed with moderate to severe plaque psoriasis (Psoriasis Area and Severity Index [PASI] of 12 or higher and a score of 3 or 4 on the modified Investigator Global Assessment [IGA]) that was poorly controlled with other treatment.3 The co-primary endpoints were PASI 75 and a score of 0 or 1 on the modified IGA at week 12. At 12 weeks, the proportion of patients receiving secukinumab 150 mg or 300 mg who achieved PASI 75 and a modified IGA score of 0 or 1 in both trials was significantly higher than those taking placebo (Table II). In addition, the FIXTURE trial demonstrated that a higher proportion of patients in the 150 mg and 300 mg secukinumab groups achieved primary efficacy outcomes as compared with patients taking etanercept (Table II).3 The time to reach a 50% reduction in baseline PASI was 3 weeks for 300 mg secukinumab and 3.9 weeks for 150 mg secukinumab, significantly shorter than 7 weeks for etanercept (P<.001 for both).3 Of those who achieved PASI 75 with secukinumab in the ERASURE trial, PASI 75 was maintained from week 12 to week 52 in 80.5% of patients (161 of 200) administered 300 mg and in 72.4% of patients (126 of 174) administered 150 mg. Maintenance of PASI 75 was achieved in the FIXTURE trial for 84.3% of patients (210 of 249) administered 300 mg and in 82.2% of patients (180 of 219) administered 150 mg vs 72.5% of patients (103 of 142) administered etanercept (300 mg, P<.001; 150 mg, P=.009).3 Two smaller randomized, double-blind, controlled phase III clinical trials were conducted to assess the efficacy and safety of selfadministration of secukinumab using a prefilled syringe (PFS)7 or autoinjector pen (Table I).8 The First Study of Secukinumab in Pre-filled Syringes in Subjects With Chronic Plaque-Type Psoriasis: Response at 12 Weeks (FEATURE) and Judging the

From the Department of Medicine, University of Toronto School of Medicine, Toronto, Ontario, Canada;1 Mediprobe Research Inc, London, Ontario, Canada;2 the Department of Medicine, Baylor University Medical Center, Dallas, TX;3 the Departments of Dermatology and Family Practice, University of Texas Southwestern Medical School, Dallas, TX;4 and the Dermatology Treatment and Research Center, Dallas, TX5 Address for Correspondence: Aditya K. Gupta, MD, PhD, FRCPC, 645 Windermere Road, London, Ontario, Canada N5X 2P1 • E-mail: agupta@execulink.com

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Table I. Study Characteristics of Phase III Trials Study

Drug arms

Erasure (n=738)3

Fixture (n=1306)3

Juncture (n=182)8

Feature (n=177)7

DB RCT

DB RCT

DB RCT

DB RCT

300 mg secukinumab (n=245)

300 mg secukinumab (n=327)

300 mg secukinumab (n=60)

300 mg secukinumab (n=59)

150 mg secukinumab (n=245)

150 mg secukinumab (n=327)

150 mg secukinumab (n=61)

150 mg secukinumab (n=59)

Placebo (n=248)

50 mg etanercept (n=326)

Placebo (n=61)

Placebo (n=59)

Week 0–4: weekly Week 5–48: every 4 weeks

Secukinumab: see ERASURE Etanercept: Week 0–12: twice weekly Week 13–51: weekly

Prefilled syringe weekly (week 0–4), then every 4 weeks (week 8 and 12)

Autoinjector pen weekly (week 0–4), then every 4 weeks (week 8 and 12)

Induction: week 12 Maintenance: week 52

Induction: week 12 Maintenance: week 52

Induction: week 12

Induction: week 12

Placebo (n=326) Regimen

Assessment

Abbreviations: DB RCT, double-blind randomized controlled trial; ERASURE, Efficacy of Response and Safety of Two Fixed Secukinumab Regimens in Psoriasis; FEATURE, First Study of Secukinumab in PFS in Subjects With Chronic Plaque-Type Psoriasis: Response at 12 Weeks; FIXTURE, Full Year Investigative Examination of Secukinumab vs. Etanercept Using Two Dosing Regimens to Determine Efficacy in Psoriasis; JUNCTURE, Judging the Efficacy of Secukinumab in Patients With Psoriasis Using Autoinjector: A Clinical Trial Evaluating Treatment Results.

Efficacy of Secukinumab in Patients With Psoriasis Using Autoinjector: A Clinical Trial Evaluating Treatment Results (JUNCTURE) studies are 52-week trials with optional extension of 3 years. Currently, 12-week data are available, with both 300 mg and 150 mg secukinumab administered with a PFS or an autoinjector significantly increasing the proportion of patients achieving PASI 75 and a modified IGA score of 0 or 1 as compared with placebo (P<.0001, Table II).7,8 Patients successfully used the PFS and the autoinjector to administer treatment, reported little pain/reaction with injections, considered both devices easy to use, and were satisfied with the self-injection procedure.7,8 The Efficacy and Safety of Intravenous and Subcutaneous Secukinumab in Moderate to Severe Chronic Plaque-type Psoriasis (STATURE) and the Efficacy and Safety of Subcutaneous Secukinumab (AIN457) for Moderate to Severe Chronic Plaque-type Psoriasis Assessing Different Doses and Dose Regimens (SCULPTURE) phase III clinical trials are additional studies to assess alternate treatment regimens of secukinumab. The STATURE trial assessed higher doses for partial responders9 and the SCULPTURE trial compared the maintenance of two regimens (fixed interval vs retreatment as needed)10; results have yet to be published in full. Recently, interim results from the ongoing Efficacy of Secukinumab Compared to Ustekinumab in Patients With Plaque-type Psoriasis (CLEAR) trial (NCT 02074982) comparing secukinumab with ustekinumab were SKINmed. 2015;13:303–306

released.4,11 Secukinumab (300 mg SC) administered weekly (weeks 0–3) followed by monthly (week 4–48 inclusive) has produced PASI 75 in significantly more patients by week 4 as compared with ustekinumab (P<.0001), while 79% and 57.6% of patients achieved PASI 90 with secukinumab and ustekinumab by week 16, respectively (P<.0001).4 Moreover, completely clear skin (PASI 100) was achieved in 44.3% of secukinumab patients vs 28.4% of ustekinumab patients (P<.0001).4 Safety Secukinumab was well tolerated and safe. Across the four phase III clinical trials from baseline to week 12, 691 patients received 300 mg secukinumab, 692 patients received 150 mg secukinumab, and 694 patients received placebo. The proportion of patients who experienced any adverse event (AE) was 56.2%, 59.5%, and 49.0% for 300 mg secukinumab, 150 mg secukinumab, and placebo, respectively.3,7,8 Common AEs, including infections, are presented in Table III.2,3,7,8 There was the possibility of Candida infections and neutropenia occurring with secukinumab, with Candida infections reported in 3.3% secukinumab (300 mg), 1.7% secukinumab (150 mg), and 0.28% placebo patients (ERASURE, FIXTURE: baseline to 52 weeks; FEATURE, JUNCTURE: baseline to 12 weeks). Candida infections were mild or moderate and self-resolved or resolved with treatment.3,7,8 Neutropenia was observed in a few cases, with

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Table II. Clinical Efficacy Outcomes of Phase III Trials at Week 12 Erasure3

Fixture3

PASI 75

IGA

Secukinumab 300 mg, %

81.6

65.3

76.1

Secukinumab 150 mg, %

71a

51a

Placebo, %

4.4 –

Etanercept, %

a

IGA

Feature7

PASI 75

IGA

PASI 75

IGA

61.8

86.7

73.3

c

75.9

69c

67a,b

51.1a,b

71.7c

53.3c

41c

2.4

4.9

2.8

3.3

0

0

0

43.6

27

a

PASI 75

Juncture8

a,b

a,b

c

c

52.5c

Abbreviations: ERASURE, Efficacy of Response and Safety of Two Fixed Secukinumab Regimens in Psoriasis; FEATURE, First Study of Secukinumab in PFS in Subjects With Chronic Plaque-Type Psoriasis: Response at 12 Weeks; FIXTURE, Full Year Investigative Examination of Secukinumab vs. Etanercept Using Two Dosing Regimens to Determine Efficacy in Psoriasis; JUNCTURE, Judging the Efficacy of Secukinumab in Patients With Psoriasis Using Autoinjector: A Clinical Trial Evaluating Treatment Results; PASI 75, ≥75% reduction in Psoriasis Area and Severity Index. 2011 modified Investigator Global Assessment (IGA) score or 0 (clear) or 1 (almost clear) on a 5-point scale, with a ≥2-grade improvement from baseline. aP<.001, secukinumab compared with placebo. bP<.001, secukinumab compared with etanercept. c P<.0001, secukinumab compared with placebo.

Table III. Collective Adverse Events From Four Phase III Clinical Trials (>1% Patients up to Week 12)2,3,7,8 Secukinumab 300 mg, % (n=691)

Secukinumab 150 mg, % (n=692)

Placebo, % (n=694)

Nasopharyngitis

11.4

12.3

8.6

Oral herpes

1.3

0.1

0.3

Pharyngitis

1.2

1.0

0

Rhinitis

1.4

1.4

0.7

Rhinorrhea

1.2

0.3

0.1

Upper respiratory tract infection

2.5

3.2

0.7

Diarrhea

4.1

2.6

1.4

Headache

6.5

5.5

5.2

Urticaria

0.6

1.2

0.1

Adverse Event Infections

Other

nine cases of grade 3 in the secukinumab groups combined, and no cases of grade 4 in ERASURE and FIXTURE combined.3 No cases of grade 3 or 4 neutropenia were reported in FEATURE or JUNCTURE, with grade 1 or 2 neutropenia in 5% to 9% of patients in the secukinumab groups.7,8 Immunogenicity was evaluated at baseline and throughout the entire duration of the clinical trials. Of the patients administered secukinumab, less than 1% developed antibodies against secukinumab.2 There were no deaths associated with treatments, and nonfatal serious AEs were rare (300 mg: 14 events; 150 mg: 14 events; placebo: 9 events). Discontinuation rates caused by AEs were also low, with 2.1%, 1.0%, and 1.7% of patients discontinuing in the 300 mg secukinumab, 150 mg secukinumab, and placebo groups, respectively.3,7,8 There were three cases of exacerbation of Crohn’s disease with secukinumab exposure.2 SKINmed. 2015;13:303–306

Conclusions Secukinumab has been approved by the US FDA for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy.2 Although 150 mg may be acceptable for some patients, the recommended dose is 300 mg SC weekly for 5 weeks, followed by monthly injections for maintenance. Phase III clinical trials demonstrated the clinical efficacy of 150 mg and 300 mg secukinumab with a higher proportion of patients achieving PASI 75 as compared with placebo during short-term or induction periods, as well as maintaining responses long-term.3,6,12 New data from the ongoing CLEAR trial suggest that secukinumab is superior to ustekinumab,4,11 while longer-term extension studies to the published clinical trials are underway (NCT01640951 and

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NCT01132612). Infections have occurred with secukinumab; therefore, caution is warranted in patients with chronic or recurrent infections.2,3 High efficacy rates, the success of maintenance treatment, and reported improvement in quality of life, coupled with acceptable safety and tolerability, make secukinumab a welcome addition to the growing arsenal of biologics available for the treatment of psoriasis. As for now, its main competitors are ustekinumab (anti–IL-12/17) and the anti-tumor necrosis factor products adalimumab, etanercept, and infliximab. References 1 Perera GK, Di Meglio P, Nestle FO. Psoriasis. Annu Rev Pathol. 2012;7:385–422. 2 Novartis Pharmaceuticals Corporation. COSENTYX (secukinumab) injection, for subcutaneous use [Internet]. http://www.accessdata.fda.gov/drugsatfda_docs/ label/2015/125504s000lbl.pdf. Accessed May 31, 2015. 3 Langley RG, Elewski BE, Lebwohl M, et al. Secukinumab in plaque psoriasis––results of two phase 3 trials. N Engl J Med. 2014;371:326–338.

6 Rich P, Sigurgeirsson B, Thaci D, et al. Secukinumab induction and maintenance therapy in moderate-to-severe plaque psoriasis: a randomized, double-blind, placebocontrolled, phase II regimen-finding study. Br J Dermatol. 2013;168:402–411. 7 Blauvelt A, Prinz JC, Gottlieb AB, et al. Secukinumab administration by pre-filled syringe: efficacy, safety and usability results from a randomized controlled trial in psoriasis (FEATURE). Br J Dermatol. 2015;172:484–493. 8 Paul C, Lacour JP, Tedremets L, et al. Efficacy, safety and usability of secukinumab administration by autoinjector/pen in psoriasis: a randomized, controlled trial (JUNCTURE). J Eur Acad Dermatol Venereol. 2015;29:1082–1090. 9 Thaci D, Humeniuk JM, Frambach Y, et al. Secukinumab in moderate-to-severe plaque psoriasis: Results from the Secukinumab Trial Analyzing the Potential of Intravenous Administration to Upgrade the Response in Psoriasis (STATURE) [abstract]. J Ger Soc Dermatol. 2014;12(suppl):13. 10 Mrowietz U, Papavassilis C, Leonardi C, Toth D, Thurston HJ. Secukinumab retreatment-as-needed maintenance regimen: Efficacy and safety outcomes from the SCULPTURE study [abstract]. J Am Acad Dermatol. 2014;70:AB188.

4 Karon A. AAD Annual Meeting: Secukinumab beat ustekinumab for psoriasis, with difference by week four [Internet]. Dermatol. News [cited 2015 Mar 27]. http:// www.edermatologynews.com/news/conference-news/ american-academy-of-dermatology-annual-meeting/ single-article/secukinumab-beat-ustekinumab-for-psoriasis-with-difference-by-week-four/5830955460dc62d46 3e0abc4a6521a7e.html. Accessed May 31, 2015.

11 Novartis Pharmaceuticals. Efficacy of Secukinumab Compared to Ustekinumab in Patients With Plaquetype Psoriasis, NCT 02074982 [Internet]. [cited 2015 Mar 27]. https://clinicaltrials.gov/ct2/show/NCT0207 4982?term=NCT02074982&rank=1. Accessed May 31, 2015.

5 Ohtsuki M, Morita A, Abe M, et al. Secukinumab efficacy and safety in Japanese patients with moderate-to-severe plaque psoriasis: subanalysis from ERASURE, a randomized, placebo-controlled, phase 3 study. J Dermatol. 2014;41:1039–1046.

12 Papp KA, Langley RG, Sigurgeirsson B, et al. Efficacy and safety of secukinumab in the treatment of moderate-to-severe plaque psoriasis: a randomized, doubleblind, placebo-controlled phase II dose-ranging study. Br J Dermatol. 2013;168:412–421.

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Volume 13 • Issue 4

The Heymann File Warren R. Heymann, MD, Section Editor

Dermatofibromas: From “Ho-Hum” to “OMG!” Warren R. Heymann, MD

B

e honest. When patients point out lesions of concern, and your diagnosis is a dermatofibroma (DF), what do you tell them? I routinely state that these are benign lesions of no significance––period. If they ask me if they should be excised, I will often lift up my right leg and show them that my lesion is still intact (Figure). While the above scenario still holds true for the majority of cases, there have been a flurry of recent papers changing my approach to these lesions so that I will not be so cavalier in the future.

as lupus erythemtosus, dermatomyositis, sarcoidosis, and HIV infection, not all patients with MEDFs demonstrate immunodysregulation. Other conditions associated with MEDFs include pregnancy, hyperlipidemia, atopic dermatitis, and pulmonary hypertension.5 Multiple eruptive plaque-like DFs have been reported in a 44-year-old man with rheumatoid arthritis who had been treated with both etanercept and adalimumab.6

Description

Of the multiple variants of DFs, the cellular, aneurysmal, and atypical variants have a significant tendency for local recurrence. Although extremely rare, DFs may metastasize and be fatal. In a review of 16 cases of morphologically benign DFs with locoregional or distant metastases, primary tumors tended to be large and cellular, although aggressive behavior could not be predicted based on morphologic features alone. Metastases mostly involved the lungs (12 patients) and lymph nodes (8 patients). Six patients died of the disease, with a median time to death of 64 months. Patients with common DFs have a recurrence rate of less than 2%, even when incompletely excised. The recurrence rate in these atypical, aneurysmal, and cellular variants is up to 20%, often with multiple local recurrences. The authors suggest that these lesions require careful clinical follow-up.7 Is there a better way to predict potential aggressive behavior of DFs?

DFs (fibrous histiocytomas) are common benign tumors demonstrating myofibrocytic differentiation, as documented by CD10 and actin immunoperoxidase stains. Factor XIIIa, while utilized routinely, labels the interstitial dendritic cells rather than the authentic tumor cells.1 Aside from the classical histopathologic appearance (interlacing fascicles of spindled cells arranged in a storifom pattern), several histologic variants including aneurysmal, hemosiderotic, cellular, epithelioid, atypical, lipidized, clear cell, palisading, atrophic, keloidal, granular cell, myxoid, lichenoid, balloon cell, and signet-ring cell types have been described. Pathologic features of several variants may be present in the same lesion. DFs are usually noted in middle age, with a slight female predominance. They present as firm red-brown papulonodules, usually on the extremities. Patients may give a history of prior trauma or insect bites at the site.2 Squeezing the lesion may result in dimpling of the lesion (the Fitzpatrick sign).3 The most common dermatoscopic pattern is a central white patch and a peripheral pigment network.4 Most patients have just a few lesions. Multiple eruptive DFs (MEDFs) are diagnosed based on the (arbitrary) presence of five to eight lesions developing within 4 months. While such lesions are characteristically attributed to patients with disorders who have altered immune states, such

Variations

Predicting Aggressive Behavior Array-based comparative genomic hybridization (aCGH) is currently the optimal technique to assess the entire genetic profile in order to evaluate copy number variations and gains or loses of chromosomes (or parts of them). One group evaluated seven patients with aggressive DFs, six having metastases, which proved to be fatal in two patients. Clinically, the mean size of the lesions was 3 cm. Only two of the seven lesions were completely excised. Histologically, mitotic figures ranged from three to 25 per 10

From the Departments of Medicine and Pediatrics, Division of Dermatology, Cooper Medical School of Rowan University, Marlton, NJ Address for Correspondence: Warren R. Heymann, MD, Cooper Medical School of Rowan University, Departments of Medicine and Pediatrics, Division of Dermatology, 100 Brick Road, Suite 306, Marlton, NJ 08053 • E-mail: wrheymann@gmail.com

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the heymann file Conclusions These studies have altered the way I view DFs. For the overwhelming majority, there is no cause for concern (the “ho-hum” lesion); yet, we need to be vigilant for the rare DF with metastatic potential (the “OMG” lesion). If a DF appears clinically atypical—either large or changing—perform a biopsy. If the histology suggests one of the disconcerting variants (cellular, aneurysmal, or atypical), make sure the lesion is completely excised. Should there be a localized recurrence, consider performing aCGH to determine metastatic risk. If there are significant chromosomal aberrations, these patients must be followed with careful, longterm scrutiny. References 1 McCalmont TH. Everything you wanted to know about dermatofibroma but were afraid to ask. J Cutan Pathol. 2014;41:5–8.

Figure. The author’s dermatofibroma, a characteristic firm nodule with central hypopigmentation (adjacent to a junctional nevus).

2 Alves JP, Matos DM, Barreiros HF, Bártolo EA. Variants of dermatofibroma. An Bras Dermatol. 2014;89:472–477.

high-power fields, and focal necrosis was present in five cases. Five patients demonstrated chromosomal aberrations by aCGH, compared with controls (8 cases of classic DFs and 2 small cellular DFs), which demonstrated no genomic aberrations. The authors concluded that the varying number of chromosomal aberrations observed in these lesions may reflect a biologic continuum from benign common DFs (no chromosomal anomalies) to atypical DFs (some chromosomal aberrations) to malignant DFs (multiple chromosomal abnormalities).8 To date, at least 35 cases of cutaneous metastasizing dermatofibromas have been reported. In another study utilizing aCGH, five primary tumors of metastasizing DFs were compared with five patients with atypical DFs and five with benign cellular DFs. Substantial differences between the groups were found both in the frequency of chromosomal aberrations, ranging from none in benign lesions to the highest rate in fatal metastasizing cases. These findings confirm the above study, suggesting that aCGH may be a tool in recognizing those DFs with aggressive or metastatic potential.9

3 Zaballos P, Puig S, Llambrich A, Malvehy J. Dermoscopy of dermatofibromas: a prospective morphological study of 412 cases. Arch Dermatol. 2008;144:75–83. 4 Parish LC, Yazdanian S, Lambert WC, Lambert PC. Dermatofibroma: a curious tumor. Skinmed. 2012;10:268– 270. 5 Zaccaria E, Rebora A, Rongioletti F. Multiple eruptive dermatofibomas and immunosuppression: report of two cases and review of the literature. Int J Dermatol. 2008;47:723–727. 6 Caldarola G, Bisceglia M, Pellicano R. Multiple eruptive plaque-like dermatofibromas during anti-TNF-α treatment. Int J Dermatol. 2013;52:638–641. 7 Doyle LA, Fletcher CD. Metastasizing “benign” cutaneous fibrous histiocytoma: A clinicopathologic analysis of 16 cases. Am J Pathol. 2013;37:484–495. 8 Mentzel T, Wiesner T, Cerroni L, et al. Malignant dermatofibroma: clinicopathological, immunohistochemical, and molecular analysis of seven cases. Mod Pathol. 2013;26:256–267. 9 Charli-Joseph Y, Saggini A, Doyle LA, et al. DNA copy number changes in tumors within the spectrum of cellular, atypical, and metastasizing fibrous histiocytoma. J Am Acad Dermatol. 2014;71:256–263.

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July/August 2015

Volume 13 • Issue 4

HISTORY OF DERMATOLOGY SOCIETY NEWSLETTER Eve Lowenstein, MD, PhD, Section Editor

Suppuration Following Hair Implantation Mark Bernhardt, MD

This patient came to the speaker in August, 1914, with the following symptoms: the scalp was covered with suppurative folliculitides, each suppurating follicle pierced by a hair…. Some of the hairs were very firmly attached and some could be easily extracted, having on the ends of the hair a very small golden hook with an eyelet, through which the hair passed like a thread through a needle… ––Dr B. Lapowski. J Cutan Dis incl Syph. 1915;33:325.

two parts of the donor’s hair would luxuriantly wave. Or not. Besides the delicacy and tedium of the procedure, the large percentage of implants that would fall out, and the restrictions on routine hair care so as not to disturb the implants, this case report amply demonstrates the attending risks of infection, scarring, and foreign body retention that plagued hair implant surgery. It soon, too, became obsolete.

If hairs be wires, black wires grow on her head.––Sonnet 130, William Shakespeare

Ironically, it was the successful hair transplantation performed by Norman Orentreich in 1952 that resuscitated the moribund field of hair implants. A public now aware that they need not accept baldness but were perhaps unable or unwilling to pay the expense of hair transplants were easy marks for charlatans and unscrupulous practitioners. Details of knotting vs anchoring and human hair vs synthetic fibers (mainly nylon) could not obscure the fundamental fact that all hair implants shared the complications described a half century before. Not until 1979, largely through the campaigning of an outraged San Francisco hair transplant surgeon, Peter Panagotacos, did California become the first state to ban hair implant clinics. The Food and Drug Administration followed suit 5 years later, outlawing all synthetic hair implants.

T

he key distinction between hair implants vs transplants is that in the latter viable hair follicles are surgically harvested from the patient and then transposed to a different area of the body. Hair implant surgery uses bits of the hair shaft, someone else’s hair, or even artificial fibers. Ernst Schweninger, who stuck hairs into granulating wounds, made the first attempt at hair implantation in 1875. This botched experiment was followed in 1898 by Menahem Hodara’s even odder technique. Using the analogy that branches can grow roots if planted in the proper soil, Hodara ploughed shallow furrows in the scalp with a scarifier into which grooves he dropped bits of hair clippings. Apparently only Hodara believed his method worked. The third approach––as practiced by Franz Szekaly and published by Adolf Haves––would be the model for all subsequent hair implantation systems. A long strand of woman’s hair was knotted in the middle by extremely thin (0.05 mm) gold wire. This golden knot was then stuck into the scalp, theoretically forming an anchor from which the

Some ideas refuse to die. Since the 1990s, several companies claim that improvements in their hair product and/or anchoring system make them a safe, viable alternative to the now fully entrenched hair transplantation industry. Ivory of Paris, MedicapBiofibre from Italy, and Japan’s Nido all say they have the necessary documentation. As of the time of writing this contribution, the US government begs to differ.

Address for Correspondence: Mark Bernhardt, MD, Private Practice, 1601 East Broward Boulevard, Fort Lauderdale, FL 33301 • E-mail: cheesedb@aol.com

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July/August 2015

Volume 13 • Issue 4

CASE STUDY Vesna Petronic-Rosic, MD, MSc, Section Editor

Twenty-Nail Dystrophy and Darier’s (Darier-White) Disease Virendra N. Sehgal, MD;1 Kingshuk Chatterjee, DNB;2 Anita Chaudhuri, MD;3 Prashant Verma, MD;4 Sonal Sharma, MD5 A 35-year-old married man presented with progressive distortion of all the nails of the hands and toes for the past 30 years. Initially, his parents noticed yellowish discoloration and roughness of the thumb nail at the age of 5 years. Since then, the changes have been insidious to involve the other nails. Currently, the nails are lusterless, rough, ridged, and difficult to trim. In addition, the patient has had dark, dirty-looking raised eruptions over the skin, attended by generalized itching, corresponding to the onset of the nail lesions. His mother experienced similar disease. Examination of the nails was marked by alternating elevation and depression (ridging) and/or pitting, lack of luster, roughening, sandpaper texture, and splitting, along with muddy, grayish white discoloration. Dystrophy of the nails was prominent. The changes were bilateral and symmetrical, affecting all 10 fingers and 10 toes (Figure 1). (SKINmed. 2015;13:313–315)

T

he patient showed no signs of dermatitis, lichen planus, or psoriasis on the skin or mucous membranes. Hair and teeth were normal. No alterations of the patellae or other bones were present. Mycelia and/or spores could not be demonstrated on potassium hydroxide mount prepared from scrapings of the lesions of the skin as well as from the nails. Examination of the skin surface was conspicuous for presence of skin-colored, yellow or yellow-brown, rough, firm, mildly greasy papules and/or plaques occupying the whole of the skin surface including scalp, forehead, behind and in front of the ears, nasolabial folds and the adjoining cheeks, front and back of the chest, groin, and natal cleft (Figure 2). On removal of the crusts, pitlike depressions were demonstrated at the summit of the papules. Systemic examination was within normal limits. Results from complete hemogram, liver and renal function studies, and lipid profile were within normal limits. Hematoxylin-eosin–stained serial sections prepared from punch biopsies of the representative skin and nail lesions were examined with light microscopy. The sections from the skin were characterized by hyperkeratosis, focal parakeratosis, and papillomatosis. Multiple suprabasal clefts separating the epidermis along with ac-

antholysis were outstanding. Corps ronds were present (Figure 3). The section from the nail biopsy was characterized by orthokeratosis, mild epithelial hyperplasia, and hypergranulosis. There was focal spongiosis with spongiotic vesicle formation. Subepithelial tissue showed moderate perivascular lymphohistiocytic infiltrates, suggestive of nonspecific dermatitis (Figure 4). Discussion Ever since the inception of the concept of twenty-nail dystrophy (TND), the condition has been identified by roughness, longitudinal striations, ridges, splits, pitting, distal chipping, onychorrhexis, onychoschizia, and loss of luster on multiple nail plates. All 20 nails are uniformly and simultaneously affected.1 Characteristically, the nails acquire a rough, sandpaper-like appearance.2,3 The condition is infrequent and has been sparingly reported. Although its association with other dermatoses is known, only a few reports are on record.3 TND and Darier’s disease coexisting concurrently in a patient is unique, and is yet another addition to the list of associated dermatoses. TND is an exclusive idiopathic disease characterized by dystrophic changes of all 20 nails in children.1 It is largely sporadic1,3; however,

From the Dermato-Venereology (Skin/VD) Center,1 Sehgal Nursing Home, Panchwati-Delhi, India; Department of Dermatology2, Bankura Sammilani Medical College, Bankura, West Bengal, India; Department of Dermatology3, Burdwan Medical College and Associated Hospital, Burdwan, India; Departments of Dermatology and STD4, and Department of Pathology5, University College of Medical Sciences, and Associated Guru Teg Bahadur Hospital, Shahdara, Delhi, India Address for Correspondence: Virendra N. Sehgal MD, Dermato Venerology (Skin/VD) Center, Sehgal Nursing Home, A/6 Panchwati, Delhi-110 033, India • E-mail: drsehgal@ndf.vsnl.net.in

SKINmed. 2015;13:313–315

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Figure 1. Twenty-nail dystrophy depicting alternating elevation and depression (ridging) and/or pitting, lack of luster, roughening, sandpaper texture, splitting, and muddy grayish white color.

Figure 3. Section of skin showing hyperkeratosis and papillomatosis. Numerous lacunae with elongated papillae lined by single layer of cells (villi). A few grains are visible in the stratum corneum along with a few desquamated cells (hematoxylin-eosin stain, original magnification ×40).

Figure 2. Yellow or yellow-brown, rough, firm, mildly greasy papules and/or plaques over the leg.

Figure 4. Nail section showing mild hyperplastic epithelium with mononuclear inflammatory infiltrate in the subepithelial tissue (hematoxylin-eosin stain, original magnification ×40).

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Table. Twenty Nail Dystrophy: Concomitant Dermatoses Author(s) Robert

5

James et al6 Crosby et al

7

Taniguchi et al8 Peloro and Pride9 Scardamaglia et al

10

Santoro and Sloan11 Current case

Concomitant Dermatoses

Age at Onset, y

Sex

Cases, No.

Alopecia areata

9

Male

One

Ichthyosis vulgaris

13

Male

One

Koilonychia

11

Male

One

Alopecia universalis and ichthyosis vulgaris

7

Female

One

Vitiligo

10

Female

One

Incontinentia pigmenti

Birth

Female

One

Sarcoidosis

One

Darier’s (Darier-White) disease

5

Male

One

its idiopathic connotation has come under close scrutiny, because similar types of nail changes have been described in nail-patella syndrome, pachyonychia congenita, hydrotic ectodermal dysplasia,4 and inherited autosomal dominant conditions. Its association with multiple acquired dermatoses,2 such as lichen planus, psoriasis, alopecia areata, dermatitis, ichthyosis vulgaris, vitiligo, incontinentia pigmenti, and specific immunoglobulin A deficiency syndrome are well-known (Table). TND follows a slowly progressive course, irrespective of the associated disorder.4 In the current report, the thumb nails were involved initially and then progressed slowly to involve all 20 nails. Concurrent coexistence of Darier’s (Darier-White) disease is intriguing and is being reported for the first time. Darier’s disease is a dominantly inherited condition affecting the skin, nails, and mucosae.12 Skin signs generally develop between the ages of 6 and 20, although lesions may be overlooked until aggravated by heat, sweat, or sunlight. In the case under review, the patient’s mother had a known case of Darier’s disease, and the patient developed the skin lesions after the age of 5 years. The distinctive lesion of the disease is a warty plaque formed by coalescing firm, greasy, skincolored papules. The seborrheic areas of the trunk and face are predominantly affected. Pruritus is invariably common and often intractable.12 The characteristic nail changes include onychoschizia and red or white longitudinal bands of varying width, often ending in a pathognomonic V-shaped notch at the free margin of the nail.12 It is best to perform a longitudinal biopsy13 of the affected nail to confirm or exclude associated dermatoses.

References

2 Sehgal VN, Sharma S, Khandpur S. Twenty-nail dystrophy originating from lichen planus. Skinmed 2005;4:58– 59. 3 Sehgal VN. Twenty nail dystrophy trachyonychia: an overview. J Dermatol. 2007;34:361–366. 4 Pavone L, LiVolti S, Guarneri B, et al. Hereditary twenty-nail dystrophy in a Sicilian family. J Med Genet. 1982;19:337–340. 5 Horn RT Jr, Odom RB. Twenty-nail dystrophy of alopecia areata. Arch Dermatol. 1980;116:573–574. 6 James WD, Odom RB, Horn RT. Twenty-nail dystrophy and ichthyosis vulgaris. Arch Dermatol. 1981;117:316. 7 Crosby DL, Swanson SL, Fleischer AB. Twenty-nail dystrophy of childhood with koilonychia. Clin Pediatr (Phila). 1991;30:117–119. 8 Taniguchi S, Kutsuna H, Tani Y, et al. Twenty-nail dystrophy (trachyonychia) caused by lichen planus in a patient with alopecia universalis and ichthyosis vulgaris. J Am Acad Dermatol. 1995;33:903–905. 9 Peloro TM, Pride HB. Twenty-nail dystrophy and vitiligo: a rare association. J Am Acad Dermatol. 1999;40:488–490. 10 Scardamaglia L, Howard A, Sinclair R. Twenty-nail dystrophy in a girl with incontinentia pigmenti. Australas J Dermatol. 2003;44:71–73. 11 Santoro F, Sloan SB. Nail dystrophy and bony involvement in chronic sarcoidosis. J Am Acad Dermatol. 2009;60:1050–1052. 12 Sehgal VN, Srivastava G. Darier’s (Darier-White) disease/ keratosis follicularis. Int J Dermatol. 2005;44:184–192.

Conclusions In Darier’s disease, the nail matrix and nail bed have acantholytic dyskeratosis akin to that seen in involved skin with the addition of multinucleate giant cells and epithelial hyperplasia of the nail bed,14 however, these features were conspicuously absent in the current case. SKINmed. 2015;13:313–315

1 Hazelrigg DE, Duncan WC, Jarratt M. Twenty-nail dystrophy in childhood. Arch Dermatol. 1977;113:73–75.

315

13 Hanno R, Mathes BM, Krull EA. Longitudinal nail biopsy in evaluation of acquired nail dystrophies. J Am Acad Dermatol. 1986;14:803–809. 14 Ronchese F. The nail in Darier’s disease. Arch Dermatol. 1965;91:617–618.

Twenty-Nail Dystrophy and Darier’s Disease


MEDIA PARTNER


July/August 2015

Volume 13 • Issue 4

CASE STUDY

Chlorambucil-Induced Radiation Recall Dermatitis Eileen Clark, MD;1 Michael Boffa, MD;1 Claude Magri, MD;2 Victor Muscat, MD2

A 65-year-old woman was diagnosed with low-grade non-Hodgkin lymphoma (Figure 1). She was treated with six cycles of cyclophosphamide, hydroxydaunorubicin, oncovin (vincristine), and prednisolone (CHOP) and three cycles of fludarabine and mitoxantrone. Ten months later she received radiotherapy to the left groin (total dose of 50 Gy in 25 fractions over 5 weeks) without complications. (SKINmed. 2015;13:317–319)

A

fter 1 year, she developed submandibular lymphadenopathy and was subsequently treated with radiotherapy to the head and neck. A total of 50 Gy in 25 daily fractions over 5 weeks was prescribed to fields extending from the base of the skull to the heads of the clavicles, with shielding of the spinal cord. This therapy was complicated by severe ulcerated acute radiation dermatitis, oral mucositis, and oropharyngeal candidiasis. She was treated conservatively and the symptoms subsided within a few weeks. She then received radiotherapy for right inguinal lymphadenopathy (total dose of 40 Gy in 20 fractions over 5 weeks) without complications. The patient had a relapse 8 months later and was started on chlorambucil 16 mg daily and prednisolone 15 mg daily. Seven days following initiation of this treatment she presented to the dermatology department with a burning, erythematous dermatitis that initially appeared on the right side of her neck. A similar eruption followed on the left side of her neck and within a few days there was involvement of the anterior chest wall (Figure 2). There was no response to oral antibiotics. Other medications included metformin 500 mg three times per day, bumetanide 1 mg daily, and spironolactone 100 mg daily. It was noted that the erythematous dermatitis on the neck and anterior chest wall was sharply demarcated and remained limited to an area that corresponded precisely to the area where severe, ulcerated acute radiation dermatitis had developed following ra-

diotherapy 8 months previously. The patient also commented that the burning sensation of the dermatitis was very similar to the pain she experienced secondary to the acute radiation dermatitis. A skin biopsy taken from the right side of her neck showed disordered proliferation of histiocytes and lymphocytes within the superficial dermis with associated marked disruption and some necrobiosis of the collagen, consistent with radiation damage. Chlorambucil-induced radiation recall dermatitis (RRD) was diagnosed. This resolved within a few days of chlorambucil withdrawal and application of topical steroids. Unfortunately the patient died 1 week later and she was never rechallenged with chlorambucil. Discussion RRD is an inflammatory reaction similar to acute radiation dermatitis. It is triggered by the administration of certain drugs and occurs in previously irradiated fields.1 Radiation recall may affect organs other than the skin, causing, among others, radiation recall pneumonitis, esophagitis, and mucositis. Clinically, RRD presents with painful erythema and may be associated with vesiculation, desquamation, and ulceration. Histological features include epidermal dysplasia, necrotic keratinocytes, a mixed inflammatory reaction, and sometimes psoriasiform dermatitis.2 Dermal features may include fibrosis, vasodilatation, and atypical fibroblasts. These histological features mimic those of severe sunburn or acute radiation dermatitis.

From the Departments of Dermatology1 and Oncology,2 Sir Paul Boffa Hospital, Floriana, Malta Address for Correspondence: Eileen Clark, MD, Sir Paul Boffa Hospital, Department of Dermatology, Harper Lane, Floriana, Malta • E-mail: jclark@maltanet.net

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Table. Chemotherapeutic Agents Associated With Radiation Recall Dermatitis

Non-Hodgkin Lymphoma: 6 cycles of CHOP + 3 cycles of fludarabine and mitoxantrone. 10 months later Radiotherapy to left groin: No complications 1 year later Radiotherapy for submandibular lymphadenopathy:

Anthracyclines

Daunarubicin, doxorubicin, idarubicin

Antitumor antibiotics

Bleomycin, dactinomycin

Antimetabolites

Capecitabine, cytarabine, fluorouracil, gemcitabine, hydroxyurea, methotrexate, pemetrexed

Alkylating agents

Cyclophosmadide, lomustine, melphalan

Alkaloids

Docetaxel, etoposide, paclitaxel, vinblastine

Severe ulcerated acute radiation dermatitis + Radiotherapy to right inguinal lymphadenopathy: No complications 8 months later Relapse: Chlorambucil 16 mg daily + prednisolone 15 mg daily 7 days later Radiation recall dermatitis on the neck and chest area

Figure 1. Summary of disease course and treatments.

The time interval between radiation and administration of the recall-inducing drugs is variable and may range from a few days up to 15 years.1,4 The shorter the time interval the larger the risk of development of RRD and the greater its severity.5,7 The time of onset of RRD varies from within a few minutes of administration of the first dose of the triggering drug (parenteral route) to a number of days (usually with oral drugs).4 Time of onset and severity of RRD appear to depend on the total dose of radiation received in the area.4,8 Two case reports have been described in patients receiving various doses of radiotherapy followed later by bleomycin or docetaxel. They developed RRD only in those skin sites that received the highest radiation dose.9,10 Development of RRD does not require an acute skin reaction during radiation, however. In fact, most cases of RRD occur in previously irradiated areas uncomplicated by acute radiation dermatitis.4,7 Interestingly, in the case we are presenting, RRD developed in only the head and neck area, which was the only previously irradiated area that was complicated by acute, severe radiation dermatitis. As a result of the technique used to deliver the radiotherapy, this was also the area that received the highest radiation dose. The duration of RRD symptoms is associated with the route of administration of the drug causing RRD. Usually RRD lasts longer (up to months) when secondary to orally administered drugs, while RRD secondary to intravenously administered drugs often resolves within 2 weeks.11–13

Figure 2. Burning erythematous dermatitis on the neck and anterior chest wall that followed chlorambucil administration and was limited to an area previously complicated by severe acute radiation dermatitis.

RRD was first described in 1959 with the antitumor antibiotic actinomycin D.3 Since then it has been described with other chemotherapeutic agents (Table).4,5 RRD has also been associated with antituberculous agents,6 tamoxifen,3 simvastatin, interferon α2b,5 and UV light exposure.7 SKINmed. 2015;13:317–319

Several etiologic mechanisms for RRD have been proposed. Radiotherapy-induced local vascular permeability or proliferative changes may affect the subsequent pharmacokinetics of certain drugs.13 In addition, radiation-induced depletion and/or damage to epithelial stem cells may result in RRD when a triggering drug is administered.14 Surviving stem cells might maintain an adequate functional role by cycling at a much faster rate, making them more susceptible to damage by drugs active in rapidly proliferating cells. RRD could also be an idiosyncratic drug hypersensitivity reaction involving direct nonimmune activation of inflammatory pathways analogous to fixed-drug eruptions.4

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RRD may resolve spontaneously and simple close observation may suffice in mild cases.7 Treatment includes withdrawal or reduction of the dose of the offending drug and administration of corticosteroids (topical, oral, or parenteral) and nonsteroidal anti-inflammatory agents. Recurrence of RRD on rechallenge with the offending drug is unpredictable and often milder.4 Conclusions Chlorambucil is known to cause radiation enhancement (augmentation of acute radiotherapy effects by chemotherapy given within 7 days of radiation).1 To our knowledge, however, this is the first report of this agent being associated with RRD. References 1 Apisarnthanarax N, Duvic M. Dermatologic complications of cancer chemotherapy: radiation-associated reactions. In: Kufe DW, Pollock RE, Weichselbaum R, eds. Holland-Frei Cancer Medicine. 6th ed. Hamilton (ON): BC Decker Inc; 2003. 2 Smith KJ, Germain M, Skelton H. Histopathologic features seen with radiation recall or enhancement eruptions. J Cutan Med Surg. 2002;6:535–540.

5 Hird AE, Wilson J, Symons S, et al. Radiation recall dermatitis: case report and review of literature. Curr Oncol. 2008;15:53–62. 6 Extermann M, Vogt N, Forni M, et al. Radiation recall in a patient with breast cancer treated for tuberculosis. Eur J Clin Pharmacol. 1995;48:77–78. 7 Azria D, Magne N, Zouhair A, et al. Radiation recall: a well recognized but neglected phenomenon. Cancer Treat Rev. 2005;31:555–570. 8 Cassady JR, Richter MP,Piro AJ, Jaffe N. Radiation-adriamycin interactions: preliminary clinical observations. Cancer. 1975;36:946–969. 9 Stelzer KJ, Griffin TW, Koh WJ. Radiation recall skin toxicity with bleomycin in a patient with Kaposi sarcoma related acquired immune deficiency syndrome. Cancer. 1993;71:1322–1325. 10 Yeo W, Leung SF, Johnson PJ. Radiation-recall dermatitis with docetaxel: establishment of a requisite radiation threshold. Eur J Cancer. 1997;33:698–699. 11 Burstein HJ. Side effects of chemotherapy. Case 1. Radiation recall dermatitis from gemcitabine. J Clin Oncol. 2000;18:693–694. 12 Ortmann E, Hohenberg G. Treatment side effects. Case 1 Radiation recall phenomenon after administration of capecitabine. J Clin Oncol. 2002;20:3029–3030.

3 D’Angio GJ, Farber S, Maddock CL. Potentiation of x-ray effects of actinomycin D. Radiology. 1959;73:175–177.

13 Bostrom A, Sjolin-Forsberg G, Wilking N, Berh J. Radiation recall: another call with tamoxifen. Acta Oncol. 1999;38:955–959.

4 Camidge R, Price A. Characterizing the phenomenon of radiation recall dermatitis. Radiother Oncol. 2001;59:237–245.

14 Hellman S, Botnick LE. Stem cell depletion: an explanation of the late effects of cytotoxins. Int J Radiat Oncol Biol Phys. 1977;2:181–184.

Smallpox (Vaiolo umano florido all’apice dell’eruzione pustolosa). Courtesy of Museo delle Cere Anatomiche L. Cattaneo, University of Bologna, Italy. Photo by Cristian Mancini. Submitted by Diana Garrisi, London, UK SKINmed. 2015;13:317–319

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Please forward your completed application for processing to: Larry Millikan, MD, Secretary-Treasurer General Ms Anna Gjeci, Executive Secretary 1508 Creswood Road Philadelphia, PA 19115, USA Tel: 215-677-3060 Cell: 267-438-2543 Fax: 215-695-2254 E-mail: IACDworld@yahoo.com Web: www.IACDworld.org SMCOMP_v10_i2_ADS.indd 396 121 SMCOMP_v10_i1_ADS.indd SMCOMP_v9_i5_ADS.indd 60

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IMPORTANT INFORMATION ABOUT July/August 2015

SOOLANTRA®

Volume 13 • Issue 4

(ivermectin) Cream, 1% CASE STUDY

Annular Elastolytic Giant Cell Granuloma and Temporal Arteritis Following Herpes Zoster SOOLANTRA Cream is supplied in a child-resistant capped tube.

BRIEF SUMMARY This summary contains important information about SOOLANTRA (soo lan’ trah) Cream. Read this information carefully before you prescribe SOOLANTRA Cream. For full Prescribing Information and Patient Information please see the package insert.

• To open, gently press down on the child resistant cap and twist counterclockwise. To avoid spilling, do not squeeze the tube while opening or closing. • To close, gently press down on the child resistant cap and twist

Amalia Panzarelli, MD;1 Katrina Fernández, MD2 clockwise.

WHAT IS SOOLANTRA CREAM? SOOLANTRA Cream is a topical prescription medicine indicated for the treatment of the inflammatory lesions of rosacea.

WHAT ARE THE INGREDIENTS IN SOOLANTRA CREAM?

Active ingredient: ivermectin. Inactive ingredients: carbomer copolymer A 70-year-old woman, who presented with pain and functional limitation of her right shoulder, without any previous traumatic type B, performed, cetyl alcohol,and citricshe acid monohydrate, dimethicone, edetate incident, was evaluated in an emergency department. A shoulder x-ray was received an intrajoint injection of an WHO IS SOOLANTRA CREAM FOR? disodium, glycerin, isopropyl palmitate, methylparaben, oleyl alcohol, unspecified amount of triamcinolone. Forty-eight hours later, she noticed a papulovesicular and bullous eruption with a dermatomal SOOLANTRA Cream is indicated for people with inflammatory lesions phenoxyethanol, polyoxyl 20 cetostearyl ether, propylene glycol, distribution on known her nape, supraclavicle, andisleft and antebrachial regions (T1-T2-C5-C6-8). A diagnosis of herpes zoster (HZ) of rosacea. It is not if SOOLANTRA Cream safebrachial and effective propylparaben, purified water, sodium hydroxide, sorbitan monostearate, for children. Advise patients to not use SOOLANTRA was made, for your which she received valacyclovir 1 Cream g everyfor8ahours for 10 days, pregabalin 75 mg every 8 hours, and topical acyclovir, and stearyl alcohol. condition for which it was not and remind them to not giveresults from general laboratory tests were normal or negative. (SKINmed. with good response. Theprescribed lesions and pain subsided, and SOOLANTRA Cream to other people, even if they have the same symptoms 2015;13:321–324) as it may harm them.

WHAT SHOULD I ASK MY PATIENTS BEFORE PRESCRIBING SOOLANTRA CREAM? ne month later, papules and erythematous annular Before you prescribe SOOLANTRA Cream, ask your patients if they:

O

plaques with diameters of up to 10 cm with hyperpigmented centers and discrete atrophy appeared over • areHZ pregnant planning to become It is notand known the scars or(nape, upper thirdpregnant. of the back, leftif arm and SOOLANTRA Cream can harm an unborn baby. forearm), which extended to the contralateral arm and legs with are breastfeeding or plan toSome breastfeed. is not known a• tendency to converge. of theIt lesions wereif smaller and in SOOLANTRA Cream passes into breast milk and if it can harm a baby. a linear arrangement, reminiscent of the Köbner phenomenon (Figure 1 and Figure 2). • have any other medical conditions.

WHAT ARE THE MOST COMMON SIDE EFFECTS OF SOOLANTRA CREAM? The patient had been in good general health, with no medical The most commonly reported side effects when using SOOLANTRA Cream history of diabetes, thyroid neurologic disease,your malignancy, include skin burning sensation andorskin irritation. Remind patients to tell risk you iffactors they havefor anyhuman side effect that bothers them or that does not go or immunodeficiency virus infection. away.had These are not allhypertension of the possible side of SOOLANTRA Cream. She moderate thateffects was treated with losartan. For more information, see the full Prescribing Information.

Results from laboratory tests demonstrated an elevated erythrocyte sedimentation rate (ESR) of 40/58 mm/h, a C-reactive You are encouraged to report negative side effects of prescription drugs to protein of 2.3 mg/L (normal value, 0.02–1.35), the FDA atlevel www.fda.gov/medwatch or call 1-800-FDA-1088. You mayand also a contact GALDERMA AT normal 1-866-735-4137. and or negative lipid, platelet count of LABORATORIES, 247,000/mm3,L.P. hepatic, renal, thyroid, and antinuclear antibody tests. A chest HOW SHOULD PATIENTS USEand SOOLANTRA CREAM? x-ray was unremarkable, results from an abdominal-pelvic • SOOLANTRA Cream is for use on the face only and should not be used in echosonogram revealed a left renal cyst. the eyes, mouth, or vagina.

SOOLANTRA applied tothe thefollowing: affected areas the face A• skin biopsy Cream of theshould lesionberevealed anoforthokeraonce a day. totic basket horny layer; discrete acanthosis; interstitial lymphoplasmohistiocytic granulomatous infiltrate in the mid-dermis APPLYING SOOLANTRA CREAM: with foreignamount body–type giant cells, some of which were phago• A pea-sized of SOOLANTRA Cream should be applied to each area of the face (forehead, chin, nose, each cheek) that is affected.

WHERE SHOULD I GO FOR MORE INFORMATION ABOUT SOOLANTRA CREAM? • This Brief Summary summarizes the most important information about SOOLANTRA Cream. For full Prescribing Information and cytizing (Figure 3 and Patientbasophilic Informationelastic please fibers see the(elastophagocytes) package insert. • Go to4); www.soolantra.com or callfor 1-866-735-4137 Figure and weak positivity Alcian blue.

A diagnosis of annular elastolytic giant cell granuloma (AEGCG) Trademarks are the property of their respective owners. was established, and treatment was initiated with oral prednisone 30GALDERMA mg/d, which improved patient’s LABORATORIES, L.P., the Fort Worth, Texascondition. 76177 USA When the dose was decreased, however, the eruption relapsed. Revised: December 2014

One month later, she was admitted to the emergency service of another clinical center for craniofacial pain along the bilateral temporal arteries that had developed for 2 weeks, difficulty in opening her mouth, general malaise, and transient visual loss of the right eye with high conjunctival aggregation based on the treating neurologist’s report. Results from quantitative digital electroencephalography were normal and contrast-enhanced magnetic resonance imaging showed the presence of Gold vasculitis that affected theJ,trajectory of References: 1. Stein L, Kircik L, Fowler et al; Ivermectin Phase III Study Group. Efficacy and safety the temporal arteries, primarily the right one. No biopsy was of ivermectin 1% cream in treatment of papulopustular performed. The patient had abnormal laboratory test values— rosacea: results of two randomized, double-blind, ESR of 100 mm/h (bypivotal Westergren method), C-reactive protein vehicle-controlled studies. J Drugs Dermatol. 2014;13(3):316-323. Data on file. of Galderma levels of 20.7 mg/L, and a2.platelet count 350,000/mm3— Laboratories, 3. Taieb A, Ortonne JP, Ruzicka T, and normal or L.P. negative urinalysis, immunorheumatological, et al; Ivermectin Phase III Study Group. Superiority of angiotensin-converting and glucose 0.75% tolerance tests. ivermectin 1% creamenzyme, over metronidazole cream in treating inflammatory lesions of rosacea: a randomized, investigator-blinded trial. Br J Dermatol. In press.

the lips and eyes. SeeAvoid alsocontact pages with 267–269.

From Dermatology1 and Pathology,2 Private Practice in Clinica Vista Alegre, Caracas, Venezuela

All trademarks are the property of their respective Address for Correspondence: Amalia Panzarelli, MD, owners. Clínica Vista Alegre, PB No. 10, Calle 3. Urbanización Vista Alegre, ©2015 Laboratories, Caracas,Galderma 1021 Venezuela • E-mail:L.P. boreal.star@gmail.com Galderma Laboratories, L.P. 14501 N. Freeway, Fort Worth, TX 76177 IVM-143 Printed in USA 02/15 SKINmed. 2015;13:321–324

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Figure 1. Confluent annular plaques with erythematous border and central clearing on the neck and back.

Figure 3. Granulomatous infiltrate in the mid-dermis (hematoxylin and eosin stain, Ă&#x2014;40).

Figure 4. Histiocytic infiltrate scattered among elastotic fibers and foreign body giant cells (hematoxylin and eosin stain, Ă&#x2014;100).

pantoprazole 40 mg/d for nearly 1 year, which gradually reduced the TA until it cleared. Her headaches diminished, her visual acuteness returned to normal, and the skin lesions diminished, nearly disappearing.

Figure 2. Annular plaques on the lateral aspect of the right arm.

A diagnosis of temporal arteritis (TA) was made, for which the patient received steroids intravenously 1 mg/kg/d for 5 days. On release, she continued treatment with prednisone 100 mg/d and SKINmed. 2015;13:321â&#x20AC;&#x201C;324

She has been followed for 2 years and has sporadically experienced small outbreaks or mild relapses of AEGCG, primarily on the upper third of the back, which have been controlled with topical clobetasol and oral pentoxifilline 400 mg/d. There have been no new neurologic manifestations..

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Discussion AEGCG was initially termed actinic granuloma by O’Brien in 1975,7 but reports of similar cases in the skin without solar elastosis on nonphotosensitive areas challenged and disproved the solely actinic origin of this condition, and the more descriptive AEGCG was proposed by Hanke in 1979,8 becoming the most commonly used term. AEGCG has been reported over burn scars and after intense solar exposure and is frequently associated with episodes of phototoxicity caused by prolonged ingestion of doxycycline, suggesting that increases in temperature—not solar radiation—modifies the antigenicity of the elastic fibers.3 It has been speculated that solar radiation, heat, or other unknown factors transform the antigenicity of elastic fibers and induce the immunocellular reaction. Immunohistochemical studies have demonstrated that CD4+ cells predominate over CD8+ cells in the inflammatory infiltrate, supporting this theory.2,9 AEGCG cases are associated with systemic sarcoidosis, cutaneous amyloidosis, molluscum contagiosum, lung epidermoid carcinoma, and T-cell cutaneous lymphomas.2 We hypothesize that the varicella zoster virus is one such that transforms this antigenicity. Histopathologically, the most frequent finding is an interstitial granulomatous infiltrate in the mid-dermis, primarily comprising foreign body–type giant cells that phagocytize the degenerated elastic fiber, known as giant cell pattern AEGCG,10 the pattern seen in our patient. TA is the most common primary systemic vasculitis in adults and is characterized by a granulomatous mixture of medium and large vessels, especially the extracranial branches of the carotid and the aorta and its large branches. Clinically, it usually appears as intense and persistent headaches in the areas adjacent to the affected arteries (90% of patients), often accompanied by transient visual loss (30% to 54%), resulting from the hypoperfusion of the optic nerve, retina, or choroid, which could lead to permanent loss of vision if not treated opportunely.11

In 1989, a case of a 79-year-old man with generalized annular granuloma that preceded TA was reported.5 Some authors4 claim that this condition was erroneously diagnosed, because the histopathology was more consistent with AEGCG, with which we agree. Two additional cases6 of AEGCG were associated with TA. One of the patients, presenting with bitemporal headaches and scalp tenderness, was treated with high doses of prednisone, which resolved the clinical manifestations. Recently, in another report,4 a 71-year-old man developed AEGCG preceding the development of TA, which occurred while the steroid dose was being decreased. Increasing the dose did not prevent the loss of vision, although it relieved the headaches. The most widely used serologic markers in the follow-up of TA patients are ESR by Westergren method; C-reactive protein; and high platelet count (>400 ×103/L), which, if associated with a high ESR, has a high predictive value of TA.11 Our patient had a high ESR, ranging between 50 mm/h and 100 mm/h, which declined with the administration of steroids, as did C-reactive protein. The patient never developed thrombocytosis. Conclusions This case demonstrates the importance of appropriate follow-up of HZ and the many cutaneous reactions that occur after its resolution. The association between AEGCG and TA is not exceptional, because these entities have similar histopathologic characteristics, such as elastic tissue damage, granulomatous infiltration, and T-cell predominance in the infiltrate. Any headache episodes in older patients without migraines or other neurologic findings should be investigated. Systemic steroids remain the most common therapeutic approach, and they should be initiated immediately and aggressively to prevent loss of vision and other ischemic events. References

Histopathologic examination of TA is characterized by disruption of the internal elastic lamina and a nonsuppurative granulomatous infiltrate by giant cells, which resides around the disintegrated elastic fibers.4,11 Researchers have emphasized the significance of solar elastosis in AEGCG and other diseases, such as TA.12 Due to the similarity of the histopathologic findings between AEGCG and TA, both diseases appear to be related conditions—an association that has been reported sporadically. SKINmed. 2015;13:321–324

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1 Chang SE, Bae GY, Moon KC, et al. Subcutaneous granuloma annulare following herpes zoster. Int J Dermatol. 2004;43:298–299. 2 Ventura F, Vilarinho C, Da Luz Duarte M, et al. Two cases of annular elastolytic giant cell granuloma: different response to the treatment. Dermatol Online J. 2010;16:11. 3 Campos-Muñoz L, Díaz-Díaz RM, Quesada-Cortés A, et al. Annuar elastolytic giant cell granuloma: a case report located in non-sun exposed areas. Actas Dermosífilogr. 2006;97:533–535. 4 Shoimer I, WismerJ. Annularelastolytic giant cell granuloma associated with temporal arteritis leading to blindness. J Cutan Med Surg. 2011;15:293–297.

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5 Fukai K, Ishii M, Kobayashi H, et al. Generalized granuloma annulare in a patient with temporal arteritis: are these conditions associated? Clin Exp Dermatol. 1990;15:70–72. 6 Lau H, Redid BJ, Weadon D. Actinic granuloma in association with giant cell arteritis: are both caused by sunlight? Pathology. 1997;29:260–262. 7 O’Brien JP. Actinic granuloma: an annular connective tissue disorder affecting sun- and heat-damaged (elastotic) skin. Arch Dermatol. 1975;111:460–466. 8 Hanke CW, Bailin PL, Roenigk HH Jr. Annular elastolytic giant cell granuloma. A clinicopathologic study of five cases and a review of similar entities. J Am Acad Dermatol. 1979;1:413–421.

9 Doulaveri G, Tsagroni E, Giannadaki M, et al. Annular elastolytic giant cell granuloma in a 70-year-old woman. Int J Dermatol. 2003;42:290–291. 10 Gutierrez-Gonzalez E, Gomez-Bernal S, Alvarez-Perez A, et al. Elastolytic giant cell granuloma: clinicpathologic review of twenty cases. Dermatol Online J. 2013;19:20019. 11 Falardeau J. Giant cell arteritis. Neurol Clin. 2010;28:581– 591. 12 O’Brien JP, Regan W. Actinically degenerate elastic tissue is the likely antigenic basis of actinic granuloma of the skin and of temporal arteritis. J Am Acad Dermatol. 1999;40:214–222.

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July/August 2015

Volume 13 • Issue 4

CASE STUDY

Basal Cell Carcinoma in a Patient With Brooke–Spiegler Syndrome María Elisa Vega-Memije, MD;1 Leticia Boeta-Ángeles, MD;2 Juan Carlos Cuevas-González, PhD1

A 46-year-old woman was diagnosed with Brooke-Spiegler syndrome (BSS) with lesions on her head, predominantly on the center of her face, auricles, and scalp. The facial lesions were polymorphic, pale, confluent, skin-colored, and papular, whereas the scalpel lesions appeared as erythematous and violet lumps that varied in size (Figure 1A, B). (SKINmed. 2015;13:325–328)

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he patient stated that the lesions appeared initially during puberty and that she had sought medical attention to remove the scalp lesions, which have since increased in size, causing discomfort. The histopathologic diagnosis was a combination of cylindroma, spiradenoma, and trichoepithelioma (TE). The patient claimed that several months ago, one of the lesions on the upper lip became ulcerated and had not resolved. Consequently, an ulcerated basal cell carcinoma (BCC) that lay adjacent to a TE was discovered by histopathologic study, as evidenced by the presence of randomly distributed nests of basaloid cells in palisade arrangement in the periphery and surrounded by clear retraction spaces. The tumor population had hyperchromatic nuclei with an ill-defined and relatively small cytoplasm, comprising mitotic and apoptotic cells. Cells that resided in the periphery of the neoplastic nests were cylindrical, with a small cytoplasm and large, strongly basophilic nuclei (Figure 2A, B). The epithelial nests of basaloid cells in palisade arrangement formed structures that appeared like small atrophic hair follicles. These appeared as infundibulo-cystic structures surrounded by foreign body granulomas, lax mesenchymal stroma, being slightly cellular and located between and around epithelial nests. This resulted in grooves between the tumor mesenchyme and the stroma of the dermis, mesenchymal papillary bodies, amy-

loid deposit, and chronic inflammatory process were adjacent to the described lesion (Figure 2C, D). An immunohistochemical panel was run to confirm the diagnosis, wherein the sample was positive against antibodies to Ki 67 (clone name BGX-297, 1:100), p53 (clone name BP53-12), and proliferating cell nuclear antigen (PCNA) (clone name PC10, 1:200), yielding a definitive diagnosis of BCC-TE (Figure 3A–D). Discussion BSS is a rare autosomal dominant disorder that is characterized by a predisposition to developing multiple neoplasias of cutaneous adnexal tumors. Few cases of BSS have been reported.1 BSS is caused by mutation of the suppressor gene CYLD on chromosome 16q,2 and, in general, clinical evidence first appears between the second and third decades of life,3–7 primarily in women.1 The tumors grow in size and number with age.8 In our case, the patient reported that the lesions developed in puberty and that she had undergone surgical removal of some neoformations that had developed over several years and caused her discomfort. Some researchers state that trichoepitheliomas and cylindromas are not the only tumors that appear in BSS patients and that spiradenomas and syringomas should also be considered.9 In addition, the association of BSS with the appearance of basal cell

From the Dermatopathology Department, Hospital General Dr. Manuel Gea González Mexico City1 and Hospital Juárez Centro,2 Mexico City, Mexico Address for Correspondence: María Elisa Vega Memíje, MD, Calzada de Tlalpan 4800, Col. Sección XVI, Tlalpan, CP 14080, México D.F. • E-mail: elisavega50@gmail.com

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Figure 1. Centrofacial polymorphic lesions with ulcer on upper lip (basal cell carcinoma) (A) and multiple violet-colored erythematous tumors on the scalp (B).

Figure 2. Presence of nests and cords of basaloid cells and retraction spaces (hematoxylin and eosin stain, original magnification ×10) (A). Hyperchromatic nucleus with small and ill-defined cytoplasm with presence of atypical mitosis (hematoxylin and eosin stain, original magnification ×40) (B). Transition zone between basal cell carcinoma and trichoepithelioma (hematoxylin and eosin stain, original magnification ×10) (C). Epithelial nests of basaloid cells forming mesenchymal bodies, and presence of infundibulocystic structures over a lax stroma (hematoxylin and eosin stain, original magnification ×10) (D). SKINmed. 2015;13:325–328

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Figure 3. Positivity of trichoepithelioma to proliferating cell nuclear antigen (original magnification ×10) (A). Immunostaining of proliferating cell nuclear antigen in the basal cell carcinoma sample (original magnification ×10) (B). Anti-Ki67 staining in basal cell carcinoma (original magnification ×40) (C). Ki67 in the area corresponding to trichoepithelioma (original magnification ×10) (D).

adenomas and adenocarcinomas of the parotid gland has been reported.3 There is predisposition toward malignant transformation of preexisting tumors,1 which can be attributed to findings that CYLD promotes the differentiation of A431 keratinocyte tumor cells by inhibiting c-Jun-NH2 terminal kinase.2 CYLD mediates and participates in inflammatory disorders12 and various carcinomas. The absence of functional CYLD in tumor cells results in the hyperactivation of antiapoptotic signals, altering the balance between proliferation, differentiation, and apoptosis.2 Our patient had multiple trichoepitheliomas, cylindromas, and spiradenomas, with one lesion becoming ulcerated, prompting a diagnosis of BCC; therefore, clinicians must determine whether the TE is linked to the BCC as part of BSS or represents indeSKINmed. 2015;13:325–328

pendent pathology. Few such cases have been reported, and this association has not been extensively studied, preventing us from identifying the mutated gene. In BSS, the involvement of other organs is rare. Researchers have reported a case in which the patient developed a cylindroma in the parotid gland,10,11 while others noted rectosigmoiditis in another BSS patient.11 Various treatments have been proposed for adnexal tumors, such as dermabrasion, electrodessication, cryotherapy, and surgical excision1; however, in the presence of malignant neoplasms, such as BCC, surgical excision with lesion-free margins is the preferred treatment, necessitating an accurate diagnosis. Due to of the difficulty in making the histopathologic diagnosis between TE and BCC, a series of immunohistochemical markers was developed to help pathologists differentiate between the

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lesions. Investigators reported significant differences using Ki67, which was positive in 51.25% of BCC vs 30.5% of TE cases (P=.002), and PCNA, which was found in 52.25% of BCC compared with 34.35% of TE samples (P=.005). The expression of p53 was similar (31.75% vs 33.75%, respectively) and was thus excluded as an auxiliary marker.13 We applied the immunohistochemical panel to confirm our definitive diagnosis and noted that the lesion that corresponded to the BCC showed greater positivity against the Ki67 and PCNA antibodies and that anti-p53 was slightly positive in the TE and BCC cases. Ultimately, our diagnosis was made based on the clinical findings and the histopathologic results of the immunohistochemical panel. Conclusions

3 Kalina P, Azhary R. Brooke-Spiegler syndrome with multiple scalp cylindromas and bilateral parotid gland adenomas. Case Rep Radiol. 2012;2012:249583. 4 Bandmann HJ, Hamburguer D, Romiti N. Brooke-Spiegler phakomatose. Hantarzt. 1965;16:450–453. 5 Welch JP, Wells RS, Kerr CB. Ancell-spigler cylindromas (turban tumor) and Brooke Fordyce trichoepitheliomas: evidence for a single entity. J Med Genet. 1968;5:29–35. 6 Rasmussen JE. A syndrome of trichoepitheliomas, milia and cylindromas. Arch Dermatol. 1975;111:610–614 7 Kaddu S, Kerl H. Appendage tumors of the skin. In: Freedberg IM, Eisen AZ, Wolff K, Austen FK, Goldsmith LA, Katz SI, eds. Fitzpatrick´s Dermatology in General Medicine. 6th ed. London, England: McGraw-Hill; 2003:785– 808. 8 Mataixa J, Bañulsa J, Botellaa R, Laredob C, Lucasa A. Síndrome de Brooke-Spiegler: una entidad heterogénea. Actas Dermosifiliogr. 2006;97:669–672. 9

We have encountered an unusual clinical situation in which the neoformations that might be present must be diagnosed accurately by clinical-pathologic correlation. More studies are needed to determine whether patients with BSS will develop malignant neoplasms or whether existing neoplasms will undergo malignant transformation. Appropriate treatment of BSS will improve the patient’s quality of life.

Uede K, Yamamoto Y, Furukawa F. Brooke-Spiegler syndrome associated with cylindroma, trichoepithelioma, spiradenoma, and syringoma. J Dermatol. 2004;31:32– 38.

10 Jungehülsing M, Wagner M, Damm M. Turban tumour with involvement of the parotid gland. J Laryngol Otol. 1999;113:779–783. 11 Peltonen S, Kankuri-Tammilehto M. Brooke-Spiegler syndrome associated with ulcerative rectosigmoiditis. Acta Derm Venereol. 2013;93:112–113.

1 Osama E, Dhuha A, Elshahat A, Ahmed A. Brooke-Spiegler syndrome. Gulf J Dermatol Venereol. 2011;18:52–56.

12 Zhang J, Stirling B, Temmerman ST, et al. Impaired regulation of NF-kappaB and increased susceptibility to colitis-associated tumourigenesis in CYLD-deficient mice. J Clin Invest. 2006;116:3042–3049.

2 Alameda JP, Fernandez-Acenero MJ, Moreno-Maldonado R, et al. CYLD regulates keratinocyte differentiation and skin cancer progression in humans. Cell Death Dis. 2011;2:e208.

13 Abdelsayed RA, Guijarro-Rojas M, Ibrahim NA, Sangueza OP. Immunohistochemical evaluation of basal cell carcinoma and trichepithelioma using Bcl-2, Ki67, PCNA and P53. J Cutan Pathol. 2000;27:169–175.

References

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July/August 2015

Volume 13 • Issue 4

CASE STUDY

Cutaneous Necrotic Papule as Invasive Aspergillosis in a Heart Transplant Patient Edidiong C.N. Kaminska, MD;1 Susan Pei, BA;2 Sonya Kenkare, MD;2 Vesna Petronic-Rosic, MD, MSc;2 Maria M. Tsoukas, MD, PhD2

A 46-year-old African American man presented with a 3- to 4-day history of a new painful lesion on his left lower extremity. Other reported symptoms included a productive cough and chest pain; the patient denied fever and chills. His medical history was significant for a heart transplant 4 months prior to presentation followed by transplant rejection 2 weeks after the transplant. Medications included an antirejection/immunosuppressive regimen consisting of prednisone, tacrolimus, mycophenolate mofetil, and prophylaxis treatment with valganciclovir and trimethoprim-sulfamethoxazole. (SKINmed. 2015;13:329–330)

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hysical examination disclosed a gelatinous, necrotic, and tender papule with a central eschar on the left lower extremity (Figure 1). Results from chest x-ray of the lungs demonstrated near-complete opacification of the right upper lobe associated with right-sided volume loss and patchy left midzone opacities. A punch biopsy was performed on the left leg lesion. The biopsy specimen displayed a dense, diffuse mixed inflammatory infiltrate composed of neutrophils, lymphocytes, histiocytes, and extravasated erythrocytes. Within the infiltrate, numerous fungal elements were identified (Figure 2). Results from periodic acid-Schiff stain and methenamine silver stain confirmed many septate hyphae and fungal elements (Figure 3). Sputum and tissue cultures grew a filamentous fungus consistent with Aspergillus fumigatus. Prior to speciation, the patient was treated with empiric antifungal and antibacterial coverage with voriconazole, vancomycin, cefepime, and metronidazole. Once the organism was identified, the regimen was changed to liposomal amphotericin B and micafungin. Despite appropriate treatment, the patient died 7 days after presentation. Discussion Invasive fungal infections (IFIs) continue to be a major cause of morbidity and mortality in solid organ transplant recipients. The most common pathogens that cause IFI are Candida species, fol-

lowed by Aspergillus and Cryptococcus.1 Aspergillus fumigatus is an opportunistic pathogen that causes 90% of invasive aspergilloses and is associated with a 50% to 95% mortality rate.2 Cutaneous aspergillosis is usually a secondary cutaneous infection in the course of hematogenous dissemination of systemic aspergillosis. Skin lesions occur in 5% to 10% of patients with disseminated aspergillosis.3 Primary cutaneous disease is rare, usually associated with trauma, and most commonly caused by A flavus, A terreus, A niger, or A utus.4 Risk factors for secondary cutaneous aspergillosis include an immunosuppressed state such as neutropenia from hematologic malignancy or chemotherapy, immunosuppressive therapy, and acquired immunodeficiency syndrome. In the immunocompromised host, the most common manifestation of an Aspergillus infection is invasive pulmonary aspergillosis characterized by hyphal invasion and destruction of pulmonary tissue.5 Hematogenous dissemination can follow and occurs in 20% to 50% of these patients. It most commonly involves the central nervous system and the gastrointestinal tract6; however, secondary Aspergillus infection of the skin is possible even in the absence of clinically evident pulmonary aspergillosis.7 The clinical presentation of cutaneous aspergillosis may differ based on an individual’s immune status. It has been suggested that in immunocompromised patients, rapidly growing lesions with an area of central necrosis may be a typical clinical manifes-

From the NorthShore University HealthSystem,1 and the Section of Dermatology, University of Chicago Pritzker School of Medicine, Chicago, IL2 Address for Correspondence: Maria M. Tsoukas, MD, PhD, Department of Dermatology, University of Illinois College of Medicine at Chicago, 808 S. Wood Street, Chicago, IL 60612 • E-mail: tsoukasm@uic.edu

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Figure 1. Gelatinous, necrotic, and tender papule with a central eschar on the left lower extremity.

Figure 3. Periodic acid-Schiff stain (×20 magnification) confirming many septate hyphae and fungal elements.

spiratory tract, serum, and urine should be examined mycologically, prior to heart transplant.8 Although an optimal approach for prophylactic antifungal therapy has yet to be determined, preventive measures, such as environmental controls and chemoprophylaxis, may be beneficial in high-risk patients. References 1 Montejo M. Epidemiology of invasive fungal infection in solid organ transplant. Rev Iberoam Micol. 2011;28:120– 123. 2 Abad A, Fernández-Molina JV, Bikandi J, et al. What makes Aspergillus fumigatus a successful pathogen? Genes and molecules involved in invasive aspergillosis. Rev Iberoam Micol. 2010;27:155–182. 3 Brinca A, Serra D, Brites MM, et al. Cutaneous aspergillosis in a heart-transplant patient. Indian J Dermatol Venereol Leprol. 2011;77:719–721.

Figure 2. Hematoxylin and eosin stain (×40 magnification) showing inflammatory infiltrate and fungal elements.

4 Tahir C, Garbati M, Nggada HA, et al. Primary cutaneous aspergillosis in an immunocompetent patient. J Surg Tech Case Rep. 2011;3:94–96.

tation of cutaneous aspergillosis compared with that in immunocompetent patients where lesions appear as small, red discrete papules, sometimes with a pustule in the center of the papule.7 Conclusions Traditional first-line treatment for disseminated and limited cutaneous aspergillosis is high-dose intravenous amphotericin B. Voriconazole is also approved as a first-line agent. Surgery may be used as an adjunctive therapeutic option in primary cutaneous aspergillosis. To avoid this infection, specimens from the reSKINmed. 2015;13:329–330

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5 Walsh TJ, Dixon DM. Nosocomial aspergillosis: environmental microbiology, hospital epidemiology, diagnosis and treatment. Eur J Epidemiol. 1989;5:131–142. 6 Allo MD, Miller J, Townsend T, et al. Primary cutaneous aspergillosis associated with Hickman intravenous catheters. N Engl J Med. 1987;317:1105–1108. 7 Schimmelpfenning C, Naumann R, Zuberbier T, et al. Skin involvement as the first manifestation of systemic aspergillosis in patients after allogeneic haematopoietic cell transplantation. Bone Marrow Transplant. 2001;27:753–755. 8 Hummel M, Thalmann U, Jautzke G, et al. Fungal infections following heart transplantation. Mycoses. 1992;35:23–34.

Cutaneous Necrotic Papule as Invasive Aspergillosis


July/August 2015

Volume 13 • Issue 4

CASE STUDY

Benign Eccrine Tumors Presenting on the Penis: Common Tumors at an Uncommon Site Aaron Wei Min Tan, MBBS; Mark Jean Ann Koh, MBBS, MRCPCH, FAMS (Dermatology); See Ket Ng, MBBS, MMed (Int Med)

Case 1 A 60-year-old Chinese man presented to the dermatology clinic with an asymptomatic, 0.5×0.5-cm erythematous papule on the penile shaft for a 2-year duration (Figure 1a). His medical problems consisted only of well-controlled hypothyroidism and hypertension. The initial clinical diagnoses considered were pyogenic granuloma or condyloma accuminatum. The excisional biopsy revealed a polypoidal lesion entirely covered by epidermis, with a proliferation of cuboidal, basaloid cells, consistent with an eccrine poroma (Figure 1b). Case 2 A 28-year-old Chinese man presented with an asymptomatic fusiform, 1.4×0.4-cm nodule over the ventral aspect of the prepuce, for a 10-year duration (Figure 2a). His medical history was otherwise unremarkable. Lymphangioma was the initial clinical diagnosis but biopsy results revealed large collapsed cystic spaces within the superficial dermis lined by a double layer of epithelial cells with eosinophilic cytoplasm, without evidence of decapitation secretion, consistent with an eccrine hidrocystoma (Figure 2b). (SKINmed. 2015;13:331–333)

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ccrine glands are ubiquitously distributed, including on the glans penis and foreskin, but not on the lips, external ear canal, clitoris, or labia minora. Eccrine poromas and hidrocystomas are both benign sweat gland tumors. Other eccrine tumors include hidroacanthoma simplex, nodular hidradenomas, and syringomas. The eccrine poroma, first described by Pinkus and colleagues,1 classically presents as an asymptomatic skin-colored to slightly erythematous, sharply circumscribed, firm papule or nodule on non–hair-bearing surface of the feet or hands, with a characteristic collarette of scale. Clinically, a poroma may resemble a papilloma, viral wart, pyogenic granuloma, fibroma, or hypertrophic scar. Histologically, an eccrine poroma is a sharply demarcated tumor of cuboidal or basaltic cells within an acanthotic epidermis, extending into the dermis. Sweat duct lumina are often present within the tumor. The cells may contain glycogen, which gives the appearance of “clear cells,” and stain positively with periodic acid-Schiff but are diastase labile. Complete surgi-

cal excision of a benign eccrine poroma accords an excellent prognosis. To our knowledge, eccrine poroma on the penis has not been previously reported in the English literature. Whereas, its malignant counterpart—porocarcinoma—has been studied.2 Eccrine porocarcinoma is a rare malignancy with a 50% metastasis rate to regional lymph nodes and an overall poor prognosis.3 It is important to note that a long-standing eccrine poroma may undergo malignant transformation,4 although porocarcinoma may also arise de novo.2 Investigators have postulated that activation of cyclin D1 and the phosphorylated product of a retinoblastoma, possibly in conjunction with dysfunctions of p53 and/or its family, might play a role in the malignant transformation of eccrine duct cells or from preexisting poroma into eccrine porocarcinoma.5 Hidrocystomas can be either eccrine or apocrine in origin. Eccrine hidrocystomas result from cystic dilatation of excretory eccrine glands caused by retention of sweat. They present as small, tense, thin-walled cysts, occurring singly or in

From the National Skin Centre, Singapore Address for Correspondence: Aaron Wei Min Tan, MBBS, National Skin Centre, 1 Mandalay Road, Singapore 308205 • E-mail: aarontan@nsc.gov.sg

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a a

b b

Figure 1. (a) A lesion presenting as a solitary pink, telangiectatic papule over the dorsal surface of the penile shaft. (b) Histologic findings reveal an epidermal proliferation of bland cuboidal, basaloid cells with ductal structures within, consistent with an eccrine poroma. (Hematoxylin and eosin stain, original magnification ×100.)

Figure 2. (a) A serpiginous, skin-colored, cystic nodule over the ventral prepuce. (b) Dermal cystic spaces lined by a double layer of epithelial cells with eosinophilic cytoplasm, without evidence of decapitation secretion. (Hematoxylin and eosin stain, original magnification ×100.)

groups over the periorbital and malar regions and may enlarge or regress in size according to the ambient temperature. Multiple eyelid apocrine hidrocystomas are a presenting feature of Schöpf-Schulz-Passarge syndrome, whereas Graves’ disease has been associated with multiple eccrine hidrocystomas.6

published in the English literature,7,8 and its clinical presentation bears striking similarity to our second patient. This is, however, the first report of an eccrine hidrocystoma of the penis.

The differential diagnoses for a cystic lesion on the penis include epidermal cysts, congenital median raphae cysts, sclerosing lymphangitis, and acquired lymphangioma.

Conclusions

Cystic sweat gland tumors arising on the penis are rare, although aprocrine hidrocystomas of the penile shaft have been SKINmed. 2015;13:331–333

These two cases illustrate that benign eccrine tumors, i.e. eccrine poroma and eccrine hidrocystoma, may appear on the penis, an unusual site for such tumors. A biopsy is instrumental in the evaluation.

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References 1 Goldman P, Pinkus H, Rogin JR. Eccrine poroma; tumors exhibiting features of the epidermal sweat duct unit. AMA Arch Dermatol. 1956;74:511–521.

5 Chen SY, Takeuchi S, Moroi Y, et al. Significance of cyclin D1-, product of retinoblastoma (pRb), p53, p63 and p73 expression in eccrine poroma and eccrine porocarcinoma. J Dermatol Sci. 2009;56:69–72.

2 Grayson W, Loubser JS. Eccrine porocarcinoma of the penis. J Urol. 2003;169:611–612.

6 Kim YD, Lee EJ, Song MH, et al. Multiple eccrine hidrocystomas associated with Graves’ disease. Int J Dermatol. 2002;41:295–297.

3 Shaw M, McKee PH, Lowe D, Black MM. Malignant eccrine poroma: a study of twenty-seven cases. Br J Dermatol. 1982;107:675–680.

7 Lopez V, Alonso V, Jorda E, Santonja N. Apocrine hidrocystoma on the penis of a 40-year-old man. Int J Dermatol. 2013;52:502–504.

4 Spencer DM, Bigler LR, Hearne DW, Davis LS, Pellegrini A. Pedal papule. Eccrine porocarcinoma (EPC) in association with poroma. Arch Dermatol. 1995;131:211, 214.

8 Mataix J, Banuls J, Blanes M, Pastor N, Betlloch I. Translucent nodular lesion of the penis. Apocrine hidrocystoma of the penis. Arch Dermatol. 2006;142:1221–1226.

SKINart Mark Bernhardt, MD, Section Editor Dermatology is such a visual field that it is not surprising that many of its practitioners are also attracted to the visual arts. With this occasional feature, we recognize our colleagues who passionately integrate art with their profession. Whether creators or collectors, their artistic insights manage to find outlets in their dermatologic careers. And vice versa. If you or a dermatologist you know has an art-career link you would like to share, please send it to Mark Bernhardt, MD, at cheesedb@aol.com for consideration. All artwork should be of publishable quality and any textual exegesis should be limited to approximately 100 words. Please include your hometown and e-mail address. We at SKINmed look forward to your contributions to this novel insight into our colleagues’ lives and livelihood.

Time frozen in a silver box This piece was made during a jewelry class taught by a master silversmith, Mary Ann Scheer in 2007–8. She pushed me to my limits like the best of my mentors in dermatology, starting with Thomas B. Fitzpatrick. The watch parts are from my family’s store and are embedded in plastic. Making tightly fitting boxes are skill-building projects in silversmithing similar to perfecting one’s suturing skills in dermatologic surgery. Lowell A. Goldsmith, MD Chapell Hill, NC e-mail: lag1959@gmail.com SKINmed. 2015;13:331–333

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July/August 2015

Volume 13 • Issue 4

Industry update Jo-Ann Kalaka-Adams, Section Editor

Galderma Product Line Expands as Promised by President Todd Zavodnick Jo-Ann Kalaka-Adams

G

alderma Laboratories, L.P., has won FDA approval for Epiduo® Forte Gel, its new antibiotic-free treatment for acne, and for Restylane® Lyft (formerly Perlane®)-L) with Lidocaine to lift the cheeks and improve smile lines. Earlier this year, the company launched Benzac® Acne Solutions, its first OTC product to treat acne. Epiduo® Forte Gel markedly improves severe acne Galderma’s Epiduo® Forte (adapalene and benzoyl peroxide) Gel, 0.3%/2.5%, is a once-daily, topical treatment for moderate to severe acne vulgaris. The FDA approval was based on a 12-week, multicenter, randomized, double-blinded study of 217 patients. The results showed superiority of Epiduo® Forte Gel over vehicle gel at week 12 for the Investigator’s Global Assessment Success Rate and for changes in inflammatory and non-inflammatory lesion count. Subjects with “severe” acne (50%) at baseline were required to become “clear” or “almost clear” within the trial period to be considered a treatment success. Marked improvement in severe acne was observed in 50.5% of subjects treated with Epiduo® Forte Gel. According to dermatologist and principal investigator Jonathan Weiss, MD, patients using Epiduo® Forte Gel saw improvement at week 1 with efficacy continuing to improve through week 12. The product was shown to be safe and well tolerated, and most adverse events were mild to moderate in severity. The most commonly reported adverse events (≥1%) in patients treated with Epiduo® Forte Gel were skin irritation, eczema, atopic dermatitis, and a skin burning sensation. The antibiotic-free product can be considered for long-term use and offers convenience in a pump with once-daily dosing. Epiduo® Forte Gel becomes available by prescription in September 2015. Restylane® Lyft corrects volume loss in mid-face area The injectable Restylane® Lyft with Lidocaine is the first FDAapproved filler to provide fullness to the cheeks and to correct and smooth the nasolabial folds (smile lines) in patients over the SKINmed. 2015;13:335

age of 21. “Achieving natural-looking lift in the cheek area is one of my most frequent requests,” says dermatologist and principal investigator Robert Weiss, MD. “The results show that Restylane® Lyft can provide an effective option for patients who desire lift—not just volume— in their cheeks.” In Dr. Weiss’s 200-patient study, 88.7% of patients treated with Restylane® Lyft showed improvement in fullness in the right and left midface areas (combined) at 2 months, and more than half of patients maintained improvement for 12 months. The most common adverse events were tenderness, redness, bruising, swelling and itching, all of which decreased in severity over time and most were resolved within 2 weeks. Restylane® Lyft with Lidocaine is available only through a physician. Complete instructions for use are at www.RestylaneUSA.com. Benzac® Acne Solutions available without prescription Early this year, Galderma launched its first OTC regimen for the treatment of stubborn acne and prevention of new breakouts. In a clinical study, 91% of patients saw improvement in their acne in two weeks when using the new 3-step Benzac® Acne Solutions, which includes the Benzac® Skin Balancing Foaming Cleanser, Benzac® Intensive Spot Treatment and Benzac® Blemish Clearing Hydrator. According to dermatologist Jeanine Downie, MD, Benzac® is the only skincare line to use East Indian Sandalwood Oil, a key ingredient known to have antibacterial and anti-inflammatory properties and to sooth the skin. In addition to salicylic acid, Benzac® also contains Kakadu plum, an antioxidant super fruit known for having the highest natural concentration of vitamin C to brighten the skin; lemon myrtle, a natural astringent to help reduce excess oil; and zinc to prevent loss of skin moisture. Safe for sensitive skin, Benzac® is dermatologist-tested, non-comedogenic, and free of artificial fragrances and dyes. The Benzac® Complete Acne Solutions Regimen is available at major retailers, Benzac.com, and Amazon.com.

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July/August 2015

Volume 13 • Issue 4

ERRATUM SKINmed. 2013;11:167. Anonymous Dermatopathologists: A Socioeconomic Solution to a Medical Problem Cindy Wassef, BA; Peter C. Lambert, BA, MA; Claude E. Gagna, PhD; Gretchen Harmon, BA; W. Clark Lambert, MD, PhD The incorrect affiliation was listed for Gretchen Harmon. The correct affiliation is New York Medical College, Valhalla, NY. The authors regret the error.

VINTAGE LABEL

Courtesy of BuyEnlarge, Philadelphia, PA

Editorial

ABOUT OUR JOURNAL SKINmed: Dermatology for the Clinician®, print ISSN 1540-9740, online ISSN 1751-7125, is published bimonthly by Pulse Marketing & Communications, LLC, located at 4 Peninsula Avenue, Sea Bright, NJ 07760. Printed in the USA. Disclaimer: The Publisher, Editors, and Editorial Board cannot be held responsible for errors or any consequences arising from the use of information contained in this journal; the views and opinions expressed herein do not necessarily reflect those of the Publisher, Editors, and Editorial Board, neither does the publication of advertisements constitute any endorsement by the Publisher, Editors, and Editorial Board of the products or services advertised. The Publisher, Editors, Editorial Board, Reviewers, Authors, and Affiliated Agents shall not be held responsible or in any way liable for the continued accuracy of the information or for any errors, inaccuracies, or omissions of any kind in this publication, whether arising from negligence or otherwise, or for any consequences arising thereafter.

MANAGING EDITOR Marla Kipp marla@skinmedjournal.com

COPYEDITOR Elizabeth Holcomb eholcomb@skinmedjournal.com

MEDIA WEB DIRECTOR Joan Osgoodby joan@skinmedjournal.com

Composition Paul Bennett paul@skinmedjournal.com

Publishing PUBLISHER Art Kalaka

Corporate President Arthur Kalaka akalaka@skinmedjournal.com

Copyright: © 2015 Pulse Marketing & Communications, LLC. All rights reserved. No part of this publication may be reproduced, stored, or transmitted in any form or by any means without the prior permission in writing from the Publisher. Requests should be addressed to the Permissions Editor at: Pulse Marketing & Communications, LLC, 4 Peninsula Avenue, Sea Bright, NJ 07760.

Chief Executive Officer Jo-Ann Kalaka-Adams jadams@skinmedjournal.com

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Abstracting & Indexing: The journal is indexed in Index Medicus/MEDLINE.

Lebanese Dermatological Society

SKINmed. 2015;13:336

Associate Publisher James R. Adams jadams@skinmedjournal.com

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Belarusian Society of Dermatovenereologists and Cosmetologists

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IMPORTANT INFORMATION ABOUT

SOOLANTRA®

(ivermectin) Cream, 1% BRIEF SUMMARY This summary contains important information about SOOLANTRA (soo lan’ trah) Cream. Read this information carefully before you prescribe SOOLANTRA Cream. For full Prescribing Information and Patient Information please see the package insert. WHAT IS SOOLANTRA CREAM? SOOLANTRA Cream is a topical prescription medicine indicated for the treatment of the inflammatory lesions of rosacea. WHO IS SOOLANTRA CREAM FOR? SOOLANTRA Cream is indicated for people with inflammatory lesions of rosacea. It is not known if SOOLANTRA Cream is safe and effective for children. Advise your patients to not use SOOLANTRA Cream for a condition for which it was not prescribed and remind them to not give SOOLANTRA Cream to other people, even if they have the same symptoms as it may harm them. WHAT SHOULD I ASK MY PATIENTS BEFORE PRESCRIBING SOOLANTRA CREAM? Before you prescribe SOOLANTRA Cream, ask your patients if they: • have any other medical conditions. • are pregnant or planning to become pregnant. It is not known if SOOLANTRA Cream can harm an unborn baby. • are breastfeeding or plan to breastfeed. It is not known if SOOLANTRA Cream passes into breast milk and if it can harm a baby.

SOOLANTRA Cream is supplied in a child-resistant capped tube. • To open, gently press down on the child resistant cap and twist counterclockwise. To avoid spilling, do not squeeze the tube while opening or closing. • To close, gently press down on the child resistant cap and twist clockwise. WHAT ARE THE INGREDIENTS IN SOOLANTRA CREAM? Active ingredient: ivermectin. Inactive ingredients: carbomer copolymer type B, cetyl alcohol, citric acid monohydrate, dimethicone, edetate disodium, glycerin, isopropyl palmitate, methylparaben, oleyl alcohol, phenoxyethanol, polyoxyl 20 cetostearyl ether, propylene glycol, propylparaben, purified water, sodium hydroxide, sorbitan monostearate, and stearyl alcohol. WHERE SHOULD I GO FOR MORE INFORMATION ABOUT SOOLANTRA CREAM? • This Brief Summary summarizes the most important information about SOOLANTRA Cream. For full Prescribing Information and Patient Information please see the package insert. • Go to www.soolantra.com or call 1-866-735-4137

Trademarks are the property of their respective owners. GALDERMA LABORATORIES, L.P., Fort Worth, Texas 76177 USA Revised: December 2014

WHAT ARE THE MOST COMMON SIDE EFFECTS OF SOOLANTRA CREAM? The most commonly reported side effects when using SOOLANTRA Cream include skin burning sensation and skin irritation. Remind your patients to tell you if they have any side effect that bothers them or that does not go away. These are not all of the possible side effects of SOOLANTRA Cream. For more information, see the full Prescribing Information. You are encouraged to report negative side effects of prescription drugs to the FDA at www.fda.gov/medwatch or call 1-800-FDA-1088. You may also contact GALDERMA LABORATORIES, L.P. AT 1-866-735-4137. HOW SHOULD PATIENTS USE SOOLANTRA CREAM? • SOOLANTRA Cream is for use on the face only and should not be used in the eyes, mouth, or vagina. • SOOLANTRA Cream should be applied to the affected areas of the face once a day. APPLYING SOOLANTRA CREAM: • A pea-sized amount of SOOLANTRA Cream should be applied to each area of the face (forehead, chin, nose, each cheek) that is affected. Avoid contact with the lips and eyes.

References: 1. Stein Gold L, Kircik L, Fowler J, et al; Ivermectin Phase III Study Group. Efficacy and safety of ivermectin 1% cream in treatment of papulopustular rosacea: results of two randomized, double-blind, vehicle-controlled pivotal studies. J Drugs Dermatol. 2014;13(3):316-323. 2. Data on file. Galderma Laboratories, L.P. 3. Taieb A, Ortonne JP, Ruzicka T, et al; Ivermectin Phase III Study Group. Superiority of ivermectin 1% cream over metronidazole 0.75% cream in treating inflammatory lesions of rosacea: a randomized, investigator-blinded trial. Br J Dermatol. 2015;172(4):1103-1110.

All trademarks are the property of their respective owners. ©2015 Galderma Laboratories, L.P. Galderma Laboratories, L.P. 14501 N. Freeway, Fort Worth, TX 76177 SOL-254 Printed in USA 06/15


TREATING INFLAMMATORY LESIONS OF ROSACEA CAN BE TOUGH…

PRESCRIBE

A TOUGH TOPICAL SOOLANTRA® (ivermectin) CREAM, 1%—POWERFUL AND RAPID RESULTS FROM A ONCE-DAILY TOPICAL1,2*† • –20.5 (–64.9%) mean inflammatory lesion count reduction at week 122*† • Better efficacy from once-daily Soolantra Cream, 1% vs twice-daily metronidazole 0.75% cream as early as 3 weeks3‡ • Specifically formulated for patients with inflammatory lesions of rosacea—Cetaphil® Moisturizing Cream was the basis for the vehicle2

www.soola n t ra .com/h cp Important Safety Information Indication: SOOLANTRA® (ivermectin) Cream, 1% is indicated for the treatment of inflammatory lesions of rosacea. Adverse Events: In clinical trials with SOOLANTRA® Cream, the most common adverse reactions (incidence ≤1%) included skin burning sensation and skin irritation. Warnings/Precautions: Not for oral, ophthalmic, or intravaginal use. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088. Please see brief summary of Prescribing Information on adjacent page. * The efficacy and safety of SOOLANTRA® Cream, 1% once daily was evaluated in subjects aged ≥18 years in 2 identically designed phase 3 clinical trials (N=1371). Final results were comparable between the 2 studies, with the least favorable results presented here. † A phase 3, multicenter, randomized, double-blind, 12-week, vehicle-controlled, parallel-group study assessing the efficacy and safety of SOOLANTRA® Cream, 1% once daily in 683 subjects with moderate to severe papulopustular rosacea (Investigator Global Assessment [IGA] score of 3 or 4). ‡ An investigator-blinded, multicenter, randomized, parallel-group study comparing the efficacy and safety of SOOLANTRA® Cream, 1% once daily with metronidazole 0.75% cream twice daily in 962 subjects with moderate to severe papulopustular rosacea (IGA score of 3 or 4) over a 16-week treatment period.


Skinmed July/August, 2015