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May/June 2014 • Volume 12 • Issue 3 EDITORIAL Franz Kafka and the Doctor’s Dilemma

COSMETIC SCIENCE Hot Topics in the Cosmetics Industry

COMMENTARY Cutaneous Reactions to Bed Bug Bites

CORRESPONDENCE Kafka and the Enigmatic Case of Cutaneous Myiasis

Lambert, Wassef, and Lambert

Goddard

ORIGINAL CONTRIBUTIONS Low-Level Laser/Light Therapy for Androgenetic Alopecia Gupta, Lyons, and Abramovits

Motives for Cosmetic Procedures in Saudi Women Al-Natour

Epstein

Fernandez-Flores and Saeb-Lima

A Rare Case of Aplasia Cutis With Vanishing Twin Syndrome and Unusual Presentation

Garg, Jabeen, Agarwal, Chander, and Agarwal

BOOK REVIEW Atlas of Dermoscopy Lee

A High Glycerol–Containing Leave-On Scalp Care Treatment to Improve Dandruff

Harding, Matheson, Hoptroff, Jones, Luo, Baines, and Luo

REVIEW Cutaneous Malignancies in Immunosuppressed Organ Transplant Recipients Sosa Seda, Zubair, and Brewer

Self Assessment Examination Lambert

CORE CURRICULUM Basal Cell Carcinoma: Pathophysiology Sehgal, Chatterjee, Pandhi, and Khurana

DEPARTMENTS PERILS OF DERMATOPATHOLOGY New Wine in Old Bottles: The Coming Deluge of Aggressive Cutaneous Cancers and Precancers

Lebanese Dermatological Society

Wassef, Lee, Lambert, Patel, and Lambert

Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society


Finacea® (azelaic acid) Gel, 15% is a topical prescription medication used to treat inflammatory papules and pustules of mild to moderate rosacea.

Rosacea is with her wherever she goes . So is Finacea . ®

It’s true. Rosacea is complex and it’s with them for life. Finacea® treats the papules and pustules with associated erythema of mild to moderate rosacea. Although some reduction of erythema which was present in patients with papules and pustules of rosacea occurred in clinical studies, efficacy for treatment of erythema in rosacea in the absence of papules and pustules has not been evaluated. You have made Finacea® the #1 Dermatologist-prescribed topical rosacea brand.1

INDICATION & USAGE Finacea® (azelaic acid) Gel, 15% is indicated for topical treatment of inflammatory papules and pustules of mild to moderate rosacea. Although some reduction of erythema which was present in patients with papules and pustules of rosacea occurred in clinical studies, efficacy for treatment of erythema in rosacea in the absence of papules and pustules has not been evaluated. IMPORTANT SAFETY INFORMATION Skin irritation (e.g. pruritus, burning or stinging) may occur during use with Finacea®, usually during the first few weeks of treatment. If sensitivity or severe irritation develops and persists during use with Finacea®, discontinue use and institute appropriate therapy. There have been isolated reports of hypopigmentation after use of azelaic acid. Since azelaic acid has not been well studied in patients with dark complexion, monitor these patients for early signs of hypopigmentation. Avoid contact with the eyes, mouth, and other mucous membranes. In case of eye exposure, wash eyes with large amounts of water. Wash hands immediately following application of Finacea®. Avoid use of alcoholic cleansers, tinctures and astringents, abrasives and peeling agents. Avoid the use of occlusive dressings or wrappings. In clinical trials with Finacea®, the most common treatment-related adverse events (AE’s) were: burning/stinging/tingling (29%), pruritus (11%), scaling/dry skin/xerosis (8%) and erythema/irritation (4%). Contact dermatitis, edema and acne were observed at frequencies of 1% or less. Finacea® is for topical use only. It is not for ophthalmic, oral or intravaginal use. Patients should be reassessed if no improvement is observed upon completing 12 weeks of therapy. Please see Brief Summary of full Prescribing Information on adjacent page. 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.

1. According to IMS NPATM (National Prescription Audit) July 2010-October 2013 © 2014 Bayer HealthCare Pharmaceuticals. Bayer, the Bayer Cross, Finacea and the Finacea logo are registered trademarks of Bayer. All rights reserved. FIN-10-0001-14 | February 2014


TABLE OF CONTENTS May/June 2014 • Volume 12 • Issue 3

EDITORIAL

Franz Kafka and the Doctor’s Dilemma ...................................................................................................... 139

W. Clark Lambert, MD, PhD; Cindy Wassef, BS; Peter C. Lambert, BA, MA

COMMENTARY

Cutaneous Reactions to Bed Bug Bites....................................................................................................... 141

Jerome Goddard, PhD

ORIGINAL CONTRIBUTIONS

Low-Level Laser/Light Therapy for Androgenetic Alopecia ........................................................................ 145

Aditya K. Gupta, MD, PhD, FRCPC; Danika C. A. Lyons, MSc; William Abramovits, MD

Motives for Cosmetic Procedures in Saudi Women .................................................................................... 150

Sahar H. Al-Natour, MD

A High Glycerol–Containing Leave-On Scalp Care Treatment to Improve Dandruff ..................................... 155

Clive R. Harding, BS; Jane R. Matheson, PhD; Michael Hoptroff, BS; David A. Jones, PhD; Yanjun Luo, PhD; Fiona L. Baines, PhD; Shengjun Luo, PhD

Review

Cutaneous Malignancies in Immunosuppressed Organ Transplant Recipients .......................................... 164

Ivette M. Sosa Seda, MD; Adeel Zubair, BS; Jerry D. Brewer, MD

Self Assessment Examination ................................................................................................................... 173

W. Clark Lambert, MD, PhD

CORE CURRICULUM Virenda N. Sehgal, MD, Section Editor

Basal Cell Carcinoma: Pathophysiology ................................................................................................... 176

Virendra N. Sehgal, MD; Kingshuk Chatterjee, DNB; Deepika Pandhi, MD; Ananta Khurana, MD

Departments Perils of Dermatology

W. Clark Lambert, MD, PhD, Section Editor

New Wine in Old Bottles: The Coming Deluge of Aggressive Cutaneous Cancers and Precancers ............ 183

Cindy Wassef, BA; Brian Lee, MD; Peter C. Lambert, MA; Laju Patel, MD; W. Clark Lambert, MD, PhD

Cosmetic Science

Howard A. Epstein, PhD, Section Editor

Hot Topics in the Cosmetics Industry ........................................................................................................ 187

Howard A. Epstein, PhD

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TABLE OF CONTENTS July/August 2013••Volume Volume12 11••Issue Issue34 May/June 2014

CORRESPONDENCE

Kafka and the Enigmatic Case of Cutaneous Myiasis ................................................................................ 191

Angel Fernandez-Flores, MD, PhD; Marcela Saeb-Lima, MD

A Rare Case of Aplasia Cutis With Vanishing Twin Syndrome and Unusual Presentation .......................... 192

Taru Garg, MD; Masarat Jabeen, MD; Soumya Agarwal, MD; Ram Chander, MD; Kiran Agarwal, MD

ERRATA .................................................................................................................................................... 194

Book Review Jennifer L. Parish, MD, Section Editor

Atlas of Dermoscopy ................................................................................................................................. 196

Jason B. Lee, MD

ABOUT OUR JOURNAL

Editorial

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.

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

Lebanese Dermatological Society

135

Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society


FOR INTERDIGITAL TINEA PEDIS DUE TO TRICHOPHYTON RUBRUM AND EPIDERMOPHYTON FLOCCOSUM IN ADULT PATIENTS

INTRODUCING LUZU L U ZU FA S T: 2 W E EK S, 14 DOS E S Efficacy demonstrated at 4 weeks post-treatment The only topical azole antifungal approved to treat interdigital tinea pedis with once-daily dosing over a 2-week period

Indications and Usage LUZU (luliconazole) Cream, 1% is indicated for the topical treatment of interdigital tinea pedis, tinea cruris, and tinea corporis caused by the organisms Trichophyton rubrum and Epidermophyton floccosum in patients 18 years of age and older. Important Safety Information • LUZU is indicated for topical use only and is not indicated for ophthalmic, oral or intravaginal use. • LUZU should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Caution should be exercised when LUZU is prescribed for nursing mothers. Except as otherwise indicated, all product names, slogans, and other marks are trademarks of the Valeant family of companies. © 2014 Valeant Pharmaceuticals North America LLC.

DM/LUZ/13/0004

• The most common adverse reactions in clinical

trials were application site reactions, which occurred in less than 1% of subjects in both LUZU and vehicle arms. Most adverse reactions were mild in severity.

Please see full Brief Summary of Prescribing Information on adjacent page. Reference: LUZU [prescribing information]. Bridgewater, NJ: Medicis, a division of Valeant Pharmaceuticals; 2013.


S:7�

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION FOR LUZU (luliconazole) This Brief Summary does not include all the information needed to use LUZU safely and effectively. See full Prescribing Information for LUZU. LUZU (luliconazole) Cream, 1% for topical use Initial U.S. Approval: 2013 Rx Only INDICATIONS LUZU (luliconazole) Cream, 1% is an azole antifungal indicated for the topical treatment of interdigital tinea pedis, tinea cruris, and tinea corporis caused by the organisms Trichophyton rubrum and Epidermophyton floccosum, in patients 18 years of age and older. DOSAGE AND ADMINISTRATION For topical use only. LUZU Cream, 1% is not for ophthalmic, oral, or intravaginal use. When treating interdigital tinea pedis, a thin layer of LUZU Cream, 1% should be applied to the affected area and approximately 1 inch of the immediate surrounding area(s) once daily for two (2) weeks. When treating tinea cruris or tinea corporis, LUZU Cream, 1% should be applied to the affected area and approximately 1 inch of the immediate surrounding area(s) once daily for one (1) week. CONTRAINDICATIONS None ADVERSE REACTIONS

Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug, and may not reflect the rates observed in practice. In three Phase 3 clinical trials, 616 subjects were exposed to LUZU Cream, 1%: 305 with interdigital tinea pedis and 311 subjects with tinea cruris. Subjects with interdigital tinea pedis or tinea cruris applied LUZU Cream, 1% or vehicle cream once daily for 14 days or 7 days, respectively, to affected and adjacent areas. During clinical trials with LUZU Cream, 1% the most common adverse reactions were application site reactions which occurred in less than 1% of subjects in both the LUZU and vehicle arms. Most adverse reactions were mild in severity. Post-Marketing Experience The following adverse reactions have been identified during post-marketing use of luliconazole cream, 1%: contact dermatitis and cellulitis. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. DRUG INTERACTIONS The potential of luliconazole to inhibit cytochrome P-450 (CYP) enzymes 1A2, 2C9, 2C19, 2D6, and 3A4 was evaluated in vitro. Based on in vitro assessment, luliconazole at therapeutic doses, particularly when applied to patients with moderate to severe tinea cruris, may inhibit the activity of CYP2C19 and CYP3A4. However, no in vivo drug interaction trials have been conducted to evaluate the effect of luliconazole on other drugs that are substrates of CYP2C19 and CYP3A4. Luliconazole is not expected to inhibit CYPs 1A2, 2C9 and 2D6 based on in vitro assessment. The induction potential of luliconazole on CYP enzymes has not been evaluated. USE IN SPECIFIC POPULATIONS

Pregnancy: Pregnancy Category C.

to pregnant female rats. No treatment related effects on maternal toxicity or malformations were noted at 25 mg/kg/day (3 times the MRHD based on BSA comparisons). Increased incidences of skeletal variation (14th rib) were noted at 25 mg/kg/day. No treatment related effects on skeletal variation were noted at 5 mg/kg/day (0.6 times the MRHD based on BSA comparisons). Subcutaneous doses of 4, 20 and 100 mg/kg/day luliconazole were administered during the period of organogenesis (gestational days 6-18) to pregnant female rabbits. No treatment related effects on maternal toxicity, embryofetal toxicity or malformations were noted at 100 mg/kg/day (24 times the MRHD based on BSA comparisons). In a pre- and post-natal development study in rats, subcutaneous doses of 1, 5 and 25 mg/kg/day luliconazole were administered from the beginning of organogenesis (gestation day 7) through the end of lactation (lactation day 20). In the presence of maternal toxicity, embryofetal toxicity (increased prenatal pup mortality, reduced live litter sizes and increased postnatal pup mortality) was noted at 25 mg/kg/day. No embryofetal toxicity was noted at 5 mg/kg/day (0.6 times the MRHD based on BSA comparisons). No treatment effects on postnatal development were noted at 25 mg/kg/day (3 times the MRHD based on BSA comparisons). Nursing Mothers It is not known whether luliconazole is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when LUZU Cream, 1% is administered to women who are breastfeeding. Pediatric Use The safety and effectiveness of LUZU Cream, 1% in pediatric patients have not been established. The number of pediatric patients ≼12 years of age were too small to adequately assess safety and efficacy. Geriatric Use Of the total number of subjects in clinical studies of LUZU Cream, 1%, 8 percent were 65 and over, while 1.4 percent were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies to evaluate the carcinogenic potential of LUZU Cream, 1% have not been conducted. Luliconazole revealed no evidence of mutagenic or clastogenic potential based on the results of two in vitro genotoxicity tests (Ames assay and Chinese hamster lung cell chromosomal aberration assay) and one in vivo genotoxicity test (mouse bone marrow micronucleus test). In a fertility study in rats, subcutaneous doses of 1, 5 and 25 mg/kg/day luliconazole were administered prior to and during mating and through early pregnancy. Treatment related effects on reproductive function were noted in females (decreased live embryos and decreased corpus luteum) at 5 and 25 mg/kg/day and males (decreased sperm counts) at 25 mg/kg/day. No treatment related effects on fertility or reproductive function were noted at 1 mg/kg/day (0.1X MRHD based on BSA comparisons). PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) Inform patients that LUZU Cream, 1% is for topical use only. LUZU Cream, 1% is not intended for intravaginal or ophthalmic use. Manufactured for: Medicis, a division of Valeant Pharmaceuticals North America LLC, Bridgewater, NJ 08807

There are no adequate and well-controlled studies of LUZU Cream, 1% in pregnant women. LUZU Cream, 1% should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The animal multiples of human exposure calculations were based on daily dose body surface area (BSA) comparisons (mg/m2) for the reproductive toxicology studies described in this section and in Section 13.1. The Maximum Recommended Human Dose (MRHD) was set at 8 g 1% cream per day (1.33 mg/kg/day for a 60 kg individual which is equivalent to 49.2 mg/m2/day). Systemic embryofetal development studies were conducted in rats and rabbits. Subcutaneous doses of 1, 5 and 25 mg/kg/day luliconazole were administered during the period of organogenesis (gestational days 7-17)

Manufactured by: DPT Laboratories, Ltd., San Antonio, TX 78215 Product of Japan Issued: 11/2013 140127 DM/LUZ/13/0005(1)


May/June 2014

Volume 12 • Issue 3

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

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

Virendra N. Sehgal, MD Delhi, India

Anthony A. Gaspari, MD Baltimore, MD

Jasna Lipozencic, MD, PhD Zagreb, Croatia Eve J. Lowenstein, MD, PhD New York, NY

Robert L. Baran, MD Cannes, France Anthony V. Benedetto, DO Philadelphia, PA

Michael Geiges, MD Zurich, Switzerland

George M. Martin, MD Kihei, HI

Charles Steffen, MD Oceanside, CA

Brian Berman, MD, PhD Miami, FL

Michael H. Gold, MD Nashville, TN

Marc S. Micozzi, MD, PhD Rockport, MA

Orin M. Goldblum, MD Indianapolis, IN

Alexander J. Stratigos, MD Athens, Greece

George F. Murphy, MD Boston, MA

Lowell A. Goldsmith, MD, MPH Chapel Hill, NC

James S. Studdiford III, MD Philadelphia, PA

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

Robert J. Thomsen, MD Los Alamos, NM

Jack M. Bernstein, MD Dayton, OH Sarah Brenner, MD Tel Aviv, Israel Henry H.L. Chan, MB, MD, PhD, FRCP Hong Kong, China 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 Boni E. Elewski, MD Birmingham, AL Charles N. Ellis, MD Ann Arbor, MI Howard A. Epstein, PhD Philadelphia, PA

Aditya K. Gupta, MD, PhD, FRCPC London, Ontario, Canada Seung-Kyung Hann, MD, PhD Seoul, Korea

Oumeish Youssef Oumeish, MD, FRCP Amman, Jordan

Roderick J. Hay, BCh, DM, FRCP, FRCPath London, UK María Daniela Hermida, MD Buenos Aires, Argentina Warren R. Heymann, MD Camden, NJ Tanya R. Humphreys, MD Bala-Cynwyd, PA

Joseph L. Pace, MD, FRCP Naxxar, Malta Art Papier, MD Rochester, NY Johannes Ring, MD, DPhil Munich, Germany Roy S. Rogers III, MD Rochester, MN Donald Rudikoff, MD New York, NY

Camila K. Janniger, MD Englewood, NJ

Robert I. Rudolph, MD Wyomissing, PA

Abdul-Ghani Kibbi, MD Beirut, Lebanon

Vincenzo Ruocco, MD Naples, Italy

Andrew P. Lazar, MD Washington, DC

Noah Scheinfeld, MD, JD New York, NY

138

Riccarda Serri, MD Milan, Italy

Julian Trevino, MD Dayton, OH Graham Turner, PhD, CBiol, FSB Port Sunlight, UK Snejina Vassileva, MD, PhD Sofia, Bulgaria Daniel Wallach, MD Paris, France Michael A. Waugh, MB, FRCP Leeds, UK Wm. Philip Werschler, MD Spokane, WA Joseph A. Witkowski, MD Philadelphia, PA Ronni Wolf, MD Rechovot, Israel Matthew J. Zirwas, MD Columbus, Ohio


May/June 2014

Volume 12 • Issue 3

Editorial

Franz Kafka and the Doctor’s Dilemma W. Clark Lambert, MD, PhD;1 Cindy Wassef, BS;2 Peter C. Lambert, BA, MA3 “Plus ça change, plus c’est la même chose.” Alphonse Karr

I

n the enigmatic short story, A Country Doctor, Franz Kafka describes a primary care physician who is called to see a reputedly very ill patient on a snowy night in what is now known as rural Czech Republic.1 His problem is that he lacks a horse, his own having died the previous night from overwork and exposure, and the only source of a replacement is a lecherous stablehand who is determined to attack the doctor’s assistant.

nosis following a superficial examination), insists he sleep naked beside the patient, thus exposing his own flesh to the infection. This he does, but the family further insists he remain with the patient. By the time he escapes, still naked, the doctor’s assistant has been attacked and his practice ruined.

The Doctor’s Duty and His Choice

In telling this story, Kafka precisely identifies the key vulnerability of the primary physician: how do you respond when faced with this choice? You must either desert your patient or commit/abet a crime? This is a dilemma faced almost exclusively by physicians, who have a dual duty to both their patients and to society. Moreover, it is not a dilemma exclusive to early 20th-century Czech physicians. Substitute “traditional doctor’s practice” for the doctor’s horse, “HMO/thirdparty payer” for the lecherous stableboy, “ICD-10 codes/ Obamacare” for the snowstorm, and “plaintiff’s malpractice attorneys/defensive medicine” for the patient’s family and you have the same dilemma faced by 21st-century American physicians. Thus, “The more things change, the more they stay the same.”

The doctor must choose between caring for the patient and protecting his assistant. On the one hand, he is called upon to fulfil his duty as a physician, to see the patient, but in doing so he must abrogate his duty as a citizen/human being. On the other hand, he is called upon for his duty as a citizen, to protect the girl who is, after all, his employee, but to do this he must neglect the patient. He chooses his duty as a physician, goes to the patient, makes the diagnosis of myiasis (as is well documented in the correspondence by Drs Angel Fernandez-Flores and Marcela Saeb-Lima in this issue of the Journal2), and reassures the terrified patient, who had given up all hope and wished only to die, that the lesion, despite its fearful appearance, is “not so bad.” Thus, as a physician he has done well, he has made a difficult diagnosis (as reviewed by Fernandez-Flores and Saeb-Lima, myiasis is not common in the Czech Republic) that has resulted in great relief to the patient and probably eventually saved his life. As a citizen, however, he has failed, as attested to by the horrible cries of the girl recorded later in the story.

The Take-Home Lesson

It is almost reassuring to learn that previous physicians endured the same problems we face and survived. Almost. References

The Sequelae The doctor’s problems are not yet over, however. The skeptical family, unconvinced (the physician had initially missed the diagSee also page 191.

1 Kafka F. A Country Doctor. Prague, Czech Republic: Twisted Spoon Press; 1997:11–22. 2 Fernandez-Flores A, Saeb-Lima M. Kafka and the enigmatic case of cutaneous myiasis. SKINmed. 2014:12:191–192.

From the Departments of Dermatology and Pathology and Laboratory Medicine, Rutgers University – New Jersey Medical School, Newark, NJ;1 Rutgers University – New Jersey Medical School, Newark, NJ;2 and St. Georges University School of Medicine, St. Georges, Grenada, W.I.3 Address for Correspondence: W. Clark Lambert, MD, PhD, Rutgers University, Medical Science Building, Room H576, 185 South Orange Avenue, Newark, NJ 07103 • E-mail: lamberwc@njms.rutgers.edu

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GENTLE REJUVENATION FOR SENSITIVE SKIN

O B A G I ® G E N T L E R E J U V E N AT I O N FOR SENSITIVE SKIN

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Dispense Obagi Gentle Rejuvenation when your patient requires a tender touch. It’s the calm for compromised skin.

Except where otherwise indicated, all product names, slogans and other marks are trademarks of the Valeant family of companies. © 2013 Obagi Medical Products, Inc., a division of Valeant Pharmaceuticals North America LLC.

12/13 DM/GRS/13/0003

www.obagi.com


May/June 2014

Volume 12 • Issue 3

COMMENTARY

Cutaneous Reactions to Bed Bug Bites Jerome Goddard, PhD

Once considered a pest of the past, bed bugs have re-emerged with a vengeance worldwide over the past decade, with numerous reports of infestations in homes, hotels, apartments, businesses, hospitals, libraries, movie theaters, and even public transportation.1–4 State and federal agencies have vacillated as to whether to label bed bugs as a medically important pest or health hazard, with most thinking they are simply a nuisance causing mechanical irritation and aggravation; however, a body of evidence is now accumulating that these blood-sucking pests produce a wide range of health effects in people, some severe.5–11 Varying reactions Not everyone bitten by bed bugs displays cutaneous reactions. In fact, studies show that between 30% and 60% of people bitten exhibit no reaction at all (and may be totally unaware they have been bitten).10,12,13 I personally have fed bed bugs on myself many times with no reaction (Figure),14 and there are other examples of researchers in the pest control and entomology disciplines who report the same thing. One major research question yet to be answered is whether repeated exposure leads to sensitivity, ie, the lack of reaction in some people is only because they have not yet been bitten enough to become sensitive. There is some evidence supporting this view. One researcher10 found that the reaction time in volunteers steadily decreased as the number of feedings increased over time. On the other hand, there are examples of people (like myself ) with multiple exposures over a period of years with no change in reaction status. Another interesting phenomenon is people reacting to bed bug bites upon the very first exposure. A colleague of mine reacted with erythematous, intensely pruritic lesions 3 days following the very first time she was knowingly bitten by bed bugs.9 Therefore, it is reasonable to assume that cross-reactivity to salivary proteins in various blood-sucking insects may contribute to the response.

Cutaneous reactions with immunologic mechanisms have been variously clinically described by the timing of their appearances as “immediate” (within 30 minutes), “late” (6–8 hours), or “delayed” (≥24–48 hours).15 Immediate and late reactions have been associated with the presence of specific antibodies to antigens deposited in the skin, while delayed reactions have been associated with cell-mediated mechanisms.15 Sometimes, cutaneous reactions have occurred later than immediate, late, or biphasic reactions reported from fire ant venom, insulin, or delayed reactions to purified protein derivative, and appear similar to previously reported blistering reactions that occur days after insect bites.16,17 Immediate, IgE-mediated, immunologic reactions to insect salivary antigens have been implicated in bullous reactions,16 and such reactions are usually more commonly associated with tuberculin-like proteins in hyperimmunized individuals. In addition, we poorly understand the ”lighting-up” phenomenon in which lesions re-develop at sites of previous lesions following exposure at a site distal to the original.18 This presumably results from antigens residing at the bite site for an extended period of time and from these antigens responding to inflammatory mediators circulating in response to new bites. Finally, one of the most unusual bite reactions to bed bugs involves a severe necrotizing vasculitis similar to that seen in Churg-Strauss syndrome.5 This means that, at least for some people, bed bug bite reactions can be quite serious. Allergens in Saliva Two studies in our laboratory have demonstrated that bed bug allergens (excluding inhalant allergens similar to those involved in cockroach allergy) are apparently contained in bed bug saliva. In one set of experiments, bed bugs with their salivary glands removed were still able to bite and puncture human skin but unable to feed to repletion and cause skin lesions in a reactive individual.19 One can conclude from this work that: (1) bed bug

From the Department of Biochemistry, Molecular Biology, Entomology and Plant Pathology, Mississippi State University, Mississippi State, MS Address for Correspondence: Jerome Goddard, PhD, Mississippi State University, Clay Lyle Entomology Building, Department of Biochemistry, Molecular Biology, Entomology and Plant Pathology, 100 Twelve Lane, Mississippi State, MS 39762 • E-mail: jgoddard@entomology.msstate.edu

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May/June 2014

COMMENTARY and federal health agencies may reconsider their stance that bed bugs are mostly just a nuisance. Acknowledgements Dr Monica Embers, Tulane National Primate Research Center, provided helpful comments during the preparation of this manuscript. This contribtuion has been approved for publication as journal article J-12332 of the Mississippi Agriculture and Forestry Experiment Station, Mississippi State University. References 1 Doggett S, Russell RC. The resurgence of bed bugs, Cimex spp., in Australia: experiences from down under: Proceedings of the 6th International Conference on Urban Pests. Budapest, Hungary; July 13–16, 2008: 1–30.

Figure. Bed bugs feeding on human skin (photo copyright 2007 by Jerome Goddard, PhD).

saliva is the putative cause of bite reactions in sensitive individuals, and (2) bed bug saliva is necessary for successful blood feeding, probably because of the presence of anticoagulants. In the second experiment, bed bug salivary gland extract caused release of several potent pro-inflammatory cytokines and chemokines in macrophage cell lines, suggesting that this is what happens in vivo, leading to development of cutaneous lesions.20 These data provide proof, in principle, that bed bug saliva, on its own, has the ability to induce inflammation, leading to development of cutaneous lesions. In other, unpublished, work from our laboratory we utilized hyperimmune human serum from a man who frequently feeds bed bugs on himself and used indirect fluorescent antibody (IFA) staining to detect bed bug antigens (potential allergens). We obtained positive IFA results from bed bug salivary glands but no reactions from the proboscis itself or the cuticle. Further, IFA studies of surfaces where bed bugs were allowed to walk on a microscope slide showed no positive reaction (fluorescence). Interestingly, bed bug feces were IFA positive, but tick feces used as a negative control were also positive. The significance of this finding is unknown at this time. Future Directions Many aspects of human bed bug bite reactions remain to be elucidated. Even though the bed bug sialome has been published,21 further work is needed to determine exactly which of these proteins in saliva serve as allergens and which of them could be exploited for clinical applications such as diagnostic tests or immunotherapy. For example, our lab has identified a 75 kD immunoreactive band in Western blot assays on a patient highly sensitive to bed bug bites. The incidence and extent of ChurgStrauss–like reactions to bed bug bites in the general population needs clarification, as well as additional careful pathology to describe these very serious inflammatory reactions. Perhaps state SKINmed. 2014;12:141–143

142

2 Miller D. Bed bugs (Hemiptera: Cimicidae). In: Capinera JL, ed. Encyclopedia of Entomology. New York, NY: Springer International; 2008:405–417. 3 Potter MF. The perfect storm: an extension view on bed bugs. Am Entomol. 2006;52:102–104. 4 Potter MF, Rosenberg B, Henriksen M. Bugs without borders: defining the global bed bug resurgence. Pest World. Sept/Oct, 8–20, 2010. 5 de Shazo RD, Feldlaufer MF, Mihm MC, Goddard J. Bullous reactions to bed bug bites reflect cutaneous vasculitis. Am J Med. 2012;125:688–694. 6 Doggett S, Dwyer DE, Penas PF, Russell RC. Bed bugs: clinical relevance and control options. Clin Microbiol Rev. 2012;25:164–192. 7 Goddard J, de Shazo RD. Bed bugs (Cimex lectularius) and clinical consequences of their bites. JAMA. 2009;301:1358–1366. 8 Goddard J, de Shazo RD. Psychological effects of bed bug attacks (Cimex lectularius L.). Am J Med. 2012;125:101–103. 9 Goddard J, Edwards KT, de Shazo RD. Observations on development of cutaneous lesions from bites by the common bed bug, Cimex lectularius L. Midsouth Entomol. 2011;4:49–52. 10 Reinhardt K, Kempke RA, Naylor RA, Siva-Jothy MT. Sensitivity to bites by the bedbug, Cimex lectularius. Med Vet Entomol. 2009;23:163–166. 11 Susser SR, Perron S, Fournier M, et al. Mental health effects from urban bed bug infestation (Cimex lectularius L.): a cross-sectional study. BMJ Open. 2012;2(5). 12 Pritchard MJ, Hwang SW. Severe anemia from bed bugs. CMAJ. 2009;181:287–288. 13 Ryckman RE. Dermatological reactions to the bites of four species of triatominae (hemiptera: reduviidae) and Cimex lectularius L. (hemiptera: cimicidae). Bull Soc Vector Ecol. 1985;10:122–125. 14 Goddard J, de Shazo RD. Multiple feeding by the common bed bug, Cimex lectularius L., without sensitization. Midsouth Entomol. 2009;2:90–92.

Cutaneous Reactions to Bed Bug Bites


May/June 2014

COMMENTARY

15 Joneja JV, Bielory L. Understanding Allergy, Sensitivity, and Immunity. New Brunswick, NJ: Rutgers University Press; 1994. 16 Leverkus M, Jochim RC, Schad S, et al. Bullous allergic hypersensitivity to bed bug bites mediated by IgE against salivary nitrophorin. J Invest Dermatol. 2006;126:91–96. 17 Sansom JE, Reynolds NJ, Peachy RD. Delayed reaction to bed bug bites. Arch Dermatol. 1992;128:272–273. 18 McKiel JA, West AS. Nature and causation of insect bite reactions. Ped Clin North Am. 1961;8:795–814.

19 Goddard J, Edwards KT. Effects of bed bug saliva on human skin. JAMA Dermatol. 2013;149:372–373. 20 Goddard J, Hasenkampf N, Edwards KT, de Shazo R, Embers ME. Bed bug saliva causes release of monocytic inflammatory mediators: plausible cause of cutaneous bite reactions. Int Arch Allergy Immunol. 2013;161:127– 130. 21 Francischetti IM, Calvo E, Andersen JF, et al. Insight into the sialome of the bed bug, Cimex lectularius. J Proteome Res. 2010;9:3820–3831.

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May/June 2014

Volume 12 • Issue 3

Original contribution

Low-Level Laser/Light Therapy for Androgenetic Alopecia Aditya K. Gupta, MD, PhD, FRCPC;1,2 Danika C. A. Lyons, MSc;2 William Abramovits, MD3–9 Abstract Androgenetic alopecia (AGA) is a persistent and pervasive condition that affects men worldwide. Some common treatment options for AGA include hair prosthetics, oral and topical medications, and surgical hair restoration (SHR). Pharmaceutical and SHR treatments are associated with limitations including adverse side effects and significant financial burden. Low-level laser or light (LLL) devices offer alternative treatment options that are not typically associated with adverse side effects or significant costs. There are clinic- and home-based LLL devices. One home-based laser comb device has set a standard for others; however, this device requires time devoted to carefully moving the comb through the hair to allow laser penetration to the scalp. A novel helmet-like LLL device for hair growth has proven effective in preliminary trials and allows for hands-free use. Regardless, there are few clinical trials that have been conducted regarding LLL devices for AGA and results are mixed. Further research is required to establish the true efficacy of these devices for hair growth in comparison to existing alternative therapies. (SKINmed. 2014;12:145–147)

H

air loss is a common condition associated with significant psychological distress.1,2 Androgenetic alopecia (AGA), also known as male pattern baldness, is a form of hair loss characterized by genetic- and hormone-related components.3 Although the complete pathophysiology of AGA is unknown, testosterone, type I and II 5α-reductase enzymes, and dihydrotestosterone (a testosterone metabolite) are known contributors.3 There are a number of treatments available for AGA. These treatments include oral and topical medications, surgical hair restoration, prosthetics (hairpieces or hair extensions), and clinic- or home-based low-level laser/light therapies (LLLTs). Treatments for hair loss are not mutually exclusive and are often combined to enhance total hair growth. Use of low-level lasers/light as a treatment for hair loss is controversial as the ability of lasers or light to induce hair growth is not well established.4,5

Lasers, Light, and Laser/Light Exposure Therapy Lasers, light-emitting diodes (LED), and light vary based on a number of parameters, including wavelength (color [nm]), amplitude (brightness), fluence (energy over an area [J/cm2]), irradiance (power over an area, over a period of time [mW/cm2]), coherence, and polarization.6 Mester first noted laser-induced hair growth incidentally while investigating how low-level laser exposure may contribute to skin cancer7; however, the optimal timing and combination of the various laser/light parameters to precipitate hair growth has not been determined. Anecdotally, the optimal wavelengths for therapeutic application of lasers/ lights in human beings range from 600 nm to 1400 nm.6,8–11 The most common wavelengths specified for therapeutic hair growth range from 600 nm to 950 nm.11

From the Department of Medicine, University of Toronto School of Medicine, Toronto, Ontario, Canada;1 Mediprobe Research Inc, London, Ontario, Canada;2 Dermatology Treatment and Research Center, Dallas, TX;3 Department of Dermatology, Baylor University Medical Center, Dallas, TX;4 University of Texas Southwestern School of Medicine, Dallas, TX;5 University of Texas Medical Branch, Galveston, TX;6 Health Sciences Center, Texas Tech University, Lubbock, TX;7 Texas A&M Health Science Center College of Medicine, Dallas, TX;8 University of North Texas Health Science Center, Fort Worth, TX9 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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ORIGINAL CONTRIBUTION

Several possible mechanisms of action for laser/light-induced hair growth have been purported. Light irradiation may alter mitochondrial respiration through absorption of light by cytochrome c oxidase resulting in an increase in adenosine triphosphate (ATP) production.6,11,12 ATP molecules contain energy necessary for cellular functioning such as intracellular signaling leading to cell proliferation.13 Alternatively, light irradiation may (1) release nitric oxide inhibition over cytochrome c oxidase-mediated mitochondrial respiration, thus increasing mitochondrial respiration rate and ATP production11; (2) convert molecules into a triplet state thereby allowing the interaction with groundstate oxygen resulting in the production of singlet oxygen; and (3) increase the production of superoxide anions through modulation of respiratory (redox) chains. Singlet oxygen molecules at low concentrations and cellular redox state may also facilitate cell proliferation.11 Just as the effects of irradiation on biological tissue may vary based on the parameters applied, the effects of irradiation may vary based on the properties of the biological tissue and its underlying cellular state at the time of the irradiation.11 Thus, the copious number of permutations of light parameters and the influence of baseline biological tissue properties may account for inconsistency in the literature regarding the efficacy of lasers for hair growth. Clinical Trials for LLLT-Induced Hair Growth in Humans There are low-level laser/light devices designed for use in medical clinics and devices designed for use at home. Home-based devices are often less effective and necessitate additional treatments to achieve noticeable hair growth due to their use of lower power and longer wavelengths (630–670 nm) than clinic-based devices14; however, home-based devices offer comfort, convenience, and privacy that clinic-based devices cannot provide. Hence, there is a significant demand for home-based low-level laser/light devices that encourage the production of new devices. Researchers15 conducted an exploratory analysis of the efficacy and safety of a hood-like laser device for hair growth from Sunetics International (Dallas, TX). The device is designed for clinic-based use and boasts 100 laser diodes at a wavelength of 650 nm and a power output of 5 mW. The authors subjected 7 participants diagnosed with AGA to laser treatments 2 times a week for 20 minutes, over a 3- to 6-month period. Vellus and terminal hair count, shaft diameter, and subjective hair-growth ratings were recorded at baseline and post-treatment. The authors reported an average decrease in vellus hairs, an average increase in terminal hairs, and an average increase in hair shaft SKINmed. 2014;12:145–147

diameter. None of the changes from baseline reached statistical significance, but the small sample size utilized in the study may account for this. The HairMax LaserComb (HMLC; Boca Raton, FL) is a homebased device. This 635 nm to 655 nm device was recently evaluated in a thorough, double-blind, randomized-controlled trial in 269 men and women with AGA.16 Participants were randomized into 1 of 8 groups (women: 9-beam HMLC or sham, 12-beam HMLC, or sham; men: 7-, 9-, or 12-beam HMLC or sham) and instructed to use the device 3 times a week for 26 weeks. The authors reported that the average change in terminal hairs per cm2 from baseline to 26 weeks was significantly higher in all 5 of the laser groups than in the sham groups (women: P=.0001 and P=.0001; male: P=.0017, P=.0249, and P=.0028).16 In 2009, researchers published a randomized, double-blind clinical trial evaluating the same laser comb device.9 A total of 123 men with AGA were instructed to use the laser comb or sham-control device at home 3 times a week for 26 weeks. Change in terminal hair density in a 2.9 cm diameter region of the scalp was compared between the two groups. The average change in density from baseline to post-treatment in the laser group (19.8 hairs per cm2) was significantly higher than the average change in density in the sham group (sham: â&#x20AC;&#x201C;7.6 hairs per cm2; P<.0001).9 Similarly, in 2003, researchers noted an average increase in hair count and an increase in tensile strength following a 26-week regimen of HMLC use in 35 individuals with AGA but did not report any statistical comparison of change in hair count and tensile strength from baseline to post-treatment follow-up.17 In 2012, a home-based, hands-free helmet LLLT device for hair growth, iGrow (Apira Science, Inc, Boca Raton, FL), received US Food and Drug Administration approval.18 The device is equipped with 20 lasers (5 mW) and 31 LEDs, as well as auxiliary features such as adjustability and iPod/Mp3 compatibility. A preliminary double-blind, randomized clinical trial of the helmet yielded optimistic results.19 A total of 44 men with AGA were recruited to undergo 60 treatments of 25-minute duration over 16 weeks. Twenty-two men were assigned to laser treatment (655 nm, 67.3 J/cm2) and 19 were assigned to the sham group. The authors noted a 35% increase in hair count and a significant difference between groups in the average change in hair count from baseline (P=.011).19 Complete information regarding methodology, outcome measures, inclusion and exclusion criteria, and statistical analyses appears to be unavailable at this time; however, similar helmet- or hat-like devices have been recently introduced speaking to the utility of hands-free LLLT devices for use at home.

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ORIGINAL CONTRIBUTION

Investigators evaluated another helmet-like device, Oaze Hair Beam (Won Technology, Co, Ltd, Daejeon, South Korea), in a randomized, double-blind clinical trial.20 Forty participants (men and women with AGA) were randomly assigned to laser treatment (n=20) or sham device treatment (n=20); they were instructed to use the device for 18 minutes, once a day for 24 weeks. The authors noted significant differences between groups in the average change in hair density (P=.003) and thickness (P=.01) following 24 weeks of treatment.20 The authors did not perform any statistical comparison within groups to evaluate whether the average change in hair density and thickness from baseline to post-treatment were significant. Conclusions Hair loss is a common disorder associated with significant psychological trauma. The use of low-level laser/light devices to promote hair growth as a treatment for hair loss has yielded some positive results; however, the optimal combination of wavelength, irradiation, fluence, pulse structure, and timing of application for promotion of hair growth require further research. Furthermore, the number of thorough, objective, and stringently regulated clinical trials utilizing proper statistical analyses to evaluate the efficacy of LLLT devices for hair growth is lacking. Thus, a sizeable portion of the literature is anecdotal in regards to the efficacy of LLLT devices for hair growth. References 1 Cash TF. The psychological effects of androgenetic alopecia in men. J Am Acad Dermatol. 1992;26:926–931. 2 Cash TF. The psychology of hair loss and its implications for patient care. Clin Dermatol. 2001;19:161–166. 3 Kaufman KD. Androgens and alopecia. Mol Cell Endocrinol. 2002;198:89–95. 4 Avram MR, Leonard RT, Epstein ES, Williams JL, Bauman AJ. The current role of laser/light sources in the treatment of male and female pattern hair loss. J Cosmet Laser Ther. 2007;9:27–28. 5 Gupta AK, Daigle D. The use of low-level light therapy in the treatment of androgenetic alopecia and female pattern hair loss. J Dermatol Treat. 2014;25:162–163. 6 Chung H. The nuts and bolts of low-level laser (Light) therapy. Ann Biomed Eng. 2012;40:516–33. 7 Mester E, Szende B, Gärtner P. [The effect of laser beams on the growth of hair in mice]. Radiobiol Radiother (Berl). 1968;9:621–626.

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8 Avci P, Gupta GK, Clark J, Wikonkal N, Hamblin MR. Lowlevel laser (light) therapy (LLLT) for treatment of hair loss. Lasers Surg Med. 2014;46:144–151. 9 Leavitt M, Charles G, Heyman E, Michaels D. HairMax LaserComb® laser phototherapy device in the treatment of male androgenetic alopecia: a randomized, doubleblind, sham device-controlled, multicentre trial. Clin Drug Investig. 2009;29:283–292. 10 Ghanaat M. Types of hair loss and treatment options, including the novel low-level light therapy and its proposed mechanism. South Med J. 2010;103:917–921. 11 Hamblin MR. Mechanisms of laser-induced hair regrowth [Internet]. cosmediclaserclinic.com. 2013. http://www. cosmediclaserclinic.com/video/laser_hair_restoration/ Induced_Laser_Hair_regrregr_Harvard_Medical.pdf Accessed March 29, 2014. 12 Karu T. Primary and secondary mechanisms of action of visible to near-IR radiation on cells. J Photochem Photobiol B. 1999;49:1–17. 13 Lodish H, Berk A, Matsudaira P, et al. Chemical and molecular foundations: life begins with cells. In: Molecular Cell Biology. 5th ed. New York, NY: W.H. Freeman and Company; 2004:9–15. 14 Metelitsa AI, Green JB. Home-use laser and light devices for the skin: an update. Semin Cutan Med Surg. 2011;30:144–147. 15 Avram MR. The use of low-level light for hair growth: Part I. J Cosmet Laser Ther. 2009;11:110–117. 16 Jimenez JJ, Wikramanayake TC, Bergfeld W, et al. Efficacy and safety of a low-level laser device in the treatment of male and female pattern hair loss: a multicenter, randomized, sham device-controlled, double-blind study. Am J Clin Dermatol. 2014 Jan 29. [Epub ahead of print] 17 Satino JL, Markou DO. Hair regrowth and increased hair tensile strength using the HairMax LaserComb for lowlevel laser therapy. Int J Cosmet Surg Aesthetic Dermatol. 2003;5:113–117. 18 Apira Science. 510(k) Summary K122248, IGrow, Apira Science, Inc. [Internet]. FDA 510(k) Premarket Notification Database; 2012. http://www.accessdata.fda.gov/ cdrh_docs/pdf12/K122248.pdf Accessed March 29, 2014. 19 Lanzafame RJ. The growth of human scalp hair mediated by visible red light laser and LED sources in males. 2011. Available at: http://www.igrowlaser.com/themes/ shared/resources/pdf/iGrow_Clinical_Trial_Abstract. pdf. Accessed March 29, 2014. 20 Kim H, Choi JW, Kim JY, et al. Low-level light therapy for androgenetic alopecia: a 24-week, randomized, double-blind, sham device-controlled multicenter trial. Dermatol Surg Off Publ Am Soc Dermatol Surg Al. 2013;39:1177–1183.

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Michael H. Gold, Md • Lawrence Charles Parish, Md • Wm. Phillip Werschler, Md Joel Cohen, Md • dr. Erin Gilbert, Md, Phd • dr. Miles Graivier, Md • Michael Kane, Md Mukta Sachdev, Md • dr. Julie Woodward, Md, Phd TRIALS INCLUDED:

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May/June 2014

Volume 12 • Issue 3

Original contribution

Motives for Cosmetic Procedures in Saudi Women Sahar H. Al-Natour, MD Abstract The media-fuelled obsession with beauty in modern society has led more women to seek elective cosmetic procedures to meet the portrayed ideals of beauty in different cultures. This study gives insights into incentives and desires to undergo cosmetic procedures in a conservative society with strict religious practices where women are veiled. Questionnaire data were obtained from 509 Saudi women who responded to a survey distributed randomly to a sample of Saudi women aged 17 to 72 years. At least 1 elective cosmetic procedure was performed in 42% of the women, of whom 77.8% wore a veil. Another 33% considered having a procedure. The motives for seeking a cosmetic procedure were to improve self-esteem in 83.7%, attract a husband in 63.3%, or prevent a husband from seeking another wife in 36.2%. The decision to seek a procedure was affected by the media, with high peer influence. Motivation for elective cosmetic procedures in Saudi women is influenced by a combination of emotional and cultural factors, level of education, marital status, and religious beliefs. The veil is not an impediment for seeking such procedures. The limitation of the study was missing data analysis as some items in the questionnaire were completed inaccurately or left unanswered. (SKINmed. 2014;12:150–153)

E

ven though the fountain of youth and beauty has been sought in both men and woman since historical times, the fascination of physical beauty is becoming more and more prevalent in today’s society. Cosmetic procedures have increased by astounding percentages in the United States, reaching to 457% since 1997,1 and seem to be undaunted by the current financial crisis. There are many published studies largely in Western countries as well as in the Far East on various aspects of cosmetic procedures and on the incentives/motives to seek such procedures. Published data/studies are absent in conservative parts of the world such as Saudi Arabia and the neighboring Arab Gulf States where women are veiled. Objectives The present study looked into the factors that influenced or motivated patients to seek elective cosmetic procedures in Saudi women. This project investigated the physical, psychosocial, and religious factors associated with women’s desire to consider or seek elective cosmetic procedures. Material and Methods A questionnaire was randomly distributed in public places to a sample of 700 Saudi women from various social classes and of different ages from 5 major cities in Eastern Saudi Arabia. A total

of 509 women responded (72.7%) and formed the basis of this study. The data were entered and analyzed by SPSS for Windows (SPSS Inc, Cary, NC). Results

Demographic data The ages of the 509 women who responded to the questionnaire ranged from 15 to 72 years, with a mean age of 35 years. Of these, 56% were married, 36.3% were single, 3.7% were divorced, and 2.4% were widowed. The education level of the 509 women was that of a college degree or higher in 76.3%, high school in 20.6%, and elementary in 3.1%. Housewives or unemployed single women comprised 35.2% of the total patients, whereas 30% were working in the educational sector, 23.7% in the health sector, 10.3% in administrative/business sector, and 0.8% in the cosmetic field. Of the women who participated in this survey, 87.4% were either partially or totally veiled: head scarf only in 37.3% and the niqab (face and hair veil) in 50.1%. The number of women who had undergone at least one elective cosmetic procedure was 212 (41.65% ), while 168 ( 33%) of those who did not have a procedure had either wanted or considered having one, raising the number of those who underwent or desired an elective procedure to 380 (74.65%) of the total.

From the Department of Dermatology, University of Dammam, King Fahd University Hospital, Al-Khobar, Saudi Arabia Address for Correspondence: Sahar H. Al-Natour, MD, C/O Aramco, PO Box 2106, Dhahran 31311, Saudi Arabia • E-mail: saharnatour@yahoo.com

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ORIGINAL CONTRIBUTION

Table I. Reasons for Not Having Any Cosmetic Procedure (N=297)

Table III. Elective Cosmetic Procedures Performed (N=212)

Reason

No. (%)

Procedure

No. (%)

Satisfied with appearance/not in need

200 (67.3)

Laser/IPL hair removal

114 (53.8)

Fear of complications

117 (39.4)

Tattoo removal

9 (0.9)

Religious reasons

69 (23.2)

Chemical peels

58 (27.4)

Financial reasons

49 (16.5)

Botox

46 (21.7)

Refusal of guardian

35 (11.8)

Electrolysis

38 (17.9)

Rejection of society

13 (4.4)

Rhinoplasty

26 (12.3)

Psychological reasons

9 (3.0)

Fillers

23 (10.8)

Liposuction

21 (9.9)

Breast augmentation

19 (9)

Tummy tuck

19 (9)

No. (%)

Dermabrasion

13 (6.1)

Financial

113 (67.26)

Sclerotherapy

9 (4.2)

Too busy

114 (67.85)

Face lift

4 (1.9)

Religious

76 (45.23)

Mesotherapy

3 (1.4)

Objection by guardian/relatives

90 (53.57)

Fear of complications

49 (29.16)

Table II. Reasons for Patients Wanting But Not Having a Procedure (N=168) Reason

Table IV. Motives for Seeking an Elective Cosmetic Procedure (N=380)

The reasons for patients not having any cosmetic procedure are summarized in Table I and those wanting but not having a procedure are summarized in Table II. The elective cosmetic procedures that were performed are summarized in Table III. The majority (89.1%) of the women had 1 to 3 cosmetic procedures porformed and 77.8% of those who had undergone a procedure were veiled. The age at which the first cosmetic procedure was performed was between 20 and 30 years in 53.4%, 31 and 40 years in 26.4%, 41 and 50 years in 18.3%, 51 and 60 years in 1.4%, and older than 61 years in 0.5% of patients. The motives for seeking an elective cosmetic procedure are shown in Table IV. The decision to seek a procedure was influenced by the media in 48.3% of patients, mainly by television (81.8%). Other influencing sources were magazines (46.5%), Internet (38.9%), radio (6.3%), and promotional meetings (3.8 %). Of patients who answered the questionnaire, 67.3% had at least one friend who had a cosmetic procedure performed. The procedure was performed in secrecy in 30.9% of the women because of either religious (3.1%) or cultural (96.9 %) reasons. Close family members were among those informed of their proSKINmed. 2014;12:150â&#x20AC;&#x201C;153

Motive

No. (%)

Improve self-esteem

318 (83.7)

Dissatisfaction with appearance

198 (52.2)

To attract a husband (single, divorced, widow)

240 (63.3)

Prevent husband from seeking another wife

138 (36.2)

Prevent husband from divorcing wife

4 (1.0)

Improve interpersonal relationships

70 (18.3)

Improve quality of life

24 (6.3)

cedure: sister (96%), mother (84%), husband (83%), friend (63%), father (39%), daughter (34%), and fiancĂŠ (9%). A preference for a female doctor/provider was demonstrated in 47% of the women and a male doctor in 23.5%; 29.5% of patients were indifferent to the sex of the doctor/provider. The reasons for a sex preference were religious in 28.5% and cultural in 16.2% and the belief that the selected provider was better trained in 55.4%. Other characteristics looked for in a provider included older and more experienced in 92.7% and Westerntrained in 40%, with a preference to have the procedure performed within the United Kingdom in 58.7%. The characteristics of women seeking the most procedures were those who were married (61.6%) and with a higher education

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ORIGINAL CONTRIBUTION years, as much of the recent literature describes the typical patient accepting and most likely to undergo such procedures in today’s society is much younger.7,8

Table V. Correlation of Veil Practice and Having a Cosmetic Procedure Had Cosmetic Procedure Veil practice

Yes

No

Total

Hijab (head veil)

77

109

186

Niqab (head + face)

81

169

250

No veil

45

18

63

Total

203

296

499

In this study, the majority of the women (53.4%) seeking elective cosmetic procedures were between the ages of 20 and 30 years, while 44.7% were between the ages of 31 and 50 years.

(85.2%) and those who were either housewives (28.8%) or working in the health (28.3%) or educational (24.3%) fields. Of those who had an elective cosmetic procedure, 77.8% were either partially or completely veiled. The correlation of the practice of wearing a veil and having a cosmetic procedure is summarized in Table V. Discussion Even though the fascination with elective cosmetic procedures seems to be a worldwide phenomenon, some lingering thoughts remain that women in conservative societies are less driven to undergo such procedures. This study proves the contrary and those women have the same motives and incentives whether they live in liberal or conservative societies and irrespective of religious beliefs. Even more striking is that veiled women similarly undergo such procedures to improve their physical appearance and the practice of wearing a veil is not a deterrent. Two hundred and twelve (41.65%) of the 509 women surveyed reported that they had undergone an elective surgical or nonsurgical cosmetic procedure. This figure exceeds the 5% of the 559 women reported by one investigation2 who had at least one procedure and the 3.4%3 and 7.7%4 reported in other investigations. In addition, another 33% of the participants who did not seek a cosmetic procedure said they would consider having a procedure in the future, and this correlates with the 34% who indicated that they would consider one for themselves at the time of the study or in the future in a telephone survey of 1000 American households.5 Similar lower and higher numbers have been reported internationally.2,5,6 The differences may reflect survey methodology or socioeconomic factors of the respective samples. Although people of all ages are electing to undergo cosmetic surgery, the prototype of a woman seeking cosmetic procedures is thought to be of an older woman trying to take years off and regain some of her youth; however, that has changed over the SKINmed. 2014;12:150–153

Contrary to other studies indicating that fewer women motivated to undergo cosmetic surgery were married compared with those not wishing to do so,4,9 this study demonstrated that the majority (61.65%) of the Saudi women who had undergone a procedure or surgery were in fact married. An interpretation of this could be that married women on average are less motivated to enhance their physical appearance because they don’t obtain much social advantage from doing so in the West. Saudi women, however, are part of a society where polygamy is commonly practiced and some married women can feel threatened by their husbands seeking other wives. As a result, more Saudi married women are electing to seek cosmetic procedures to boost their marriages and meet their husbands’ standards of beauty. Researchers have reported contradictory results regarding the correlation between the level of education and desire to seek elective cosmetic procedures. The level of education appears to be a determining factor in the motivation to seek cosmetic surgery by some women9 but a deterring factor by others3,10,11 despite the fact that women with a higher level of education are in a better financial state to afford cosmetic surgery. This study shows that 85.2% of the women who sought a procedure had a university degree, in contrast to 13.26% who received a secondary or high school education. In concordance with the author’s findings, a recent study found that 73% of their patients who elected for cosmetic surgery had a university education, whereas only 23% received a high school diploma.9 The highly educated women in this study group were turning to more elective cosmetic procedures in hope to improve job prospects, while housewives and unemployed single women were undergoing cosmetic procedures for fear of abandonment or to improve their chances of finding a husband, respectively. The decision to either consider or seek an elective cosmetic procedure was influenced by the media in 48.3% of the women, and, of these, television shows and advertisements (81.8%) and magazines (46.5%) had the greatest influence. The mass media and the expansive coverage of cosmetic surgery on television and in magazines were also reported to have an impact on women’s knowledge and attitudes about cosmetic surgery, inspiring women to pursue cosmetic surgeries and treatments in recent reports.2,10 In addition to the influence of the media, the deci-

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sion to seek a procedure was associated with high peer influence (two thirds of participants) in this study, which was similarly (68%) demonstrated by another investigation.2 Although cosmetic procedures are now more widespread and accepted worldwide, a social stigma still remains that leads women to have these procedures in relative secrecy. The findings of investigators2 in which more than half of the respondents indicated they would be embarrassed to tell people other than family and close friends about having a cosmetic procedure in American women, are in line with the attitudes of Saudi women in this study.

Acknowledgements Drs Khulood Al-Nutaifi and Fahad Al-Ajmi assisted in the distribution of the questionnaires. References

A strong correlation between self-esteem and enhancement of physical appearance and cosmetic surgery motivation was well demonstrated in this study and was also in line with others’ findings.4,12 Unique factors deterring Saudi women from having procedures include cultural norms, social stigmata, religious beliefs, and restrictions led by husbands and guardians. This is reflected in the 44% of women in this study who did not perform a procedure even though they desired having one. This is contrary to findings in the West where parents and guardians commonly pay for cosmetic procedures such as rhinoplasties and breast augmentations as graduation gifts in adolescents, for example.1 Moreover, financial considerations and time restrictions seemed to have a great impact on a Saudi woman’s interest in cosmetic surgery, where two thirds of the women said they would have a procedure if they had the money and if their time permitted. This is in contrast to findings where less than 30% of American women said they would have surgery if they had unlimited financial resources.2 Conclusions The results of this study confirm that women in the conservative society of Saudi Arabia are clearly aware of the most popular surgical and nonsurgical cosmetic procedures as a means of enhancing physical appearance and emotional health and have similar motives and incentives to undergo elective procedures as women in other societies. The practice of wearing a veil did not restrict awareness or access to cosmetic procedures. Religious and cultural beliefs and practices, social stigmata, and restrictions of guardians were the main deterrents unique to this group of women.

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1 Haas CF, Champion A, Secor D. Motivating factors for seeking cosmetic surgery: a synthesis of the literature. Plast Surg Nurs. 2008;28:177–182. 2 Sarwer DB, Cash TF, Magee L, et al. Female college students and cosmetic surgery: an investigation of experiences, attitudes, and body image. Plast Reconstr Surg. 2005;115:931–938. 3 Javo LM, Sorlie T. Psychosocial predictors of an interest in cosmetic surgery among young Norwegian women: a population-based study. Plast Reconstr Surg. 2009;124:2142–2148. 4 von Soest T, Kvalem IL, Skolleborg KC, et al. Psychological factors predicting the motivation to undergo cosmetic surgery. Plast Reconstr Surg. 2006;117:51–62. 5 American Society for Aesthetic Plastic Surgery. Cosmetic Surgery National Data Bank-2003 Statistics. New York: American Society for Aesthetic Plastic Surgery; 2004. 6 Frederick DA, Lever J, Peplau LA. Interest in cosmetic surgery and body image: views of men and women across the lifespan. Plast Reconstr Surg. 2007;120:1407–1415. 7 Cooper LB. Nursing student’s perception of clients undergoing elective cosmetic surgery. Plast Surg Nurs. 2007;27:158–162. 8 Rohrich, RJ. Stream lining cosmetic surgery patient selection-Just say no! Plast Reconstr Surg. 1999;104:220– 221. 9 Zahiroddin AR, Kandjaini AR, Khalighi E. Do mental health and self-concept associate with rhinoplasty requests? J Plast Reconstr Aesthet Surg. 2008;61:1100– 1103. 10 Didie ER, Sarwer DB. Factors that influence the decision to undergo cosmetic breast augmentation surgery. J Womens Health. 200l;12:241–253. 11 Dalgard OS, Mykletun A, Rognerud M, et al. Education, sense of mastery and mental health: Results form a nationwide health monitoring study in Norway. BMJ Psychiatry. 2007;7:20. 12 Kamburoglu HO, Ozgur F. Postoperative satisfaction and the patient’s body image, life satisfaction, and selfesteem: a retrospective study comparing adolescent girls and boys after cosmetic surgery. Aesthet Plast Surg. 2007;31:739–745.

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May/June 2014

Volume 12 • Issue 3

Original contribution

A High Glycerol–Containing Leave-On Scalp Care Treatment to Improve Dandruff Clive R. Harding, BS;1 Jane R. Matheson, PhD;1 Michael Hoptroff, BS;2 David A. Jones, PhD;1 Yanjun Luo, PhD;2 Fiona L. Baines, PhD;1 Shengjun Luo, PhD2 Abstract Dandruff is a common cosmetic condition associated with flaky scalp skin and pruritus. It is generally treated with regular use of antifungal-based shampoos. Research into factors underlying the characteristic skin lesions has revealed perturbations in epidermal differentiation and a dramatic deterioration in the associated process of stratum corneum (SC) maturation. These observations suggest that directly addressing the quality of the SC could have a scalp benefit. In this study, the authors investigated the efficacy of a moisturising leave-on lotion (LOL) containing a high concentration of glycerol (10%) and other known skin benefit agents (saturated fatty acid and sunflower seed oil) to reduce dandruff over an 8-week treatment period with 3 applications per week. Results of expert visual grading and biophysical measurements of SC parameters (transepidermal water loss and hydration) revealed a significant reduction in the dandruff condition over this period, with significant improvement in both SC water barrier function and hydration. These scalp skin benefits were maintained for up to a week following cessation of the treatment. This study indicates that use of a glycerol-rich substantive LOL, designed to directly improve the quality of the SC barrier can have a significant impact on the dandruff condition. (SKINmed. 2014;12:155–161)

D

andruff is a common cosmetic condition characterized by the appearance of white flakes both on the scalp surface and in the hair.1,2 The scalp is particularly prone to pruritis,3 and the dandruff condition is often associated with extreme itch.4 The severity of dandruff can range from a mild scaling of the scalp surface, similar in appearance to the dry skin commonly experienced on other body sites, to the more severe condition of seborrhoeic dermatitis (SD) that is associated with distinct erythema.5,6 Despite visual similarities, however, the extent to which mild scalp scaling and dry skin are biochemically and ultrastructurally similar remains to be defined. The differential diagnosis of dandruff and SD remains a clinical one, based on the characteristic morphology of scaling and erythema and the distribution of lesions on the scalp, within the nasolabials folds, eyebrows, postauricular areas, and parts of the upper torso. Currently, there is no absolute agreement on the symptomatic and etiologic link between the two conditions, leading to some confusion between dandruff and SD.7–9 It is generally agreed that the dandruff condition is far more common than SD and is restricted to the scalp with the presence of terminal hair.10

The commensal yeast Malassezia is historically and widely regarded as a strong contributor to the onset and exacerbation of the condition,11–12 a fact supported by the well-established efficacy of a range of antifungal technologies as treatments.13–15 Modern molecular techniques have identified at least 14 distinct Malassezia species,16,17 and it is now generally recognized that Malassezia globosa and Malassezia restricta are the dominant species present on the human scalp,18,19 and both are implicated in the development of both dandruff and SD. The precise role of the microbial contribution remains unclear, however, and recent advances in the detailed knowledge of the total scalp microbiome revealed by culture-independent methods suggests that dandruff is more likely a condition linked to the balance between bacteria and fungi present on the host scalp surface.20 Clearly, the commensal nature of Malassezia, readily detectable on healthy scalps, indicates that there are factors beyond these yeasts that make certain individuals more prone to the development of dandruff. The current scientific consensus is that dandruff development is influenced by the interplay between 3 major factors: Malassezia colonization, sebum production, and an individual sensitiv-

From Unilever Research & Development, Port Sunlight Laboratory, Bebington, United Kingdom;1 and Unilever Research & Development, Shanghai, China2 Address for Correspondence: Clive R. Harding, BS, Unilever Research & Development, Port Sunlight Laboratory, Quarry Road East, Bebington, CH63 3JW, United Kingdom • E-mail: clive.harding@unilever.com

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ity that predisposes to the condition.21 The interdependence of these factors defines the onset, nature, and most likely the severity of dandruff development. At puberty, the sebaceous glands mature and produce greater amounts of sebum22 and these sebaceous lipids represent a vital nutrient supply to support the growth of Malassezia. It is generally accepted that the dramatic onset of sebum production provides the ideal microenvironment in which Malassezia and other microbes proliferate and can trigger the development of dandruff. The precise nature of this predisposition remains to be fully elucidated, as many factors, including environmental stresses such as climate and seasonality, microbial colonization, and hormonal changes, can influence scalp health.23 Recently, we have proposed that a critical factor that may underlie the individual susceptibility to dandruff is the intrinsic quality of the scalp epidermis and in particular that of the SC.24 The SC is the major protective barrier against external insults (eg, microbes, oxidative stressors, UV irradiation, and toxic materials) and acts as the primary epidermal barrier to water loss, maintaining hydration, flexibility, and integrity of the scalp.25,26 It is now well established that the levels of essential SC barrier lipids are dramatically reduced in subjects with dandruff,27 leading to a loss of structural organization within the intercellular space of the tissue, associated with an elevated transepidermal water loss (TEWL),28 but are subsequently restored by effective antifungal treatment.28,29 Studies in other pathologic scaling conditions such as atopic dermatitis and psoriasis have emphasised that the loss of integrity of the SC barrier (as observed in dandruff) is a key factor contributing to a hyperproliferative and inflammatory phenotype and there is a growing realization that effective moisturization regimens and mild cleansing have a significant role to play in improving the quality of the SC and treating these pathologic scaling conditions.30,31 Similarly, although dandruff is a relatively mild condition, SC integrity is nevertheless clearly compromised. In an attempt to investigate the relative contribution of SC quality and integrity in impacting the dandruff condition, either from a predisposition or a severity perspective, we have sought to understand the impact that traditional moisturizing technologies (ie, nonantifungal technology) can have on treating this condition. In this study, we report on the ability of a simple glycerol-based technology containing saturated fatty acids that are known to be important for barrier function to improve the dandruff condition and conclude that improvement in basic SC barrier properties can lead to a reduction in the severity of this condition even in the absence of any topical antifungal treatment. SKINmed. 2014;12:155–161

Materials Three different formulations (1 shampoo and 2 leave-on formulations) were utilized in the course of this study. A standard beauty shampoo containing no antifungal ingredients was used in all 3 phases of the study, ie, in the run-in, treatment, and post-treatment (regression) phases. The test formulation was a simplified moisturizing LOL (MLOL), containing known skin care benefit agents: 10% glycerol, 2.5% stearic acid, and 0.6 % sunflower seed oil (INCI: glycerol, stearic acid, glycol stearate, glyceryl stearate, isopropyl palmitate, sunflower seed oil, phenoxyethanol, dimethicone, magnesium aluminium silicate, methyl parabens, propyl parabens, carbomer 980, and disodium EDTA). The placebo LOL (PLOL) was based on the same formulation with all of the humectant/emollient (skin benefit) ingredients removed. Study Design The study was reviewed and approved by a local independent ethics committee (Joint Research Ethics Committees, Bangkok, Thailand) and was performed in line with good clinical practice. Written informed consent was obtained from all volunteers prior to study participation. The primary objective of the study was to demonstrate that the MLOL, relative to the PLOL, decreased visible adherent flakes and that an antidandruff benefit could be maintained for a period of time after withdrawal of the MLOL, ie, during the regression phase. This was a randomized, double-blind, placebo-controlled, halfhead design study. To standardize scalp condition prior to study start, all subjects used the standard beauty shampoo at home 3 times per week for at least 14 days. All subjects had not used any antidandruff products for 2 months prior to study commencement. Trained experts performed visual assessment on the severity of the dandruff flakes on the scalp surface according to the Unilever Total Weighted Head Score Adherent Flake methodology (TWHS AF) as detailed elsewhere.27,33 Instrumental measurements were performed on a single scalp site chosen at baseline as the area on each half head with the highest dandruff site grade. Subjects sat in controlled environmental conditions (temperature 20°C±1°C, humidity 50%±5%) with the measurement sites exposed by hair partings prior to the measurements being taken. Subjects remained in these controlled conditions while the instrumental measurements were carried out. The scalp barrier function (TEWL) was measured using an AquaFlux (AF102/103; Biox Systems Ltd, London, England). Scalp hydra-

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tion level was then assessed by measuring conductance with the DermaLab USB (hydration module, pin probe; Cortex Technology, Hadsund, Denmark). A total of 277 healthy subjects (113 men and 164 women), aged 18 to 60 years, with dandruff were enrolled into the study. For inclusion, both halves of the head had to exhibit a TWHS AF measure equivalent ≥32 with a grade C lesion present, and for the difference in TWHS AF between the two sides of the scalp to be <12. After the run-in phase, 157 subjects (73 men and 84 women) maintained the required level of dandruff and were accepted into the test phase and randomized to products. At the baseline visit, the products were allocated to the right/left side of each subject’s head according to preprepared randomization tables using sex as the stratification factor. During the 8-week treatment phase, there were 24 LOL product application visits (3 times per week immediately after last hair wash). TWHS AF assessment with defined biophysical measurements (scalp barrier TEWL and scalp hydration level) was undertaken every 2 weeks starting at the baseline visit. All visual and instrumental measurements were taken 48±4 hours after the last hair wash/LOL application and right before the next hair wash and LOL application. During the treatment phase, all product application was conducted at the study site. After the whole head hair wash by clinical staff using the standard dosage of the beauty shampoo, test formulations were applied by experienced operatives according to written standard operation procedure. For the application of the LOL, several hair partings were made from frontal to occipital area with the help of a long tail comb, and the LOL was directly spread onto the scalp utilizing a 1 mL needleless syringe. A total of 3 mL of each LOL was applied across the half scalp area and followed by a 1-minute massage by clinical personnel. During the 8-week regression phase, subjects were asked to use the beauty shampoo at home 3 times per week. There were 4 TWHS AF assessments together with biophysical measurements (TEWL and scalp moisture level) at the end of weeks 1, 2, 4, and 8. Two additional TWHS AF assessments were conducted 48 hours after each beauty shampoo wash during the first week of the regression phase. Statistical Analysis All statistical analyses were conducted using SAS (version 9.3; SAS Institute, Cary, NC). A P value of ≤.05 (two-sided) was used to determine statistical significance. To compare the effects of the two products over time, the TWHS AF, TEWL, and SKINmed. 2014;12:155–161

DermaLab moisture data were analyzed using mixed models. The baseline value, subject age, assessor, and side of head were included as covariates. Additional factors were also included as fixed effects to adjust for any potential effects of product, time point, sex, and their interactions (two-way and three-way). A repeated statement with UN@CS covariance structure for visits and product and the ddfm=KR option were used. After fitting the full model, surplus terms were removed using a backwards selection procedure (if P>0.1), with the product by visit interaction retained in order to obtain estimates of interest. Subjects with missing data were included in the analysis, unless all postbaseline measurements were missing. For the DermaLab and TEWL measurements, the statistical assumptions of the model were better met by applying a log transformation to the data. Results

Antidandruff efficacy This study was conducted in subjects with dandruff, with a scalp condition that would normally be treated effectively through the use of an antifungal formulation. In this study, a small but highly significant antidandruff benefit was seen with the MLOL (Figure 1). The MLOL had a significantly better antidandruff effect compared with the PLOL at all time points in the test phase (P<.01) and maintained this benefit for 1 week following cessation of treatment (P<.01). The general decrease in TWHS AF seen during the first 2 weeks with the PLOL is consistent with the benefit normally observed in antidandruff studies for placebo treatment and is attributed to the enhanced removal of sebum, Malassezia yeast, and other microbes that occurs with regular shampooing, thereby lessening the microbial load present within the surface layers of the SC. The MLOL showed significantly superior scalp barrier benefit, as measured by a reduced TEWL when compared with the PLOL at all time points during the test phase (P<.01) and maintained a better barrier function for 1 week (3 beauty shampoo washes) (P<.01) following the cessation of treatment. Overall, during the treatment phase, there was an 8% reduction in TEWL for the MLOL compared with the placebo group and this level of benefit was maintained (increasing to a 10% reduction) for 1 week following treatment. Finally (Figure 3), the MLOL provided a significantly higher moisturizing benefit on the scalp at all time points during the test phase (P<.01) and maintained this benefit for 1 week (P<.01) post-treatment. During the overall test phase, the MLOL treatment gave a 26% increase in moisturization level as measured by the DermaLab meter and maintained a 23% increase in moisturization value, post-treatment despite 3 washes with the standard beauty shampoo. The reason for the apparent decrease in hy-

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Figure 1 

Regression phase

Treatment phase

Regression phase

TEWL g/m2h, mean±SE

TWHS AF Equivalent, mean±SE

Treatment phase

    Figure

1. Changes in total weighted head score adherent   flake methodology (TWHS AF) associated with a moisturizing leave-on lotion (MLOL; solid triangles) and a placebo   leave-on lotion (PLOL; open circles) during a 16-week   study incorporating an 8-week treatment phase (0–8)   followed by an 8-week period of no treatment (regression   phase). SE indicates standard error.

Figure 2. Changes in transepidermal water loss (TEWL) associated with a moisturizing leave-on lotion (MLOL;   filled triangles) and a placebo leave-on lotion (PLOL; open circles) during a 16-week study incorporating an 8-week treatment phase (0–8 weeks) followed by an 8-week period with no treatment (regression phase). SE indicates standard error. Figure 3.

   

Discussion During the past 40 years, the most effective cosmetic treatment for dandruff has been the topical use of an antifungal, such as zinc pyrithione, selenium sulphide, or an imidazole (eg, climbazole and ketoconazole) usually delivered from a shampoo, rinseoff format.32–34 The combination of washing away adherent flakes and inhibiting the growth of the Malassezia yeasts and other microbes associated with the condition generally leads to an effective resolution of dandruff during several weeks, although the condition invariably returns. Although antifungal activity is the main driver of efficacy it has also been recognized that certain antifungal actives have additional properties that may contribute to the overall clinical efficacy, such as the intrinsic anti-inflammatory benefits of certain azoles, eg, ketoconazole35 and climbazole.33 Nevertheless, in the more severe SD condition, the specific additional use of an anti-inflammatory agent is often required to achieve successful resolution.36 SKINmed. 2014;12:155–161

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Treatment phase

Regression phase

DermaLab Moisture, mean±SE

dration measured in the MLOL- vs PLOL-treated sites following   4 weeks of regression (between weeks 12 and 16; Figure 3) during a period when the whole head was returned to a normal beauty shampoo regimen is unclear. It may reflect the delayed result of the better moisturized scalp (MLOL) responding to the increased intrinsic harshness of the beauty shampoo regimen.

Figure 3. Changes in scalp SC hydration associated with a moisturizing leave-on lotion (MLOL; filled triangles) and a placebo leave-on lotion (PLOL; open circles) during a 16-week study incorporating an 8-week treatment phase (0–8 weeks) followed by an 8-week period with no treatment (regression phase). SE indicates standard error.

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Historically, the general effectiveness of antifungals in combating cosmetic dandruff has led to a lack of sustained research into the development of other replacement or complimentary cosmetic treatments. Until recently, this scientific inertia has persisted despite the long-held knowledge that (1) Malassezia are commensal organisms37 and the presence of Malassezia alone is not sufficient to cause dandruff, and (2) that the characteristic flaking observed represents an aberrant maturation of the SC, reflecting, in turn, a perturbation in the underlying quality of epidermal differentiation.27,28,38 Logically, it seems reasonable to expect that improving these aspects of perturbed cutaneous function could improve dandruff and, in turn, make the scalp less prone to those very same environmental stressors such as microbes and harsh surfactants that are likely to be responsible for initiating or exacerbating the condition. Although a normalization of scalp barrier lipids28,29 and other aspects of skin differentiation39 is reported to accompany zinc pyrithione treatment, this effect is believed to be an indirect change arising from the removal or reduction of the microbes and associated metabolites. Thus, it is the reduction in the microbial challenge, achieved through an antifungal mechanism of the active that subsequently leads to the recovery and normalization of epidermal cellular processes, including keratinocyte proliferation and lipid biosynthesis. Subsequently, as the underlying epidermal layers recover, there is a gradual restoration in the quality of the SC barrier over a period of 1 to 2 weeks. Given this scenario, the opportunity exists to consider the use of skin benefit agents to directly improve the quality of the SC barrier and to establish whether these technologies can influence the overall performance of the antidandruff benefit, as defined by readily measureable parameters including the overall magnitude of TWHS AF reduction, the speed at which the dandruff lesions are resolved, or the enhancement of the duration of the antidandruff benefit following cessation of the treatment regimen. To the best of our knowledge this is the first study to demonstrate that the use of conventional skin care actives such as glycerol, emollients, and lipids—in this case saturated fatty acids that are known to be incorporated into the SC40—can achieve a significant improvement in dandruff, even in the absence of any coapplication or prior treatment with topical antifungal or anti-inflammatory agents. Here, we report that the combination of the aforementioned ingredients significantly improved scalp barrier function, as measured by TEWL, enhanced scalp moisturization, and reduced visible flakes as measured by TWHS AF. The reduced flaking may reflect two properties of the treatment: (1) improved barrier function and (2) the hydrolysis of aberrantly retained corneodesmosomes in the superficial layers of the SKINmed. 2014;12:155–161

SC. It is well recognized in classical skin xerosis that an inability to hydrolyze corneodesmosomes in the SC leads to the characteristic symptoms of dry flaky skin.41 Recently, we reported that impaired corneodesmosome retention is also a characteristic feature of dandruff.38 Although it is likely that the known corneodesmolytic activity of glycerol42 is ameliorating the degree of visible flaking through this mechanism, glycerol has many functional benefits43 as well as providing enhanced humectancy to facilitate other enzymatic processes vital for correct SC function. Sunflower seed oil is a well-known skin benefit agent containing linoleic acid, an essential fatty acid, vital for maintaining skin quality44 and in particular the synthesis of unique long chain ceramides critical for the correct formation of intercellular bilayer lipids in the SC.45,46 We previously reported that dandruff is associated with a decreased presence of linoleic acid-containing ceramides27 and that topical application of this fatty acid, as the triglyceride, can improve the levels of this unique structural ceramide.46 Recently, we postulated that intrinsic SC barrier quality may represent a key factor predisposing individuals to dandruff. In this context, the demonstration that improvements in scalp barrier benefits (as defined by TEWL) are still measureable 1 week after product cessation against the placebo is a positive indication that direct improvement in scalp SC quality may help delay the return of dandruff and potentially reduce susceptibility to the condition. Although the effect demonstrated in this study is modest, it is likely that increased, perhaps daily use, would prove beneficial. It is also likely that a more optimally formulated LOL containing the current benefit ingredients, alongside the addition of other ingredients known to improve the quality of the SC and the underlying scalp epidermis, is likely to lead to a more substantial and demonstrable benefit. Such an assertion is supported by the contribution of effective skin moisturization to the management of more severe flaking disorders such as atopic dermatitis.30,44 Indeed, we have shown that a combination of glycerol and niacinamide (unpublished data) also provides a significant antidandruff benefit with sustained scalp skin improvement during the regression phase. It has been reported that the use of an LOL containing an anti-inflammatory agent47 has a significant impact on dandruff, although in this instance the LOL also contained an antifungal, making an absolute assessment of the benefit of the anti-inflammatory alone problematical. Other studies have reported on the ability of wellknown moisturization ingredients (such as urea and lactic acid) and skin benefit agents such as modified hydroxyacids to provide effective treatment of dry, itchy, subclinically inflamed scalp skin and dandruff, respectively.48,49

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This novel approach to improving dandruff described here is currently restricted to a leave-on format. The amount of skin benefit agents that remain on the scalp surface after rinsing is assumed to be crucial for long-term antidandruff effects,50 and, in this context, delivery and substantiation of both hydrophobic and hydrophilic actives associated with skin care onto the scalp surface and down into the infundibulum from a rinse-off shampoo format represents a formidable technical challenge. In contrast, cosmetically, and sensorially acceptable LOLs to deliver these classes of benefit agents for improved scalp health are achievable. Conclusions This study demonstrates the ability of a simple glycerol-based moisturization technology, known to be important for barrier function, to improve the dandruff condition and supports the concept that improvement in basic SC barrier properties can lead to a reduction in the severity of this condition even in the absence of any topical antifungal treatment. These observations support the potential for enhanced scalp benefits to be derived in the future from the combination of conventional antidandruff shampoos (ie, containing antifungal technology that is effectively delivered from a rinse-off formula) with leave-on formulations, as described here, that directly improve the quality of the SC barrier. References 1 Shuster S. The aetiology of dandruff and the mode of action of therapeutic agents. Br J Dermatol. 1984;111:235– 242. 2 Hay RJ, Graham-Brown RAC. Dandruff and seborrhoeic dermatitis: causes and management. Clin Exp Dermatol. 1997;22:3–6 3 Piérard-Franchimont C, Hermanns JF, Degreef H, Piérard GE. From axioms to new insights into dandruff. Dermatology. 2000;200:93–98 4 Bin Saif GA, Ericson ME, Yosipovitch G. The itchy scalp--scratching for an explanation. Exp Dermatol. 2011;20:959–968. 5 Schwartz JR, Messenger AG, Tosti A, et al. A comprehensive pathophysiology of dandruff and seborrhoeic dermatitis—towards a more precise definition of scalp health. Derm Venereol. 2013;27:131–137. 6 Hay RJ. Malassezia, dandruff and seborrhoeic dermatitis: an overview. Br J Dermatol. 2011;165:suppl 2:2–8.

10 Szepietowski JC, Reich A. Wesolowska-Szepietowski E, et al. Quality of life in patients suffering from seborrhoeic dermatitis: influence of age, gender and educational level. Mycoses. 2008;52:357–363. 11 Pierard-Franchimont C, Arresse J, Durupt G, et al. Correlation between Malassezia spp. load and dandruff severity. J Mycol Med. 1998;8:83–86 12 Faergamann J, Jones T, Hettler O, et al. Pityrosporum ovale (Malassezia furfur) as the causative agent of seborrhoeic dermatitis: new treatment options. Br J Dermatol. 1996;134 suppl 46:12–15. 13 Marks R, Pearse AD, Walker AP. The effects of a shampoo containing zinc pyrithione on the control of dandruff. Br J Dermatol. 1985;112:415–422. 14 Schmidt-Rose T, Braren S, Folster H, et al. Efficacy of a piroctone olamine/climbazole shampoo in comparison with a zinc pyrithione shampoo in subjects with moderate to severe dandruff. Int J Cosmet Sci. 2011;33:276–282. 15 Billhimer W, Bryant P, Murray K, et al. Results of clinical trial comparing 1% zinc pyrithione and 2% ketoconazole shampoos. Cosm Derm. 1996;9:34–39. 16 Ashbee HR. Update on the genus Malassezia. Med Mycol. 2002;45:287–303. 17 Gaitanis G, Velegraki A, Mayser P, et al. Skin diseases associated with Malassezia yeasts: facts and controversies. Clin Dermatol. 2013;31:455–463. 18 Tajima M, Sugita T, Nishikawa A, et al. Molecular analysis of Malassezia microflora in seborrheic dermatitis patients: comparison with other diseases and healthy subjects. J Invest Dermatol. 2008;128:345–351 19 Jang SJ, Lim SH, Ko JH, et al. Investigation of the distribution of malassezia yeasts on the normal Korean skin by 26S rDNA PCR-RFLP. Ann Dermatol (Seoul). 2009;21:18–26. 20 Clavaud C, Jourdain R, Bar-Hen A, et al. Dandruff is associated with disequilibrium in the proportion of the major bacterial and fungal populations colonizing the scalp. PLoS One. 2013;8:e58203. 21 DeAngelis YM, Gemmer CM, Kaczvinsky JR, et al. Three etiologic facets of dandruff and seborrheic dermatitis: Malassezia fungi, sebaceous lipids, and individual sensitivity. J Invest Dermatol Symp Proc. 2005;10:295–297. 22 Pochi PE, Strauss JS. Endocrinologic control of the development of the human sebaceous gland. J Invest Dermatol. 1974;62:191–201. 23 Pierard-Francimont C, Xhauflaire-Uhoda E, Pierard GE. Revisiting dandruff. Int J Cosmet Sci. 2006;28:311– 318.

7 Pierard-Franchimont C, Xhauflaire-Uhoda G, Pierard G. Revisiting dandruff. Intl J Cosm Sci. 2006;28:311–318.

24 Turner GA, Hoptroff M, Harding CR. Stratum corneum dysfunction in dandruff. Int J Cosmet Sci. 2012;34:298– 306.

8 Dessinioti C, Katsambas A. Seborrheoic dermatitis: etiology, risk factors, and treatments: Facts and controversies. Clinics Dermatol. 2013;31:343–351.

25 Harding CR. The stratum corneum: structure and function in health and disease. Dermatol Ther. 2004;17:6– 15.

9 Schwartz RA, Janusz CA, Janniger CK. Seborrheic dermatitis: an overview. Am Fam Physician. 2006;74:125–130.

26 Feingold KR, Denda M. Regulation of permeability barrier homeostasis. Clin Dermatol. 2012;30:263–268.

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27 Harding CR, Moore AE, Rogers JS, et al. Dandruff: a condition characterised by decreased levels of intercellular lipids in scalp stratum corneum and impaired barrier function. Arch Derm Res. 2002;294;221–230. 28 Warner RR, Schwartz JR, Bolssy Y, et al. Dandruff has an altered stratum corneum ultrastructure that is improved with zinc pyrithione shampoo. J Am Acad Derm. 2001;45;897–903. 29 Rogers JR, Moore AE, Meldrum H, et al. Increased scalp lipids in response to anti-dandruff treatment containing zinc pyrithione. Arch Derm Res. 2003;295:127– 129. 30 Wirén K, Nohlgård C, Nyberg F, et al. Treatment with a barrier-strengthening moisturizing cream delays relapse of atopic dermatitis: a prospective and randomized controlled clinical trial. J Eur Acad Dermatol Venereol. 2009;23:1267–1272. 31 Del Rosso JQ, Levin J. The clinical relevance of maintaining the functional integrity of the stratum corneum in both healthy and disease-affected skin. J Clin Aesthet Dermatol. 2011;4:22–42. 32 Marks R, Pearse AD, Walker AP. The effects of a shampoo containing zinc pyrithione on the control of dandruff. Br J Dermatol. 1985;112:415–422. 33 Turner GA, Matheson JR, Li GZ, et al. Enhanced efficacy and sensory properties of an anti-dandruff shampoo containing zinc pyrithione and climbazole. Int J Cosmet Sci. 2013;35:78–83. 34 Danby FW, Maddin WS, Margesson LJ, et al. A randomized, double-blind, placebo-controlled trial of ketoconazole 2% shampoo versus selenium sulfide 2.5% shampoo in the treatment of moderate to severe dandruff. Am Acad Dermatol. 1993;29:1008–1012. 35 Faergemann J, Borgers M, Degreef H. A new ketoconazole topical gel formulation in seborrhoeic dermatitis: an updated review of the mechanism. Expert Opin Pharmacother. 2007;8:1365–1371. 36 Del Rosso JQ. Adult seborrheic dermatitis: a status report on practical topical management. J Clin Aesthet Dermatol. 2011;4:32–38.

39 Kerr K, Darcy T, Henry J, et al. Epidermal changes associated with symptomatic resolution of dandruff: biomarkers of scalp health. Int J Dermatol. 2011;50:102– 113. 40 Ananthapadmanabhan KP, Mukherjee S, Chandar P. Stratum corneum fatty acids: their critical role in preserving barrier integrity during cleansing. Int J Cosmet Sci. 2013;35:337–345. 41 Harding CR, Watkinson, A, Rawlings A, et al. Dry skin, moisturisation and corneodesmolysis. Int J Cosmet Sci. 2000;22:21–52. 42 Rawlings AV, Harding CR, Watkinson A, et al. The effect of glycerol and humidity on desmosome degradation in stratum corneum. Arch Dermatol Res. 1995;287:457–464. 43 Fluhr JW, Darlenski R, Surber, C. Glycerol and the skin: holistic approach to its origin and functions. Br J Dermatol. 2008;159:23–34. 44 Del Rosso JQ. Repair and maintenance of the epidermal barrier in patients diagnosed with atopic dermatitis: an evaluation of the components of a body washmoisturizer skin care regimen directed at management of atopic skin. Clin Aesthet Dermatol. 2011;4:45–55. 45 McCusker MM, Grant-Kels JM. Healing fats of the skin: the structural and immunologic roles of the omega-6 and omega-3 fatty acids. Clin Dermatol. 2010;28:440– 451. 46 Conti A, Rogers J, Verdejo P, et al. Seasonal influences on stratum corneum ceramide 1 fatty acids and the influence of topical essential fatty acids. Int J Cosmet Sci. 1996;18:1–12. 47 Schweiger D, Rippke F, Drescher P, et al. Highly effective rinse-off/leave-on scalp care treatments to reduce moderate to severe dandruff. J Cosm Derm Sci Applic. 2013;3:46–55. 48 Schweiger D, Baufeld C, Drescher P, et al. Effficacy of a new tonic containing urea, lactate, polidocanol and glycyrrhiza inflate root extract in the treatment of a dry itchy and subclinically inflamed scalp. Skin Pharm Physiol. 2013;26:108–118.

37 McGinley KJ, Leyden JJ, Marles RR, et al. Quantitative microbiology of the scalp in non-dandruff, dandruff and seborrhoeic dermatitis. J Invest Dermatol. 1975;64:401–405.

49 Seite S, Rougier A, Talarico S. Randomised study comparing the efficacy and tolerance of a lipohydroxyacid shampoo to a ciclopiroxolamine shampoo in the treatment of scalp sebottheoic dermatitis. J Cosmet Dermatol. 2009;8:249–253.

38 Singh B, Harding CR. Persistence of corneodesmosomes and elevation of protease inhibitors LEKTI and SCCA1 in dandruff. J Am Acad Dermatol Suppl. 2013;68-AB36.

50 Schwartz JR, Shah R, Krigbaum J, et al. New insights on dandruff/seborrhoeic dermatitis: The role of the scalp follicular infundibulim in effective treatment strategies. Br J Dermatol. 2011;165 suppl 2:18–23.

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Editors: Michael H. Gold, MD Lawrence Charles Parish, MD Wm. Philip Werschler, MD Joel Cohen, MD Dr. Miles Graivier, MD Derek Jones, MD Bruce Katz, MD Mukta Sachdev, MD Ava Shamban, MD Danny Vleggaar, MD

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May/June 2014

Volume 12 • Issue 3

REVIEW

Cutaneous Malignancies in Immunosuppressed Organ Transplant Recipients Ivette M. Sosa Seda, MD;1 Adeel Zubair, BS;2 Jerry D. Brewer, MD1 Abstract During the past century, organ transplantation has delivered the miracle of life to more than 500,000 patients in need. Secondary malignancies have developed as an unforeseen consequence of intense immunosuppressive regimens. Cutaneous malignancies have been recognized as the most frequent cancer that arises post-transplantation. Among organ transplant recipients (OTRs), skin cancer is a substantial cause of morbidity and potential mortality. The authors discuss epidemiology and clinical presentation of cutaneous malignancies; associated risk factors; recommendation for the care of immunosuppressed OTRs, and emerging therapies on the horizon. (SKINmed. 2014;12:164–173)

I

n 2011, the United States had 26,744 solid organ transplant recipients (OTRs) living with functional allograft organs, according to the United Network for Organ Sharing. Of those, 5658 were living donors. The most frequent transplants were of the kidney, followed by the liver and the heart. Other transplants included multiorgan, lung, pancreas, and intestine (Table I). As of January 25, 2013, there were 126,938 patients on the waiting list for transplant, including 125,035 adults and 1903 pediatric patients.1 Since the advent of organ transplantation, more than 500,000 individuals have received transplants in the United States. There have been many advances in both the technique in performing the transplant as well as the long-term immunosuppression.2–5 These advances have led to an overall increase in quality of life and survival of patients undergoing organ transplantation in the past decades. These increases in survival and quality of life are attributed to better immunosuppressive regimens, improved treatment of infectious processes, and increased use of human leukocyte antigen–matched organs from donors.6–11 As such, the rise of transplantation and survival being treated with immunosuppressants has shown an upsurge in the population at high risk for cutaneous malignancies.12

One of the earliest case reports of cutaneous malignancies in OTRs was published in 1969. Following this, there have been a variety of different studies evaluating the prevalence of cutane-

ous malignancies in OTR. One such study conducted at Oxford13 reviewed OTR over a 21-year span and determined that the incidence of cutaneous neoplasms increase with the length of immunosuppression. The increasing success of transplants denotes a greater susceptible population requiring primary prevention and treatment to prevent cutaneous malignancies. Prompt referral, adequate skin vigilance, and early recognition of skin cancer are essential to minimize morbidity and potential mortality. Epidemiology of Cutaneous Malignancies in OTRs Cutaneous malignancies (95%) are the most frequent cancer associated with immunosuppressed organ recipients. For many patients, skin cancer is a manageable condition, although it can become a significant medical challenge if not appropriately treated. Hundreds of cases of nonmelanoma skin cancer have been reported in high-risk post-transplant patients with the possibility of metastasis and death.14 Squamous cell carcinoma Squamous cell carcinoma (SCC) has been reported as the most common post-transplantation malignancy.14 The increased incidence is estimated between 50- and 250-fold for SCC. The

See also page 183. From the Department of Dermatology,1 Mayo Medical School,2 Mayo Clinic, Rochester, MN Address for Correspondence: Jerry D. Brewer, MD, Department of Dermatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 • E-mail: brewer.jerry@mayo.edu

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Table I. Solid Organ Transplantation Rates in the United States in 2011 Transplanted organ

No. (N=26,744)

Percentage

Kidney

16,057

60.0

Liver

5,806

21.7

Heart

1,949

1.0

Lung

1,779

3.0

Kidney and pancreas

791

7.3

Pancreas

260

6.7

Intestines

77

0.1

Heart and lung

25

0.3

Modified from Transplant Patient Data Source with permission of the United Network for Organ Sharing.1

risk for metastasis has increased to 8% in OTRs compared with the general population (0.5%–5%).15 An increase in skin cancer over time has been recorded in latitudes closer to the Equator.16 Heart and lung transplant recipients have a higher risk of developing SCC in comparison with the renal and liver population. One possible explanation is the more intense immunosuppressive regimens and older age at the time of transplant.15,17

post-transplant melanomas diagnosed in 638 patients. The overall survival was significantly worse in OTRs with melanomas. In addition, it was also confirmed that there is no increased incidence of recurrence of melanoma in patients with a history of melanoma before organ transplant. Melanoma mortality is higher among OTRs, resulting in 30% in 5 years compared with the general population, in which 15% of cases result in death.24

Basal cell carcinoma

Cutaneous malignancy can behave aggressively regardless of age. One study evaluated a pediatric population who received organ transplant at 18 years of age or younger. It was reported that SCC of the lip developed in 29%, with melanoma representing 14% of skin cancer, and both were overrepresented by this population. Alarmingly, the mortality incidence of lymph node metastasis was 9% and 8%, respectively, in these pediatric patients.32–34

Basal cell carcinoma (BCC) is the most common type of cutaneous malignancy in the immunocompetent population; however, the traditional incidence of BCC/SCC ratio 1:4 is reversed in OTRs with predominant SCC.18,19 BCC risk in OTRs has increased 10-fold.20,21 Studies have reported that BCC can be more common than SCC during the first years of transplantation.22 Even more fascinatingly, BCC may be more common in liver transplant recipients compared with other OTRs.23 Malignant melanoma The incidence of malignant melanoma has been reported 2.1fold and up to 8-fold greater than the immunocompetent population.24,25 Risk factors for developing melanoma are similar in the general population including the presence of multiple nevi and fair skin. There are 3 clinical distinct scenarios in OTRs: (1) patients with history of melanoma prior to transplant, (2) transplant recipients who develop melanoma as a consequence of direct transmission from the organ donor, and (3) de novo melanoma post-transplantation.26 The mean time for melanoma development in the OTR population is 61 months after organ transplantation.27–31 Recently, researchers studied the largest group of patients with melanoma in the OTR setting, with 724 SKINmed. 2014;12:164–173

Development of cutaneous metastasis is a longsuffering complication of OTR. Metastatic skin cancer is often fatal.14 Merkel cell carcinoma is also an aggressive tumor, with a 68% lymph node metastasis and 56% mortality rate.34 The aggressiveness of skin cancer has been reported with younger age at onset, with the presence of SCC characterizing multiple aggressive skin tumors in these patients. Other uncommon cutaneous tumors can present with metastatic likelihoods, aggressive courses, and poor prognoses in OTR. On physical examination, they can manifest as nonspecific cutaneous nodules. Other types of cutaneous malignancies include Kaposi sarcoma, with an increased incidence of 84-fold; Merkel cell carcinoma, with an increased relative risk of 5- to 10-fold15; and eccrine carcinoma, atypical fibroxanthoma, malignant fibrous histiocytoma, angiosarcoma, and cutaneous T- and B-cell lymphomas.22,34,35

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Cutaneous Malignancy and Immunosuppression Increased immunosuppression has been linked to an increased number of cutaneous malignancies that act more aggressively in these patients. Two different mechanisms have been proposed to explain the acceleration of skin cancer in transplant recipients: (1) the drugs used in transplantation may be directly carcinogenic,36,37 and (2) immunosuppressive medications lead to impaired immune surveillance and failure to eradicate cells from precancerous stages.38 Cyclosporine (CsA) is the most common immunosuppressive drug used in OTRs. It acts by binding to the cytoplasmic protein cyclophilin. The CsA-cyclophilin complex inhibits calcineurin, which dephosphorylates the transcription factor NFAT required for the transcription of interleukin-2 (IL-2). As a direct consequence, IL-2 production is blocked, reducing the effector T cells. The reported data have proven that CsA administration enhances skin cancer risk.39,40 Corticosteroids have been the principal maintenance suppression; nonetheless, adverse effects of long-term use have led to alternative corticosteroid-sparing regimens.15 Azathioprine photosensitizes skin in combination with UV-A radiation. It induces mutagenic metabolites causing oxidative DNA damage.41 Studies have shown that patients taking azathioprine have accelerated carcinogenesis, with a 5-fold increased risk of developing SCC.42,43 Another frequent immunosuppressive drug is mycophenolate mofetil. It is a potent immunosuppressant that inhibits purine synthesis through the reversible inhibition of inosine monophosphate dehydrogenase. It has been reported that it reduces the risk of developing skin cancer in OTRs.44 The first 3 months of transplantation pose a higher risk of rejection; therefore, higher doses of immunosuppression are needed. Increased risk of developing cutaneous malignancies has been shown with the use of induction therapy with antithymocyte globulin, OKT3, or monoclonal IL-2 receptor antibodies.45 Several studies have shown that dual immunosuppression compared with triple immunosuppression are associated with a lower risk of developing cutaneous malignancies.46 Monotherapy groups have revealed a substantial reduction in the incidence of cutaneous malignancies as well. Once the OTR has developed a cutaneous malignancy, it is imperative that the dosage of immunosuppression be evaluated. Many studies discuss the need to lower immunosuppression after development of a neoplasm but this must be weighed carefully with the chances of allograft rejection. Lowering immunosuppression can lower the chances of metastasis. Of note, once malignancy metastases appear, there is no benefit in the reSKINmed. 2014;12:164–173

duction of immunosuppression;47–49 therefore, the ultimate goal should be to achieve a balance of reducing the incidence of cutaneous malignancies while ensuring allograft survival. Newer immunosuppressive medications have been reported to have a lower carcinogenic potential such as mammalian target of rapamycin (mTOR) inhibitors. Sirolimus and everolimus are nonnephrotoxic immunosuppressants. They induce apoptosis by p-53–dependent and –independent pathways, and by inducing inhibition of IL-10.50 Sirolimus binds to the FK-binding protein 12, inhibiting the mTOR pathway and subsequently preventing IL-2 activation of B and T cells. A recent multicenter, prospective, randomized trial reported that renal transplant patients taking sirolimus developed significantly lower risk of cutaneous carcinoma compared with standard immunosuppressive protocols.51 The most common reported adverse effect of Sirolimus is dyslipidemia and myelosuppression. Caution should be taken at the time of administration due to mTOR potent antiangiogenic properties. Changing immunosuppressive drugs to sirolimus may be instituted after 6 months post-transplantation with stable graft function and appropriate wound healing.17 Thus, the earlier the conversion from calcineurin inhibitor to newer mTOR inhibitors, the greater the efficacy of antitumoral effect. Sun Exposure: Major Risk Factor Solar radiation is the most common factor in the development of cutaneous malignancies in immunocompetent and immunosuppressed populations. UV-B (280–320 nm) and UV-A (320–400 nm) contributes to photocarcinogenesis. DNA from basal keratinocytes directly receives energy from UV-B–forming photoproducts. Cyclobutane pyrimidine dimers (CPDs) and pyrimidine-6,4-pyrimidone photoproducts commonly induce DNA damage with its leading signature mutation in p53 gene.52 Similarly, UV-A can produce CPDs in addition to oxidative DNA damage, also contributing to carcinogenesis.53 In transplant recipients, the risk of skin cancer has been correlated with cumulative sun exposure radiation.19 UV radiation and long-term exposure in combination with immunosuppression leads to skin neoplasms, which, in normal circumstances, would have been eliminated. Interestingly, OTRs at low altitudes have less intense UV exposure with no substantial increased risk of skin cancer.21,54 There is convincing evidence that UV radiation is a major preventable cause in the development of skin cancer.33 Other Risk Factors and Cofactors Several risk factors have been reported to promote the development of cutaneous tumors in OTRs. Fair-skinned complexion or

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susceptibility to burn (Fitzpatrick skin phototype I to III), freckled complexion, blue eyes, and red or blonde hair are important risk factors that contribute to the development of cutaneous carcinomas. Moreover, factors that appear to increase the risk of skin cancer are cumulative sun exposure, immunosuppression regimen, and history of skin cancer prior to transplantation.55 Further risk pertains to those with history of lymphoma/leukemia, prior transplantation, and history of biologic therapies.32 Neoplastic Cofactor Human papillomavirus (HPV) is also associated with an increased risk of cutaneous malignancies. It has been reported that OTRs have low- to medium-risk HPV types.56 The HPV oncoproteins E6 and E7 are potent oncogenes that may result in malignant conversion of virally infected cells. The evidence suggests an active role in the pathogenesis of actinic keratoses and SCC, after the identification of HPV 8, 9, and 15 in these cutaneous lesions.57 The incidence of HPV DNA in skin cancer, mainly in SCC, is greater in OTRs compared with the immunocompetent population. HPVâ&#x20AC;&#x2122;s precise mechanism of action inducing oncogenic transformation requires further investigation. Photosensitivity Cofactor Voriconazole is an antifungal medication used for the treatment of invasive aspergillosis. It induces photosensitivity, accelerating risk of cutaneous malignancies. Several studies have reported ag-

gressive SCC in OTRs treated with voriconazole. It has been postulated that voriconazole induces photosensitivity in immunosuppressed patients with increased risk of carcinogenesis.58 Further studies are needed to identify true susceptible individuals, including OTRs. Several risk factors have been identified for the development of cutaneous carcinoma, including older age, longer duration and intensity of immunosuppression, sun exposure, HPV infection, and photosensitivity.33 The development of cutaneous malignancies in OTRs is a result of the complex interaction between all of the aforementioned factors. Therefore, further research is necessary to appropriately identify its role in cutaneous carcinogenesis and OTRs. Recognition of Cutaneous Malignancy Nonmelanoma skin cancer, including BCC and SCC, accounts for the most common cutaneous malignancy in OTRs. BCC often appears as papulonodules with prominent telangiectasias, an erythematous plaque, or a papule with rolled border and central hemorrhagic crust, even as an indurated scar-like appearance (Figure 1A and 1B). SCC is the most frequent cutaneous malignancy, with a 4:1 ratio in immunosuppressed OTRs. It is characterized by scaly pink plaques or hyperkeratotic nodules. Increased aggressiveness of SCC in these patients is manifested by increased risk of metastasis compared with the general population (Figure 2A and 2B).16,59

B

A

Figure 1. (A) A renal transplant patient with invasive infiltrating basal cell carcinoma. (B) Post-Mohs micrographic surgery defect demonstrating significant subclinical extension of this tumor. Modified with permission from Singh et al.74 SKINmed. 2014;12:164â&#x20AC;&#x201C;173

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B

A

Figure 2. (A) A lung transplant patient with an aggressive form of squamous cell carcinoma. (B) Discontiguous intransit metastasis post-Mohs micrographic surgery.

Malignant melanoma is less common in OTRs but it may be fatal if not appropriately diagnosed. It usually appears as a brown/black macule with color variation and irregular borders. Infrequently, melanomas lacking pigment appear. They are termed amelanotic and may be mistaken as SCC, BCC, or wart. Moreover, changing, pigmented skin growth should be evaluated to exclude the possibility of melanoma. Precursors of SCC, actinic keratoses, are known as “precancer” and are most frequently encountered on sun-damaged skin. They usually appear as scaly papules with associated erythema on chronically sun-exposed areas (Figure 3). Actinic keratoses in immunosuppressed OTRs have a much greater predisposition for malignant transformation, as well as SCC and melanoma, and have superior potential for metastasis in this population; therefore, appropriate biopsy for any possible cutaneous neoplasm should be performed.

Figure 3. An organ transplant recipient with extensive actinic damage of the legs. SKINmed. 2014;12:164–173

Most importantly, OTRs may experience fast growth of either cutaneous neoplasm. A key signal that might identify the presence of cutaneous malignancy is a new, changing or enlarging cutaneous growth. In addition, if the skin lesion has increased in size or shape, bleeds, itches, or causes discomfort should prompt medical evaluation. Transplant recipients with cutaneous malignancy should undergo thorough aggressive treatment to prevent future dispersal of cutaneus disease.

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High-Risk Transplant Recipients Individuals with medical history of actinic keratosis or skin cancer before transplantation should be considered at high risk for developing cutaneous malignancies. Careful monitoring is essential for these patients, with the following physical characteristics: fair-skinned, freckled complexion, blue eyes, and red or blonde hair. Moreover, there is a greater risk of developing skin cancer if the patient has extensive evidence of sun exposure. Photodamage is represented by the presence of atrophy, pigment variation, telangiectasias, and roughness of the skin. Nonetheless, every patient regardless of their skin color may develop cutaneous malignancy in the setting of immunosuppression.33 Thus, early identification with frequent skin examination allows prompt intervention for successful eradication. Recommendations

Education Emphasis remains on prevention and awareness in this population. Education on sun-protective measures is fundamental. This includes the use of protective clothing, broad-spectrum sunscreen and lip balm with sun protection factor (SPF) 15 or higher, minimizing outdoor activities between the hours of 10 AM and 4 PM, and avoiding any sunburning with natural light or suntanning with artificial light.2,33,60,61 Education, monthly self-skin examination, and for those with history of skin cancer, lymph node self-skin node examination, should be undertaken. The best mechanism for delivering education has not been found. Written educational materials with representative photographs are essential for education. Certainly, counseling of parents about the benefits of sunscreen application can effectively prevent future skin cancer in the pediatric transplanted population. At the Mayo Clinic, a specialty dermatology clinic within the transplant center provides preventive education and early intervention for the specific needs of OTRs. Low-risk patients should receive an annual skin examination by transplant and primary care physicians. High-risk patients should be sent for dermatologic evaluation on a regular basis.62

Acitretin is a known teratogenic retinoid. It should not be used in pregnant women or those of childbearing potential. Isotretinoin is an alternative in women because it has a shorter half-life compared with acitretin. To minimize side effects, acitretin can be started at a low dose of 10 mg per day with increments every month up to 20 to 30 mg per day. An expected side effect is hyperlipidemia. It should be aggressively managed, specifically when used in heart transplant recipients.63 Laboratory tests should be performed at baseline including fasting lipid panel, liver function tests, serum creatinine, and complete blood cell count. Tests may be rechecked with every dose elevation if stable every 3 months. Effective management of adverse effects is usually dose-dependent. Typically, it is better tolerated by reduction of 25% of the original dose.46,64 Systemic retinoid therapy reduces morbidity and mortality in patients with high-risk tumors, albeit it does not completely replace surgery. In addition, field therapy with the use of topical retinoids, 5-fluorouracil, imiquimod, diclofenac, resurfacing peels, liquid nitrogen, carbon dioxide laser, and photodynamic therapy are alternative modalities in high-risk patients, including transplant recipients.33,50,63,65â&#x20AC;&#x201C;68

Adjustment of Immunosuppressive Medication Improved prognosis in patients with high-risk cutaneous malignancy may be achieved with the revision of immunosuppressants. Substantial reduction or discontinuation of the immunosuppressive regimen is an effective strategy for the reduction of cutaneous neoplasms as well as internal malignancies.17,39 Individual adjustment of immunosuppression can be achieved by reducing the dosage levels, decreasing the amount of drugs in multidrug regimens, or conversion to calcineurin inhibitor protocols based on mTOR inhibitors such as sirolimus or everolimus. The clinical implication of reduction of immunosuppressive regimens entails acute and chronic graft rejection, including death.69 Therefore, all modification should be addressed in a multidisciplinary approach by the transplant team to deliver comprehensive care and to maintain a good graft function in the lowest level of immunosuppression.15,17 Management Strategies

Chemopreventive Therapy Systemic retinoids are used as chemoprevention of cutaneous malignancy. Patients with multiple SCCs (>5) per year should be considered for systemic retinoids.16,17 Studies have revealed a significant decrease in new SCCs over 6 months of therapy.16 SKINmed. 2014;12:164â&#x20AC;&#x201C;173

Chemoprevention once instituted should be a lifelong therapy because a rebound effect may occur.

Follow-Up Schedule Dermatologist evaluation and care are essential to provide aggressive treatment to prevent potentially fatal metastasis. Appropriate clinical follow-up for OTRs can be tailored according to

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Table II. Periodical Cutaneous Evaluations in Organ Transplant Recipients Medical History

Dermatology Examination Interval, mo

No actinic keratosis or skin cancer

12a

EGFR Inhibitors

Actinic keratoses

6

One nonmelanoma skin cancer

6

Multiple nonmelanoma skin cancers (>1)

2â&#x20AC;&#x201C;4

High-risk squamous cell carcinoma or melanoma

3

Metastatic squamous cell carcinoma or melanoma

2

Epidermal growth factor receptor (EGFR) inhibitors show an overexpression in SCC. Monoclonal antibody against EGFR, cetuximab, is used for the treatment of metastatic SCC of the head and neck. A recent study of advanced or metastatic cutaneous SCC has reported a disease clearance rate of 81% (95% confidence interval, 63%â&#x20AC;&#x201C;93%) with a mean overall survival and progressionfree survival in the intention-to-treat population. This intravenous infusion therapy has several side effects, including acneiform eruption and infections; however, acneiform eruption was significantly associated with extended progression-free survival.70,71 Mortality caused by alveolar hemorrhage in 2 lung transplant patients has been reported. Extreme caution is advised in this population.70

Therapies on the Horizon

Modified with permission from Otley et al.62 a Patients should have an initial dermatologic evaluation prior to organ transplant. High-risk patients should be examined by a dermatologist at least on a yearly base.

individual risk factors (Table II).62 High-risk metastatic SCC or melanoma should be closely followed, because most recurrences occur within 3 years. Full skin and lymph node examination and appropriate review of systems are essential clinical aspects of follow-up visits. If multiple cutaneous malignancies appear, regular follow-up is critical.

Treatment In general, managing immunocompromised individuals should parallel the treatment of the immunocompetent population. Surgical excision is typically curative for melanoma and nonmelanoma skin cancer. Mohs micrographic surgery entails complete removal of cutaneous malignancy with effective control of margins. It is considered the most advantageous therapeutic modality for the management of cutaneous malignancies in the setting of immunosuppressed OTRs. Nonaggressive and low-aggressive cutaneous malignancies can be managed with topical therapy, electrodesiccation and curettage, cryotherapy, or photodynamic therapy. Radiation is used for nonsurgical candidates, but may be used as adjunctive therapy after incomplete resection in the presence of lymph node or perineural involvement. For patients with metastasis adjuvant radiation, chemotherapy and staging by sentinel lymph node are useful alternatives for treatment. Systemic retinoids may prevent, decrease, or halt progression of skin cancer burden in the immunosuppressed OTR. Adjustment of immunosuppressed regimen is an adjuvant strategy for OTRs with catastrophic cutaneous malignancies. Management of complicated and advanced cutaneous malignancies in the imSKINmed. 2014;12:164â&#x20AC;&#x201C;173

Capacitadine Capacitadine is a prodrug of 5-fluorouracil, first approved for the treatment of metastatic breast cancer and metastatic colorectal cancer. With its use, a decrease in new tumor development has been reported.72,73 It is essential to screen for dihydropyrimidine dehydrogenase before initiating treatment. Deficiency may lead to severe toxicity. Recent studies have described the use of oral capecitabine as an effective chemopreventive treatment of nonmelanoma skin cancer in OTRs. The incidence rate of nonmelanoma skin cancer was reported to decrease by 0.33 for SCC, 0.04 for BCC, and 2.45 for actinic keratosis; however, significant toxicities were reported, including fatigue, hand-andfoot syndrome, diarrhea, and neutropenic fever.73 Innovative therapies are being explored. Further studies in larger OTR populations are needed to evaluate reliable clinical response. Conclusions Organ transplantation has offered the wonderful opportunity of life to more than 500,000 patients in the United States. Cutaneous malignancies are the most common neoplasm after transplantation with the potential for substantial morbidity and mortality. Emphasis on education, frequent vigilance, early detection, and aggressive intervention are crucial components to decrease cutaneous complications. Therapeutic management and multidisciplinary collaboration of cutaneous malignancies in OTRs is essential to achieve successful medical care. As a consequence of immunosuppression, OTRs should be educated and more carefully followed after transplantation.

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References 1 Transplant Patient DataSource. www.patients.unos.org/ data.htm. Accessed January 25, 2013. 2 Kempf W, Mertz KD, Kanitakis J, Hofbauer GF. Critical skin cancer in organ transplant recipients-a dermatopathological view. Curr Probl Dermatol. 2012;43:18–35. 3 Belloni-Fortina A, Piaserico S, Bordignon M, et al. Skin cancer and other cutaneous disorders in liver transplant recipients. Acta Derm Venereol. 2012;92:411–415. 4 Robbins HY, Arcasoy SM. Malignancies following lung transplantation. Clin Chest Med. 2011;32:343–355. 5 Marks R. Skin cancer after transplantation: where did we come from, where do we go? Cancer Treat Res. 2009;146:5–7.

18 Hardie IR, Strong RW, Hartley LC, Woodruff PW, Clunie GJ: Skin cancer in Caucasian renal allograft recipients living in a subtropical climate. Surgery. 1980;87:177– 183. 19 Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med. 2003;348:1681– 1691. 20 Jensen P, Hansen S, Moller B, et al. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol. 1999;40(2 pt 1):177–186. 21 Lindelof B, Sigurgeirsson B, Gabel H, Stern RS. Incidence of skin cancer in 5356 patients following organ transplantation. Br J Dermatol. 2000;143:513– 519.

6 Carpenter CB. Improving the success of organ transplantation. N Engl J Med. 2000;342:647–648.

22 Ferrandiz C, Fuente MJ, Ribera M, et al. Epidermal dysplasia and neoplasia in kidney transplant recipients. J Am Acad Dermatol. 1995;33:590–596.

7 Takemoto SK, Terasaki PI, Gjertson DW, Cecka JM. Twelve years’ experience with national sharing of HLAmatched cadaveric kidneys for transplantation. N Engl J Med. 2000;343:1078–1084.

23 Feuerstein I, Geller AC. Skin cancer education in transplant recipients. Prog Transplant. 2008;18:232– 241; quiz 242.

8 Printz C. Study finds heart transplant patients may be at risk for serious skin cancers. Cancer. 2012;118:3. 9 Sachse MM, Ehrich JH, Pape L, et al. SPF 50 for organ transplant patients--over the top? Nephrol Dial Transplant. 2009;24:2601. 10 Euvrard S, Claudy A. Post-transplant skin cancer: the influence of organ and pre-transplant disease. Cancer Treat Res. 2009;146:65–74. 11 Ulrich C, Degen A, Patel MJ, Stockfleth E. Sunscreens in organ transplant patients. Nephrol Dial Transplant. 2008;23:1805–1808. 12 Kovach BT, Stasko T. Skin cancer after transplantation. Transplant Rev (Orlando). 2009;23:178–189. 13 Bordea C, Wojnarowska F, Millard PR, et al. Skin cancers in renal-transplant recipients occur more frequently than previously recognized in a temperate climate. Transplantation. 2004;77:574–579. 14 Sheil AG, Disney AP, Mathew TH, Amiss N. De novo malignancy emerges as a major cause of morbidity and late failure in renal transplantation. Transplant Proc. 1993;25(1 pt 2):1383–1384. 15 Zwald FO, Brown M. Skin cancer in solid organ transplant recipients: advances in therapy and management: part I. Epidemiology of skin cancer in solid organ transplant recipients. J Am Acad Dermatol. 2011;65:253–261; quiz 262. 16 Bavinck JN, Tieben LM, Van der Woude FJ, et al. Prevention of skin cancer and reduction of keratotic skin lesions during acitretin therapy in renal transplant recipients: a double-blind, placebo-controlled study. J Clin Oncol. 1995;13:1933–1938. 17 Zwald FO, Brown M. Skin cancer in solid organ transplant recipients: advances in therapy and management: part II. Management of skin cancer in solid organ transplant recipients. J Am Acad Dermatol. 2011;65:263–279; quiz 280.

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24 Kubica AW, Brewer JD. Melanoma in immunosuppressed patients. Mayo Clin Proc. 2012;87:991–1003. 25 Hollenbeak CS, Todd MM, Billingsley EM, et al. Increased incidence of melanoma in renal transplantation recipients. Cancer. 2005;104:1962–1967. 26 Kovach BT, Stasko T. Use of topical immunomodulators in organ transplant recipients. Dermatol Ther. 2005;18:19– 27. 27 Prinz Vavricka BM, Hofbauer GF, Dummer R, French LE, Kempf W. Topical treatment of cutaneous Kaposi sarcoma with imiquimod 5% in renal-transplant recipients: a clinicopathological observation. Clin Exp Dermatol. 2012;37:620–625. 28 Zavos G, Karidis NP, Tsourouflis G, et al. Nonmelanoma skin cancer after renal transplantation: a single-center experience in 1736 transplantations. Int J Dermatol. 2011;50:1496–1500. 29 Mahalingam M. Renal transplant, immunosuppression and skin cancer: “the good, the bad and the ugly”. Eur J Dermatol. 2011;21:156. 30 Lopez-Pintor RM, Hernandez G, de Arriba L, de Andres A. Lip cancer in renal transplant patients. Oral Oncol. 2011;47:68–71. 31 Serdar ZA, Eren PA, Canbakan M, et al. Dermatologic findings in renal transplant recipients: Possible effects of immunosuppression regimen and p53 mutations. Transplant Proc. 2010;42:2538–2541. 32 Otley CC, Cherikh WS, Salasche SJ, et al. Skin cancer in organ transplant recipients: effect of pretransplant end-organ disease. J Am Acad Dermatol. 2005;53:783– 790. 33 Otley CC, Pittelkow MR. Skin cancer in liver transplant recipients. Liver Transpl. 2000;6:253–262. 34 Penn I, First MR. Merkel’s cell carcinoma in organ recipients: report of 41 cases. Transplantation. 1999;68:1717–1721.

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35 Douds AC, Mellotte GJ, Morgan SH. Fatal Merkelcell tumour (cutaneous neuroendocrine carcinoma) complicating renal transplantation. Nephrol Dial Transplant. 1995;10:2346–2348. 36 Czarnecki D, Watkins F, Leahy S, et al. Skin cancers and HLA frequencies in renal transplant recipients. Dermatology. 1992;185:9–11. 37 Hojo M, Morimoto T, Maluccio M, et al. Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature. 1999;397:530–534. 38 Servilla KS, Burnham DK, Daynes RA: Ability of cyclosporine to promote the growth of transplanted ultraviolet radiation-induced tumors in mice. Transplantation. 1987;44:291–295. 39 Dantal J, Hourmant M, Cantarovich D, et al. Effect of long-term immunosuppression in kidney-graft recipients on cancer incidence: randomised comparison of two cyclosporin regimens. Lancet. 1998;351:623–628. 40 Kessler M, Jay N, Molle R, Guillemin F. Excess risk of cancer in renal transplant patients. Transpl Int. 2006;19:908–914. 41 O’Donovan P, Perrett CM, Zhang X, et al. Azathioprine and UVA light generate mutagenic oxidative DNA damage. Science. 2005;309:1871–1874. 42 George R, Weightman W, Russ GR, et al. Acitretin for chemoprevention of non-melanoma skin cancers in renal transplant recipients. Australas J Dermatol. 2002;43:269–273. 43 Ingvar A, Smedby KE, Lindelof B, et al. Immunosuppressive treatment after solid organ transplantation and risk of post-transplant cutaneous squamous cell carcinoma. Nephrol Dial Transplant. 2010;25:2764–2771. 44 O’Neill JO, Edwards LB, Taylor DO. Mycophenolate mofetil and risk of developing malignancy after orthotopic heart transplantation: analysis of the transplant registry of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2006;25:1186–1191.

51 Euvrard S, Morelon E, Rostaing L, et al. Sirolimus and secondary skin-cancer prevention in kidney transplantation. N Engl J Med. 2012;367:329–339. 52 de Graaf YG, Rebel H, Elghalbzouri A, et al. More epidermal p53 patches adjacent to skin carcinomas in renal transplant recipients than in immunocompetent patients: the role of azathioprine. Exp Dermatol. 2008;17:349–355. 53 van der Horst GT, Meira L, Gorgels TG, et al. UVB radiation-induced cancer predisposition in Cockayne syndrome group A (Csa) mutant mice. DNA Repair (Amst). 2002;1:143–157. 54 Birkeland SA, Lokkegaard H, Storm HH. Cancer risk in patients on dialysis and after renal transplantation. Lancet. 2000;355:1886–1887. 55 Mehrany K, Weenig Otley CC. Increased cutaneous squamous chronic lymphocytic 2005;53:1067–1071.

RH, Lee KK, Pittelkow MR, metastasis and mortality from cell carcinoma in patients with leukemia. J Am Acad Dermatol.

56 Stockfleth E, Nindl I, Sterry W, et al. Human papillomaviruses in transplant-associated skin cancers. Dermatol Surg. 2004;30(4 pt 2):604–609. 57 McLaughlin-Drubin ME, Munger K. The human papillomavirus E7 oncoprotein. Virology. 2009;384:335– 344. 58 Martinez JC, Otley CC, Okuno SH, Foote RL, Kasperbauer JL. Chemotherapy in the management of advanced cutaneous squamous cell carcinoma in organ transplant recipients: theoretical and practical considerations. Dermatol Surg. 2004;30(4 pt 2):679–686. 59 Bouwes Bavinck JN, Vermeer BJ, van der Woude FJ, et al. Relation between skin cancer and HLA antigens in renal-transplant recipients. N Engl J Med. 1991;325:843–848. 60 Surber C, Pittelkow M, Lautenschlager S. Photoprotection in transplant recipients. Curr Probl Dermatol. 2012;43:171–196.

45 Martinez JC, Otley CC, Stasko T, et al. Defining the clinical course of metastatic skin cancer in organ transplant recipients: a multicenter collaborative study. Arch Dermatol. 2003;139:301–306.

61 Kuschal C, Thoms KM, Schubert S, et al. Skin cancer in organ transplant recipients: effects of immunosuppressive medications on DNA repair. Exp Dermatol. 2012;21:2–6.

46 Kovach BT, Sams HH, Stasko T. Systemic strategies for chemoprevention of skin cancers in transplant recipients. Clin Transplant. 2005;19:726–734.

62 Otley CC. Organization of a specialty clinic to optimize the care of organ transplant recipients at risk for skin cancer. Dermatol Surg. 2000;26:709–712.

47 Williams NC, Tong A, Howard K, et al. Knowledge, beliefs and attitudes of kidney transplant recipients regarding their risk of cancer. Nephrology (Carlton). 2012;17:300–306.

63 Rook AH, Jaworsky C, Nguyen T, et al. Beneficial effect of low-dose systemic retinoid in combination with topical tretinoin for the treatment and prophylaxis of premalignant and malignant skin lesions in renal transplant recipients. Transplantation. 1995;59:714– 719.

48 Wells JL, 3rd, Shirai K. Systemic therapy for squamous cell carcinoma of the skin in organ transplant recipients. Am J Clin Oncol. 2012;35:498–503. 49 Stucker F, Marti HP, Hunger RE: Immunosuppressive drugs in organ transplant recipients--rationale for critical selection. Curr Probl Dermatol 2012, 43:36-48. 50 Bangash HK, Colegio OR. Management of nonmelanoma skin cancer in immunocompromised solid organ transplant recipients. Curr Treat Options Oncol. 2012;13:354–376.

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64 Otley CC, Stasko T, Tope WD, Lebwohl M. Chemoprevention of nonmelanoma skin cancer with systemic retinoids: practical dosing and management of adverse effects. Dermatol Surg. 2006;32:562–568. 65 Euvrard S, Verschoore M, Touraine JL, et al. Topical retinoids for warts and keratoses in transplant recipients. Lancet. 1992;340:48–49.

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66 Thorne EG. Long-term clinical experience with a topical retinoid. Br J Dermatol. 1992;127 suppl 41:31–36.

70 Leard LE, Cho BK, Jones KD, et al. Fatal diffuse alveolar damage in two lung transplant patients treated with cetuximab. J Heart Lung Transplant. 2007;26:1340–1344.

67 Athar M, Walsh SB, Kopelovich L, Elmets CA. Pathogenesis of nonmelanoma skin cancers in organ transplant recipients. Arch Biochem Biophys. 2011;508:159–163.

71 Maubec E, Petrow P, Scheer-Senyarich I, et al. Phase II study of cetuximab as first-line single-drug therapy in patients with unresectable squamous cell carcinoma of the skin. J Clin Oncol. 2011;29:3419–3426.

68 Sommerer C, Hartschuh W, Enk A, et al. Pharmacodynamic immune monitoring of NFAT-regulated genes predicts skin cancer in elderly long-term renal transplant recipients. Clin Transplant. 2008;22:549– 554.

72 Endrizzi BT, Lee PK. Management of carcinoma of the skin in solid organ transplant recipients with oral capecitabine. Dermatol Surg. 2009;35:1567–1572. 73 Jirakulaporn T, Endrizzi B, Lindgren B, et al. Capecitabine for skin cancer prevention in solid organ transplant recipients. Clin Transplant. 2011;25:541–548.

69 Sandborn WJ, Hay JE, Porayko MK, et al. Cyclosporine withdrawal for nephrotoxicity in liver transplant recipients does not result in sustained improvement in kidney function and causes cellular and ductopenic rejection. Hepatology. 1994;19:925–932.

74 Singh MK, Brewer, JD. Current approaches to skin cancer management in organ transplant recipients. Semin Cutan Med Surg. 2011;30:35–47.

SELF ASSESSMENT EXAMINATION W. Clark Lambert, MD, PhD Instructions: For each numbered question, choose the single most appropriate lettered response. 1. The most common type of cancer that arises in the post-transplantation population has been recognized as cancer of the: a. Colon. b. Genito-urinary system. c. Lung. d. Naso-pharynx. e. Skin. 2. The most common type of skin cancer in the general population is: a. Angiosarcoma. b. Basal cell carcinoma. c. Baso-squamous carcinoma. d. Malignant melanoma. e. Squamous cell carcinoma.

5. In the absence of a sensitizing agent such as psoralen, ultraviolet radiation (UVA and/or UVB) induces, in the DNA of basal keratinocytes, each of the following except: a. Cyclobutane pyrimidine dimers. b. DNA interstrand cross-links. c. Mutations in the p53 gene. d. Oxidative DNA damage. e. Pyrinidine-6,4-pyrimidone photoproducts. ANSWERS TO CME EXAMINATION: 1. e.

2. b.

3. e.

4. b.

3. The most common type of skin cancer in the posttransplantation population overall is: a. Angiosarcoma. b. Basal cell carcinoma. c. Baso-squamous carcinoma. d. Malignant melanoma. e. Squamous cell carcinoma.

4. Which of the following types of skin cancer has been found to be more common in liver transplantation recipients, and in other transplant recipients, in the first years post-transplantation, compared to its incidence in the overall post-transplantation population? a. Angiosarcoma. b. Basal cell carcinoma. c. Baso-squamous carcinoma. d. Malignant melanoma. e. Squamous cell carcinoma.

5. b.

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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Finacea® (azelaic acid) Gel, 15% is a topical prescription medication used to treat inflammatory papules and pustules of mild to moderate rosacea.

Rosacea is with her wherever she goes . So is Finacea . ®

It’s true. Rosacea is complex and it’s with them for life. Finacea® treats the papules and pustules with associated erythema of mild to moderate rosacea. Although some reduction of erythema which was present in patients with papules and pustules of rosacea occurred in clinical studies, efficacy for treatment of erythema in rosacea in the absence of papules and pustules has not been evaluated. You have made Finacea® the #1 Dermatologist-prescribed topical rosacea brand.1

INDICATION & USAGE Finacea® (azelaic acid) Gel, 15% is indicated for topical treatment of inflammatory papules and pustules of mild to moderate rosacea. Although some reduction of erythema which was present in patients with papules and pustules of rosacea occurred in clinical studies, efficacy for treatment of erythema in rosacea in the absence of papules and pustules has not been evaluated. IMPORTANT SAFETY INFORMATION Skin irritation (e.g. pruritus, burning or stinging) may occur during use with Finacea®, usually during the first few weeks of treatment. If sensitivity or severe irritation develops and persists during use with Finacea®, discontinue use and institute appropriate therapy. There have been isolated reports of hypopigmentation after use of azelaic acid. Since azelaic acid has not been well studied in patients with dark complexion, monitor these patients for early signs of hypopigmentation. Avoid contact with the eyes, mouth, and other mucous membranes. In case of eye exposure, wash eyes with large amounts of water. Wash hands immediately following application of Finacea®. Avoid use of alcoholic cleansers, tinctures and astringents, abrasives and peeling agents. Avoid the use of occlusive dressings or wrappings. In clinical trials with Finacea®, the most common treatment-related adverse events (AE’s) were: burning/stinging/tingling (29%), pruritus (11%), scaling/dry skin/xerosis (8%) and erythema/irritation (4%). Contact dermatitis, edema and acne were observed at frequencies of 1% or less. Finacea® is for topical use only. It is not for ophthalmic, oral or intravaginal use. Patients should be reassessed if no improvement is observed upon completing 12 weeks of therapy. Please see Brief Summary of full Prescribing Information on adjacent page. 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.

1. According to IMS NPATM (National Prescription Audit) July 2010-October 2013 © 2014 Bayer HealthCare Pharmaceuticals. Bayer, the Bayer Cross, Finacea and the Finacea logo are registered trademarks of Bayer. All rights reserved. FIN-10-0001-14 | February 2014


May/June 2014

Volume 12 • Issue 3

Core curriculum Virendra N. Sehgal, MD, Section Editor

Basal Cell Carcinoma: Pathophysiology Virendra N. Sehgal, MD;1 Kingshuk Chatterjee, DNB;1 Deepika Pandhi, MD;2 Ananta Khurana, MD2

Basal cell carcinoma (BCC) is the most common skin cancer in humans, which typically appears over the sun-exposed skin as a slowgrowing, locally invasive lesion that rarely metastasizes. Although the exact etiology of BCC is unknown, there exists a well-established relationship between BCC and the pilo-sebaceous unit, and it is currently thought to originate from pluri-potential cells in the basal layer of the epidermis or the follicle. The patched/hedgehog intracellular signaling pathway plays a central role in both sporadic BCCs and nevoid BCC syndrome (Gorlin syndrome). This pathway is vital for the regulation of cell growth, and differentiation and loss of inhibition of this pathway is associated with development of BCC. The sonic hedgehog protein is the most relevant to BCC; nevertheless, the Patched (PTCH) protein is the ligand-binding component of the hedgehog receptor complex in the cell membrane. The other protein member of the receptor complex, smoothened (SMO), is responsible for transducing hedgehog signaling to downstream genes, leading to abnormal cell proliferation. The importance of this pathway is highlighted by the successful use in advanced forms of BCC of vismodegib, a Food and Drug Administration-approved drug, that selectively inhibits SMO. The UV-specific nucleotide changes in the tumor suppressor genes, TP53 and PTCH, have also been implicated in the development of BCC. (SKINmed. 2014;12:176–181)

C

utaneous malignancies may arise either from keratinocytes or adnexal structures. Hair follicles and eccrine, apocrine, and sebaceous glands are its usual sites. They may arise from multiple origins. Skin cancers have been broadly divided into melanoma and nonmelanoma skin cancer (NMSC). NMSC consists of squamous cell carcinoma and basal cell carcinoma (BCC). Among them, BCC accounts for 75% to 90% of skin cancers and has been regarded as the most common human malignancy.1,2 “Ulcus rodens/Jakob”3 was coined for the first time for the entity known as BCC today. “Carcinoma epitheliale adenoides”4 was described in 1900 to define BCC as a malignant, locally invasive, and destructive cancer. Three years after, the term “Basalzellenkrebs”5 was developed, proposing a classification of skin tumors, using histo-genetic principles, emphasizing that the tumor originated in the basal layer of the epidermis or hair follicle; thereafter, many workers6 have proposed different names for the tumor, and the controversy prevails regarding the cellular origin of BCC due to its locally aggressive but overall benign course and rare tendency to metastasize. This has also triggered a debate of whether BCC is truly a malignant tumor or just a “semi-malignant tumor;” nevertheless, the World Health Or-

ganization’s7 classification has retained the term BCC. Significant scientific research has been performed since 1974 to focus on the ultrastructural, biochemical, genetic, molecular, and immunologic undertones to define their role. Accordingly, several mysteries surrounding BCC have been resolved, while a few remain. BCC affects men more commonly than women. Risk Factors The most significant risk factor for BCC to develop appears to be exposure to UV radiation.8 Early exposure during childhood and adolescence is associated with a significant increase in risk of the disease. In general, all NMSCs are more common in persons with fair skin, blond/red hair, and light eye color and those who have Fitzpatrick9 skin types I and II. Apart from that, cumulative occupational exposure for an individual during their lifetime is another important variable that has been recognized in BCC; however, sufficient data with substantial conclusions are lacking in order to incriminate occupational UV exposure in the development of the disease. This subject must continue to be further researched.10

From the Dermato-Venereology (Skin/VD) Center, Sehgal Nursing Home, Panchwati, and the Department of Dermatology Bankura Sammilani Medical College West Bengal;1 and the Department of Dermatology and STD, University College of Medical Sciences, and Associated Guru Teg Bahadur Hospital, Shahdara,2 Delhi, India Address for Correspondence: Virendra N. Sehgal, MD, DermatoVenerology (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

According to the available epidemiologic data, predilection for BCC has been noted in childhood, in the age group of 0 to 19 years, in individuals with a history of intense exposure to UV radiation. Lesions most commonly occur on a background of chronic photo-damaged skin. They are typically located over the head and neck region.8 The presence of large numbers of nevi, freckles, and solar elastosis are the other predisposing risk factor(s); however, a history of acne is protective11,12 (Table I).

Table I. Basal Cell Carcinoma: Risk Factors UV radiation Ionizing radiation13 Immunosuppression drugs,14 renal transplantation15 Arsenic16 Psoralen and UV-A radiation17 Genodermatoses

Predisposing Genodermatoses The presence of single/multiple BCC in the absence of any predisposing factor(s), manifesting early in life, should arouse doubt in the clinician about the possibility of heritable disorders. These disorders18 are classified into 3 well-known groups, with oculo-cutaneous albinism19 as another addition (Table II). Pathophysiology Genodermatoses studies have led to major breakthroughs in the understanding of molecular changes that are now being mooted towards the formation of BCC. During the past 80 years, different hypotheses have been proposed to explain the nature and origin of cells of BCC. Histopathologic variability of this tumor has not been in consonance with derivation from any individual epithelial structure. This tumor is generally considered to originate from pluri-potent cells of epidermis, which may explain the propensity of the tumor to differentiate to any of the epithelial structures, under the control of signaling pathways20 and genetic constitution.21

The relevance of recent numerous studies, focusing on the newer insights into the pathogenesis of BCC should be taken into perspective. Embryologically, both the bulge and hair matrix regions of the fetal hair follicle are a rich source for stem cells, the rapidly proliferating cells, more so with their abilities to facilitate molecular signaling between the mesenchymal dermal papillae and the developing hair follicle. This physiologic conversion22 has been found critical in the histo-genesis of BCC. BCC has positively been associated with human leukocyte antigen-DR1 (HLA-DR1) and human leukocyte antigen-DR7 (HLA-DR7), in the immunocompetent population, but substantial evidence is lacking.23 Numerous studies24,25 on the Goltz-Gorlin syndrome or the nevoid BCC syndrome (NBCCS) have emphasized on the role of the hedgehog (Hh) signaling pathway, resulting from a germline mutation of the Patched (PTCH) gene on the chromosome 9q26–3q27, coding a receptor for the Hh pathway.

Table II. Basal Cell Carcinoma: Predisposing Genodermatoses Genetic Syndromes With BCC as a Prominent Feature Gorlin syndrome Bazex–Dupré–Christol syndrome Rombo syndrome Generalized follicular basaloid hamartoma syndrome Happle-Tinschert syndrome

Genetic Syndromes With BCC as an Ancillary Feature Bloom syndrome

Syndromes With Dubious Association With BCC Sturge–Weber syndrome

Werner syndrome

Klippel–Trenaunay syndrome

Rothmund–Thomson syndrome

Wyburn–Mason syndrome

Cowden syndrome Schöpf–Schulz–Passarge syndrome Epidermodysplasia verruciformis Oculo-cutaneous albinism Fitzpatrick9 skin type I and II, IV, V, and VI Hermansky-Pudlak syndrome

Abbreviation: BCC, basal cell carcinoma. SKINmed. 2014;12:176–181

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Recently, PTCH mutations have been identified in sporadic BCCs as well.28 The Hh family consists of a large number of intercellular signaling proteins that play an essential role in patterning invertebrate as well as vertebrate embryos.29 This family of proteins owes its name to the appearance of the mutant fruit fly, with abnormal proteins, simulating a curled-up hedgehog. They were identified, at first, to regulate the segment polarity and tissue organization in Drosophila melanogaster (fruit fly).30 It is now well-established that the Hh pathway has a significant role in human development and cutaneous carcinogenesis. Contrary to fruit flies, vertebrates have evolved 3 different types of homologs for the Hh gene, including the sonic, desert and Indian types. The differences in these 3 types of genes lie in their patterns of expression in different animals. The Hh protein of the vertebrate sonic-type gene (SHH) has two terminals. The Cterminal peptide diffuses from the cell, whereas the N-terminal is associated with the cell surface. PTCH is a membrane receptor that acts as a human tumor suppressor protein. Binding of SHH to PTCH is paramount in activating signals that regulate growth and patterning embryos.31 Another important component of the SHH pathway is a transmembrane protein called smoothened (SMO). It is inhibited by PTCH, in the absence of Hh, blocking the expression of the target genes. This inhibitory effect of PTCH is nullified by the binding of Hh to PTCH. Two types of PTCH genes have been implicated in carcinogenesis. PTCH-1 is crucial for embryonic development, and its germline inactivation has been linked to the development of BCC. For BCC, rather than acting on an individual basis, the PTCH-2 modulates carcinogenesis in association with PTCH-1 haploinsufficiency.32,33 The hedgehog interacting protein (HIP) has recently been identified as a novel component of the vertebrate signaling pathway. It seems to encode a membrane glycoprotein that binds to the SHH protein with an affinity comparable to that of PTCH-1. There are other components of this complex signaling pathway. A simplified model has been described34 (Figure 1), according to which PTCH-1 mutation may lead to aberrant activation of the SHH pathway, with increased target gene activation; however, the precise mechanisms leading to abnormal cell proliferation and differentiation have not yet been elucidated.35 Nevertheless, it is worthwhile to take stock of the plausible sequence of events that activate the pathway to comprehend its intricacies. Two components, namely off-state (first) and activated (second), seem to play a significant role. The former (first) PTCH-1 represses SMO activity. Gli2 and Gli3, the effectors of the Hh pathway, are phosphorylated by a kinase cascade, which includes PKA, CK1, and GSK3β. They are directed to the proteasomal SKINmed. 2014;12:176–181

Figure. The hedgehog (Hh) signaling pathway.

degradation pathway via the SPOP complex. A fraction of the Gli2/3 protein is processed into a repressor form, Gli-R, which inhibits Hh target gene transcription. Whereas the activated (second) Hh ligand binding to PTCH-1 abrogates its inhibitory effect on SMO, allowing SMO to translocate into the primary cilium and induce accumulation of the Gli-Sufu complex at the tip of the primary cilium. Activation of the Hh pathway results in accumulation of Gli-A and initiation of the transcription of Hh target genes such as PTCH1, GLI1, and HHIP 3. Germline mutation of one PTCH-1 gene is seen in NBCCS. Mutations of both the alleles are required. PTCH-1 mutations have been identified in 30% to 40% of sporadic BCCs.36,37 Recently, mutation of the PTCH-2 gene localized on chromosome 1p32.1–32.3 has also been identified in a case of sporadic BCC.38 Studies have shown consistent overexpression of the PTCH-1 mRNA in sporadic BCC by RT-PCR and in situ hybridization methods. PTCH-2 levels are high not only in BCC but also in normal epidermis.39 Mutation of SMO has also been identified in sporadic BCC.40 Several reports41,42 have highlighted an increase in Gli-1 mRNA correlating with the overexpression of PTCH mRNA, as well as Gli-1 protein levels, in sporadic BCC and in the basal layer of epidermis in the tumorigenic regions. Unchanged expression of Gli-2 mRNA in sporadic BCC and unequivocal expression of Gli-3 mRNA levels in normal epidermis and sporadic BCC have also been observed. Activation of SHH target genes expression, including HIP and Wnt, has also been observed in sporadic BCC.43,44 Thus, both PTCH and SMO mutations can trigger overactivation of the SHH pathway and result in the increased expression of the

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downstream target genes via the Gli family of transcriptional factors. Gli-1 activates platelet-derived growth factor receptor-α polypeptide (PDGFRA), which, in turn, upregulates the RASMAPK1/RAS-ERK pathway. Activation of the RAS-MAPK1 pathway causes cell proliferation by inhibiting apoptosis. Increased expression of PDGFRA has been observed in mouse and human models and may be important in BCC pathogenesis.45 Forkhead box (FOX) proteins have also been incriminated in the physiopathology of BCC. These proteins regulate cell proliferation, growth, differentiation, longevity, and transformation. The FOXE1 transcription factor is likely a direct downstream target gene of Gli-2. FOX E1 has been documented to be expressed in human basal keratinocytes and BCC. Also, the 1B isoform of the FOXM1 gene is upregulated in BCC.46 Cadherin-associated protein, beta 1 (CTNNB1), also known as b-catenin, is a nuclear effector of WNT and a downstream mediator of the SHH pathway. CTNNB1 activity increases transcription of genes involved in tumor formation. Among these genes are MYCN and cyclin D1, which contribute to cellular proliferation and matrix meta-llopeptidase 7 (MMP 7), whose gene product may facilitate stromal invasion by tumors. In BCC, however, whether SHH pathway misregulation, WNT pathway upregulation, nuclear CTNNB1 accumulation, and cellular proliferation are mechanistically linked remains a matter of dispute.47,48

The connection between BCC pathogenesis and misregulation of the SHH pathway due to inactivating PTCH1 mutations and activating SMO mutations is well-documented. Upregulation of Hh signaling is the pivotal abnormality in BCC.47 Approximately 90% of sporadic BCCs have loss of function in at least one allele of PTCH-1 and 10% have activating mutations of the downstream SMO protein.48,49,50 The loss-of-function mutation of the PTCH-1 includes germline mutations found in the Gorlin syndrome. With these mutations and dysregulations of the Hh pathway, SMO is active, resulting in continuous target gene activation. The expression of mRNAs from these target genes is increased in BCCs. Mutations of the p53 tumor suppressor gene has been documented in 50% of cases of sporadic BCC.51 Conclusions BCC is the most frequently encountered human malignancy. It seems to emanate from the epidermis, the precise origin of which is still unknown and thus not clearly elucidated. The underlying pathophysiology of this tumor includes an interaction among various proteins involved in cellular proliferation and differentiation. The Hg and PTCH pathways seem to be the clues to help understand the pathophysiology of this malignancy, for which further research is needed. References

Aberrant SHH signaling may also lead to BCC expressing increased levels of antiapoptotic proto-oncogene, BCL2 (B-cell CLL/lymphoma 2). BCL2 is expressed in the basal cell layer of the epidermis and a 2- to 3-fold increase is seen in BCCs. Although a link between SHH misregulation and BCL2 has been suggested, results on BCL2 gene expression in BCCs have been inconsistent.49 The N-myc proto-oncogene (MYCN) is a member of the Myc family of transcriptional activators and a potential downstream effector of the SHH pathway. MYCN upregulation has been associated with BCC. Immunohistochemistry and fluorescence in situ hybridization has depicted increased MYCN production in 73% of 220 BCCs. Aggressive infiltrative BCCs have higher MYCN gene expression than nodular and superficial BCCs.50 RUXN3, a member of the runt-related transcription factor (RUNX) gene family, is a tumor suppressor gene. It is normally expressed in the basal layers of the epidermis. Researchers51 demonstrated that the RUNX3 gene is overexpressed in BCCs, compared with expression in normal epidermis. The Hh pathway is an important regulator of embryologic development and is also involved in carcinogenesis. A proper understanding of this signaling pathway, its aberrant activation and associated molecular components, seems pertinent in the perspective of emerging targeted therapeutic modalities. SKINmed. 2014;12:176–181

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1 Miller DL, Weinstock MA. Nonmelanoma skin cancer in the United States: incidence. J Am Acad Dermatol. 1994;30:774–778. 2 Jemal A, Siegel R, eds. Cancer Facts and Figures 2011. Atlanta, GA: American Cancer Society, Inc; 2011. 3 Jacob A. Observations respecting an ulcer of peculiar character, which attacks the eyelids and other parts of the face. Dublin Hospital Rep Commun Med Surg. 1827;4:232–239. 4 Krompecher E. Der drusenartige Oberflachenepithelkrebs.Carcinoma epi- theliale adenoides. Beitrz path Anat u z adg Path. 1900;28:1–41. 5 Krompecher E. Der Basalzellenkrebs. Jena: GustavFischer; 1903 6 Kasper M, Jaks V, Hohl D, Toftgård R. Basal cell carcinoma—molecular biology and potential new therapies. J Clin Invest. 2012;122:455–463. 7 Ten Seldam RE, Helwig EB. Histological Typing of Skin Tumours. Geneva, Switzerland: World Health Organization; 1974. 8 Gallagher RP, Hill GB, Bajdik CD, et al. Sunlight exposure, pigmentary factors, and risk of nonmelanocytic skin cancer. I. Basal cell carcinoma. Arch Dermatol. 1995;131:157–163. 9 Fitzpatrick TB. The validity and practicality of sunreactive skin types I through VI. Arch Dermatol. 1988;124:869–871.

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10 Fartasch M, Diepgen TL, Schmitt J, Drexler H. The relationship between occupational sun exposure and nonmelanoma skin cancer clinical basics, epidemiology, occupational disease evaluation, and prevention. Dtsch Arztebl Int. 2012;109:715–720. 11 Kricker A, Armstrong BK, English DR, Heenan PJ. A dose–response curve for sun exposure and basal cell carcinoma. Int J Cancer. 1995;60:482–488. 12 Kricker A, Armstrong BK, English DR, Heenan PJ. Does intermittent sun exposure cause basal cell carcinoma? A case–control study in Western Australia. Int J Cancer. 1995;60:489–494. 13 Ron E. Cancer risks from medical radiation. Health Phys. 2003;85:47–59. 14 Ho WL, Murphy GM. Update on the pathogenesis of post-transplant skin cancer in renal transplant recepients. Br J Dermatol. 2008;158:217–224. 15 Moloney F, Comber H, Conton P, Murphy G. The role of immunosuppression in the pathogenesis of basal cell carcinoma. Br J Dermatol. 2006;154:790–791. 16 Yu HS, Liao WT, Chai CY. Arsenic carcinogenesis in the skin. J Biomed Sci. 2006;13:657–666. 17 Nijsten TE, Stern RS. The increased risk of skin cancer is persistent after discontinuation of psoralen+ ultraviolet A: a cohort study. J Invest Dermatol. 2003;121:252– 258. 18 Castori M, Morrone A, Kanitakis J, Grammatico P. Genetic skin diseases predisposing to basal cell carcinoma. Eur J Dermatol. 2012;22:299–309. 19 Chatterjee K, Rasool F, Chaudhuri A, et al. Basal cell carcinoma, oculo-cutaneous albinism and actinic keratosis in a Native Indian. Indian J Dermatol. 2013;58:377–379. 20 Bale AE, Yu KP. The hedgehog pathway and basal cell carcinomas. Hum Mol Genet. 2001;10:757–762. 21 Epstein E Jr. Genetic determinants of basal cell carcinoma risk. Med Oncol. 2001;36:555–558. 22 Harris PJ, Takebe N, Ivy SP. Molecular conversations and the development of the hair follicle and basal cell carcinoma. Cancer Prev Res. 2010;3:1217–1221.

29 Athar M, Tang X, Lee JL, et al. Hedgehog signalling in skin development and cancer. Exp Dermatol. 2006;15:667– 677. 30 Barnes EA, Kong M, Ollendorf V, et al. Patched 1 interacts with cyclin B1 to regulate cell cycle progression. EMBO J. 2001;20:2214–2223. 31 Gailani MR, Ståhle-Bäckdahl M, Leffel DJ, et al. The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. Nat Genet. 1996;14:78–81. 32 Kim MY, Park HJ, Baek SC, et al. Mutations of the p53 and PTCH gene in basal cell carcinomas: UV mutation signature and strand bias. J Dermatol Sci. 2002;29:1–9. 33 Smyth I, Narag MA, Evans T, et al. Isolation and characterization of human patched 2 (PTCH2), a putative tumour suppressor gene in basal cell carcinoma and medulloblastoma on chromosome 1p32. Hum Mol General. 1999;8:291–297. 34 Undén AB, Zaphiropoulos PG, Bruce K. Human patched (PTCH) mRNA is overexpressed consistently in tumor cells of both familial and sporadic basal cell carcinoma. Cancer Res. 1997;57:2336–2340. 35 Lam CW, Xie JW, To KF, et al. A frequent activated smoothened mutation in sporadic basal cell carcinoma. Oncogene. 1999;18:833–836. 36 Dahmane N, Lee J, Robins P. Activation of the transcription factor Gli-1 and the Sonic hedgehog signalling pathway in skin tumours. Nature. 1997;389:876–881. 37 Green J, Leigh IM, Poulsom R, et al. Basal cell carcinoma development is associated with induction of the expression of the transcription factor Gli-1. Br J Dermatol. 1998;139:911–915. 38 Tojo M, Kiyosawa H, Iwatsuki K, et al. Expression of a sonic hedgehog signal transducer, hedgehog interacting protein, by human basal cell carcinoma. Br J Dermatol. 2002;146:69–73. 39 Xie J, Murone M, Luoh SM, et al. Activating smoothened mutations in sporadic basal-cell carcinoma. Nature. 1998;391:90–92.

23 Bonamigo RR, de Carvalho AV, Sebastiani VR, da Silva CM, de Zorzi Pinto AC. HLA e câncer de pele. An Bras Dermatol. 2012;87:9–18.

40 Iwasaki JK, Srivastava D, Moy RL, Lin HJ, Kouba DJ. The molecular genetics underlying basal cell carcinoma pathogenesis and links to targeted therapeutics. J Am Acad Dermatol. 2012;66:167–178.

24 Holíková Z, Massi D, Lotti T, Hercogová J. Insight into the pathogenesis of sporadic basal cell carcinoma. Int J Dermatol. 2004;43:865–869.

41 Teh MT, Wong ST, Neill GW, et al. FOXM1 is a downstream target of Gli1 in basal cell carcinomas. Cancer Res. 2002;62:4773–4780.

25 Murone M, Rosenthal A, De-Sauvage FJ. Hedgehog signal transduction from flies to vertebrates. Exp Cell Res. 1999;253:25–33.

42 Saldanha G, Ghura V, Potter L, Fletcher A. Nuclear betacatenin in basal cell carcinoma correlates with increased proliferation. Br J Dermatol. 2004;151:157–164.

26 Hahn H, Wojnowski L, Miller G, et al. The patched signaling pathway in tumorigenesis and development:lessons from animal models. J Mol Med. 1999;77:459–468.

43 Saldanha G, Fletcher A, Slater DN. Basal cell carcinoma: a dermatopathological and molecular biological update. Br J Dermatol. 2003;148:195–202.

27 Lupi O. Correlations between the Sonic Hedgehog pathway and basal cell carcinoma. Int J Dermatol. 2007;46:1113–1117.

44 Howell BG, Solish N, Lu C, et al. Microarray profiles of human basal cell carcinoma: insights into tumor growth and behavior. J Dermatol Sci. 2005;39:39–51.

28 Lee Y, Miller HL, Russell HR, et al. Patched 2 modulates tumorigenesis in patched 1 heterozygous mice. Cancer Res. 2006;66:6964–6971.

45 Freier K, Flechtenmacher C, Devens F, et al. Recurrent NMYC copy number gain and high protein expression in basal cell carcinoma. Oncol Rep. 2006;15:1141–1145.

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46 Salto-Tellez M, Peh BK, Ito K, et al. RUNX3 protein is overexpressed in human basal cell carcinomas. Oncogene. 2006;25:7646–7649.

49 Xie J, Murone M, Luoh SM et al. Activating smoothened mutations in sporadic basal cell carcinoma. Nature. 1998;391:90–92.

47 Hutchin M. Sustained Hedgehog signaling is required for basal cell carcinoma proliferation and survival: conditional skin tumorigenesis recapitulates the hair growth cycle. Genes Dev. 2005;19:214–223.

50 Epstein E. Basal cell carcinoma: attack of the hedgehog. Nature. 2008;8:743–754.

48 Gailani MR, Stahle-Backdahl M, Leffell DJ et al. The role of human homologue of Drosophila patched in sporadic basal cell carcinomas. Nat Genet. 1996;14:78–81.

51 Ziegler A, Leffell DJ, Kunala S, et al. Mutation hotspots due to sunlight in the p53 gene of nonmelanoma ski cancers. Proc Natl Acad Sci USA. 1993;90:4216– 4220.

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 189)

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Volume 12 • Issue 3

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

New Wine in Old Bottles: The Coming Deluge of Aggressive Cutaneous Cancers and Precancers Cindy Wassef, BA;1 Brian Lee, MD;1 Peter C. Lambert, MA;2 Laju Patel, MD;1 W. Clark Lambert, MD, PhD1

A

mong the most surprising things one learns as a beginning pathology resident is the profoundly different labeling given to cutaneous, UV radiation–induced keratinocytic lesions vs squamous lesions in other tissues. The former are classified as “actinic keratosis,” even if they appear quite aggressive (Figure 1), but if they are labeled as cancers, no particular concern is taken. A locally destructive procedure, or at most local excision, is usually considered adequate treatment. If recurrence occurs (an unusual problem), a second such procedure is considered adequate. In marked contrast, squamous lesions elsewhere are labeled as cancer early in their course (Figure 2) and much more aggressive treatment is performed. Why the difference? There is a response limiting the aggressiveness of the former lesions that does not protect against the latter (although extremely rare exceptions do occur, probably as a result of histological mimicry1). Protection Against Cutaneous Tumors Skin cancers, especially those caused by UV radiation, are apparently held in check by factors such as a reactive immune system, something that is still poorly understood. There are many mechanisms that may be involved in microtumor regression and removal. Studies characterizing the microenvironment of basal cell carcinoma (BCC) suggest that the interplay between the immunologic antitumor response (CD8+ T cells, interferon signals, interleukin [IL] 12, IL-23) vs the immunosuppressive cytokines and cellular entities (CD3+CD25+Foxp3+ Treg, immature dendritic cells, Th2 cytokines) governs the mechanism of microtumor suppression.2 Immunohistochemical analysis of spontaneously regressing BCCs indicates an elevation of CD3+/CD4+/CD25+ T cells infiltrating regressing tumors.3 Cytokines from activated CD4+ T cells and interferon gamma, which initiate a Th1 cytokine-mediated antitumor immune response, may also be important contributors to

BCC regression. In contrast, CD4+CD25+Foxp3+ Tregs4 and other immunosuppressive cells such as CD163+ M2 macrophages play significant roles in inducing peripheral T-cell tolerance and trigger the initiation and progression of carcinogenesis. The tumor-stromal interaction or the contractual interaction between the normal and tumor cells may also play a crucial role in forming “pseudocapsules” that confine the histopathologically observed cancerous foci.2,5 Aggressive Actinic Keratosis, BCC, and Squamous Cell Carcinoma With the current marked increase in solid organ transplantation comes the increased use of immunosuppressants, which are known to promote carcinogenesis, particularly in the skin where cutaneous cancers account for fully 40% of post-transplant cancers. The incidence of squamous cell carcinoma (SCC) has been reported to be 65 to 250 times greater in solid organ transplant patients vs immunocompetent individuals.6 With better and more effective immunosuppressants, the incidence of skin cancer has been increasing in correlation with increased overall survival post-transplantation.7 In addition to the increase in the number of cancerous lesions in transplant recipients, an increase in their aggressiveness has also been noted in many studies.6 In a study of cardiothoracic transplant recipients, data on 619 patients indicated that 27 developed some form of aggressive cutaneous malignancy. This was defined in the study as having one of the following characteristics: local infiltration, lymph node metastases, poor differentiation, or relapse following treatment. Malignant melanomas were also classified as aggressive cutaneous lesions. Patients developed very aggressive cutaneous disease, with the average time to death after diagnosis of cutaneous malignancy 20 months with13 of the 27 patients dying by the end of the study. On histology, 15 of 20 squamous cell lesions were characterized as poorly differentiated.8

See also page 164. From the Department of Dermatology, Rutgers University – New Jersey Medical School, Newark, NJ;1 St. George’s University School of Medicine, Grenada, WI2 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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Figure 1. Actinic keratosis. Despite manifest cellular atypia and obvious extensions into the dermis, this lesion is labeled as precancerous. (Hematoxylin and eosin, original magnification ×260.)

In a more recent study, SCCs and BCCs in organ transplant recipients were compared with those of nontransplant controls. SCCs in organ transplant recipients occurred at younger ages, and there was an increased incidence of primary tumors, deep vertical extension of tumors, lymph node involvement, and recurrence. BCCs in organ transplant recipients also occurred at a younger age when compared with nontransplant controls.7

Figure 2A. Squamous cell carcinoma in situ (erythroplasia of Queyrat), glans penis. Despite its subtle appearance, this lesion is labeled as cancerous. (Hematoxylin and eosin, original magnification ×260.)

The amount of immunosuppression appears to play a role in the incidence of cutaneous cancer.6 In one extreme case, a 71-year-old cardiac transplant patient developed 417 SCCs over a 20-year period while taking cyclosporine 150 mg twice per day, prednisone 7 mg daily, and azathioprine 100 mg daily. This patient developed 334 SCCs, 83 SCCs in situ, and many actinic keratoses. A reduction in the amount of immunosuppressants was deemed necessary to decrease the amount and progression of cutaneous malignancies.9 A literature review found numerous studies that support the finding of decreased skin cancer incidence in transplant patients with less immunosuppression, with one Norwegian study concluding that patients taking triple immunosuppression had a 2.8 times greater chance of developing SCC compared with patients taking dual therapy.10 In another study, kidney transplant patients were divided into two groups and given either normal- (150–250 ng/mL blood concentration) or low- (75–125 ng/mL blood concentration) dose cyclosporine immunosuppression. Those receiving the normal dose had a significantly higher incidence of multiple (>10) lesions than those receiving the low dose (21 vs 0, P<.02).11 In addition to an SKINmed. 2014;12:183–185

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Figure 2B. The Ki67 immunostain confirms this lesion’s high rate of proliferation. (Ki67, original magnification ×260.) Aggressive Cutaneous Cancers and Precancers


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increase in incidence, aggressiveness of lesions was elevated with the use of immunosuppression. In the same review, it was found that 4 of 6 transplant patients had a significant reduction in skin cancer incidence following cessation of immunosuppression.10

References

The risks and benefits of reducing immunosuppression need to be assessed on a case-by-case basis, but there is little doubt that decreasing immunosuppression leads to a decrease in the development of skin cancer. Thus, the dermatologist who manages these patients is going to have to be involved in an entirely new area of medicine: management of immunosuppression in transplant recipient patients. New Wine in Old Bottles The days when we may comfortably label skin lesions that might be labeled elsewhere as invasive carcinomas as “actinic keratoses” are ending. Should the patient undergo immunosuppression, the biological behavior of these lesions is likely to be far different. Because these lesions are extremely common, this is likely to have a profound effect on how skin pathology specimens are diagnosed and how these diagnoses are interpreted. When this interpretation is made will also be a factor. The Coming Deluge Because skin cancers and precancers arise approximately 5 to 7 years after initiation of immunosuppression and because the numbers of solid organ transplants are rising rapidly, with the majority of recipients less than this interval post-transplant, we can reasonably expect a rapid rise in patients experiencing this undesirable complication. Add to this list patients receiving other forms of immunosuppression for psoriasis or rheumatoid arthritis and the enormity of this new problem becomes manifest.

1 Fernandes H, Fernandes N, Bhattacharya S, et al. Molecular signatures linked with aggressive behavior in basal cell carcinoma: a report of six cases. Am J Dermatopathol. 2010;32:550–556. 2 Kaporis HG, Guttman-Yassky E, Lowes MA, et al. Human basal cell carcinoma is associated with Foxp3+ T cCells in a Th2 dominant microenvironment. J Invest Dermatol. 2007;127:2391–2398 3 Hunt M, Halliday G, Weedon D, et al. Regression in basal cell carcinoma: an immunohistochemical analysis. Br J Dermatol. 1994;130:1–8 4 Fujimura T, Kaizaki A, Kambayashi Y, et al. Basal cell carcinoma with spontaneous regression: a case report and immunohistocehmical study. Case Reports Dermatol. 2012;4:125 5 Klein G. Toward a genetics of cancer resistance. Proc Natl Acad Sci USA. 2009;106:859–863. 6 Rangwala S, Tsai KY. Roles of the immune system in skin cancer. Br J Dermatol. 2011;165:953–965. 7 Lott DG, Manz R, Koch C, Lorenz RR. Aggressive behavior of nonmelanotic skin cancer in solid organ transplant recipients. Transplantation. 2010;90:683–687. 8 Veness MJ, Quinn DI, Ong CS, et al. Aggressive cutaneous malignancies following cardiothoracic transplantation: the Australian experience. Cancer. 1999;85:1758– 1764. 9 Liu AS, Eriksson E. Four hundred seventeen squamous cell cancers in a heart transplant patient. Ann Plast Surg. 2011;67:545–546. 10 Otley CC, Maragh SL. Reduction of immunosuppression for transplant-associated skin cancer: rationale and evidence of efficacy. Dermatol Surg. 2005;31:163–168. 11 Dantal J, Hourmant M, Cantarovich D, et al. Effect of long-term immunosuppression in kidney-graft recipients on cancer incidence: randomised comparison of two cyclosporin regimens. Lancet. 1998;351:623–628.

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May/June 2014

Volume 12 • Issue 3

COSMETIC SCIENCE Howard A. Epstein, PhD, Section Editor

Hot Topics in the Cosmetics Industry Howard A. Epstein, PhD

C

osmetic products have been in continuous use for more than 2000 years to treat and adorn the body. The cosmetics industry is a major global financial entity. For this reason, the cosmetics industry is an easy target of attack for numerous consumer interest groups who question the safety of various ingredients used in cosmetic products. At times, the concern appears to be an excuse to request donations to continue their efforts by appealing to serious health concerns. Frequently, the issues popularized by such interest groups are based on emotional concerns rather than solid scientific evidence.

with claims that it treats or prevents disease or otherwise affects the structure or any function of the body will cause the product to be considered a drug under the FD&C Act, section 201(g).

The cosmetics industry does have an excellent safety record; yet, marketing influences have been known to execute marketing and sales campaigns that appear to promote exaggerated product claims in violation of the Food and Drug Administration (FDA) Drug and Cosmetic Act. The situation is further complicated by the fact that the FDA Title 21 of the Food, Drug, and Cosmetic (FD&C) Act1 has not been revised since 1938. Techniques developed as a result of the human genome project have advanced since that time, enhancing our understanding of the molecular biology of skin. Cosmetic science has made significant advances, and it is appropriate to revise the FD&C Act accordingly.

When the FDA determines the law is violated, the initial step is to send a warning letter by certified mail to the manufacturer/ distributor or promoter of the product, referencing the law and the violation identified. This is a common practice for the FDA. Only recently, the FDA has been monitoring the Internet for advertising of products that are misbranded. The recipient is given a brief period of time to correct the violation. Warning letters issued by the FDA may be read online as they are published by the FDA.3

FDA Sends Warning Letters Regarding Misbranded Product in the Marketplace The FDA does not have the legal authority to approve cosmetic products prior to a market launch. Under the law, cosmetic products may not be “adulterated” or “misbranded.” The manufacturer is responsible for the safety and labeling of the product commercialized. Labeling of a cosmetic product is regulated by the FDA. The regulations are intended to protect consumers from health hazards and deceptive practices. The label must not contain false or misleading information, label information must be properly displayed, and labeling must not violate the requirements of the Poison Prevention Packaging Act of 1970 [FD&C Act, sec. 602; 21 U.S.C. 362].2 In addition, promoting a product

During 2012, the FDA sent warning letters to at least 12 companies involved in the manufacturing, distribution, and promotion of cosmetic products, advising that their products were in violation of the FD&C Act. A warning letter typically advises that the product is misbranded and is commercialized as an unapproved new drug.

Safety of Cosmetic Ingredients There are a few ingredients that frequently appear on the list of consumer group’s safety campaigns. Parabens, phthalates, siloxanes, lead, and 1, 4-dioxane are examples found as ingredients of concern on the Internet. The parabens and phthalates are reported to be endocrine disruptors.4,5 Parabens Limited studies have suggested that butyl and possibly propylparaben can mimic the effect of the endocrine hormone estrogen when tested at high concentrations using in vitro models and in female mice.6 A direct link between underarm product use and breast cancer has not been found by epidemiologists. In fact, many chemical entities with estrogenic effects are found in plants consumed as foods.

From H. Epstein, Philadelphia, PA Address for Correspondence: Howard A. Epstein, PhD, Philadelphia, PA • E-mail: HEpsteinskincare@yahoo.com

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Some of these phytoestrogens, when tested using similar methodology as used to evaluate the parabens, show similar effects. Parabens have been found to be 10,000 times weaker than the most potent phytoestrogens and 100,000 times less potent than estradiol, which is naturally produced by the body.7 Currently, there is no evidence to suggest a link between breast cancer and use of parabens in cosmetic products including deodorants. The FDA has confirmed this opinion in their posting addressing parabens in cosmetics. The page was updated on November 8, 2013.8 Phthalates Various chemical forms of phthalates are used in vinyl flooring, detergents, pharmaceuticals, nail polish, hair spray, soaps, shampoos, perfumes, and other skin care products. Dibutyl phthalate is the most common plasticizer used in cosmetic products. Recent surveys reported by the FDA indicate this material is no longer commonly used in cosmetics; diethylphthalate is now used more frequently.4 The National Institute for Environmental Safety and Health established an expert panel during the years 1998–2000 that concluded reproductive risks from exposure to phthalates was minimal to negligible in most cases. During 2001, the Centers for Disease Control and Prevention (CDC) released a report on March 21, 2009, describing a survey of a small segment of the US population found to have environmental chemicals in their urine. The study included evaluation for phthalates. In 2002, the Cosmetic Ingredient Review expert panel reviewed the data generated for phthalates, including the CDC reports generated from 1985 through 2002. The CDC report noted elevated levels of phthalates excreted by women of child-bearing age, but it was concluded that none of the reports or other data evaluated did not establish an association between the findings and a health risk. For this reason, the FDA determined that there was no scientific basis to take regulatory action against cosmetics containing phthalates.4

2010 that concluded the presence of phthalates in children’s and other consumer products has decreased. Siloxanes Siloxanes are a class of chemicals that serve as building blocks of silicone polymers used in industrial and consumer products including cosmetics, antiperspirants, shampoos, and skin care lotions. During December 2005, the Environmental Protection Agency posted siloxane D5 in drycleaning applications on the Internet. The fact sheet reported that results of a cancer study on siloxane D5 in rodents submitted to under Toxic Substances Control Act section 8(e) indicated a potential risk to human health workers in the drycleaning industry. In February 2003, Dow Corning reported the results of a 2-year chronic toxicity and carcinogenicity study on D5 using rats. Preliminary results showed that female rats exposed to the highest concentration of D5 exhibited a statistically significant increase in uterine tumors.9 There is uncertainty about the relevance of uterine tumors in rodents to humans, and this ability to calculate cancer potency of D5 for humans is uncertain. At this time, health authorities have not found the siloxanes to be a significant risk to human health in cosmetic products. This finding was supported by a paper published in 2011, concluding the safety of cyclic siloxanes in cosmetic products.10 Currently, D4 (cyclotetrasiloxane) and D5 (cyclopentasiloxane) are likely to have restricted use under Environment Canada’s regulations for environmental concerns. Conclusions Cosmetics are one of the safest categories of consumer products. Safety concerns raised by nongovernment organizations that are not supported by sound reliable scientific studies will only result in cosmetic products that are more expensive and will not have a higher degree of safety. References

The FDA and other regulatory agencies including Canada and the European Union countries continue to monitor levels of phthalates in cosmetic products.4 Consumers should be aware that adults and infants are exposed to phthalates from several sources including air, drugs, food, plastics, and water, in addition to cosmetics. With respect to cosmetics, consumers who remained concerned about products containing phthalates in their cosmetic products should check the ingredient labeling and avoid products containing fragrances, where there is a possibility of the fragrance containing a phthalate that would not have to be listed as a fragrance component. The FDA conducted a survey in SKINmed. 2014;12:187–189

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1 US Food and Drug Administration Protecting and Promoting Your Health. Regulatory Information. Federal Food, Drug, and Cosmetic Act. Available at: www.fda. gov/regulatoryinformation/legislation/federalfooddrugandcosmeticactFDCAct. Accessed December 17, 2012 2 Fair Packaging and Labeling Act. Available at: www.fda. gov/regulatoryinformation/legislation/ucm148722. htm. Accessed December 17, 2012. 3 US Food and Drug Administration Protecting and Promoting Your Health. Cosmetics. Warning letters address drug claims made for products marketed as cosmetics. Available at: www.fda.gov/cosmetics/guidanceregulatoryinformation/complianceenforcement/warningletters/ ucm081086.htm. Accessed December 18, 2012.

Hot Topics in the Cosmetics Industry


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Cosmetic Science

4 US Food and Drug Administration Protecting and Promoting Your Health. Cosmetics. Phthalates. Available at: http://www.fda.gov/cosmetics/productsingredients/ingredients/ucm128250.htm. Accessed January 19, 2014. 5 Sathyanarayana S, Karr CJ, Lozano P, et al. Baby care products: possible sources of infant phthalate exposure. Pediatrics. 2008;121:260–268. 6 Jones J. Can rumors cause cancer? J Natl Cancer Inst. 2000;92:1469–1471. 7 Mirick DK, Davis S, Thomas DB. Antiperspirant use and the risk of breast cancer. J Natl Cancer Inst. 2002;94:1578–1580.

Historical Diagnosis and treatment

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8 US Food and Drug Administration Protecting and Promoting Your Health. Cosmetics. Parabens. Available at: http://www.fda.gov/cosmetics/productsingredients/ ingredients/ucm128042.htm. Accessed January 23, 2014. 9 EPA Office of Pollution Prevention and Toxics (7404). Siloxane D5 in drycleaning applications fact sheet. December 2005. Available at: http://www.epa.gov/dfe/ pubs/garment/d5fs3.pdf. Accessed January 23, 2014. 10 Johnson W Jr, Bergfeld WF, Belsito DV, et al. Safety assessment of cyclomethicone, cyclotetrasiloxane, cyclopentasiloxane, cyclohexasiloxane, and cycloheptasiloxane. Int J Toxicol. 2011;(6 suppl):149S–227S.

(Continued from page 181)

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May/June 2014

Volume 12 • Issue 3

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Kafka and the Enigmatic Case of Cutaneous Myiasis Angel Fernandez-Flores, MD, PhD;1 Marcela Saeb-Lima, MD2 To the Editor:

Discussion

Around December, 1916, Franz Kafka wrote A Country Doctor, an enigmatic short story, qualified by some as a waking dream.1 As is most of Kafka’s work, it is full of secondary subconscious meanings. It presents a surreal scenario that involves the reader in the landscape of a never-ending snowy winter night.

In spite of the many subconscious, secondary, Freudian, and sexual innuendos of this story, dermatologically this appears to be quite a straightforward description of a typical case of cutaneous myiasis. Sometimes, in this condition, the larvae can be seen at the floor of the ulcer when first inspected.2 This is because the caudal ends of the maggots have to remain visible at the surface of the lesion for the larvae to breathe,3 and sometimes the wound is not deep and/or the maggots are so numerous that they can be seen as a bunch of worms protruding from the lesion.2 The size of the worms, as described in the story (“long and thick as my little finger”), seems a bit exaggerated, as myiasis worms are a few millimeters long most of the time; however, in certain species, the larvae can reach up to 2 cm in length.4

The Story In the story, a doctor is called in the middle of the night to attend a patient in a faraway village. When he arrives, he is conducted to the patient’s (a boy’s) room, who appears “emaciated, no fever, not cold, not warm, eyes empty” and who begs the doctor to let him die. After a very superficial, brief examination (just laying his head on the patient’s breast) the doctor concludes that the boy is healthy (although “his circulation is a little bad”) and that “the best thing would be to shove him out of bed.” “I have been called upon again unnecessarily,” he thinks. Only when the boy’s sister waves a handkerchief soaked in blood does the doctor admit that “the boy might in fact be sick.” Then a new inspection reveals the cause of the disease: “a wound the size of a saucer has opened up in his right side, in the area of the hip.” “Rosecolored, with many different shades, dark in the depths, becoming lighter at the edges, tender and grainy, with blood gathering unevenly at different points, open like a mine in the light of day.” There is an even more interesting surprise, however, because “when regarded at greater proximity,” he sees “worms, as long and thick as my little finger, pink in color and also spattered with blood; anchored in the wound’s interior, they turn toward the light with white heads, with many little legs.” The following is even stranger: the relatives force the doctor to undress and lay naked by the side of the patient’s wound. In such intimacy, the doctor confesses to the boy, “I, who have been in all the rooms of all the patients, far and wide, say to you: your wound is not so bad.” He also suspects that the lesion was caused by an accident: “many offer their sides and hardly hear the ax in the forest, to say nothing of their hearing its approach.”

Another interesting point is the doctor’s comment that the worms had “many little legs.” Because larvae have not yet developed legs, this observation deserves an explanation: maggots are provided with rows of many tiny hooks.4 This can be seen under close inspection with the naked eye (Figure). Their function is to make the larvae’s penetration of the tissue easier, serving as studs. This is why patients may notice something moving inside the wound, with an accompanying “crawling” sensation. Also, such hooks are important in the differential diagnosis of cases of infestation by other arthropods, such as tungiasis, in which the cuticle of the insect is smooth. As soon as the doctor properly diagnosed the case in Kafka’s story, he calmed the patient about the prognosis: “your wound is not so bad,” he said. Most cases of myiasis actually have a good prognosis if the maggots are removed and the wound is debrided; however, heavy infestations, or those located in delicate areas, such as the nose, eye, or ear, can result in the patient’s death.5 It is also interesting that the doctor’s comment on how the wound originated was that it was caused by an accident (and later sec-

See also page 139. From the Department of Cellular Pathology, Hospital El Bierzo, Ponferrada, Spain;1 and the Department of Pathology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, INER/CIENI, Hospital Angeles Lomas, Centro Medico ABC, Mexico City, México2 Address for Correspondence: Angel Fernandez-Flores, MD, PhD, Servicio de Anatomía Patologica, Hospital El Bierzo, Medicos sin Fronteras 7, 24411, Ponferrada, Spain • E-mail: dermatopathonline@gmail.com

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CORRESPONDENCE has been reported.6 Kafka, on the other hand, probably had limited medical knowledge; although he started some studies of chemistry in the University of Prague, he abandoned them 2 weeks later. Conclusions Even though the description fits perfectly with what is seen in myiasis, the scenario is impossible in practical terms: myiasis does not occur in cold winter, when flies are not alive.

Figure. Maggots in which rows of many tiny hooks can be seen.

Acknowledgements

ondarily infected by the worms) and not caused directly by the maggots. In myiasis, the adult flies, attracted by the bad smell, only deposit their eggs in already infected wounds or body orifices with poor hygiene.

Dr Javier Baquera, pathologist from the Department of Pathology, Centro Médico ABC, Mexico City, provided the figure. References 1 Winkelmann RK, Barker SM. Factitial traumatic panniculitis. J Am Acad Dermatol. 1985;13:988–994. 2 Moreno A, Marcoval J, Peyri J. Traumatic panniculitis. Dermatol Clin. 2008;26:481–483.

Kafka may have based the description of this specific wound on a precise observation of a real patient with myiasis. Despite the cold climate that characterizes Prague (the city where Kafka was born and in which he spent most of his life) most of the year, myiasis can occur there. Even though the disease is mainly seen in warmer countries, at least one case of myiasis in a patient from Moravia

3 Lee DJ, Kim YC. Traumatic panniculitis with hypertrichosis. Eur J Dermatol. 2011;21:258–259. 4 Lee JH, Jung KE, Kim HS, et al. Traumatic panniculitis with localized hypertrichosis: two new cases and considerations. J Dermatol. 2013;40:139–141.

A Rare Case of Aplasia Cutis With Vanishing Twin Syndrome and Unusual Presentation Taru Garg, MD; Masarat Jabeen, MD; Soumya Agarwal, MD; Ram Chander, MD; Kiran Agarwal, MD To the Editor: A 3-day-old baby girl presented with irregular 2 × 2- to 5.5cm stellate-shaped shiny atrophic plaques on the scalp, right side of the trunk, and legs in an asymmetric manner favoring the right side. The overlying skin showed a few crusted erosions with surrounding hyperpigmentation. There was no evidence of ophthalmologic, skeletal, or neurologic complaints and there was no family history of similar lesions. The child had been a result of a twin pregnancy, in which the other fetus died in utero at around 29 weeks of gestation. The mother had no history of herpes sim-

plex virus (HSV) or varicella zoster virus (VZV) infection nor had she taken any significant medication during her pregnancy. Histopathology of the lesion on the right thigh showed epidermal ulceration with a mild perivascular chronic inflammatory infiltrate and loss of appendages. Results from radiography and ultrasonography of the skull revealed no abnormality. The lesions healed completely within a month with no intervention. Discussion Aplasia cutis congenita (ACC) is a rare and serious congenital defect of the skin, which may be associated with fetal papyraceous

From Lady Hardinge Medical College & Smt. S. K. Hospital, New Delhi, India 110001 Address for Correspondence: Soumya Agarwal, MD, Add- K-I-94 Kavi Nagar, Ghaziabad, U.P, India 201001 • E-mail: scorpsoumya@gmail.com

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CORRESPONDENCE

Figure 1. Stellate-shaped, shiny, atrophic plaque on the right side of the trunk.

Figure 2. An irregular atrophic plaque covered with hemorrhagic crusting.

or placental infarct.1 There is a proposed classification system that consists of 9 groups according to lesional distribution and potential associations including infections, malformations, epidermal nevi, genetic syndromes, and teratogens.1 ACC is a rare congenital anomaly of the skin that affects 1 in every 10,000 live births.2 The association of ACC with vanishing twin syndrome is even more rare. It has been hypothesized that intrauterine death of one of the twins causes the release of thrombosis-promoting material from the dead fetus, causing extensive placental infarctions, disseminated intravascular coagulation, or direct fetal injuries leading to vascular insufficiency of the skin.2,3 Intrauterine trauma, maternal transmission of HSV or VZV, and teratogenic insult with such medications as methimazole, misoprostol, and valproic acid have been implicated.4 Although ACC most frequently involves the scalp with a solitary, sharply demarcated, round or stellate defect, further examination may be warranted in more complex presentations. Around 10% of all nonscalp variants of ACC are associated with fetus papyraceus; however, instances of scalp lesions in an infant with ACC and fetus papyraceus have only rarely been reported.5 Affected patients in ACC group 5 (ACC with fetus papyraceous or placental infarct) usually show linear areas of absence of skin that have an extensive and symmetric pattern of distribution along the flanks and the lateral aspects of the extremities often in a stellate configuration.6 Our patient had an asymmetrical distribution of the skin lesions. The asymmetry might reflect an interplay of mechanical factors and direct fetal injuries caused by the release of thrombogenic material from the dead fetus, in addition to the embryologic predisposition. The disappearance of one or more fetuses during a multifetal gestation is known as vanishing twin syndrome. Conditions asSKINmed. 2014;12:191â&#x20AC;&#x201C;194

sociated with this syndrome can be the complete reabsorption of the dead fetus, the formation of a fetus papyraceus, as happened in our case, or the development of a subtle abnormality on the placenta such as a cyst, subchorionic fibrin, or amorphous material.7 The timing of this event is extremely important in order to predict the outcome of the viable twin and the maternal complications. It is normally believed that if the event occurs during the first trimester, the remaining fetus will have mild to moderate untoward effects. If the event occurs during the second half of pregnancy, the fetus could develop cerebral palsy or extensive aplasia cutis. The abortion of the first fetus occurred at 29 weeks of gestation in our case, explaining the occurrence of wide, instead of linear, skin lesions. The site of extensive aplasia cutis can be a portal of entry for microorganisms in a neonate, leading to secondary infections and septicaemia. This emphasizes the importance of maintaining complete asepsis to prevent complications such as bacteremia and late disfiguring scars. A multidisciplinary approach involving neonatologists, obstetricians, dermatologists, plastic surgeons, physiotherapists, and psychologists is needed to help both patients and their families to cope with such an unpredictable disease as ACC. Our case fits into ACC group 5,1 a rare entity but with asymmetrical distribution of lesions, which is an extremely uncommon feature in patients with ACC group 5. Conclusions ACC is a rare congenital defect of the skin variably associated with the absence of the underlying subcutaneous fat and bone. The exact etiology of this condition remains unknown. The scalp is the most commonly affected site, while the trunk and/or extremeties can be involved in 10% of patients.

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CORRESPONDENCE

References 1 Frieden IJ. Aplasia cutis congenita: a clinical review and proposal for classification. J Am Acad Dermatol. 1986;14:646–660. 2 Maccario S, Fasolato V, Brunelli A, Martinelli S. Aplasia cutis congenita: an association with vanishing twin syndrome. Eur J Dermatol. 2009;19:372–374. 3 Wadams S, Garrett-Cox R, Kitteringham L. Aplasia cutis in association with a triplet pregnancy and fetus papyracceus. Arch Dis Child Fetal Neonatol Ed. 2008;93:F206.

4 Kelly BJ, Samolitis NJ, Xie DL, Skidmore RA. Aplasia cutis congenita of the trunk with fetus papyraceus. Pediatr Dermatol. 2002;19:326–329. 5 Mannino FL, Jones KL, Benirschke K. Congenital skin defects in fetus papyraceus. J Pediatr. 1977;4:559–564. 6 Cambiaghi S, Schiera A, Tasin L, Gelmetti C. Aplasia cutis congenita in surviving co-twins: four unrelated cases. Pediatr Dermatol. 2001;18:511–515. 7 Léauté-Labrèze C, Depaire-Duclos F, Sarlangue J, et al. Congenital cutaneous defects as complications in surviving co-twins. Arch Dermatol. 1998;134:1121–1124.

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ERRATA Skinmed. 2005;4:151. Lupus Miliaris Disseminatus Faciei. Part I: Significance of Histopathologic Undertones in Diagnosis. Virendra N. Sehgal; Govind Srivastava; Ashok K. Aggarwal; Viswanath Reddy Belum; Sonal Sharma Dr. Belum’s name was incorrect in the author line of this contribution. The corrected author line appears above. Skinmed. 2005;4:234. Lupus Miliaris Disseminatus Faciei. Part II: An Overview. Virendra N. Sehgal; Govind Srivastava; Ashok K. Aggarwal; Viswanath Reddy Belum; Sonal Sharma Dr. Belum’s name was incorrect in the author line of this contribution. The corrected author line appears above. Skinmed. 2014;12:9. There Is More to Infection Control Than Just Gloves in the Dermatology Office. Lawrence Charles Parish, MD, MD (Hon); Jack M. Bernstein, MD Dr. Bernstein’s name was incorrect in the author line of this contribution. The corrected author line appears above. SKINmed. 2014;12:191–194

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May/June 2014 2014

Volume 12 â&#x20AC;˘ Issue 3

Book Review Jennifer L. Parish, MD, Section Editor

Atlas of Dermoscopy By Marghoob AA, Malvehy J, Braun RP. Second Edition. London, England: Informa Healthcare. 2012. Pages 384. $249.95 The second edition of Atlas of Dermoscopy is much more than an atlas. It is a comprehensive 384-page reference text book on dermatoscopy that covers the entire breadth of the subject. Each topic is written by experts in the field who have published extensively in their respective areas of expertise. The first part of the book covers principles of dermatoscopy, histopathologic correlates of dermatoscopic structures, and a two-step algorithm of dermatoscopy. The subsequent sections on nonmelanocytic lesions, algorithmic method for assessing melanocytic lesions, melanocytic nevi, and melanoma comprise the core part of the book. The last part of the book includes topics such as dermatoscopy of specific sites, trichoscopy, and more coverage on vascular structures. At the end of each topic, complete references are found for further detailed reading on the subject. The book is easy to navigate, as the table of contents is well organized and easy to read with an accompanying comprehensive index at the end of the book. Second Edition Update

Organization The organization of the book is similar to the first edition, except that additional topics such as dermatoscopy of hair, scalp, and mucosal lesions have been added in the second addition. There are notable differences, however, between the first and second editions. In the first edition, two cases were illustrated on each page, for the most part, each consisting of a smaller clinical image and a much larger dermatoscopic image accompanied by legends for both. In the new edition, the format is similar but the images are smaller, accommodating up to four cases on a page. There are some subtle differences in the quality of the images, as those in the first edition are brighter and more vibrant compared with the ones in the second edition. The larger image size and the glossy paper used in the first edition may account for the perceived quality differences. By no means are the images in the second edition substandard; they are consistently good to excellent. Another difference is the font size of the text, which is notably smaller in the second edition. For those nearing the age when presbyopia sets in, you will probably need your reading glasses.

Illustrations In return for these differences, the readers are rewarded with an extensive library of images and exhaustive coverage of the ever increasing knowledge base of dermatoscopy. In the section on Pattern Analysis, for example, the number of illustrated cases in the first edition pale in comparison with the number of cases in the second edition, 10 cases in the former and 44 cases in the latter. Comparing the sections on Vascular Lesions, there are 13 cases that are illustrated in the first edition, whereas 25 cases are illustrated in the second edition. The second edition is also complemented by many more colorful diagrams that facilitate understanding concepts in dermatoscopy and recognizing the diverse dermatoscopic structures and patterns. Indeed, the Atlas of Dermoscopy was in need of a new edition because of the profound expansion of application of dermatoscopy. Recommended The new updated edition is sure to please both novices and experts alike with its extensive repertoire of new and old images and appropriately distributed updated material. Readers will find the new edition practical, comprehensive, and illuminating. It is a reference textbook that every practicing dermatoscopist should own.

Reviewed by Jason B. Lee, MD, Professor of Dermatology and Cutaneous Biology, Jefferson Medical College of Thomas Jefferson University, 833 Chestnut Street, Suite 740, Philadelphia, PA 19107 â&#x20AC;˘ E-mail: jason.lee@jefferson.edu

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• Lack of energy, trouble breathing or stops breathing, a slow heart beat, confusion, sweating, restlessness, muscle spasms or twitching. WHAT ARE THE POSSIBLE SIDE EFFECTS OF MIRVASO GEL? The most common side effects of using MIRVASO Gel include: • redness, flushing, burning sensation of the skin, skin irritation Skin redness and flushing may happen about 3 to 4 hours after applying MIRVASO Gel. Ask your patients to tell you if they get skin redness and flushing that is uncomfortable. Mirvaso and Galderma are registered trademarks. ©2013 Galderma Laboratories, L.P. Galderma Laboratories, L.P. 14501 N. Freeway Fort Worth, TX 76177 MIR-164B Printed in USA 08/13 Mirvaso Brief Summary HCP R3.indd 1

References: 1. Fowler J Jr, Jackson JM, Moore A, et al; Brimonidine Phase III Study Group. Efficacy and safety of once-daily topical brimonidine tartrate gel 0.5% for the treatment of moderate to severe facial erythema of rosacea: results of two randomized, double-blind, vehicle-controlled pivotal studies. J Drugs Dermatol. 2013;12(6):650-656. 2. Mirvaso [package insert]. Galderma Laboratories, L.P. Fort Worth, TX; 2013.

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Help your patients with facial erythema of rosacea experience...

Not an actual patient. Individual results may vary. Results are simulated to show a 2-grade improvement of erythema. At hour 12 on day 29, 22% of subjects using Mirvaso Gel experienced a 2-grade improvement of erythema compared with 9% of subjects using the vehicle gel.*

RAPID AND SUSTAINED ERYTHEMA REDUCTION BROUGHT TO YOU BY ® M I R V A S O ( b r i m o n i d i n e ) T O P I C A L G E L , 0 . 3 3 %† • The first and only FDA-approved topical treatment specifically developed and indicated for the facial erythema of rosacea1 • Fast results that last up to 12 hours1 • The most commonly reported adverse events in controlled clinical studies included erythema (4%), flushing (2%), skin-burning sensation (2%), and contact dermatitis (1%)2 Important Safety Information Indication: Mirvaso® (brimonidine) topical gel, 0.33% is an alpha-2 adrenergic agonist indicated for the topical treatment of persistent (nontransient) facial erythema of rosacea in adults 18 years of age or older. Adverse Events: In clinical trials, the most common adverse reactions (≥1%) included erythema, flushing, skin-burning sensation, and contact dermatitis. Warnings/Precautions: Mirvaso Gel should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud’s phenomenon, orthostatic hypotension, thromboangiitis obliterans, scleroderma, or Sjögren’s syndrome. Alpha-2 adrenergic agents can lower blood pressure. Mirvaso Gel should be used with caution in patients with severe or unstable or uncontrolled cardiovascular disease. Serious adverse reactions following accidental ingestion of Mirvaso Gel by children have been reported. Keep Mirvaso Gel out of the reach of children. 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 full Prescribing Information on the following page.

See for yourself. Visit www.mirvaso.com/hcp. *Phase 3 clinical studies of 553 subjects 18 and older. Subjects were randomized 1:1 to either Mirvaso Gel or vehicle for 29 days. Subjects and clinicians were asked to grade the improvement they saw at 30 minutes and hours 3, 6, 9, and 12 following application. † Each gram of gel contains 5 mg of brimonidine tartrate equivalent to 3.3 mg of brimonidine free base.


May/June 2014