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Vol. III / Nr. 2 / 2016 ISSN 2392 – 7461 ISSN-L 2392 – 7461

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June 2016

R o m a n i a n

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o f

C L I N I CA L a n d E X P E R I M E N TA L D E R M ATO LO GY Volume I II/ Issue 2 / June 2016

EDITOR-IN-CHIEF & MANAGING EDITOR Victor Gabriel Clatici, MD, Bucharest, Romania

DEPUTY EDITOR-IN-CHIEF Cristiana Voicu, MD, Bucharest, Romania

ROMANIAN SENIOR EDITORS George Sorin Tiplica, Professor, MD, PhD, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania Virgil Patrascu, Professor, MD, PhD, University of medicine and Pharmacy Craiova, Romania Simona Fica, Professor, MD, PhD, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania Radu Vladareanu, Professor, M.D. PhD, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania Oana Andreia Coman, Professor, MD, PhD, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania Alexandru Rafila, Professor, MD, PhD, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania Sabina - Andrada Zurac, Professor, MD, PhD, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania Caius Solovan, Professor, MD, PhD, University of Medicine and Pharmacy ,,Victor Babes,, Timisoara, Romania Luiza Spiru, Professor, MD, PhD, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania Mihai Nicolescu, Professor, MD, Vicepresident of ASAS - Academy for Agriculture and Forestry Sciences Gheorghe Ionescu-Șișești, Bucharest, Romania Mihai-Lucian Pascu, Professor, National Institute for Lasers, Plasma and Radiation Physics, Magurele, Romania Stefana Jurcoane, Professor, PhD, University of Agronomics and Veterinary Medicine, Bucharest, Romania Carmen Maria Salavastru, MD, PhD, Associate Professor, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania Dana Mihaela Jianu, MD, PhD, Associate Professor “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania Ruxandra Diana Sinescu, Associate Professor, MD, PhD, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania Roxana Silvia Bumbacea, MD, PhD, Associate Professor, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania Simona Vladareanu, M.D. PhD, Associate Professor, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania Horatiu Moldovan, MD, PhD, Associate Professor, University of Medicine and Pharmacy, Tirgu-Mures, Romania Angela Staicu, National Institute for Lasers, Plasma and Radiation Physics, Magurele, Romania

INTERNATIONAL SENIOR EDITORS Cassian Sitaru, Professor, MD, PhD, University of Freiburg, Freiburg, Germany Claude Dalle, Professor, MD, Paris, France Louis Dubertret, Professor Emeritus, MD, PhD, Universite Denis Diderot, Fondation Rene Touraine, Paris, France Daniel Racoceanu, Professor, PhD, Sorbonne Universités, Université Pierre et Marie Curie, Paris, France Razvan Cristescu, MD, PhD, Merck Research Laboratories, Boston MA, USA Carmen Cantemir-Stone, PhD, Research Scientist, The Ohio State University, Columbus OH, USA Mihaela Balu, Professor, Beckman Laser Institute, University of California, Irvine, CA, USA Leonardo Marini, Professor, Skin Doctors Center, Trieste, Italy Miroslav Blumenberg, MD, PhD, Langone Medical Center, New York, USA Björn Brücher, Professor, MD, PhD, FRCS, FACS, Bon Secours Cancer Institute, Eichmond, Virginia, USA Klaus Fritz, Assoc. Prof. “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania Ijaz Jamall, PhD, American Board of Toxicology, Sacramento, USA Marco A. Pelosi III, MD, FACOG, FACS, FICS, FAACS, International Society of Cosmetogynecology Bayonne, New Jersey, USA Mehmet Ufuk Abacioglu, MD, Radiation Oncology Department, Neolife Medical Center, Istanbul, Turkey Uwe Gieler, Professor, MD, PhD, Department of Dermatology and Allergology, University Clinic Giessen (UGKM), Germany Lucia Tomas-Aragones, PhD, Department of Psychology, University of Zaragoza, Spain Jacek C Szepietowski, Professor, MD, PhD, Department of Dermatology, Venereology and Allergology, Medical University, Wroclaw, Poland Umit Tursen, Professor, MD, Mersin University, Mersin, Turkey

ROMANIAN EDITORIAL BOARD Alin Laurentiu Tatu , MD, PhD, University Dunarea de Jos, Faculty of Medicine and Pharmacy, Galati, Romania Cristian Radu Jecan, MD, PhD, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania Madalina Musat, MD, PhD, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania Valentin Calu, MD, PhD, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania Cosmin Balabuc, DDS, Victor Babeș University of Medicine and Pharmacy, Timișoara, Romania Claudia Dima, MD, PhD, National Institute of Public Health, Bucharest, Romania Ileana Turcu, Senior Researcher, “Ana Aslan” International Foundation, Bucharest, Romania Violeta Corina Cristea, MD, PhD, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania Aurel-Florentin Badiu, PhD, Academy for Agriculture and Forestry Sciences Gheorghe Ionescu-Șișești, Bucharest, Romania Loredana Manolescu, MD, PhD, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania Catalin Enachescu, MD, PhD, Research, Elias Hospital, Bucharest, Romania Alexandra Maria Hillebrand -Voiculescu, PhD, ,,Emil Racovita,, Institute of Speleology of the Romanian Academy, Bucharest, Romania Loredana Mitran, MD, PhD, Emergency Universitary Hospital Elias , Bucharest, Romania Mihai Mitran, MD, PhD, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania Carmen Sorina Martin MD, PhD, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania

INTERNATIONAL EDITORIAL BOARD Serban P. Georgescu, MD, Romanian American Biomedical Association, Boston, Massachusetts, USA Ciprian Enachescu, MD, Societé Francaise De Radiothérapie Et Oncologie, LYON, FRANCE Daniel Nichita, Md, Ms, Senior Medical Editor, Borm Bruckmeier Publishing, California, USA Raffaele Rauso, MD, University of Foggia, Foggia, Italy Nikoleta Koini, Md, Greek Medical Association, Athens-Greece Marinela van den Heuvel-Olăroiu, MD, PhD, SOAZ / RACE (Research and Advice in Care of Elderly), Maastricht, The Netherlands Carmen Dolea, MD, MPH, MBA, World Health Organization, Geneva, Switzerland Patrick Treacy, LRCSI, MICGP, MBCAM, DRCOG, DCH, H Dip Dermatology, Dublin, Ireland Tara Nekoroski, Bachelor degree, Halozyme Therapeutics, San Diego, CA, USA Elena Campione, MD, PhD, University Hospital of Rome ,,Tor Vergata,, Italy Carlo Enrico Urbani, MD, PhD, Centro Medico Althea, Milan, Italy Payam Behzadi, MSc, PhD, Islamic Azad University, Shahr-e-Qods Branch, Tehran, Iran

EDITORIAL OFFICE TEAM Ana Maria Cristina Medeleanu Ana Maria Veronica Draganita

EDITORIAL

THE SEVEN S OF SKIN® TAKE YOUR HEALTH AND BEAUTY TO THE NEXT LEVEL! Victor Gabriel Clătici

MEDICAL CODING, AN UNIVERSAL LANGUAGE IN THE 21s CENTURY Șerban P. Georgescu, Alexandru B. Tănase

DERMATOPATHOLOGY

A RETROSPECTIVE STUDY OF HISTOPATHOLOGIC CHANGES USEFUL IN DIFFERENTIATING EARLY PATCH/PLAQUE-STAGE MYCOSIS FUNGOIDES FROM MIMICKERS Tiberiu Tebeică, Răzvan Andrei, Florica Stăniceanu

104 110 117 122 128 136

CLINICAL STUDIES

HIGH RESOLUTION IMAGING TEHNIQUES FOR TRICHODYSTROPHIES IN NETHERTON SYNDROME Ioana Gencia, Florica Doroftei, Persa Ghitulescu, Caius Solovan

148

ISSN 2392 – 7461 ISSN-L 2392 – 7461

CLINICAL STUDIES

FAVRE-RACOUCHOT SYNDROME. A CLINICAL STUDY Mihail-Alexandru Badea, Horațiu Moldovan, Diana Gingean, Dana Bratu, Anton-Mihai Țilea, Andreea Marin, Morariu Silviu-Horia

REVIEW

PROPIONIBACTERIUM ACNES AND THE SKIN DISEASE OF ACNE VULGARIS Elham Behzadi, Payam Behzadi, Cristiana Voicu

UPDATES

UPDATES IN ETIOPATHOGENY AND TREATMENT OF ALOPECIA AREATA Iulia Andronache, Adina Oprea, Vasile Benea, Simona Roxana Georgescu, Oana Andreia Coman

CASE PRESENTATIONS

AMIODARONE - INDUCED SKIN PIGMENTATION: TWO CLINICAL CASES Virgil Pătrașcu, Florentina Delcea,Raluca Niculina Ciurea, Tchernev Georgi, Corneliu Cristian Georgescu, Anastasiya Atanasova Chokoeva, Andreea-Oana Enache

CASE PRESENTATIONS

A RARE ASSOCIATION BETWEEN LAUGIER-HUNZIKER, SJOGREN SYNDROMES AND OTHER AUTOIMMUNE DISORDERS- CASE REPORT AND LITERATURE REVIEW Cristiana Voicu, Ana-Livia Cărbunaru, Mihaela Berevoescu, Oana Mihalcea, Victor Gabriel Clătici

144

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CASE PRESENTATIONS

ANGIOLYMPHOID HYPERPLASIA WITH EOSINOPHILIA WITH LATER ONSET - CASE REPORT Virgil Pătraşcu, Raluca Ciurea, Marius Eugen Ciurea, Andreea - Oana Enache

NATIONAL AND INTERNATIONAL EVENTS CALENDAR

CEO Alina NICOLEANU Sales Manager Ionuţ NICOLEANU Communication Manager Alexandra MĂNĂILĂ Administrative Manager Andreea BANEA Graphic Designer Andrei ȘERBAN Key Account Managers Ioana BUTURUGĂ Dragoș CHIRIAC Web Designer Răzvan MATEI SUBSCRIPTIONS Tel.: 031.100.01.88 E-mail: office@msc-ro.com Copyright© 2016 MEDIA SYSTEMS COMMUNICATION S.R.L. All rights are reserved. For total or partial reproduction, and in any form, printed or electronic, or distribution of materials published is required only with the written consent of the publisher. The responsibility of original content of published articles belongs to original authors. Every interviewed person responds entirely for their statements. Also the buyers of advertised space are responsible for information included in their advertisements.

Editorial

The Seven S of Skin®

Take your health and beauty to the next level!

Dr. Victor Gabriel Clătici Editor-in-Chief & Managing Editor

We are living in a world of ,,first impression,, and you don't have the second chance to make a ,,good first impression,,! The skin is the most important contributor in ,,first impression,, and attractiveness, being strongly connected with the visual look and smell. Our skin is the first shield against external aggression and is permanently ,,under siege,,! The Seven S of the Skin represent a useful approach to audit the skin health and beauty, and to make the necessary corrections! First S is SUN, the most important factor in skin aging and in development of skin cancer. Sun, with the help of Ultraviolet A - UVA and B – UVB, is strongly involved in premature aging (photoaging) with wrinkles and fine lines, pigmented spots (freckles, solar lentigines etc.), loss of elasticity and resistance of the skin, and textural changes. An article published in 2013 estimated the importance of UV and sun exposure in visible aging at about 80%. And we must remember sun is strongly connected with skin cancer and cataract! The second S is a veritable ,,Trojan horse,, , respectively SUGAR! Sugar is involved in a reaction named glycation, whose results are AGEs, respectively Advanced Glycation End Products. Unfortunately for our complexion, collagen and elastin are involved in glycation, becoming stiff and malformed. At the end, we develop wrinkles and fine lines, sagginess and loss of radiance with enlarged pores. The worst news is that AGEs make your face more vulnerable to UV exposure and smoking. The next S is a genuine ,,winner,,! It is associated with premature aging and wrinkles, bags under your eyes and stained teeth, yellow fingers and thinner hair, skin cancer and improper wound healing, stretch marks and cataract! I think you know that must be about SMOKING! Smoking reduces the oxygen and nutrients in skin, triggering the destruction of collagen and elastin! First correlation between smoking and complexion was made in 1865 in Lancet, and in 1985 the ,,smoker face,, has been described! On our list, the next S is represented by,,SKIN CARE,,! A good skin care includes an adapted, individualized and personalized regimen! And the treatments with EBD – Energy Based Devices (laser, pulsed light, ultrasound, radiofrequency etc.) can be included here! STRESS and SLEEP are the next S! A good sleep and the reduction of stress levels are probably some of the quickest methods to look good and younger! The last S comes from SECOND, our permanently tribute to Chronos! Your short list to health and beauty: 1. put sunscreen on your skin, 2. cut sugar and quit smoking, 3. go to sleep!

Editorial

Medical Coding,

anUniversalLanguageinthe21sCentury Dr. Șerban P. Georgescu Chief Executive Officer / Co-founder, NotoVox

Dr. Alexandru B. Tănase Chief Medical Officer / Founder, NotoVox

Since Hippocrates, physicians have tried to classify diseases and related information (signs, symptoms, abnormal findings, social circumstances, external causes, etc). After several inconsistent approaches, the first modern system of codes named the International Classification of Causes of Death was introduced in 1900. It was followed by subsequent revisions about every decade, and renamed later as ICD, the International Classification of Diseases. In 1992 WHO published the current version, ICD-10, which was embraced gradually by most countries, with the latest adopter being United Stated in October 2015. Yet, after ten revisions and over a hundred years, the coding book has become thicker, but its structure has not changed significantly, it is still mono-hierarchical and inconsistent, with diseases classified by their anatomy and occasionally by etiology. For example, while Discoid lupus the eyelid can be found under Ophthalmology, Discoid lupus erythematosus sits under Diseases of skin, and Systemic lupus erythematosus under Musculoskeletal and Connective tissue diseases. With the transition from ICD-9 to ICD-10, the Dermatology chapter almost quadrupled, from 204 codes distributed in 3 groups, to 768 codes in 9 groups. By comparison, Cardiology increased 2.6 times and Neurology only 1.2 times. Dermatology ceased a long time ago to focus solely on the skin. It now crosses barriers and interacts with multiple specialties. Advances in genetics, pathology, immunology, or microbiome give new perspectives to etiology and pathology of dermatological conditions. And indeed, its increasing importance is reflected in the upcoming ICD-11, whose draft shows 19 Dermatology groups, including “Genetic, chromosomal and developmental disorders affecting the skin”, “Cutaneous markers of internal disorders”, and “Psychological, psychiatric, sensory and neurological disorders affecting the skin”. Thus, Dermatology continues its movement from a morphology-based specialty to an etiology-driven discipline. As ICD stands for International Classification of Diseases, these codes provide an universal language for the healthcare system, a language which crosses geographies and spans all medical specialties. Medical coding and classification systems like ICD and SNOMED (Systematized Nomenclature of Medicine) allow an easy understanding of medical diagnoses throughout the world, with no language or cultural barriers. Whether it is for clinical, research or epidemiological purposes, physicians need to communicate precisely and in meaningful ways about their patients. Diseases know no boundaries, and medical discoveries, information and therapies must be universal. While the terminologies are evolving rapidly towards knowledge-based ontologies of medical concepts, current coding softwares are slow, inefficient and counterintuitive in helping us to find the desired code. We, physicians, do not think in codes. We think in medical terms as we were taught in medical school and later in training. Novel technologies that allow doctors to seamlessly express themselves about their patients, that “translate” physician thinking into standardized, internationally recognized codes, will make communication in the global healthcare system much more efficient. In every field the world is becoming smaller by the day. Now it’s time to do the same for medical coding with solutions which bring us a common, computerized language that unifies medical specialties and physicians across the globe.

Dermatopathology

A Retrospective Study of Histopathologic Changes Useful in Differentiating Early Patch/Plaque-Stage Mycosis Fungoides from Mimickers

A RETROSPECTIVE STUDY OF HISTOPATHOLOGIC CHANGES USEFUL IN DIFFERENTIATING EARLY PATCH/PLAQUE-STAGE MYCOSIS FUNGOIDES FROM MIMICKERS STUDIU RETROSPECTIV ASUPRA MODIFICĂRILOR HISTOPATOLOGICE UTILE ÎN DIFERENȚIEREA DINTRE MYCOSIS FUNGOIDES- STADIUL INIȚIAL DE PLACĂ ȘI IMITATORI Tiberiu Tebeică1, Răzvan Andrei2, Florica Stăniceanu2, 3 Department of Histopathology, Dr Leventer Centre, Bucharest, Romania 2 Department of Pathology, ”Colentina” University Hospital, Bucharest, Romania 3 ”Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania 1

Corresponding author: Tiberiu Tebeică, MD Dr Leventer Centre, Department of Histopathology, Sevastopol 13-17, Centrul Diplomat, Ste.204, 010991 Bucharest, Romania; Phone number: +4(021)3106507; Fax: +4(021)3106508. E-Mail: tebeica@gmail.com

Conflict of interest: The authors do not have any conflict of interest to declare.

Open Access Article

Abstract Keywords: Mycosis fungoides, epidermotropism, Pautrier microabscesses, parapsoriasis.

Cite this article: Tiberiu Tebeică, Răzvan Andrei, Florica Stăniceanu, A Retrospective Study of Histopathologic Changes Useful in Differentiating Early Patch/Plaque-Stage Mycosis Fungoides from Mimickers. RoJCED 2016; 3(2):94 - 102

Introduction: The diagnosis of Mycosis fungoides (MF) in its early stages is a complex process that requires integrated interpretation of clinical, histopathological, immunohistochemical and biomolecular data. Diagnostic uncertainty when assessing biopsies from suspicious lesions of early MF is a common problem encountered in dermatopathology. Methods: In this study, a comparative analysis of microscopic changes present in 47 biopsies from early-stage lesions of 37 patients with confirmed MF and 30 biopsies from patients with various inflammatory dermatoses that mimic MF clinically or histopathologically was undertaken. Multiple histologic criteria were assesed, grouped into 5 categories: epidermal reaction, epidermotropism, presence of atypical lymphocytes, dermal reaction and dermal infiltrate. Results: Statistically significant differences (p<0.05) were recorded for the presence of epidermotropic lymphocytes, atypical lymphocytes, dermal fibrosis and a “band-like” lichenoid infiltrate in the dermis. Spongiosis and presence of low numbers of eosinophils in the inflammatory infiltrate were not significant factors for exclusion of MF. Discussion: In daily practice, when assessing biopsies taken from clinically suspicious lesions of early-stage MF, the absence of histopathological changes traditionally considered specific for MF should not prompt the exclusion of this diagnosis, an “wait-and-watch” attitude being more appropriate.

R O M A N I A N J O U R N A L o f C L I N I CA L a n d E X P E R I M E N TA L D E R M ATO LO GY

Tiberiu Tebeică, Răzvan Andrei, Florica Stăniceanu

Rezumat Cuvinte-cheie: Mycosis fungoides, epidermotropism, microabcese Pautrier, parapsoriazis.

Introducere: Diagnosticul de micozis fungoides (MF) în fază incipientă este complex, fiind un proces care necesită o interpretare integrată a datelor obținute din investigații clinice, histopatologice, imunohistochimice și biomoleculare. Incertitudinea diagnosticului la evaluarea biopsiilor obținute din leziunile suspecte de MF incipient este o problemă frecvent întâlnită în dermatopatologie. Metode: În acest studiu a fost realizată o analiză comparativă a modificărilor microscopice prezente în 47 de biopsii din leziuni de stadiu incipient prelevate de la 37 de pacienți cu MF confirmat și 30 biopsii de la pacienți cu diferite dermatoze inflamatorii care imită MF clinic sau histopatologic. Au fost evaluate mai multe criterii histopatologice, grupate în 5 categorii: reacția epidermică, epidermotropismul, prezența limfocitelor atipice, reacția dermică și infiltratul dermic. Rezultate: S-au înregistrat diferențe semnificative statistic (p <0,05) pentru prezența limfocitelor epidermotrope, a limfocitelor atipice, a fibrozei dermice și a infiltratului inflamator dermic “în bandă”. Spongioza și prezența unui număr scăzut de eozinofile în infiltratul inflamator nu au reprezentat factori semnificativi de excludere a MF. Discuţie. În practica zilnică, atunci când se evaluează biopsiile prelevate din leziuni suspecte clinic de MF în stadiul incipient, absența unor modificări histopatologice considerate în mod tradițional specifice pentru MF nu ar trebui să determine excluderea acestui diagnostic, o atitudine de urmărire clinică atentă și eventual rebiopsiere fiind mai potrivită.

Introduction Mycosis fungoides (MF), a neoplasm of skinhoming memory T cells, is the most often encountered type of cutaneous lymphoma(1). Clinically, MF cases present with persistent skin lesions of varying size and shape, usually manifesting as patches that may gradually progress to plaques and eventually tumors. Patients in early patch and plaque stages typically show a favorable prognosis, however, some cases are prone to systemic spread with involvement of lymph nodes and internal organs(2). Since the morphology of cutaneous MF lesions is variable, patients presenting especially early in the course of the disease can be mislabelled with different benign dermatoses, leading to delayed or inappropriate therapeutic measures. Many case reports and even a few systematic reviews have recognized early MF as one of the clinical masqueraders that can immitate a wide variety of inflammatory skin conditions, mainly with eczematous, psoriasiform and lichenoid characteristics(3),(4). In such instances, there may also be challenges in differentiating early MF from its benign counterparts histologically, due to the fact that the reactive infiltrate usually overwhelm the malignant lymphoma cells. Uncertainty when assessing biopsies from clinically suspicious lesions of early MF is a major issue in dermatopathology, a definitive diagnosis requiring integrated interpretation of clinical, histopathological, immunohistochemical and biomolecular data, and sometimes clinicopathological follow-up(5). In this study, we sought

to further characterize the histopathologic features of MF in a Romanian population, by analyzing biopsies taken from patch/plaque stage lesions early in the course of their disease and comparing these features with those of various inflammatory dermatoses that mimic MF histopathologically.

Methods A computer-driven quiery was performed at Colentina University Hospital, Bucharest, to retrieve all biopsies of centrally diagnosed MF cases received in the Department of Pathology between September 2009 and August 2014. We selected for the study only the cases that had a definitive diagnosis of MF in accordance with previously recommended criteria published by the International Society for Cutaneous Lymphoma (ISCL)(6). For every case there was available at least one biopsy from a patch/plaque-type lesion and selected cases were followed up for confirmation for at least one year, and up to six years from initial biopsy. We excluded the biopsies from tumoral lesions of MF, particular variants of MF, such as folliculotropic MF, granulomatous MF and the cases that showed unusual immunophenotype (CD8+ variant, CD30+ transformation). Due to the controversial nature of parapsoriasis, we also excluded all cases of small plaque parapsoriasis returned by the computer search. As per internal diagnostic protocols, cases of large plaque parapsoriasis are usually considered MF only when they meet minimum score for MF(6). In every selected study case, the final diagnosis was established by correlating histopathologic June 2016

Dermatopathology

A Retrospective Study of Histopathologic Changes Useful in Differentiating Early Patch/Plaque-Stage Mycosis Fungoides from Mimickers

findings with clinical appearance and follow-up, using medical records, photographs taken during clinical examination, clinical evaluation or direct communication with the patient’s physician. When two or three different biopsies were available from the same patient, all were included in the study. The control group included various spongiotic, lichenoid or psoriasiform simulators of MF retrieved from files. Control cases were highly suspicious of early MF on histolpathogic grounds per original pathology reports, showing different features of MF, but in none of these cases MF was considered in the clinical differential diagnosis. All control cases were discussed in multidisciplinary team and they did not achieve ISCL criteria for MF(6) at the time of biopsy or during subsequent follow-up. Hematoxilin and eosin (H&E)-stained sections were available for all biopsies belonging to study and control groups. Some cases had additional histochemical stains performed, such as periodic acid-Schiff and Perls. Immunohistochemical stains originally used for diagnostic purpose were not retrieved, since they were not subject of this study. All slides were randomized and blindly examined by two investigators under a multihead microscope (TT, RA). Multiple histologic criteria were assesed, grouped into 5 categories: epidermal reaction, epidermotropism, presence of atypical lymphocytes, dermal reaction and dermal infiltrate. Every feature was recorded as “-“ (absent) or “+” (present, at least 25% of epidermal surface in one section). When a histologic feature was present only focally or in multiple isolated foci that summed up less than

a quarter of a section, it was recorded as absent (“-“). A different semiquantification rule was used to assess the presence of certain cellular components in the composition of dermal infiltrate, namely eosinophils and plasma cells. They were considered present (“+”) when minimum 5 cells could be counted in one tissue section. For statistical analysis, an online calculator was used to calculate a z-score for each criterion, which was subsequently converted to a two-tailed p value. Results were considered statistically significant for p <0.05.

Results Our initial search in the database returned 146 cases including “mycosis fungoides” term in the pathology report, during September 2009 and August 2014. Out of these, there was a total number of 47 biopsies from patch/plaque lesions obtained from 37 patients with MF that met the inclusion criteria for MF group. Slide specimens of all cases were available for analysis. From the same pool, a total of 30 biopsies of variuos histopathologic mimickers of MF met the inlcusion criteria in the control group, as described above. It contains the following entities that showed variuos histopathologic features of MF per original biopsy report: various eczematous dermatitides, including atopic dermatitis (13 cases, 43.3%), lymphomatoid contact dermatitis (1 case, 3.3%), lymphomatoid drug eruption (1 case, 3.3%), pigmented purpuric dermatitis (1 case, 3.3%), lichen sclerosus (3 cases, 10%), lichen simplex chronicus (3 cases, 10%), actinic reticuloid (1 case, 3.3%), pityriasis lichenoides chronica (3 cases, 10%), pityriasis

Table 1. Number and distribution of selected MF and control cases MF

Mimickers

Total cases

No. of biopsies available for study

N = 47

N = 30 Eczematous dermatitides, 13 Lymphomatoid contact dermatitis, 1 Lymphomatoid drug eruption, 1 Pigmented purpuric dermatitis, 1 Lichen sclerosus, 3 Lichen simplex chronicus, 3 Actinic reticuloid, 1 Pityriasis lichenoides chronica, 3 Pityriasis rubra pilaris, 1 Psoriasis vulgaris, 3

Average age, years

56.4

54.1

Range, years

25-81

24-82

Median age, years

57.5

R O M A N I A N J O U R N A L o f C L I N I CA L a n d E X P E R I M E N TA L D E R M ATO LO GY

Tiberiu Tebeică, Răzvan Andrei, Florica Stăniceanu

rubra pilaris (1 case, 3.3%), and psoriasis vulgaris (3 cases, 10%) (Table 1). The average patient age for MF was 56.4 years (range 25-81 years; median 60 years). The average patient age for mimickers was 54.1 years (range 24-82 years, median 57.5 years). The MF cases were composed of 24 males (65%) and 13 females (35%), whereas the mimickers group was composed of 14 males (47%) and 16 females (53%) (Table 1). There were several significant differences and overlapping features between MF cases and mimi ckers. The complete results of the randomized, blinded histologic assessment were detailed in Ta-

ble 2 and particular features were illustrated in the photomicrographs. Major differences were recorded for the presence of psoriasiform hyperplasia of the epidermis, parakeratosis in elongated mounds, all types of epidermotropism, the presence of hypertrophic lymphocytes, papillary dermal fibrosis, papillary dermal edema, and disposition of dermal infiltrate. Morphologic features that could not be used to reliably differentiate MF from mimickers include the presence of spongiosis, some features of lymphocyte atypia, and low numbers of eosinophils in the dermal infiltrate.

Table 2. Comparison of histopathologic features between early MF and mimickers MF N = 47

Mimickers N = 30

z value (95% confidence level)

Two-tailed P

Epidermal reaction Spongiosis

17 (36.1%)

12 (40%)

-0.33

0.72

Psoriasiform hyperplasia

14 (29.7%)

20 (66.6%)

-3.17

0.001

Interface dermatitis

11 (23.4%)

6 (20%)

0.35

0.72

Epidermal atrophy

6 (12.7%)

2 (6.6%)

0.85

0.39

Parakeratosis

40 (85.1%)

19 (63.3%)

2.2

0.02

Basilar lymphocytes

18 (38.3%)

5 (16.6%)

2.02

0.04

Pagetoid lymphocytes

21 (44.7%)

6 (20%)

2.21

0.02

8 (17%)

0 (0%)

2.38

0.01

25 (53.2%)

5 (16.6%)

3.2

0.001

Cerebriform nuclei

2 (4.2%)

0 (0%)

1.14

0.25

Haloed lymphocytes

12 (25.5%)

7 (23.3%)

0.21

0.82

3 (6.4%)

0 (0%)

1.41

0.15

12 (25.5%)

1 (3.3%)

2.53

0.01

1 (2.1%)

0 (0%)

0.8

0.42

Papillary dermal fibrosis

39 (82.9%)

8 (26.6%)

4.94

<0.0001

Papillary dermal edema

5 (10.6%)

9 (30%)

-2.14

0.03

8 (17%)

5 (16.6%)

0.04

0.96

6 (12.7%)

5 (16.6%)

-0.47

0.63

Lichenoid band-like

34 (72.3%)

6 (20%)

4.48

<0.0001

Perivascular

20 (42.5%)

24 (80%)

-3.23

0.001

Eosinophils

6 (12.7%)

7 (23.3%)

-1.2

0.22

Plasma cells

2 (4.2%)

0 (0%)

1.14

0.25

Epidermotropism

Pautrier microabscesses Disproportionate exocytosis Lymphocyte atypia

Hyperchromasia Hypertrophic lymphocytes Dermal atypical lymphocytes Dermal reaction

Purpura Pigmented macrophages Dermal infiltrate

June 2016

Dermatopathology

A Retrospective Study of Histopathologic Changes Useful in Differentiating Early Patch/Plaque-Stage Mycosis Fungoides from Mimickers

Discussion Mycosis fungoides is a potentially challenging diagnosis to make, especially in its early stages, when patients present to the dermatologist with erythematous patches and/or plaques of variable size and shape(7). Even when the clinical appearance of the lesions strongly suggests MF, a biopsy may not bring histologic proof in favor of this diagnosis. The reasons may include, among others, the paucity and low frequency of anecdotic histopathologic criteria associated with MF, namely epidermotropism, Pautrier microabscesses and lymphocytes with cerebriform nuclei, the possibility that the biopsy site might be unrepresentative for the whole rash, or even the fact that MF infiltrates can masquerade as different reactive conditions that share similar patterns of inflamation, such as psoriasiform, lichenoid or eczematous diseases. Vice versa, even when classical clues of MF are present in a given specimen, their interpretation has to be carefully made, since various reactive inflammatory conditions have been reported to share similar histopathologic features with early MF, such as drug-induced T-cell pseudolymphoma(8),(9), lichen sclerosus et atrophicus(10), persistent pigmented purpuric dermatoses(11), actinic reticuloid(12), eczematous dermatitides(13),(14), lymphomatoid contact dermatitis(15), benign lichenoid keratosis(16), connective tissue disease(17), and skin infections and infestations(18),(19), among others. In our study, we tried to comparatively assess the frequency of occurrence of different histopathologic criteria in biopsies from early lesions of MF, respectively from various entities that microscopically mimick MF. In the category of epidermal reaction (Figure 1) we investigated the appearance of spongiosis, psoriasiform hyperplasia, interface dermatitis, epidermal atrophy and the presence of elongated mounds of parakeratosis. A significant difference between MF and mimickers group was recorded for the presence of psoriasiform hyperplasia (29.7% in MF cases vs. 66.6% in control cases, p value = 0.001). In our opinion, this finding signifies a relative lack of epidermal reactivity as a response to the presence of lymphomatous infiltrate. When occured in MF cases, psoriasiform hyperplasia was rather irregular, lichen simplex chronicus-like, and was associated in a large proportion with a dense, band-like dermal infiltrate, finding which represents a combined psoriasiform and lichenoid pattern, as previousely described for MF(20). Parakeratosis, manifested as a thin, long band on top of the affected epidermis, was observed more frequently with MF biopsies (85.1% vs. 63.3%, p value = 0.027), thus being relatively specific for early MF in certain situations. Focal spots of parakeratosis manifested as isolated columns and mounds of parakeratosis were more oftenly seen in the control group, but this feature was not recorded when parakeratosis band was not continuous over at least one quarter of biopsy section. A surprising feature was the presence of a low degree of spongiosis in relatively similar propor-

tions in both groups (36% vs. 40%). In other words, spongiosis was a rather common event in early MF. This finding suggests that, when detected in biopsies for clinical suspicion of early MF, a low degree of spongiosis should not be the sole criterion for MF exclusion.

Figure 1. Epidermal reaction in patch/plaquestage MF: (a) Spongiosis; (b) Psoriasiform hyperplasia.

To be able to quantify the degree of epidermotropism, we looked for various patterns described before in patch and plaque-type MF(21),(22), like the presence of lymphocytes aligned along the basal layer of the epidermis (basilar lymphocytes), a diffuse spread of lymphocytes into the epidermis (pagetoid lymphocytes), the presence of lymphocytes in clusters larger than 3 cells (Pautrier microabscesses) and areas of spongiosis where exocytosis of lymphocytes overwhelms the degree of intercellular edema usually seen with spongiotic dermatitides (dysproportionate exocytosis) (Figure 2). At least one type of epidermotropism was detected in 44/47 MF biopsies (93.6%) vs. 14/30 (46.6%) control biopsies (P < 0001). A noteworhty feature was the occurrence of dysproportionate exocytosis in MF cases as compared to mimickers (53.2% vs. 16%, p = 0.001). This finding correlates with the frequency of spongiosis detected in MF cases. In the same time it confirms that spongiosis may not be a truly exceptional event in early MF, but when joined by a dysproportionate number of lymphocytes in the epidermis, it may even be a feature of MF. Another notable observation regards the presence of Pautrier microasbscesses, defined as collections of intraepidermal lymphocytes devoid of spongiosis. Their presence correlates well with MF, since this feature was recorded in none of the control cases. However, in some cases belonging to the control group and labeled as spongiotic dermatitis, there could be spotted intraepidermal collections of nonlymphoid cells with abundant eosinophilic cytoplasm and a larger, pale, some-

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Dermatopathology

A Retrospective Study of Histopathologic Changes Useful in Differentiating Early Patch/Plaque-Stage Mycosis Fungoides from Mimickers

times indented nucleus with a conspicuous nucleolus. They represent clusters of Langerhans cells that have been described before as pseudo-Pautrier abscesses, and usually appear in association with inflammatory dermatoses(23). Their occurrence should not be regarded as a histopathologic clue

for MF. Besides their cytologic features, the pseudo-Pautrier collections commonly develop in a background of spongiosis, a feature that may help in their discrimination from real Pautrier microabscesses, which are devoid of spongiosis. Although traditionally linked to cutaneous lym-

Figure 2. Patterns of epidermotropism: (a) Basilar lympho-

cytes in MF; (b) Pagetoid lymphocytes in MF; (c) Pautrier microabscess in MF; (d) Pseudo-Pautrier abscess in eczematous dermatitis; (e) MF without epidermotropism.

phoma, lymphocyte atypia has been found by different investigators to represent a subjective criterion, which sometimes is difficult to assess(24),(25),(26). Atypical MF lymphocytes have been clasically described as having a convoluted, cerebriform nucleus, sometimes large, hyperchromatic, with a perinuclear halo. We tried to independently asses all these features in our study, and observed that less than one quarter of MF cases showed at least one form of lymphoid atypia (Figure 3). Although rarely seen in early stages, the specificity of this finding is very high for MF, equal to or nearly 100%, since the presence of atypical lymphocytes in the epidermis of reactive dermatoses was a extremely rare event. The single most frequent atypical feature in the control group was the perinuclear halo, which can be possibly interpreted as a processing artefact. Together with hyperchromasia, it had no discriminatory value between MF and mimicker groups. Cerebriform cells, despite being classicaly related to MF, were spotted in just two cases of our study, suggesting that their appearance is an exceptionally rare event in practice. One reason for that may be of technical nature, since cell morphology can be influenced by section thickness, tissue processing protocol, staining etc. The occurrence of hypertrophic lymphocytes was the most reliable feature of atypia, reaching statistical significance (25.5% vs. 3.3%, p = 0.011).

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Figure 3. Lymphocyte atypia in MF: (a)

Hypertrophic and hyperchromatic tumoral lymphocytes at the dermalepidermal junction; (b) Cerebriform lymphocytes in dermal infiltrate.

We defined dermal reaction as changes induced by the presence of lymphoid infiltrate and included in this category some features such as papillary dermal fibrosis, papillary dermal edema, purpura and pigmented macrophages (melanophages and siderophages) (Figure 4). Similar to other studies(27),

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Tiberiu Tebeică, Răzvan Andrei, Florica Stăniceanu

a statistically significant difference was noticed for papillary dermal fibrosis, feature commonly seen in MF group (83% vs. 26.6%, p < 0.0001). The presence of coarse, haphazardly oriented “wiry” collagen bundles in the upper dermis is one of the most reliable signs of patch and plaque-type MF, probably signifying the longstanding presence of the infiltrate at dermal level(20). It might be determined by the interaction of tumoral cells and their cytokine secretion with matrix proteins and matrix remodelation(28). Edema of the papillary dermis was deemed unusual in MF by other investigators, although it was recorded in some of our MF cases. For example, in the largest series of MF cases to date, Massone et al. recorded no papillary dermal edema in 745 biopsies(22). The presence of papillary dermal edema in 10.5% of our MF cases migh correlate with the presence of spongiosis in MF. All other dermal reaction changes did not reach statistical significance between the groups. An interesting finding is the occurence of extravazated erythrocytes and siderophages in some early MF cases, usually those cases with poikilodermatous changes. Purpura was seen with similar frequency in both our groups. When attempting a histopathologic diagnosis, the presence of siderophages naturally brings into question the possibility of a pigmented purpuric dermatosis (PPD). In some patients, MF and PPD have been shown to coexist(29), a finding challenged by other investigators(11),(30).

MF in appropriate clinical setting. But similar patterns of inflamation can be manifested in cutaneous biopsies of secondary syphilis, actinic reticuloid, lichen simplex chronicus among others, thus the architectural criteria alone are insufficient for the diagnosis of MF(31). On the other hand, a strictly perivascular infiltrate is rather common in reactive dermatoses and make MF unlikely, unless epidermotropic features or atypical lymphocytes are obvious. When looking at the composition of dermal infiltrate, there were 6 biopsies in MF group (12.7%) in which low numbers of eosinophils could be detected, at a density of minimum 5 eosinophils per section in at least one tissue section. Similarly, eosinophils were recorded in 23.3% of control cases (p = 0.22). There was no statistical difference between gropus, meaning that the presence of low numbers of eosinophils in the dermal infiltrate could not be used as a histopathologic criterion to certainly rule out early MF. None of the mimicker cases showed higher number of eosinophils. A reason for the relative paucity of eosinophils in the mimickers group might be the fact that cases with overtly more eosinophils in the infiltrate were not selected, because they did not fulfill the criteria of histopathological mimickers of MF. Contrary to our finding, Dalton et al. showed that the presence of eosinophils is unusual for early MF lesions, being a marker for spongiotic dermatitis(32). However, their threshold was set at a minimum of 3 eosinophils per section, and under this value, the autors stated that MF couldn’t be excluded when evaluating a biopsy that lacks other convincing criteria of exclusion. An argument for the presence of eosinophils in some of our early MF lesions might be unknown previous treatment of lesions with topical agents,

Figure 4. Dermal reaction in MF: (a) Fibrosis

of papillary dermis; (b) MF with purpura and siderophages (PPD-like).

Regarding the distribution of the dermal infiltrate (Figure 5), the lichenoid pattern defined as a dense, band-like infiltrate in the upper dermis correlated well with MF lesions (72.3% vs. 20%, p < 0.001). The presence of a dense lichenoid infiltrate usually explains the palpable nature of the plaquetype MF lesions, and when seen in biopsies along with other architecutral changes, like psoriasiform epidermal hyperplasia, can be highly indicative of

Figure 5. Features of dermal infiltrate: (a)

Lichenoid infiltrate in MF; (b) MF with sparse perivascular infiltrate; (c) Eosinophils in MF. June 2016

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A Retrospective Study of Histopathologic Changes Useful in Differentiating Early Patch/Plaque-Stage Mycosis Fungoides from Mimickers

especially in the setting of a clinically unresponsive rash.

Conclusions In our series of Romanian patients with early stage MF, we confirmed that the presence of epidermotropic lymphocytes, atypical lymphocytes, upper dermal fibrosis and a “band-like” lichenoid infiltrate are reliable histopathologic features. All subtypes of epidermotropism gained high specificity for early MF, but their sensitivity was usually low to be used as pivotal diagnostic criteria. Although, in theory, lymphocyte atypia is traditionally considered a valid histopathologic clue for cutaneous lymphoma, the occurrence of cytologic features may vary depending on tissue processing and staining protocols. Additionally, our study showed that morphologic criteria routinely assigned to reactive conditions, such as spongiosis, eosinophils and purpura with siderophages, were present in similar degrees in both case groups and may not allow differentiation of MF from mimickers. Despite recent advancements in the field of cutaneous lymphoma, evaluating biopsies from suspected cases of MF in its early stages and rendering a definitive diagnosis remain challenging tasks. Provided the biopsy is accompanied by

comprehensive clinical history, good description of the lesions, clinical pictures and efficient communication with reffering physician, we believe that a diagnosis of MF can be made with confidence. In certain cases, however, relying just on histopathologic criteria might prove erroneous, since there is no single criterion sensitive and specific enough to discriminate between early MF and a pletora of reactive inflammatory rashes. In daily practice, when assessing biopsies taken from clinically suspicious lesions of mycosis fungoides, the pathologist should not promptly exclude this diagnosis based solely on absence of traditional histopathologic changes, integrative interpretation together with clinical and ancillary data and possibly an “wait-and-watch” attitude being more appropriate. Acknowledgement: This study was partially presented at the 6th National Conference of the Romanian Society of Dermato-oncology, 14-16 May 2015, Cluj-Napoca, Romania. This work is licensed under a Creative Commons Attribution 4 .0 Unported License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc/4.0/

Bibliography 1. Bradford PT, Devesa SS, Anderson WF, Toro JR. Cutaneous lymphoma incidence patterns in the United States: a population-based study of 3884 cases. Blood. 2009; 113:5064–5073 2. Wernham AG, Shah F, Amel-Kashipaz R, Cobbold M, Scarisbrick J. Stage I mycosis fungoides: frequent association with a favourable prognosis but disease progression and disease-specific mortality may occur. Br J Dermatol. 2015; 173(5):1295-7 3. Nashan D, Faulhaber D, Ständer S, Luger TA, Stadler R. Mycosis fungoides: a dermatological masquerader. Br J Dermatol 2007; 156: 1-10 4. Sarantopoulos GP, Palla B, Said J, Kinney MC, Swerdlow SM, Willemze R, Binder SW. Mimics of cutaneous lymphoma: report of the 2011 Society for Hematopathology/European Association for Haematopathology workshop. Am J Clin Pathol 2013; 139: 536-551 5. Ferrara G, Di Blasi A, Zalaudek I, Argenziano G, Cerroni L. Regarding the algorithm for the diagnosis of early mycosis fungoides proposed by the International Society for Cutaneous Lymphomas: suggestions from routine histopathology practice. J Cutan Pathol 2008; 35: 549-553 6. Pimpinelli N, Olsen EA, Santucci M, Vonderheid E, Haeffner AC, Stevens S, Burg G, Cerroni L, Dreno B, Glusac E, Guitart J, Heald PW, Kempf W, Knobler R, Lessin S, Sander C, Smoller BS, Telang G, Whittaker S, Iwatsuki K, Obitz E, Takigawa M, Turner ML, Wood GS; International Society for Cutaneous Lymphoma. Defining early mycosis fungoides. J Am Acad Dermatol. 2005; 53(6):1053-63 7. Cho-Vega JH, Tschen JA, Duvic M, Vega F. Early-stage mycosis fungoides variants: case-based review. Ann Diagn Pathol 2010; 14: 369-385 8. Clark SH, Duvic M, Prieto VG. Mycosis fungoides-like reaction in a patient treated with Gleevec. J Cutan Pathol 2003; 30: 279-281 9. Wolf R, Kahane E, Sandbank M. Mycosis fungoides-like lesions associated with phenytoin therapy. Arch Dermatol 1985; 121: 1181-1182 10. Citarella L, Massone C, Kerl H, Cerroni L. Lichen sclerosus with histopathologic features simulating early mycosis fungoides. Am J Dermatopathol 2003; 25: 463-465 11. Toro JR, Sander CA, LeBoit PE. Persistent pigmented purpuric dermatitis and mycosis fungoides: simulant, precursor, or both? A study by light microscopy and molecular methods. Am J Dermatopathol 1997; 19: 108-118 12. Bakels V, Van Oostveen JW, Preesman AH, Meijer CJ, Willemze R. Differentiation between actinic reticuloid and cutaneous T cell lymphoma by T cell receptor gamma gene rearrangement analysis and immunophenotyping. J Clin Pathol 1998; 51: 154-158 13. Ackerman AB, Breza TS, Capland L. Spongiotic simulants of mycosis fungoides. Arch Dermatol 1974; 109: 218-220 14. Fisher AA. Allergic contact dermatitis mimicking mycosis fungoides. Cutis 1987; 40: 19-21 15. Orbaneja JG, Diez LI, Lozano JL, Salazar LC. Lymphomatoid contact dermatitis: a syndrome produced by epicutaneous hypersensitivity with clinical features and a histopathologic picture similar to that of mycosis fungoides. Contact Dermatitis 1976; 2: 139-143 16. Al-Hoqail IA, Crawford RI. Benign lichenoid keratoses with histologic features of mycosis fungoides: clinicopathologic description of a clinically significant histologic pattern. J Cutan

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Pathol 2002; 29: 291-294 17. Magro CM, Crowson AN, Harrist TJ. Atypical lymphoid infiltrates arising in cutaneous lesions of connective tissue disease. Am J Dermatopathol 1997; 19: 446-455 18. Capella GL, Altomare GF. Mycosis on mycosis fungoides: zoophilic dermatophytosis selectively superimposed on preexisting cutaneous T-cell lymphoma (mycosis fungoides) plaques. Mycoses 2003; 46: 67-70 19. Walton S, Bottomley WW, Wyatt EH, Bury HP. Pseudo T-cell lymphoma due to scabies in a patient with Hodgkin’s disease. Br J Dermatol 1991; 124: 277-278 20. Sanchez JL, Ackerman AB. The patch stage of mycosis fungoides: criteria for histologic diagnosis. Am J Dermatopathol 1979;1:5-26 21. Shapiro PE, Pinto FJ. The histologic spectrum of mycosis fungoides/ Sezary syndrome (cutaneous T-cell lymphoma): a review of 222 biopsies, including newly described patterns and the earliest pathologic changes. Am J Surg Pathol. 1994;18:645–667 22. Massone C, Kodama K, Kerl H, Cerroni L. Histopathologic features of early (patch) lesions of mycosis fungoides: a morphologic study on 745 biopsy specimens from 427 patients. Am J Surg Pathol. 2005; 29:550–560. 23. Candiago E, Marocolo D, Manganoni MA, Leali C, Facchetti F. Nonlymphoid intraepidermal mononuclear cell collections (pseudo-Pautrier abscesses): a morphologic and immunophenotypical characterization. Am J Dermatopathol. 2000; 22(1):1-6 24. Santucci M, Biggeri A, Feller AC, Massi D, Burg G. Efficacy of histologic criteria for  diagnosing early mycosis fungoides: an EORTC cutaneous lymphoma study group investigation. European Organization for Research and Treatment of Cancer. Am J Surg Pathol. 2000; 24:40–50 25. Smoller BR, Bishop K, Glusac E, Kim YH, Hendrickson M. Reassessment of histologic parameters in the diagnosis of mycosis fungoides. Am J Surg Pathol. 1995;19:1423–1430 26. Flaxman BA, Zelazny G, Van Scott EJ. Non specificity of characteristic cells in mycosis fungoides. Arch Dermatol. 1971;104:141–147 27. Nickoloff BJ. Light -microscopic assessment of 100 patients with patch /plaquestage mycosis fungoides. Am J Dermatopathol 1988; 10:469-77 28. Vacca A, Moretti S, Ribatti D, Pellegrino A, Pimpinelli N, Bianchi B, Bonifazi E, Ria R, Serio G, Dammacco F. Progression of mycosis fungoides is associated with changes in angiogenesis and expression of the matrix metalloproteinases 2 and 9. Eur J Cancer. 1997; 33: 1685-1692 29. Georgala S, Katoulis AC, Symeonidou S, Georgala C, Vayopoulos G. Persistent pigmented purpuric eruption associated with mycosis fungoides: a case report and review of the literature. J Eur Acad Dermatol Venereol. 2001; 15: 62-64 30. Fink-Puches R, Wolf P, Kerl H, Cerroni L. Lichen aureus: clinicopathologic features, natural history, and relationship to mycosis fungoides. Arch Dermatol 2008; 144: 1169-1173 31. Reddy K, Bhawan J. Histologic mimickers of mycosis fungoides: a review. J Cutan Pathol. 2007; 34: 519-525 32. Dalton SR, Chandler WM, Abuzeid M, Hossler EW, Ferringer T, Elston DM, LeBoit PE. Eosinophils in mycosis fungoides: an uncommon finding in the patch and plaque stages. Am J Dermatopathol. 2012; 34(6):586-91

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Clinical Studies

High resolution imaging tehniques for trichodystrophies in Netherton syndrome

HIGH RESOLUTION IMAGING TEHNIQUES FOR TRICHODYSTROPHIES IN NETHERTON SYNDROME DETECTAREA DIFERITELOR TRICODISTROFII DIN SINDROMUL NETHERON FOLOSIND TEHNICI IMAGISTICE DE ÎNALTĂ REZOLUȚIE Ioana Gencia1,4, Florica Doroftei2, Persa Ghitulescu3, Caius Solovan1,4 1 ”Victor Babes” University of Medicine and Pharmacy Timisoara, Dermatology 2 ”Petru Poni” Institute of Macromolecular Chemistry, Iasi, Romania 3 Emergency City Hospital Timisoara, Dermatology 4 Emergency City Hospital Timisoara, Dermatology, Center for morphologic study of the skin Corresponding author: Ioana Gencia, Str. Daliei, nr 17, Timișoara, Romania, phone: +40729537007 e-mail: ioanavladtm@yahoo.com

Conflict of interest: The authors do not have any conflict of interest to declare.

Open Access Article

Abstract Keywords: trichodystrophies, scanning electron microscopy, reflectance confocal microscopy, trichoscopy.

Cite this article: Ioana Gencia, Florica Doroftei, Persa Ghitulescu, Caius Solovan. High resolution imaging tehniques for trichodystrophies in Netherton syndrome. RoJCED 2016; 3(2):104 - 108

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Introduction: The pathognomonic trichodystrohy in Netherton’s syndrome is trichorrhexis invaginata. This hair shaft anomaly is not constantly present and it can be associated with other anomalies like trichorrhexis nodosa or pili torti. Methods: We retrospectively analyzed hair samples from patients diagnosed with NS over the past 10 years in the Dermatology Clinic Timisoara by using scanning electron microscopy. The samples were of scalp hair, eyebrows, eyelashes and pubic hair. We also evaluated some of these samples with trichoscopy and confocal microscopy. Results: The scanning electron microscopy results showed that trichorrhexis invaginata was evident in all cases, followed by trichorrhexis nodosa and pili torti respectively. In these patients there was more than one type of trichodystrophy present at the same time. All of these modifications were perceptible with the confocal scanning microscope and by trichoscopy. Discussion: The electron microscopy helps by supplying three-dimensional images of the hair shaft, thus enabling the observation of the hair samples with a greater clarity and sharpness than through classical methods. Also reflectance confocal microscopy and trichoscopy have proven to be very useful in the diagnosis of hair shaft anomalies.

R O M A N I A N J O U R N A L o f C L I N I CA L a n d E X P E R I M E N TA L D E R M ATO LO GY

Ioana Gencia, Florica Doroftei, Persa Ghitulescu, Caius Solovan

Rezumat Cuvinte-cheie: tricodistrofii, microscopie electronică de baleiaj, microscopie confocală, tricoscopie.

Introducere: Tricorexis invaginata este tricodistrofia patognomonică pentru sindromul Netherton. Aceasta nu este prezentă în mod constant și poate fi asociată cu alte anomalii ale firului de păr, cum ar fi tricorexis nodosa sau pili torti. Metode: Prin folosirea microscopiei electronice, am analizat mostre de fire de păr provenite de la pacienți diagnosticați cu sindrom Netherton în Clinica de Dermatologie Timișoara în ultimii 10 ani. Acestea au fost prelevate atat de la nivelul scalpului cat și sprâncenelor, genelor și părului pubian. Unele dintre aceste mostre au fost analizate și prin tricoscopie și microscopie confocală. Rezultate: Tricorexis invaginata a fost prezentă la toți pacienții, fiind urmată ca frecvență de tricorexis invaginata și pili torti. La acești pacienți aceste modificări s-au asociat în diferite combinații. Toate aceste modificări au putut fi identificate și prin tricoscopie și microcopie confocală. Concluzii: Microscopia electronică de baleiaj ajută în identifica rea acestor modificări deoarece oferă o imagine tridimensională, mai clară și mai exactă decât metodele clasice. De asemenea, microscopia confocală și tricoscopia și-au dovedit utilitatea în diagnosticul tricodistrofiilor.

Introduction Netherton syndrome (NS) is a rare autosomal recessive genodermatoses caused by loss-of-function mutations in a SPINK5 gene (serine protease inhibitor of kazal type 5) situated on chromosome 5q32. This gene encodes LEKTI-1 (lympho-epithelial kazal type related inhibitor) expressed in stratified epithelia(1). The loss of this inhibitor results in an early activation of stratum corneum tryptic/ chymotryptic protease, resulting in proteolysis of adhesion molecules(2). From the clinical point of view, it is characterized by severe skin inflammation and scaling (ichthyosiform erythroderma in newborns or ichthyosis linearis circumflexa), a specific hair shaft defect and atopic diathesis. The atopic manifestations are present in most cases, represented by: atopic dermatitis, asthma, angioedema, urticaria, high levels of IgE and hypereosinophilia(3,4). The most characteristic trichodystrophy is trichorrhexis invaginata (“bamboo hair”) in which the distal hair segment (fully keratinized and hard) is intussuscepted into the proximal one (soft due to abnormal keratinization). This anomaly is due to the abnormal cornification of the internal root sheaf. Other hair shaft defects seen in NS are trichorrhexis nodosa and pili torti. The trichorrhexis nodosa is caused by the appearance of a breach in the hair cuticle with separation associated with fraying of the exposed cortical fibers leading to a node-like swelling. The exposed fibers fracture and the shaft breaks taking the appearance of a splayed paint brush. The other trichodystrophy seen in patients with NS is pili torti characterized by the flattening and twisting of the hair shaft on

its own axis(5,6). These hair shaft abnormalities can be seen at different intervals along an otherwise straight hair shaft. Nowadays, there are a lot of tools which can be used to identify hair shaft defects ranging from trychoscope, light microscope to scanning electron microscope and even reflectance confocal microscope. In our study we used scanning electron microscopy to identify the hair shaft anomalies and on some hair samples trichoscopy associated with reflectance confocal microscopy (RCM). . Material and methods In this study we included 8 patients diagnosed with NS at the Timisoara Dermatology Clinic during a period of ten years. Their diagnosis was based on the pathognomonic triad represented by congenital ichthyosis, atopic manifestations and hair shaft anomalies and was confirmed by the presence of trichorrhexis invaginata in optical microscopy. The plucked hairs were first observed through light microscopy to confirm the presence of an abnormality and to select abnormal hairs; these hairs were then analyzed by scanning electron microscopy (SEM). The studies were performed on samples fixed on copper supports. The surface was examined by using an Environmental Scanning Electron Microscope (ESEM) type Quanta 200, operating at 20kV with secondary electrons in Low vacuum mode. For the reflectance confocal microscopic (RCM) analysis we used the VivaScope 3000 hand held device and for trichoscopy we use microDERM dermatoscopic camera. At first we identified and isolated the affected hairs from the preexisting June 2016

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High resolution imaging tehniques for trichodystrophies in Netherton syndrome

samples and then we used the confocal microscope to analyze the hair which presented trichodystrophies.

Results In scanning electron microscopy we found that trichorrhexis invaginata was evident in all cases. Trichorrhexis nodosa was seen in 62.5% of patients and pili torti in 50% of cases. Patients with

combined hair dystrophies represented 87.5%, of which 25% had findings consistent with trichorrhexis invaginata, trichorrhexis nodosa and pili torti, 37.5% had evidence of trichorrhexis invaginata and trichorrhexis nodosa and 25% presented trichorrhexis invaginata and pili torti. (Table 1) In the samples selected for trichoscopy we were able to confirm the presence of these trichodystrophies. In addition to this, by using RCM, we were

Table 1. Hair shaft anomalies found in our patients Initials, gender, age at onset L.A., F., 0-6 months

Trichorrhexis invaginata, trichorrhexis nodosa

I.V., F., 9 years

Trichorrhexis invaginata, trichorrhexis nodosa, pili torti

I.F.V., F., 2 years

Trichorrhexis invaginata, trichorrhexis nodosa, pili torti

T.M., F., 0-6 months

Trichorrhexis invaginata, trichorrhexis nodosa

L.C., M., 0-6 months

Trichorrhexis invaginata

B.E., F., 0-6 months

Trichorrhexis invaginata, trichorrhexis nodosa

L.P., M., 0-6 months

Trichorrhexis invaginata, pili torti

G.S., M., 0-4 months

Trichorrhexis invaginata, pili torti

Figure 1.

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Hair shaft anomalies

a) Trichoscopy trichorrhexis invaginata: â&#x20AC;?bamboo hairâ&#x20AC;? (30x magnification); b) Scanning electron microscopy: Trichorrhexis invaginata: intussusception of the distal hair shaft into the proximal hair shaft results in a distinctive ball-and-socket hair shaft deformity; in the areas around the intussuscepted hair shaft, there is disorganized keratinization; c) RCM the ball in socket deformity associated with abnormal keratinization on the surface of the hair shaft; d) RCM same area we but inside the shaft - the lack of continuity

R O M A N I A N J O U R N A L o f C L I N I CA L a n d E X P E R I M E N TA L D E R M ATO LO GY

Ioana Gencia, Florica Doroftei, Persa Ghitulescu, Caius Solovan

able to analyze the modifications present inside the hair shaft. Results of the SEM, RCM and trichoscopic evaluation of the hair shafts are shown in the figures below (photos from personal archive of the Emergency City Hospital Timisoara, Dermatology, Center for morphologic study of the skin). (Figs 1, 2, 3) The major hair dystrophies (trichorrhexis invaginata, trichorrhexis nodosa, pili torti) are accompa-

Figure 2.

Figure 3.

nied by minor modifications such as longitudinal fractures of the hair shaft (trichoptilosis), transversal fractures (trichoschisis), breaks, fissures and splits, as a result of the fragility of intrinsically abnormal hair.

Conclusions and discussions Our cases presented all the manifestations of NS described in literature. Although in literature trich-

a) Trichoscopy: trichorrhexis nodosa ( 80x magnification); b) Scanning electron microscopy. Trichorrhexis nodosa: the formation of nodes along the hair shaft through which breakage readily occurs; c) RCM similar image as SEM; d) RCM: a deeper horizontal section of the hair shaft

a) Trichoscopy: pili torti (30x magnification) b) Scanning electron microscopy. Pili torti: hair twisted 180Â° along its axis and transversal fracture of the hair shaft-trichoschisis; c), d) RCM pili torti associated with the granular keratinisiation characteristic for NS June 2016

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copy could be used to identify these hair shaft anomalies and could offer additional information regarding what happens underneath the surface of the hair. Seeing how with the VivaScope 3000 we could only analyze a limited area (500 m/500 m), we needed a tool in order to identify the affected hairs. Therefore, we used trichoscopy. In conclusion, electron microscopy helps by supplying three-dimensional images of the hair shaft, thus enabling the observation of the hair samples with a greater clarity and sharpness than through classical methods. Also reflectance confocal microscopy and trichoscopy have proven to be very useful in the diagnosis of hair shaft anomalies offering additional information. h

orrhexis nodosa is more frequent then trichorrhexis invaginata. In our group the incidence was reversed, the latter being present in all the patients while trichorrhexis nodosa was seen in 62,5% of cases. The explanation for this difference might the fact that our study investigated a small group of patients and the analyzed samples were obtained at different stages in their evolution. At first we focused on using optical microscopy or electron microscopy to diagnose the hair shaft anomalies because these were the proven methods. But then by using trichoscopy and confocal microscopy we demonstrated that these diagnostic tools seem to be very useful in the identification and analysis of trichodystrophies. We used SEM because it was proven that it offers the possibility of a more precise examination of cuticular scales of hair, it allows detailed observations of scale patterns and the possibility of considerable magnification(7). In addition to this, we used RCM. This choice was made because we believed that confocal micros-

High resolution imaging tehniques for trichodystrophies in Netherton syndrome

Clinical Studies

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Bibliography 1. Hovnanian A. Netherton syndrome: skin inflammation and allergy by loss of protease inhibition. Cell Tissue Res. 2013 Feb;351(2):289-300. doi: 10.1007/s00441-013-1558-1. Epub 2013 Jan 24. Review. 2. Chavanas S, Bodemer C, Rochat A, Hamel-Teillac D, Ali M, Irvine AD, et al. Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome. Nat Genet.2000;25:141–142 3. Judge MR, Morgan G, Harper JI.A clinical and immunological study of Netherton’s syndrome. Br J Dermatol. 1994; 131:615–21 4. Smith DL, Smith JG, Womg SW & De Shazo RD. Netherton's syndrome: a syndrome of

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elevated IgE and characteristic skin and hair findings. J Allergy Clin Immun 1995;95: 116–123 5. Klaus Wolff, Lowell A. Galdsmith, Stephen I. Katz, Barbara A. Gilchrest, Amy S. Paller, David J, Leffell. Distrophies of the hair and naiils. Fitzpatrick’s Dermatology in General Medicine, Eighth Edition; 2012: 1002-1008 6. Ito M, Ito K, Hashimoto K. Pathogenesis in trichorrhexis invaginata (bamboo hair).J Invest Dermatol1984;83:1–6. 7. Solovan C, Doroftei F, Pinteala M, Chiriac A, Cristea C. Scanning electron microscopic examination of the hair shaft abnormalities in Netherton’s syndrome. Int J Dermatol. 2015. 54(6): 693-694

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Clinical Studies

Favre-Racouchot Syndrome. A clinical study

FAVRE-RACOUCHOT SYNDROME. A CLINICAL STUDY STUDIU ASUPRA SINDROMULUI FAVRE-RACOUCHOT Mihail-Alexandru Badea1, Horațiu Moldovan2, Diana Gingean3, Dana Bratu4, Anton-Mihai Țilea5, Andreea Marin2, Morariu Silviu-Horia1 1 Dermatology Department, University of Medicine and Pharmacy of Târgu Mureș, Romania 2 Occupational Diseases Department, University of Medicine and Pharmacy of Târgu Mureș, Romania 3 Dermatology Clinic, Mures County Hospital of Târgu Mureș, Romania 4 Dermatology Clinic II, Clinical Hospital Colentina, Bucharest, Romania 5 Dermatology Clinic, “Dr. Carol Davila” Central University Emergency Military Hospital, Bucharest, Romania Corresponding author: Horațiu Moldovan, Senior lecturer, University of Medicine and Pharmacy of Tîrgu Mureş, 38 Gheorghe Marinescu Street, 540139 Tîrgu Mureş, Romania, phone: +40769049999, e-mail: horatiumoldovan@gmail.com

Conflict of interest: The authors do not have any conflict of interest to declare.

Open Access Article

Abstract Keywords: smoking, elderly, elastosis, undiagnosed, sun exposure.

Cite this article: Mihail-Alexandru Badea, Horațiu Moldovan, Diana Gingean, Dana Bratu, Anton-Mihai Țilea, Andreea Marin, Morariu Silviu-Horia. Favre-Racouchot Syndrome. A clinical study. RoJCED 2016; 3(2):110 - 114

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Introduction: Favre-Racouchot syndrome represents a chronic dermatosis, asymptomatic, associated with smoking, prolonged sun exposure and male sex. It presents as cysts on plaques of solar elastosis frequently localized to the face. Methods: We evaluated 7 patients aged between 56 and 88 years who presented with Favre-Racouchot syndrome. The data were processed using SPSS statistical software. We used frequency tables, so the data were expressed as absolute and relative frequencies. Given the limited we could not perform an inferential statistics. Results: All patients presented in dermatology units for other skin disorders. Three of them had another sun related dermatoses. All patients were active smokers or had a history of long term smoking. Five of them had Fitzpatrick type II phototype. Only one patient was female. None of the patients accepted treatment due to the asymptomatic character of the disease. Conclusions: The patients with Favre-Racouchot syndrome are not seeking the dermatologist for this dermatosis. The disorder is more common in male smokers with Fitzpatrick type II phototype and is mostly associated with other chronic photodermatoses. Extensive studies are needed for a more accurate characterization of the disease.

R O M A N I A N J O U R N A L o f C L I N I CA L a n d E X P E R I M E N TA L D E R M ATO LO GY

Mihail-Alexandru Badea, Horațiu Moldovan, Diana Gingean, Dana Bratu, Anton-Mihai Țilea, Andreea Marin, Morariu Silviu-Horia

Rezumat Introducere: Sindromul Favre-Racouchot reprezintă o dermatoză cronică, asimptomatică asociată cu fumatul, expunerea solară îndelungată și sexul masculin. Se prezintă sub formă de chisturi apărute pe plăci de elastoză solară și se localizează frecvent la nivelul feței. Material și Metodă: Am evaluat 7 pacienți cu sindrom Favre-Racouchot cu vârsta cuprinsă între 56 și 88 de ani. Datele au fost prelucrate utilizând softul statistic SPSS, ne-am bazat pe tabele de frecvență, astfel datele au fost exprimate prin frecvențe absolute și relative. Fiind date puține nu am putut efectua o statistică inferențială. Rezultate: Toți pacienții s-au adresat serviciului de Dermatologie pentru alte dermatoze. Trei (42.8%) dintre aceștia prezentau și alte fotodermatoze cronice (reticuloid actinic, granuloma actinic O’brien respectiv hiperplazie sebacee). Toți subiecții au fost fumători activi sau au prezentat un istoric de mari fumători. Cinci (71.4%) au avut fototipul II Fitzpatrick. Am avut un singur pacient de sex feminin (14.2%). Nici unul dintre cei șapte subiecți nu a urmat tratamentul recomandat datorită caracterului asimptomatic al bolii. Concluzii: Pacienții cu sindrom Favre-Racouchot nu se adresează medicului dermatolog pentru această dermatoză. Boala este mai frecventă la bărbații fumători cu fototip II Fitzpatrick și mare parte asociază alte fotodermatoze cronice. Sunt necesare studii mai ample pentru caracterizarea mai exactă a bolii.

Cuvinte-cheie: fumat, vârstnici, elastoză solară, expunere solară cronică.

Introduction Favre-Racouchot syndrome (FRS) represents a chronic dermatosis, asymptomatic, associated with smoking and prolonged sun exposure. It presents as cysts on plaques of solar elastosis. The most frequent locations are the periorbital and temporal regions, bilaterally, however unilaterally located cases have been described(1). Cases with localization of the disorder on the forearms and anterior thorax have also been described. An incidence of 1.4% in the population over 50 years has been reported(2). The differential diagnosis has to be made with milia, colloid milium, comedones, syringomas, trichoepitheliomas, sebaceous hyperplasia and trichostasis spinulosa. The therapy of choice is represented by CO2 laser followed by extraction of the comedones. Topical retinoids and microdermabrasion can also be used. The disease requires

long-term follow-up as cases of squamous cell carcinoma appearing on these lesions have been described(3).

Methods We evaluated 7 patients with Favre-Racouchot syndrome who presented to the Dermatology Department of the Tîrgu Mureș County Hospital, Romania, between June 2015 and February 2016. We focused on age, gender, chronic sun exposure, smoking history, associated dermatoses and Fitzpatrick skin phototype. We recommended to all the patients to stop smoking, to use sunscreens and topical retinoids or microdermabrasion. The data were processed using SPSS® statistical software. We used frequency tables, so the data were expressed as absolute and relative frequencies. Given the limited data, we could not perform an inferential statistics.

Table1. Patients Gender

Age

Smoker

Pack years

Yes 75

Examination reason Venous leg ulcer

Chronic associated photodermatoses*

Fitzpatrick phototype

None

Professional sun exposure Yes

June 2016

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Favre-Racouchot Syndrome. A clinical study

Yes 88

M M

58 56

O’Brien actinic granuloma

Venous leg ulcer

Sebaceous hyperplasia

Chronic eczema

None None

Pressure induced purpura

None

Cutaneous vasculitis

Actinic reticuloid

40 Yes Yes

Yes 59

Yes 61

O’Brien actinic granuloma

Yes

Yes I II II

Yes Yes Yes

II Yes II III

Yes

*We did not include in the chronic photodermatoses the chronic solar elastosis of the face without other superimposed lesions and did not include lesions from the photoprotected areas.

Results All patients with Favre-Racouchot syndrome from the study presented in our dermatology unit for other skin disorders. Most of the dermatoses for which the patients required a dermatological consultation were symptomatic: chronic venous ulcer, chronic eczema, contact dermatitis, actinic reticuloid. Some dermatoses were asymptomatic: O’Brien actinic granuloma, pressure induced purpura. All patients had a history of chronic sun exposure. In all patients the lesions were located on face. The age was between 56 and 88 years. The three of them had other sun related dermatoses. All patients were active smokers or had a history of long term smoking (between 20 and 40 pack years). Five of them (71.4%) had Fitzpatrick phototype II. Only one patient was female. None of the patients followed the recommended therapy on the grounds of the asymptomatic character of the disorder.

Discussions The Favre-Racouchot syndrome manifests more frequently in elderly caucasian males, with a his-

tory of extended sun exposure and severe chronic smoking(4,5). Cardoso et al describe two atypical cases of Favre Racouchot syndrome with lesions located on other sun exposed areas, on the forearms, the anterior thorax and were called actinic comedonal plaques, variants of FRS(6). Leeuwis-Fedorovich et al argue that the patients with Favre-Racouchot syndrome should have a long term follow up considering the fact that two cases of squamous cell carcinomas appeared on unilateral plaques of Favre-Racouchot(3). Although localized acne or comedonal reaction during or shortly after radiotherapy is an unusual adverse reaction, Hubiche et al.(7) have documented a case of a 58 years old patient with melanoma located to the nasal mucosa. After 3 weeks of radiotherapy this case presented in the radiation region with open and closed comedones, microcysts and no inflammatory papulo-pustular lesions. All the lesions have resolved with mechanical extraction(7). Sutherland also described a case that appeared after radiotherapy for oligodendroglioma in a young female patient(8). Hoff et al. reported a case that appeared after radiotherapy post-sur-

Picture 1. Favre-Racouchot syndrome. Clinical aspects (from personal archive of Mihail-Alexandru Badea, MD)

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R O M A N I A N J O U R N A L o f C L I N I CA L a n d E X P E R I M E N TA L D E R M ATO LO GY

Mihail-Alexandru Badea, HoraČ&#x203A;iu Moldovan, Diana Gingean, Dana Bratu, Anton-Mihai Č&#x161;ilea, Andreea Marin, Morariu Silviu-Horia

Figure 1. Gender distribution

Figure 2. Smoking history gery for nasal mucosa melanoma(9). Another case of FRS was described on the scalp after radiotherapy for astrocytoma(10). None of our seven patients were exposed to radiotherapy. Bourra H and Hassam B describe an interesting case of lupus erythematosus systemic in a female patient under chronic corticotherapy, which developed lesions of FRS. This is an interesting case considering the involvement of corticotherapy in the appearance of the acne lesions(11). FRS comedonal lesions or comedonal actinic plaques were described on old lesions of annular granuloma on photoexposed areas. Thus we can also take into account the iatrogenic role of phototherapy in the treatment of annular granuloma and other dermatoses(12). Tercedor et al reported a raised incidence of heliodermy in patients with chronic renal failure on hemodialysis, with FRS having an incidence of 5%(13). Also Ignat et al communicate an incidence of 2.8% in hemodialysed patients(14). The incidence seems to be increased in agricultural workers that work

with pesticides (25%)(15). A genetic predisposition can also be taken into account given the fact that Iwahori reported a case of father-son FRS(16). It has been reported in monozygotic twins in association with palmar keratoderma (17). Goldberg and Altman mention the association of the Favre Racouchot syndrome with other skin lesions caused by chronic sun exposure such as cutis romboidales nuchae, actinic keratosis and epitheliomas(18). Zhang and Zhu report for the first time the association of this syndrome with inferior eyelid papilloma(19). In the case of a sudden onset a biopsy should be performed to exclude an early stage of folliculotropic mycosis fungoides(20). Three of our patients had associated chronic photodermatoses: sebaceous hyperplasia, actinic reticuloid and Oâ&#x20AC;&#x2122;Brien actinic granuloma. In the management of the FRS patient there are different therapeutic approaches which are more effective in association. One can use comedonal extraction, electrocautery (slow cautery technique). Cryotherapy is also efficient. The pharmacological June 2016

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Favre-Racouchot Syndrome. A clinical study

Figure 3. Fitzpatrick phototype treatment is represented by the topical retinoids (tretinoin, adapalene, tazarotene). Recently a favorable evolution has been reported after the use of surgical techniques (dermabrasion, excision, curettage). Mavilia et al recommend CO2 laser therapy followed by the extraction of the cysts and the comedones, the method having very good cosmetic results and a rapid post therapeutic recovery(21).

Conclusions The patients with Favre-Racouchot syndrome do not address the dermatologist for this dermatosis. The disorder is more frequent in male smokers with Fitzpatrick phototype II and some patients associate other chronic photodermatoses. Other studies on larger groups are needed for a better

complex description of the disease and for a more efficient therapeutic approach.

Acknowledgments This paper is partially supported by the Grant No. 367/12/01.2015 “Study of premalignant and malignant skin lesions in people with chronic exposure to occupational and non-occupational sunlight”, approved by local ethical committee under No. 103/2015.

Bibliography 1. Kumar P, Marks R. Sebaceous gland hyperplasia and senile comedones: a prevalence study in elderly hospitalized patients.Br J Dermatol. 1987 Aug;117(2):231-6. 2. Schäfer T, Merkl J, Klemm E, Wichmann HE, Ring J; KORA Study Group. The epidemiology of nevi and signs of skin aging in the adult general population: Results of the KORA-survey 2000. J Invest Dermatol. 2006 ;126(7):1490-1496. 3. Leeuwis-Fedorovich NE, Starink M, van der Wal AC.Multifocal squamous cell carcinoma arising in a Favre-Racouchot lesion - report of two cases and review of the literature.J Dermatol Case Rep. 2015;9(4):103-136. 4. Lene Hedelund,; Hans Christian Wulf, Favre-Racouchot Disease Provoked by UV-A1 and UV-B Exposure, Arch Dermatol. 2004;140(1):129-131. 5. George C. Keough, MC; Richard A. Laws, MC; Dirk M. Elston, MC,Favre-Racouchot Syndrome: A Case for Smokers’ Comedones, Arch Dermatol. 1997;133(6):796-797. 6. Cardoso F, Nakandakari S, Zattar GA, Soares CT.Actinic comedonal plaque-variant of FavreRacouchot syndrome: report of two cases.An Bras Dermatol. 2015;90(3 Suppl 1):185-187. 7. Hubiche T, Sibaud V. Localized acne induced by radiation therapy.Dermatol Online J. 2014 18;20(2). 8. Sutherland AE, Green PJ. Favre-Racouchot syndrome in a 39-year old female following radiation therapy. J Cutan Med Surg. 2014;18(1):72-74. 9. Hoff NP, Reifenberger J, Bölke E, Homey B, Gerber PA.Radiation-induced Favre-Racouchot disease.Hautarzt. 2012;63(10):766-767. 10. Friedman SJ, Su WP. Favre-Racouchot syndrome associated with radiation therapy. Cutis. 1983;31(3):306-310. 11. Bourra H, Hassam B. Elastoidosis with cysts and comedones of Favre and Racouchot. Pan Afr Med J. 2013; 6:15-18.

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12. Sudy E, Urbina F, Espinoza X. Open comedones overlying granuloma annulare in a photoexposed area. Photodermatol Photoimmunol Photomed. 2006 ;22(5):273-274. 13. Tercedor J, López-Hernández B, Ródenas JM, Delgado-Rodríguez M, Cerezo S, SerranoOrtega S. Multivariate analysis of cutaneous markers of aging in chronic hemodialyzed patients. Int J Dermatol. 1995;34(8):546-550. 14. Ana-Sonia Ignat, Mirela Gliga, Iudita-Maria Badea, Mihail-Alexandru Badea, Elena Lefter, Silviu-Horia Morariu. Cutaneous findings in chronic kidney disease and hemodialysis. RoJCED 2015; 2(3):79-84. 15. Cellini A, Offidani A. An epidemiological study on cutaneous diseases of agricultural workers authorized to use pesticides. Dermatology. 1994;189(2):129-132. 16. Iwahori Y, Yamazaki S, Furuya T.Favre-Racouchot syndrome (élastéidose cutanée nodulaire à kystes et à comédons)-father and son and its hereditary pathogenesis. Nihon Hifuka Gakkai Zasshi. 1985;95(6):669-674. 17. Cantú JM,Macotela-Ruiz E.Concordance of marginal keratoderma of the palms and FavreRacouchot disease in MZ twins.Acta Genet Med Gemellol(Roma).1975;24(3-4):321-322. 18. Goldberg LH, Altman A. Benign skin changes associated with chronic sunlight exposure. Cutis. 1984;34:33-38. 19. Zhang R, Zhu W, Favre-Racouchot syndrome associated with eyelid papilloma: a case report. J Biomed Res. 2012;26(6):474-477. 20. Aloi F,Tomasini C, Pippione M. Mycosis fungoides and eruptive epidermoid cysts: a unique response of follicular and eccrine structures. Dermatology. 1993;187(4):273-277. 21. Mavilia L, Campolmi P, Santoro G, Lotti T. Combined treatment of Favre-Racouchot symdrome eith a superpulsed carbon dioxide laser: report of 50 cases. Dermatol Ther. 2010;23:S4-6.

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Review

Propionibacterium acnes and the skin disease of acne vulgaris

PROPIONIBACTERIUM ACNES AND THE SKIN DISEASE OF ACNE VULGARIS PROPIONIBACTERIUM ACNES ȘI IMPLICAREA LUI ÎN ACNEEA VULGARĂ

Elham BEHZADI¹, Payam BEHZADI¹, Cristiana VOICU2 Department of Microbiology, College of Basic Sciences, Shahr-e-Qods Branch, Islamic Azad University, Tehran, Iran 2 Dermatology Department, Polisano Clinic, Bucharest, Romania Corresponding author: Dr. Payam BEHZADI, Ph.D in Molecular Biology, Tehran, Fath Highway, Shahr-e-Qods, The end of Shahid Kalhor Blvd, Post Box: 37541- 374, Tel: +98-912-4799734. E-mail: behzadipayam@yahoo.com

Conflict of interest: The authors do not have any conflict of interest to declare.

Open Access Article

Abstract Keywords: Propionibacterium acnes, Acne vulgaris, skin colonization.

The human skin encompasses a vast variety of microorganisms which construct the structure of skin microflora. Bacteria and yeasts may be the pioneers of the human skin normal flora. The anatomical situations and physicochemical conditions determine the demography of the microbial populations. Among different types of microbial populations, Propionibacterium acnes is the predominant member in the skin areas of back, face and chest. Although this bacterium is part of the normal flora, Propionibacterium acnes contributes to the disease of acne vulgaris. By the progression of scientific disciplines such as Microbiology, Genetics, and Molecular Biology, it is going to be clear that some strains of Propionibacterium acnes are useful and good bacteria and some strains are harmful and bad bacteria. Therefore, in this review, the authors have a look on different characteristics of P.acnes and the related skin disease of acne vulgaris. Cite this article: Elham BEHZADI , Payam BEHZADI, Cristiana VOICU.Propionibacterium acnes and the skin disease of acne vulgaris. RoJCED 2016; 3(2):117 - 120 June 2016

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Review

Propionibacterium acnes and the skin disease of acne vulgaris

Rezumat Cuvinte-cheie: Propionibacterium acnes, acnee vulgară, colonizare cutanată.

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Pielea găzduiește o varietate de microorganisme care participă la alcătuirea microflorei cutanate. Bacteriile și fungii par a fi pionierii florei cutanate normale. Particularitățile anatomice și diferite condiții fizico-chimice influențează demografia populațiilor microbiene. În cadrul diferitelor tipuri de populații microbiene, Propionibacterium Acnes se găsește predominant în pielea de la nivelul feței și al toracelui antero-posterior. Deși această bacterie face parte din flora cutanată normală, Propionibacterium Acnes este de asemenea responsabilă de apariția acneei. Dezvoltarea unor discipline științifice precum Microbiologia, Genetica și Biologia Moleculară, va concluziona dacă anumite tulpini de Propionibacterium Acnes sunt utile și benefice iar altele sunt dăunătoare. Așadar, în revizuirea de față, autorii analizează diferite caracteristici ale P. Acnes și implicarea ei în acneea vulgară.

Introduction

The human skin and related microbiota

Propionibacterium acnes, or former Corynebacterium parvum, is an important bacterial agent which acts as a multifunctional microorganism. This bacterium is seen in different parts of the human body, from the conjunctivae, oral cavity, and nares to intestinal and respiratory tracts. The biochemical properties of P.acnes are related to the bacterial functions and activities. This bacterium is a slow growing Gram +ive, anaerobic and microaerophilic bacillus which is able to produce propionic acid as a fermentative microbial product. P.acnes populations cover 50% of the human skin normal flora; however, the number of populations differs in different parts of the body. It ranges from <10 cells/ cm2 on the nose to 107 cells/cm2 on the human facial skin. On the other hand, this bacterium may act as a skin pathogenic microorganism, which may lead to different types of skin diseases like acne vulgaris. According to previous studies, there are many factors, comprising nourishment program and skin hygiene that determine the number of bacterial populations of P.acnes as an opportunistic microbial agent causing acne vulgaris. Dekio et. al. have indicated that P.acnes encompasses several strains and the highest strain diversity has been observed on the facial skin. Among different bacterial strains of P.acnes, ST6 has a high tendency to dryness and rigid conditions(1-7). P.acnes is an interesting opportunistic bacterium which plays a significant role in both health and infection of human hosts. In addition to acne vulgaris, the ubiquitous bacterial agent of P.acnes has a bold contribution to different types of infections associated with indwelling medical devices and prostheses. Despite the vast activity regarding infectious diseases, the presence of P.acnes as an important skin microbiota prevents colonization of dangerous pathogenic microorganisms. In this review, the authors have a look on different characteristics of P.acnes and the related skin disease of acne vulgaris(7-9).

Skin is recognized as the largest outer organ in the human body which protects the inner system from outsiders and foreigners. Indeed, skin acts as the first natural barrier against microorganisms as a part of the innate immune system. Human skin involves a wide range of microflora, significantly including Acinetobacter, Candida, Corynebacterium, Malassezia, Micrococcus, Propionibacterium, Saccharomyces, Staphylococcus(10-15). Among aforementioned microorganisms, the populations of Propionibacterium are predominant bacterial microorganisms on sebum rich zones (such as chest, back, and head) and pilosebaceous follicles. In accordance with several investigations, there is a considerable variety among Propionibacterium species which comprises P.avidium, P.acnes, P.lymphophilum, P.granulosum and P.propionicum(12,15,16). Furthermore, the physicochemical conditions of the skin including glands (their size, number and functions), follicles (their size, number and functions), the density of secreted discharges like sweat, sebum, antimicrobial secretions such as defensins and dermicidin, nutrition, temperature, oxygen, pH, microbial products and their antagonistic and synergistic effects determine the residue of cutaneous normal flora populations. The ability of enzyme secretions in microorganisms is another factor in their colonization of the skin, because the presence of microbial extracellular enzymes in the human skin makes a wide range of nutrition accessible for microorganisms (12,17).

Acne Vulgaris Acne vulgaris a chronic skin condition, originating from hair follicles and the related sebaceous glands, classified as inflammatory/non-inflammatory or alternation of both. However, minor populations of patients have severe forms of acne vulgaris. There are many factors which may lead to the occurrence of acne vulgaris. One of the most im-

R O M A N I A N J O U R N A L o f C L I N I CA L a n d E X P E R I M E N TA L D E R M ATO LO GY

Elham BEHZADI , Payam BEHZADI, Cristiana VOICU

portant factors regarding the appearance of acne vulgaris is genetic predisposition, accompanied by deep hormonal changes. The prevalence of acne vulgaris in Dark skinned people, the Mediterranean region people, the Caspian Sea region and the Persian Gulf region people is higher than other parts of the world. Moreover, young boys (male teenagers) are more frequently affected by severe, nodulo-cystic forms of acne, while in women the disease is lasting longer, reaching adulthood or, in some cases, appears for the first time into the 3rd or 4th decade of life. Acne pathology comprises 4 steps including blockage of the follicle via abnormal keratinization of follicular units, overwhelmed sebum production and storage, hyperactivity of resident normal flora populations of P.acnes and the appearance of inflammation(18-23). In patients with acne vulgaris, comedones and swollen, erythematous, painful papules, pustules and nodules are seen mostly on facial skin area, back and chest (particularly on the upper chest zone). Comedones are made by abnormal secretion of lipids resulting in follicular keratinization. Simultaneously, the resident populations of P.acnes begin to proliferate within the accumulated sebum and keratinized follicle. A closed whitehead comedone consists of dead cell debris, P.acnes and the related bacterial secretions (such as hyaluronidase, neuraminidase, protease etc.), and sebum. These materials provide the proper environment for the comedones to become inflamed and breached. Among these compounds, the bacterial extracellular enzymes secreted by P.acnes cells raises up the rate of breakage of the closed comedones. The activity and proliferation of P.acnes’ bacterial cells stimulate the innate immune system with different types of chemokines and cytokines(1,24-26).

Genomics and Biofilm formation of Propionibacterium acnes The complete genome of some strains belonging to P.acnes has been determined and published. The study of complete genome sequences shows a diversity of virulence factors such as adhesins, inflammatory factors and weakening host cell factors (in particular, extracellular enzymes like protease, lipase, hydrolase etc.). The major differences between bacterial strains of P.acnes are recognized in island-like regions (ILRs) which play a key role in the expression of virulence factor genes(27-29). The diphtheroid-like bacterium of P.acnes has a predominant ability to form stable biofilms. This characteristic helps P.acnes colonies to reside on host’s skin surface, which has a protective property for the host. Simultaneously, the property of biofilm formation can be recognized as an important virulence factor for pathogenic bacterial strains. So, the ability of biofilm formation in P.acnes can be considered beneficial for useful strains and harmful for pathogenic strains. The biofilm structure is composed of bacterial poly-

saccharides which embeds the bacterial cells of P.acnes within itself. Indeed, the polysaccharide acts as a biocement. The main characteristic of biofilm is to prevent the penetration of outsider microorganisms, immune cells, and antibiotics. Thus, the biofilm structures of P.acnes strains relating to normal flora populations are good and the biofims of invasive and infectious strains of P.acnes may be life-threatening and deathful. A considerable factor which helps P.acnes to dominate other microorganisms which reside on the surface of human skin is the ability of secretion of extracellular enzyme of lipase. That is why, the bacterium of P.acnes are isolated from the fatty portion of the skin like face, back, and chest(1,30-33).

Propionibacterium acnes and host’s immune system The immunologic investigations have revealed that opportunistic pathogenic strains of P.acnes trigger the pattern recognition receptor (PRR) molecules within the host immune system. The PRRs have different types of members like TollLike Receptors (TLRs). Secretion of extracellular enzymes by P.acnes makes some injuries in host skin tissues. The damaged skin tissue stimulates TLRs (TLR-2 and TLR-4) on keratinocytes which may lead to secretion of chemokines and cytokines comprising Interleukin (IL)-1a, IL-8, and Tumor Necrosis Factor (TNF)-α. TLR-2 has a key role in association with inflammation of comedones on the host skin (1, 9, 34-36).

Treatment Treatment must address all the factors implicated in acne pathogenesis and has to be tailored to disease severity. The simultaneous use of topical retinoids and antibiotics is the best choice for a definite treatment of acne vulgaris caused by P.acnes. The use of antibiotics, especially in the form of oral consumption, is recommended for moderate to severe acne vulgaris. However, there are several reports regarding drug resistant strains against metronidazole and some members of aminoglycosides. The use of benzoyl peroxide is recommended for all forms of acne vulgaris. The use of retinoids in the form of oral consumption is the best choice for severe forms of acne vulgaris. Furthermore, hormonal therapy may be used as the second choice when hormonal disturbances or polycystic ovary syndrome have been documented(19,20,37,38).

Conclusion Acne vulgaris is a multifactorial condition. Genetic predisposition, hormonal changes, race, geographic situation, sex and bacterial strains have direct effects on the occurrence of acne vulgaris in patients. So, no single factor may be able to arise the disease of acne vulgaris. The role of P.acnes in acne pathogenesis has June 2016

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been a matter of dispute over the years; therefore future studies are mandatory in order to conclude this subject. Recent data suggests that this interesting Gram positive bacillus has the ability to act both as a skin commensal with protective action in people without acne and as a skin pathogen, by promoting follicular inflammation and hyperkeratinization in patients with acne. Its ability to form stable biofilms can be regarded as a

protective phenomenon in healthy skin as well as a dangerous mechanism for the development of antibiotic resistant strains in acne affected skin(3). This work is licensed under a Creative Commons Attribution 4 .0 Unported License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc/4.0/

Bibliography 1. Clatici VG, Ursu D, Fica S. NON INVASIVE EVALUATION OF PATIENT WITH ACNE AND ROSACEA. IMPLICATIONS IN CASE-MANAGEMENT. EVALUAREA NON-INVAZIVĂ A PACIENTULUI CU ACNEE ȘI ROZACEE. IMPLICAȚII ÎN MANAGEMENTUL DE CAZ. Romanian Journal of Clinical and Experimental Dermatology. RoJCED 2015;2(3):168-179. 2. Park HJ, Na S, Park SY, Moon SM, Cho O-H, Park K-H, et al. Clinical significance of Propionibacterium acnes recovered from blood cultures: analysis of 524 episodes. Journal of clinical microbiology. 2011;49(4):1598-601. 3. Mihai MM, Popa MI, Clatici VG, Voicu C, Maftei-Antoneag I-M, Giurcaneanu C. Propionibacterium acnes and acne etiopahogenesis. Propionibacterium acnes și etiopatogenia acneei. Romanian Journal of Clinical and Experimental Dermatology.RoJCED 2014;1(1):78-80 4. Clatici VG, Draganita AMV, Anania ETD, Fica S. PROPIONIBACTERIUM ACNES AND ANTIBIOTIC RESISTANCE–IMPACT ON PUBLIC HEALTH. PROPIONIBACTERIUM ACNES ȘI REZISTENȚA LA ANTIBIOTICE–IMPACT ASUPRA SĂNĂTĂȚII PUBLICE. Romanian Journal of Clinical and Experimental Dermatology. RoJCED 2015;2(4):242-247. 5. Dekio I, Rajendram D, Morita E, Gharbia S, Shah HN. Genetic diversity of Propionibacterium acnes strains isolated from human skin in Japan and comparison with their distribution in Europe. Journal of medical microbiology. 2012;61(5):622-30. 6. Sahdo B, Särndahl E, Elgh F, Söderquist B. Propionibacterium acnes activates caspase‐1 in human neutrophils. Apmis. 2013;121(7):652-63. 7. Alexeyev OA, Zouboulis CC. Shooting at skin Propionibacterium acnes: to be or not to be on target. Journal of Investigative Dermatology. 2013;133(9):2292-4. 8. McDowell A, Patrick S, Eishi Y, Lambert P, Eady A. Propionibacterium acnes in human health and disease. BioMed research international. 2013. 9. Ryu S, Han HM, Song PI, Armstrong CA, Park Y. Suppression of Propionibacterium acnes Infection and the Associated Inflammatory Response by the Antimicrobial Peptide P5 in Mice. PloS one. 2015;10(7):e0132619. 10. Dryden MS. Skin and soft tissue infection: microbiology and epidemiology. International journal of antimicrobial agents. 2009;34:S2-S7. 11. Ranjbar R, Amoupour M, Behzadi P. Skin Infections and Travelers. Int J Travel Med Glob Health. 2015;3(3):99-103. 12. Bojar RA, Holland KT. Acne and Propionibacterium acnes. Clinics in dermatology. 2004;22(5):375-9. 13. Behzadi E, Behzadi P. An in vitro Study on the Apoptosis Inducing Effects of Ultraviolet B light in Staphylococcus aureus. Mædica J Clin Med. 2012;7:54-7. 14. Behzadi P, Behzadi E, Ranjbar R. The effects of ultraviolet B beams on programmed cell death activities in Staphylococcus epidermidis. J Microbiol Infect Dis. 2015;5(1):21-4. 15. Behzadi P, Behzadi E. Modern Medical Mycology and Opportunistic Pathogenic Yeasts. 1st ed. Tehran: Persian Science & Research Publisher; 2011. 16. Yokota A, Tamura T, Takeuchi M, Weiss N, Stackebrandt E. Transfer of Propionibacterium innocuum Pitcher and Collins 1991 to Propioniferax gen. nov. as Propioniferax innocua comb. nov. International Journal of Systematic and Evolutionary Microbiology. 1994;44(3):579-82. 17. Eady E, Holland K. Inhibitors produced by propionibacteria and their possible roles in the ecology of skin bacteria. Proceedings of the Royal Society of Edinburgh Section B Biological Sciences. 1980;79(1-3):193-9. 18. Dawson AL, Dellavalle RP. Acne vulgaris. BMJ. 2013;346(7907):30-3. 19. Rao J. Acne Vulgaris. Medscape Reference. 2015.

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20. Thiboutot D, Gollnick H, Bettoli V, Dréno B, Kang S, Leyden JJ, et al. New insights into the management of acne: an update from the Global Alliance to Improve Outcomes in Acne group. Journal of the American Academy of Dermatology. 2009;60(5):S1-S50. 21. Knobler SL, O’Connor S, Lemon SM, Najafi M, Bhatia A, Maisonneuve J-F, et al. PROPIONIBACTERIUM ACNES AND CHRONIC DISEASES. 2004. 22. Smith RN, Mann NJ, Braue A, Mäkeläinen H, Varigos GA. The effect of a high-protein, low glycemic–load diet versus a conventional, high glycemic–load diet on biochemical parameters associated with acne vulgaris: A randomized, investigator-masked, controlled trial. Journal of the American Academy of Dermatology. 2007;57(2):247-56. 23. Shaw JC, White LE. Persistent acne in adult women. Archives of dermatology. 2001;137(9):1252. 24. Noble W. Skin microbiology: coming of age. Journal of Medical Microbiology. 1984;17(1):1-12. 25. Holland K, INGHAM E, Cunliffe W. A review the microbiology of acne. Journal of Applied Bacteriology. 1981;51(2):195-215. 26. Vowels BR, Yang S, Leyden JJ. Induction of proinflammatory cytokines by a soluble factor of Propionibacterium acnes: implications for chronic inflammatory acne. Infection and immunity. 1995;63(8):3158-65. 27. Perry A, Lambert P. Propionibacterium acnes: infection beyond the skin. Expert review of anti-infective therapy. 2011;9(12):1149-56. 28. Brzuszkiewicz E, Weiner J, Wollherr A, Thürmer A, Hüpeden J, Lomholt HB, et al. Comparative genomics and transcriptomics of Propionibacterium acnes. PLoS One. 2011;6(6):e21581. 29. Holland C, Mak TN, Zimny-Arndt U, Schmid M, Meyer TF, Jungblut PR, et al. Proteomic identification of secreted proteins of Propionibacterium acnes. BMC microbiology. 2010;10(1):1. 30. Holmberg A, Lood R, Mörgelin M, Söderquist B, Holst E, Collin M, et al. Biofilm formation by Propionibacterium acnes is a characteristic of invasive isolates. Clinical Microbiology and Infection. 2009;15(8):787-95. 31. Behzadi P, Behzadi E, Ranjbar R. Urinary tract infections and Candida albicans. Central European journal of urology. 2015;68(1):96. 32. Behzadi P, Behzadi E. Environmental microbiology. 1st ed.Tehran: Niktab Publisher; 2007. 33. Coenye T, Peeters E, Nelis HJ. Biofilm formation by Propionibacterium acnes is associated with increased resistance to antimicrobial agents and increased production of putative virulence factors. Research in microbiology. 2007;158(4):386-92. 34. Jeremy AH, Holland DB, Roberts SG, Thomson KF, Cunliffe WJ. Inflammatory events are involved in acne lesion initiation. Journal of Investigative Dermatology. 2003;121(1):20-7. 35. Kim J, Ochoa M-T, Krutzik SR, Takeuchi O, Uematsu S, Legaspi AJ, et al. Activation of tolllike receptor 2 in acne triggers inflammatory cytokine responses. The Journal of Immunology. 2002;169(3):1535-41. 36. Shaheen B, Gonzalez M. Acne sans P. acnes. Journal of the European Academy of Dermatology and Venereology. 2013;27(1):1-10. 37. Portillo ME, Corvec S, Borens O, Trampuz A. Propionibacterium acnes: an underestimated pathogen in implant-associated infections. BioMed research international. 2013;2013. 38. Eichenfield LF, Krakowski AC, Piggott C, Del Rosso J, Baldwin H, Friedlander SF, et al. Evidence-based recommendations for the diagnosis and treatment of pediatric acne. Pediatrics. 2013;131(Supplement 3):S163-S86.

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Updates

Updates in etiopathogeny and treatment of alopecia areata

UPDATES IN ETIOPATHOGENY AND TREATMENT OF ALOPECIA AREATA ACTUALITĂȚI ÎN ETIOPATOGENIA ȘI TRATAMENTUL ALOPECIEI AREATA Iulia Andronache1, Adina Oprea1, Vasile Benea1, Simona Roxana Georgescu1,2, Oana Andreia Coman1,2 1 Clinical Hospital of Infectious and Tropical Diseases “Dr. V. Babes”, Department of Dermatovenereology 2 University of Medicine and Pharmacy “Carol Davila”, Bucharest Corresponding author: Iulia Andronache, MD, Clinical Hospital of Infectious and Tropical Diseases “Dr. V. Babes”, Department of Dermatovenereology, 281 Mihai Bravu Av., Bucharest. e-mail: iuliai.andronache@gmail.com.

No conflict of interest

Open Access Article

Abstract Keywords: alopecia areata, autoimmune disease, etiopathogeny and treatment.

Alopecia areata is an autoimmune disease with possible genetic predisposition and trigger causes, with an increasing incidence, especially in children and young adults. It presents several clinical forms, with different severity and prognosis. This article describes widely the clinical forms of alopecia areata, together with their positive and differential diagnosis, evolution and prognosis, and focuses on the latest issues on its etiopathogeny. An exhaustive approach of local and general therapy currently used to treat alopecia areata or to stop its progression is also realized.

Rezumat Cuvinte-cheie:

Cite this article: Iulia Andronache, Adina Oprea, Vasile Benea, Simona Roxana Georgescu, Oana Andreia Coman. Updates in etiopathogeny and treatment of alopecia areata RoJCED 2016; 3(2):122 - 126

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alopecia areata, maladie autoimună, etiopatogenie, tratament.

Alopecia areata este o afecțiune autoimună, cu posibil determinism genetic și cauze favorizante declanșatoare, cu o incidență din ce în ce mai mare, în special la copii și tineri și care prezintă mai multe forme clinice, cu severități și prognostice diferite. Articolul prezintă pe larg formele clinice, diagnosticul pozitiv, diferențial, evoluția și prognosticul acestei afecțiuni, dar și, în special, informații recente privind cele mai noi aspecte etiopatogenice. În plus, este realizată o abordare exhaustivă a modalităților terapeutice locale și generale utilizate actualmente pentru tratarea sau oprirea evoluției alopeciei areata.

R O M A N I A N J O U R N A L o f C L I N I CA L a n d E X P E R I M E N TA L D E R M ATO LO GY

Iulia Andronache, Adina Oprea, Vasile Benea, Simona Roxana Georgescu, Oana Andreia Coman

Introduction Alopecia areata presents as patches of hair loss, reversible in most of the cases. It frequently affects children and young adults under 25 years old; men can be affected twice as more as women(1). There are many types of alopecia areata: diffuse alopecia areata – patchy alopecia areata, alopecia ophiasis, alopecia totalis, alopecia universalis. Alopecia ophiasis affects especially children and is localized on the sides and lower back of the scalp. Alopecia totalis (AT) occurs as total hair loss on the scalp and eyebrows. Alopecia universalis (AU) occurs with complete hair loss on the scalp and all hair-bearing areas (beard, eyelashes, eyebrows, trunk, arms, legs, axillary region, groin, and other hair-bearing areas) (3).

Figure 1. Alopecia areata of the left eyebrow and left frontal and temporal scalp regions (personal archive of the authors)

presence of anti-hair follicle antibodies and of the association with other autoimmune diseases: vitiligo, polyendocrinopathy syndrome, Addison disease, hypoparathyroidism, thyroid diseases such as Hashimoto’s thyroiditis, localized scleroderma). - Biermer’s anemia. - genetic factors (some antigens of the HLA complex seem to favor the appearance of alopecia areata: HLA B8, HLA B9, HLA B12 for diffuse alopecia, HLA-DRB-1104 for alopecia areata totalis or universalis and about 20% are family cases)(2). - psychological factors - stress. - endocrine factors. Associations have been reported with a variety of genes, including major histocompatibility complex (MHC) and cytokine genes, suggesting that the genetic predisposition is multifactorial in nature. A genome-wide association study confirmed the link with the MHC genes and also identified associations with other genes involved in regulating immune and inflammatory responses, and with some genes expressed in the hair follicle(5,6). The hair follicle lesion is probably mediated by T lymphocytes(7). The association between alopecia areata and other autoimmune diseases suggests that alopecia areata is itself an autoimmune disease although this is unproven. It has been proposed that the hair follicle is an immunologically ‘privileged tissue’ which is sheltered from immune surveillance by autoreactive T cells, and that failure of such immune privilege plays a key role in the pathogenesis of alopecia areata(8,9).

Clinic

Positive diagnosis

The common clinical presentation of alopecia areata is the appearance of many round or oval alopecic patches, well defined, with a diameter varying between 0,5 – 5 cm. Alopecic patches are normal-colored, glossy, hypotonic, without epidermal change and without scaling and crusting. Alopecia areata usually presents as patches of hair loss on the scalp but any hair-bearing areas can be involved (beard, eyelashes, eyebrows, trunk, arms, legs, axillary region, groin, etc). At the periphery of alopecic patches, the hair can be pulled out easily, without pain. Hair follicles have the characteristic aspect of “exclamation point”. A positive result of the pull test indicates that the disease is active. Depending on the severity of the disease we can find one or several alopecic patches, but the patches can coalesce and affect the entire scalp. The nails are involved in about 10% of patients (5). One can find some abnormalities of nails like nail pitting, sandpaper nails, Beau lines - transverse striations, trachyonychia, koilonychia, dotted leukonychia, etc.)(3). These changes of the nails can appear before, during or after the onset of alopecia areata and can persist for an indefinite period of time. From an etiopathogenetic perspective there are many factors involved: - immunological factors (alopecia areata is considered an autoimmune disease because of the

It can be made especially on clinical arguments, but it can be completed with other investigations, such as: dermoscopy, trichogramma or skin biopsy. In dermoscopy regular round yellow dots are commonly seen in areas of alopecic patches. Dermoscopy also highlights common features seen in this condition such as dystrophic hairs with fractured tips (“exclamation mark” hairs) and hairs fractured before emergence from the scalp (“cadaverized” hairs)(5). Other tests that can complete investigations are fungal culture and serology for systemic lupus erythematous.

Differential diagnosis It is not difficult because alopecia areata is easily distinguished from others alopeciae. Major diseases that are involved in differential diagnosis are: trichotillomania, tinea capitis, telogen effluvium, drug-induced anagen effluvium, systemic lupus erythematous, alopecia in secondary syphilis. Trichotillomania and traction alopecia present broken hair on alopecic patches and at the periphery of these areas, because of the mechanical factor that contributes to alopecia. Tinea capitis usually presents with alopecic scaly patches, with various dimensions and affects especially the children. Telogen or drug-induced anagen effluvium present with diffuse alopecia. In secondary syphilis, June 2016

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serology is always positive (a non treponemal test RPR/VDRL and a treponemal test TPHA/FTA)(3).

Figure 2. Alopecia areata of the scalp (personal archive of the authors)

Treatment Since the cause of alopecia areata is unknown, there is virtually no etiological treatment. Alopecia areata therapy may be local and /or general. First-line treatment includes topicalapplication of non-specific irritants (cignoline, phenol), corticosteroids, immunomodulators that produce contact dermatitis (dinitrochlorobenzene -DNCB, diphencyprone - DPCP, squaric acid dibutylester â&#x20AC;&#x201C; SADBE, dioxyanthranol-anthralin), vasodilators (minoxidil) and PUVA. In some clinical cases systemic treatment with corticosteroids, cyclosporine or isoprinosine is used(2). Topical corticosteroids are the first treatment option. Moderately potent corticosteroids are used in most cases of alopecia areata of small or medium severity, but their effectiveness is limited. They are the treatment of choice for alopecia areata in children. The use of topical corticosteroid lotions is preferred because the cosmetic acceptability of this galenic form is superior to a cream or an ointment. The main side effect of these is folliculitis. Two randomized clinical trials on clobetasol propionate 0.05% cream, or ointment have shown its effectiveness in about 20% of patients(5). In a clinical trial of 0,05% clobetasol propionate foam, 34 patients with moderate to severe alopecia areata were randomly assigned to treatment to one side of the scalp and vehicle to the other side. After 12 weeks of treatment, more sites treated with clobetasol versus vehicle had at least 50% regrowth of hair (seven of 34 vs. one of 34)(10). Clobetasol propionate applied under an occlusive dressing may be effective in some patients. In a study of 28 patients who had AT â &#x201E;AU for a mean duration of 7 years 0,05% clobetasol propionate ointment applied under an occlusive plastic film on six out of seven nights for 6 months resulted in longterm hair regrowth in five patients (18%)(11). Intralesional corticosteroids in low concentrations (2.5 - 5 mg / ml) are a second-line treatment(3). However, in extensive forms of illness in adults intralesional corticosteroids may be the first thera-

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peutic option. The most used drugs are: diluted triamcinolone acetonide for alopecia areata of the beard, triamcinolone acetonide 5 - 10mg formulation / ml for alopecia areata of the scalp and hydrocortisone acetate (25 mg / ml). Injection of alopecic patches is indicated every 4 - 6 weeks, not to exceed 3 ml/ administration. The main side effects include: injection site pain, atrophy of the skin and subcutaneous tissue (can be prevented by limiting the volume injected in one place and avoiding the injection to be too deep or too shallow), the appearance of spider veins, pigmentation changes (hypo- and hyperpigmentation). There is a risk of cataract and raised intraocular pressure if intralesional corticosteroids are used close to the eye, for treating eyebrows(12). There were 2 cases of anaphylaxis following treatment with triamcinolone acetonid(13,14). In a study from Saudi Arabia, 62% of patients achieved full regrowth with monthly injections of triamcinolone acetonide, the response being better in those with fewer than five patches of < 3 cm in diameter(15). Cignoline is an irritant derived from tar. It is applied to the scalp in low concentrations of 0.5-1%, 2 times a day, and allowed to stay on the skin for 20-60 minutes. The mechanism of action is not well enough understood. Some authors consider that it could act like dinitrochlorobenzene or diphencyprone. The main side effect is severe irritant dermatitis and as inconveniences can be mentioned the unpleasant odor and staining linen(3).

Figure 3. Alopecia areata of the scalp (personal archive of the authors)

Dinitrochlorobenzene (DNCB) is a strongly immunogenic substance and is used in serial dilutions (in acetone or fat basis) of 0.0001%, 0.001%, 0.01%, 0.1%, 0.5%, 1% and 2 %. The application starts with a concentration of 2% every 1-2 weeks until allergic contact dermatitis occurs. Following induction of the allergic contact dermatitis, dinitrochlorobenzene is applied weekly in small concentrations, so that dermatitis can be kept active for 8-12 weeks. Most patients will develop occipital and â &#x201E; or cervical lymphadenopathy during contact immunotherapy. This is usually temporary but may persist throughout the treatment period(5). Uncommon adverse effects include urticaria(16), and vitiligo(17,18). Its use is limited because there is no

R O M A N I A N J O U R N A L o f C L I N I CA L a n d E X P E R I M E N TA L D E R M ATO LO GY

Iulia Andronache, Adina Oprea, Vasile Benea, Simona Roxana Georgescu, Oana Andreia Coman

available commercial product, by the severe allergic reaction that it might produce and because of certain fears on its potential mutagenic effect (Ames1 positive test)(3). Diphencyprone (DPCP) is an immunogenic substance. The mechanism of action is the induction of an allergic contact dermatitis. It progressively replaced dinitrochlorobenzene because it doesn’t have problematic mutagenicity effects. The absence of a standardized product and the reduced stability of this molecule in pharmaceutical preparations made diphencyprone to be relatively little used(3,19). Squaric acid dibutylester (SADBE) is an immunogenic substance like diphencyprone. Topical SADBE represents a valid therapeutic option in severe alopecia areata, and may prove to be disease modifying(20). Dioxyanthranol-anthralin (Anaxeryl - dithranol 0.35%) is mixed with a fatty compound and is applied to the affected area, left for 15 minutes, then washed. In one open study, 18% of patients with extensive alopecia areata achieved cosmetically worthwhile hair regrowth(21). Since dithranol should be used frequently and in large concentrations in order to obtain an allergic reaction, its use is limited. Out of cosmetic reasons, fair-haired persons cannot use dithranol because it stains the hair. Minoxidil acts on pilosebaceous follicles similar to the “epidermal growth factor”. It seems that it might extend the anagen phase, so it would stimulate DNA synthesis in hair follicles and have a direct action on keratinocyte proliferation and differentiation. The other effect is the vasodilator one. It is used topically in concentrations of 2% and 5%, 1 ml 2 times /day, associated with topical corticosteroids and/or dioxyanthranol. In terms of cosmetics, treatment is better tolerated than cignoline. In brown women it can give facial hyperpilosity. Topical minoxidil is ineffective in AT ⁄AU. Systemic corticosteroids are used especially in cases of severe alopecia areata, alopecia totalis, alopecia universalis or rapidly progressive alopecia areata. Therapy begins with oral prednisone, which is initial administrated 0.75 mg per kg of weigh daily, then tapered during 6-8 weeks. There are several published case series of high-dose pulsed corticosteroid treatment employing different oral and intravenous regimens (intravenous prednisolone 2 g(22), intravenous methylprednisolone 250 mg twice daily for 3 days(2,23,24), oral prednisolone 300 mg once monthly(25), dexamethasone 5 mg twice weekly)(26). The results are good and show better hair regrowth at 6 months. It is well-known that most patients relapse when the corticosteroids therapy is stopped. A therapy that appears to be less aggressive is medium-dose pulsed methylprednisolone (100 mg daily, 3 days per month). According to some authors, alopecia areata can be remitted in about 55% of cases (13/23), but the result could not be maintained for a long period of time. Photochemotherapy: psoralen plus ultraviolet A (PUVA). There are 3 types: localized, mixed and

generalized. In localized PUVA, psoralen is applied locally followed by irradiation with starting dosage of 0,25J/cm2 twice weekly. The dose is increased until the area of treatment is erythematous. The best results are obtained in alopecia of the beard and alopecia ophiasis, where the rate of regrowth is about 100%. In mixed PUVA, oral psoralen and PUVA-therapy are administered on the alopecic patches, but the adverse effects are increased. Regarding generalized PUVA, oral psoralen and PUVA-therapy are administered on the whole body. PUVA is used in extensive and long-term forms of alopecia areata, forms there are resistant to treatment, and in generalized forms. In about 50-65% of cases the therapy was successful. The mechanism of action is linked to the immunosuppressive effect of PUVA on the skin (it reduces the number of Langerhans cells and it interferes with lymphocytes T antigens). The relapse rate following treatment is high. Long-term treatment increases the risk of appearance of skin carcinomas (basal cell carcinoma and squamous cell carcinoma)(2).

Figure 4. Alopecia areata of the scalp (personal archive of the authors)

Phototherapy with narrow band ultraviolet B (NBUVB - 311nm) is used because, unlike PUVA, it has a lower risk of appearance of skin carcinomas. Current data do not allow clear recommendations on the role of UVB in the treatment of alopecia areata(3). Cyclosporine: The dual properties of cyclosporine as an immunosuppressive drug and as a hypertrichotic agent make it a logical choice in treating alopecia areata(5). Doses of 4-6mg/kg/day have been shown to have a beneficial effect in some patients with alopecia areata. Cyclosporine can be combined with low dose oral prednisone and may be considered in patients with severe atopic dermatitis and alopecia areata(29). Biological agents are not proven to be effective. There are several reports of alopecia areata occurring in patients receiving anti-TNF biologic drugs for other conditions(27), and in an open-label study in 17 patients with moderate to severe alopecia areata there was no response to treatment with etanercept(28). Other tested therapies: sulfasalazine, methotrexate, isoprinosine, laser therapy. June 2016

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Nonpharmacologic methods: hair transplant, psychotherapy, hypnotherapy, aromatherapy; using of wigs and hairpieces, dermatography or semipermanent tattooed eyebrows.

losebaceous follicles after 60 days, therefore effectiveness of therapy has to be evaluated after this period. Even if the treatment is effective, there is a possibility of relapse at variable time intervals after it is stopped. Evidence in favor of one or another treatment are limited, because there are only few randomized studies, placebo – controlled. Treatment algorithm

Figure 5. Alopecia areata of the beard (personal archive of the authors)

Therapy in special cases of alopecia areata: - In children topical corticosteroid lotions or ointment can be used. PUVA and immunotherapy cannot be used. - In pregnant woman no treatment is recommended; eventually topical corticosteroid. - Eyelashes alopecia cannot be treated, all that can be done is eyelid tattoo. Progression of alopecia areata depends of many factors, spontaneous healing appearing in about 60% of cases. The results are much better if the onset of the disease is recent. From the beginning of the treatment the hair still continues to fall for 2 months, because dead hairs are released from pi-

As a conclusion, the general treatment protocol of alopecia areata depends mainly on the age and on the extent of scalp involvement, as follows: - If the patient is <10 years old, minoxidil 5% solution, topical corticosteroid or short contact anthralin are recommended. - If the patient is >10 years old and the scalp involvement is <50%, intralesional or topical corticosteroid, minoxidil 5% solution, or short contact anthralin are recommended. - If the patient is >10 years old and the scalp involvement is >50%, topical immunotherapy (DNCB, DPCP, SADBE) are recommended. • For the above patients, if poor response to immunotherapy, minoxidil 5% solution, topical corticosteroid or short contact anthralin are recommended. • For the above patients, if good response to immunotherapy, it must be continued. This work is licensed under a Creative Commons Attribution 4 .0 Unported License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc/4.0/

Bibliography 1. Diaconu JD, Coman OA, Benea V. Tratat de terapeutica dermatovenerologică. Editura Viața Medicală Românească, 2002 2. Coman OA, Pană C, Georgescu SR. Vechi și nou în etiopatogenia și tratamentul alopeciei androgenice și a peladei.Revista Medicina Modernă 2003; 3. Popescu Cătălin Mihai. Curs. Noi perspective terapeutice în alopecie 2015; www. cursurimedicale.ro 4. Bucur G, Opris DA. Boli dermatovenerice. Editura Medicala Nationala, 2002; 5. A.G. Messenger, J. McKillop, P. Farrant, A.J. McDonagh and M. Sladden. British Association of Dermatologists’ guidelines for the management of alopecia areata 2012. British Journal of Dermatology 6. Petukhova L, Duvic M, Hordinsky M et al. Genome-wide association study in alopecia areata implicates both innate and adaptive immunity. Nature 2010; 466:113–17. 7. Gilhar A, Ullmann Y, Berkutzki T et al. Autoimmune hair loss (alopecia areata) transferred by T lymphocytes to human scalp explants on SCID mice. J Clin Invest 1998; 101:62–7. 8. Paus R, Ito N, Takigawa M et al. The hair follicle and immune privilege. J Investig Dermatol Symp Proc 2003; 8:188–94. 9. Kang H, Wu WY, Lo BK et al. Hair follicles from alopecia areata patients exhibit alterations in immune privilege-associated gene expression in advance of hair loss. J Invest Dermatol 2010; 130:2677–80. 10. Tosti A, Iorizzo M, Botta GL et al. Efficacy and safety of a new clobetasol propionate 0Æ05% foam in alopecia areata: a randomized, double-blind placebo-controlled trial. J Eur Acad Dermatol Venereol 2006; 20:1243–7 11. Tosti A, Piraccini BM, Pazzaglia M et al. Clobetasol propionate 0.05% under occlusion in the treatment of alopecia totalis ⁄universalis. J Am Acad Dermatol 2003; 49:96–8. 12. Carnahan MC, Goldstein DA. Ocular complications of topical, periocular, and systemic corticosteroids. Curr Opin Ophthalmol 2000; 11:478–83 13. Downs AM, Lear JT, Kennedy CT. Anaphylaxis to intradermal triamcinolone acetonide. Arch Dermato 1998; 134:1163–4. 14. Laing ME, Fallis B, Murphy GM. Anaphylactic reaction to intralesional corticosteroid injection. Contact Dermatitis 2007; 57:132–3. 15. Kubeyinje EP. Intralesional triamcinolone acetonide in alopecia areata amongst 62 Saudi Arabs. East Afr Med J 1994; 71:674–5

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16. Tosti A, Guerra L, Bardazzi F. Contact urticaria during topical immunotherapy. Contact Dermatitis 1989; 21:196–7. 17. Henderson CA, Ilchyshyn A. Vitiligo complicating diphencyprone sensitization therapy for alopecia universalis. Br J Dermatol 1995; 133:496–7. 18. Macdonald Hull S, Norris JF, Cotterill JA.Vitiligo following sensitization with diphencyprone. Br J Dermatol 1989; 120:323. 19. Tosti A, Caponeri GM, Primativo R, Melino M, Veronesi S. Squaric acid dibutyl ester and diphencyprone in the therapy of alopecia areata. G Ital Dermatol Venereol. 1985 SepOct;120(5):371-3. 20. Dall'oglio F(1), Nasca MR, Musumeci ML, La Torre G, Ricciardi G, Potenza C,Micali G. Topical immunomodulator therapy with squaric acid dibutylester (SADBE) is effective treatment for severe alopecia areata (AA): results of an open-label, paired-comparison, clinical trial. J Dermatolog Treat. 2005 Feb;16(1):10-4. 21. Fiedler-Weiss VC, Buys CM. Evaluation of anthralin in the treatment of alopecia areata. Arch Dermatol 1987; 123:1491–3. 22. Burton JL, Shuster S. Large doses of glucocorticoid in the treatment of alopecia areata. Acta Derm Venereol 1975; 55:493–6. 23. Friedli A, Labarthe MP, Engelhardt E et al. Pulse methylprednisolone therapy for severe alopecia areata: an open prospective study of 45 patients. J Am Acad Dermatol 1998; 39:597– 602. 24. Perriard-Wolfensberger J, Pasche-Koo F, Mainetti C et al. Pulse of methylprednisolone in alopecia areata. Dermatology 1993; 187: 282–5. 25. Sharma VK. Pulsed administration of corticosteroids in the treatment of alopecia areata. Int J Dermatol 1996; 35:133–6. 26. Sharma VK, Gupta S. Twice weekly 5 mg dexamethasone oral pulse in the treatment of extensive alopecia areata. J Dermatol 1999; 26:562–5 27. Ferran M, Calvet J, Almirall M et al. Alopecia areata as another immune-mediated disease developed in patients treated with tumour necrosis factor-alpha blocker agents: report of five cases and review of the literature. J Eur Acad Dermatol Venereol 2011;25:479–84. 28. Strober BE, Siu K, Alexis AF et al. Etanercept does not effectively treat moderate to severe alopecia areata: an open-label study. J Am Acad Dermatol 2005; 52:1082–4. 29. Fitzpatrick’s Dermatology in General Medicine, McGraw Hill Medical, eighth edition, 2012.

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Case Presentations

.Amiodarone - induced skin pigmentation: two clinical clases

AMIODARONE - INDUCED SKIN PIGMENTATION: TWO CLINICAL CASES TOXIDERMIE LA AMIODARONĂ - DOUĂ CAZURI CLINICE Virgil Pătrașcu1, Florentina Delcea1,Raluca Niculina Ciurea2, Tchernev Georgi3,Corneliu Cristian Georgescu4, Anastasiya Atanasova Chokoeva5, Andreea-Oana Enache1 1 Dermatology Department, University of Medicine and Pharmacy of Craiova, Romania 2 Pathology Department, University of Medicine and Pharmacy of Craiova, Romania 3 Dermatology Department, University Hospital Lozenetz, Sofia, Bulgaria, 4 Department of Anaesthesia and Intensive Care, University of Medicine and Pharmacy of Craiova, Romania 5 Onkoderma-Policlinic for Dermatology and Dermatologic Surgery, Sofia, Bulgaria Corresponding author: Virgil Pătrașcu, Professor, MD, PhD, University of Medicine and Pharmacy, Petru Rareș Street, No 2-4, 200345, Craiova, Romania, phone: 004-0724273676, e-mail: vm.patrascu@gmail.com

Conflict of interest: The authors do not have any conflict of interest to declare.

Open Access Article

Abstract Keywords: toxidermia, amiodarone, blue-grey hyperpigmentation.

Cite this article: Virgil Pătrașcu,Florentina Delcea,Raluca Niculina Ciure, Tchernev Georgi,Corneliu Cristian Georgescu, Anastasiya Atanasova Chokoeva, Andreea-Oana Enache. Amiodarone - induced skin pigmentation: two clinical clases.RoJCED 2016;3(2):128 - 134

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Introduction: Worldwide increased consumption of pharmaceuticals products have led to the registration of more and more iatrogenic reactions, 50% of these being cutaneous. Amiodarone-induced skin pigmentation is frequently found in dermatology, with an incidence of 75%, mostly being revealed by photosensitivity and hyperpigmentation. In most cases, these symptoms are reversible, disappearing when the treatment is stopped; the vital prognosis is not affected, though there is a high impact on the patient’s quality of life. Patients and Method: We report two patients who presented with blue-gray hyperpigmentation of the face, without other symptoms. We performed clinical examination along with serum biochemical tests and histopathological examination for both patients. Results: The patients’ history revealed amiodarone administration for cardiovascular conditions, in both cases, for approximately four years. Laboratory exams were normal. Histopathological exams confirmed the diagnosis of amiodarone-induced skin pigmentation in both cases. Daily sunscreen and local depigmentation treatment was prescribed at hospital discharge for both patients. Amiodarone was replaced with another antiarrhythmic agent. In a follow-up visit two months later, the blue-gray facial hyperpigmentation had faded significantly in both cases. Conclusions: These cases correspond clinically and histologically with typical amiodarone-induced skin pigmentation, which occurred after 48 months of continuous therapy and a cumulative dose of 584 g for the first case, respectively 48 months and a cumulative dose of 365 g for the second case. Amiodarone-induced toxidermia may cause severe aesthetic problems and it may also increase the occurrence of other diseases in the context of skin aging.

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Virgil Pătrașcu,Florentina Delcea,Raluca Niculina Ciure, Tchernev Georgi,Corneliu Cristian Georgescu, Anastasiya Atanasova Chokoeva, Andreea-Oana Enache

Rezumat Cuvinte-cheie: toxidermie, amiodaronă, hiperpigmentare grialbăstruie.

Introducere: Consumul crescut de produse farmaceutice pe plan mondial face să se înregistreze tot mai multe reacții iatrogene, mai mult de jumătate dintre acestea fiind cele cutanate. Toxidermia la amiodaronă este frecvent întâlnită în practica dermatologică, având o incidență de 75 %, manifestată cel mai adesea prin fotosensibilitate și hiperpigmentări. În majoritatea cazurilor, aceste manifestări sunt reversibile și dispar la întreruperea tratamentului; ele nu pun în joc prognosticul vital, însă au un impact major asupra calității vieții pacienților. Bolnavi și metodă: Prezentăm doi pacienți care au solicitat consult dermatologic pentru hiperpigmentarea gri-albăstruie asimptomatică a faciesului. Pentru fiecare bolnav am efectuat examene clinice și paraclinice, acestea din urmă constând în investigații de laborator și examen histopatologic. Rezultate: Din anamneză reținem administrarea în cazul ambilor pacienți a amiodaronei, de aproximativ patru ani, pentru patologia cardio-vasculară. Examenele de laborator au fost în limite normale. Examenul histopatologic a confirmat în ambele cazuri diagnosticul de toxidermie la amiodaronă. La externare, pacienților li s-a recomandat utilizarea cremelor fotoprotectoare și a celor depigmentante. Amiodarona a fost înlocuită cu un alt antiartmic. Bolnavii au fost evaluați la două luni de la externare, hiperpigmentarea a scăzut în intensitate în ambele cazuri. Concluzii: Cazurile prezentate corespund clinic și histopatologic cu hiperpigmentarea tipică post amiodaronă apărută după 48 luni de terapie continuă și o doză cumulativă de 584 g pentru primul caz, respectiv 365 g după 48 de luni în cel de-al doilea caz. Toxidermia la amiodaronă ridică probleme atât din punct de vedere estetic cât și prin favorizarea apariției altor afecțiuni în contextul accentuării îmbătrânirii cutanate.

Introduction

Patients and method

Worldwide increased consumption of pharmaceuticals products have led to the registration of more and more iatrogenic reactions, 50% of these being cutaneous(1). Amiodarone has been used for over 50 years for the treatment of cardiac ventricular and supraventricular arrhythmias, with a high efficiency(2,3), but, when used for long periods of time, in high doses, it can cause a series of side effects, such as: ocular, pulmonary, thyroid disease, hepatic, neurological and cutaneous manifestations(4,5). In order to cause cutaneous side effects, amiodarone must be administered for a period of at least 20 months, with a minimum cumulative dose of 160g for hyperpigmentation, and for at least four months and a minimum cumulative dose of 40g for photosensitivity(6). The slow clearance rate, as well as a high absorption in adipose tissue, explains the late photosensitivity and hyperpigmentation remission (monthsyears)(7). In most of the cases, these disorders are reversible, disappearing when the treatment is stopped; they do not affect the vital prognosis, but they have a major impact on the patient’s quality of life.

We report two patients who presented to the dermatologist for the asymptomatic blue-gray hyperpigmentation of the face. The patients’ history revealed amiodarone administration for cardiovascular conditions in both cases for approximately four years. We performed clinical examination along with serum biochemical tests and histopathological examination for both patients. The patients were also evaluated by a cardiologist to set a clear cardiovascular diagnosis and to replace amiodarone with another antiarrhythmic agent.

Results Case I. A 75-year-old female skin photo type III, rural environment, presented with a 1 year history of asymptomatic blue-gray hyperpigmentation of the face. She had a past history of ischemic cardiomyopathy and atrial fibrillation and was taking amiodarone 200 mg/day (commenced over 4 years ago). She also mentioned that she had sun exposure without photoprotection. We also noticed pronounced wrinkling in sun-exposed areas and brown to gray-brown patches on the face and dorsal part of hands. (Figs 1, 2). A skin biopsy was performed on the left zygomatic June 2016

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Case Presentations

.Amiodarone - induced skin pigmentation: two clinical clases

Figure 1, 2.

Asymptomatic blue-gray amiodarone hyperpigmentation of the face, sparing the periocular area and the deep skin folds; thickened skin, pronounced wrinkling in sun-exposed areas and brown to gray-brown patches on the face.

region. Histopathological examination revealed parakeratosis, acanthosis and discrete spongiosis; intense chronic inflammatory infiltrate in papillary dermis, capillary ectasia and numerous macrophages with hemosiderin and melanophages (Figs 3, 4). The final diagnosis was Amiodarone-induced skin pigmentation in a patient with actinic elastosis. Case II. A 78-year-old male, skin phototype III, rural environment, presented with progressive, asymptomatic blue-gray hyperpigmentation of the face (Figs 5, 6). The lesions occurred four months before admission, following intense sun exposure. He had a past history of stage 3 arterial hypertension and chronic ischemic cardiomyopathy, and was taking aspacardin 2 tablets/day and amiodarone over the last 4 years. The patient recounted that he took 400 mg amiodarone daily in the first year and 200 mg daily thereafter.

Figure 3, 4.

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This pigmentation was not observed on other parts of the body. Laboratory blood tests were normal. The final diagnosis was Amiodarone-induced skin pigmentation. Daily sunscreen and local depigmentation treatment was prescribed at hospital discharge for both patients. Amiodarone was replaced with another antiarrhythmic agent. In a follow-up visit two months later, the blue-gray facial hyperpigmentation had faded significantly in both of the cases.

Discussion Toxidermia (drug- induced skin disorders) represents cutaneous or mucocutaneous lesions induced by a drug or its metabolites. Drug-induced skin reactions can result from both allergic (20% of cases) and nonallergic (80% of cases) mechanisms(1,8).

Skin biopsy: the epidermis shows variable parakeratosis, acanthosis and discrete spongiosis; papillary dermis presented intense chronic inflammatory infiltrate, capillary ectasia and numerous macrophages with hemosiderin and melanophages (col HE X40; col HE X 200).

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Case Presentations

Figure 5, 6.

.Amiodarone - induced skin pigmentation: two clinical clases

Asymptomatic blue-gray amiodarone hyperpigmentation of the face; thickened skin, pronounced wrinkling in sun-exposed areas.

Iatrogenic hyperpigmentation represents 10 to 20% of all cases of acquired hyperpigmentation, and the diagnosis should be suspected in cases of inexplicable hyperpigmentation, especially in elderly patients. The pathogenesis of the iatrogenic hyperpigmentations is not fully understood and depends on the implicated medication. Four mechanisms have been proposed to explain these manifestations(9): - an accumulation of melanin in dermal macrophages, following a nonspecific cutaneous inflammation and frequently worsened by sun exposure; - an accumulation of the triggering drug itself without any association with melanin, giving the appearance of free granules scattered along extracellular matrix components or in dermal macrophages that are unable to eliminate these foreign bodies. The drug may have to undergo chemical changes, causing visible hyperpigmentations (chemical sun-induced transformation of large granules into more numerous, visible and smaller granules); - the synthesis of special pigments, such as lipofuscin, probably under the direct influence of the drug; - the iron storage with destruction of the dermal vessels and extravasation of red blood cells. The main drugs implicated in causing skin pigmentation are: amiodarone, clofazimine (red-brown color), antimalarials (blue-gray or purple color), minocycline (brown skin color), tetracyclines, chlorpromazine (brown color), imipramine, cytostatic drugs, contraceptives, diltiazem, amlodipine, heavy metals (gold, silver, lead)(10).

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Amiodarone Hydrochloride (2-Butyl-3-benzofuranyl-4-[2-(diethylamino) ethoxy]-3,5-diiodophenyl Ketone Hydrochloride) is a member of a class of antiarrhythmic drugs with predominantly Class III (Vaughan Williams’ classification) effects. Amiodarone is one of the most widely prescribed antiarrhythmic drugs, due to its widely recognized efficacy(11). Being highly lipid-soluble, amiodarone is particularly concentrated in adipose tissue, muscle, as well as lungs and thyroid, and less often in kidney and brain. The half-life for amiodarone is estimated at 100 days, and an excessive quantity may persist in tissue deposits more than 9 months after cessation of therapy(7). Amiodarone has multiple side effects and in order of frequency we mention(4,5): • ocular side effects: corneal microdeposits that may cause visual disturbances, photophobia, eye dryness; • pulmonary manifestations: interstitial pneumonia or diffuse alveolar damage, bronchiolitis obliterans with irreversible lesions, pleurisy, acute respiratory distress syndrome; • hepatic manifestations - elevated serum transaminases (1,5-3 times normal), during prolonged treatment with amiodarone. Chronic hepatitis can occur which is similar histologically to alcoholic hepatitis; • neurological manifestations - peripheral sensorimotor polyneuropathy and/or myopathy, extrapyramidal tremor, cerebellar ataxia, and exceptionally, benign intracranial hypertension; • thyroid disease - hypothyroidism and hyperthyroidism; • the most common types of adverse cutaneous reactions are hyperpigmentation and phototoxic reactions.

R O M A N I A N J O U R N A L o f C L I N I CA L a n d E X P E R I M E N TA L D E R M ATO LO GY

Virgil Pătrașcu,Florentina Delcea,Raluca Niculina Ciure, Tchernev Georgi,Corneliu Cristian Georgescu, Anastasiya Atanasova Chokoeva, Andreea-Oana Enache

Hyperpigmentation occurs in approximately 4% 9% of amiodarone treated patients, and it is usually observed in men with I and II Fitzpatrick phototypes. The most commonly affected areas are the face, ear pavilions and palms(4). The pathogenesis is not fully understood. Amiodarone binds to phospholipids and makes insoluble compounds that don't follow the regular degradation pathways, which leads to their accumulation in lysosomes. Histopathology highlights the lipofuscin deposits and the inflammatory cells around small vessels(12). Skin changes (hyperpigmentation) usually occur after at least 20 months of continuous therapy with amiodarone and a total cumulative dose of more than 160 g(6). The cutaneous manifestations are represented by blue-gray pigmentation (pseudocyanotic skin pigmentation) on sun-exposed surfaces (face, ear pavilions, dorsal part of hands) in people with excessive sun exposure. The discontinuation of the treatment leads to a slow disappearance of the lesions, but complete remission is achieved after months-years, being the consequence of slow elimination of amiodarone and its metabolites from tissues. Phototoxic reactions are the most common dermatological side effect of the treatment with amiodarone, being encountered in 25-75% of patients, whereas photoallergic reactions occur in fewer patients, but the risk increases greatly with the duration of therapy(4). The pathogenesis of phototoxic reactions is realized in three sequences: in the first stage, the drug or one of its active metabolites should get in viable skin cells, after that, an adequate UV radiation which should penetrate into skin and, in the final phase, the photons are absorbed by the respectively chemical agent(13). Amiodarone and its active metabolite, monoN-desethylamiodarone, can cause a significant decrease, by up to 50 % of minimal erythema dose (MED) in UV radiation spectrum after 12 months of treatment (MED < 300mJ / cm² it's pathological) [14]. The responsible mechanism appears to be related to the production of active metabolites due to the radiation such as oxygen free radicals, which results in damage to DNA, cellular membranes and oxygenation of lipids(12). Phototoxic reactions can be experimentally elicited with UVA exposure. Skin lesions occur after at least four months of therapy and with a minimum cumulative dose of 40 g(6). From a clinical point of view, itchy erythematous and eczematous lesions in sun-exposed areas may appear, usually within several minutes of exposure to sunlight and may persist for up to 48-72 hours(15). The intensity of photoallergic and phototoxic reactions is correlated with the individual

sensitivity of the person to UV and with the duration of sun exposure. Other cutaneous manifestations that may arise or are exacerbated during the treatment with amiodarone are: pseudoporphyria, linear IgA bullous dermatosis, dermatitis herpetiformis or psoriasis. Less common dermatological manifestations include urticaria, pruritus, purpura, erythema nodosum and toxic epidermal necrolysis(16). Some studies indicate the possible carcinogenic effects of amiodarone, with some cases of basal cell carcinoma associated with chronic use of this drug being reported(17). We have made the differential diagnosis with: Kaposi's sarcoma, discoid lupus erythematosus, Riehl melanosis, erythema dyschromicum perstans (ashy dermatosis), lichen planus pigmentosus, acrocyanosis, contact dermatitis, postinflammatory hyperpigmentation, hemochromatosis, leukemia cutis. Evolution and prognosis The slow rate of elimination of amiodarone, as well as the increased rate of absorption in adipose tissue may explain the delayed disappearance of cutaneous photosensitivity and hyperpigmentation (months -years). Prophylaxis includes avoidance of sun exposure and use of sunscreen products. Treatment The basis of therapy consists in amiodarone withdrawal and favoring its elimination. Also, a switch from amiodarone to a different antiarrhythmic drug is recommended. Some authors have reported the efficacy of vitamin B6 at 300 mg per day(15). Additional therapeutic options include Q-switched ruby laser or the chemical peels. Good results have been obtained using UVB therapy, which results in increased tolerance to sunlight and prolongs the time of exposure without side effects(18). Sun protection and avoidance of sun exposure is necessary during treatment and several months after amiodarone withdrawal.

Conclusions These cases correspond clinically and histologically with typical amiodarone-induced skin pigmentation, which occurred after 48 months of continuous therapy and a cumulative dose of 584 g for the first case, respectively 48 months and a cumulative dose of 365 g for the second case. Amiodarone-induced toxidermia may cause severe aesthetic problems and also may increase the occurrence of other diseases in the context of skin aging.

June 2016

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.Amiodarone - induced skin pigmentation: two clinical clases

Bibliography 1. Roujeau JC, Bonnetblanc JM, Schmutz JL, Crickx B. Iatrogénie. Diagnostic et prévention. Toxidermies médicamenteuses. Ann Dermatol Venereol 2002; 129 :2S163-2S9. 2. Smith W. Guidelines for the diagnosis and management of arrhythmogenic right ventricular cardiomyopathy. Heart Lung Circ. 2011;20(12):757-760. 3. Van Herendael H, Dorian P. Amiodarone for the treatment and prevention of ventricular fibrillation and ventricular tachycardia. Vasc Health Risk Manag. 2010; 6:465-472. 4. Vassallo P, Trohman RG. Prescribing amiodarone: an evidence-based review of clinical indications. JAMA. 2007;298(11):1312–22. 5. HidefumiInaba, Satoru Suzuki, TeijiTaked, Satoshi Kobayashi, Takashi Akamizu,Mitsuhisa Komatsu. Amiodarone-Induced Thyrotoxicosis with Thyroid Papillary Cancer in MultinodularGoiter: Case Report. Med PrincPract 2012;21:190–192. 6. Rappersberger K, Honigsmann H, Ortel B, et al. Photosensitivity and hyperpigmentation in amiodarone-treated patients: incidence, time course, and recovery. J Invest Dermatol. 1989;93:201–9. 7. Blackshear JL, Randle HW. Reversibility of blue-gray cutaneous discoloration from amiodarone. Mayo Clin Proc 1991;66 (7) 721- 726. 8. Carmen Sorina Martin, Cristina Șerbănescu, Alexandra Nilă, Liliana Popa, Călin Giurcăneanu, Simona Fica, Antithyroid drugs – A necessary risk. RoJCED 2014; 1(1):20-23. 9. Olivier Dereure. Drug-Induced Skin Pigmentation: Epidemiology, Diagnosis and Treatment. American Journal of Clinical Dermotology. 2001; 2(4), 253-262.

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10. Ioannides MA, Moutiris JA, Zambartas C. A case of pseudocyanotic coloring of skin after prolonged use of amiodarone. IntJCardiol. 2003;90(2-3):8345-346 11. Sohns C, Zabel M. Current role of amiodarone in antiarrhythmic therapy. 2010;21(4):239243. 12. Ammoury A, Michaud S, Paul C, et al. Photodistribution of blue-gray hyperpigmentation after amiodarone treatment: molecular characterization of amiodarone in the skin. Arch Dermatol. 2008;144(1):92–96. 13. Reid L, Khammo N, Clothier RH. An evaluation of the effects of photoactivation of bithionol, amiodarone and chlorpromazine on human keratinocytes in vitro. Altern Lab Anim. 2007;35(5):471–85. 14. Ferguson J, Addo HA, Jones S, Johnson BE, Frain-Bell W. A study of cutaneous photosensitivity induced by amiodarone. Br J Dermatol 1985;113 (5) 537- 549). 15. Drucker AM, Rosen CF. Drug-induced photosensitivity: culprit drugs, management and prevention. Drug Saf. 2011;34(10):821–37. 16. Krzysztof Jaworski, Irena Walecka, Lidia Rudnicka, MaciejGnatowski. Cutaneous Adverse Reactions of Amiodarone. Med SciMonit. 2014; 20: 2369–2372. 17. Maoz KB, Dvash S, Brenner S, Brenner S. Amiodarone-induced skin pigmentation and multiple basal-cell carcinomas. Int J Dermatol. 2009;48(12):1398–400. 18. Collins P, Ferguson J. Narrow-band UVB (TL-01) phototherapy: an effective preventative treatment for the photodermatoses.Br J Dermatol. 1995;132(6):956–63.

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P SkinVision – Communication with patients has never been easier! SkinVision offers patients a mobile app, and doctors a web platform to help both parties communicate with each other in a formal, fast and secure environment. SkinVision solutions are built to support easier access to a doctor by means of the latest technologies. As a patient, it is now possible to find and communicate with a/your dermatologist inde pen dent of your location. The benefits for the patients are clear: reliable answers with minimum time loss. But what are the advantages for a clinic or an individual professional in using the SkinVision platform? By joining our platform we enable you to sell teledermatological services directly to a patient using a smartphone and our app. Our solution empowers the user to send high quality images and text content regarding a skin problem and receive your professional opinion and advice in a secure and formal manner. This type of communication already proved its benefits in a series of contexts: - Chronic disease monitoring and treatment adjustment - Pre-post interventions follow up - Preconsult information on cases, possibility of triage based on urgency - Centralized prescriptions and treatment details - On-line payment administration We standardise the communication over the internet or mobile phone that you al-

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Case Presentations

A rare association between Laugier-Hunziker, Sjogren syndromes and other autoimmune disorders - case report and literature review

A RARE ASSOCIATION BETWEEN LAUGIERHUNZIKER, SJOGREN SYNDROMES AND OTHER AUTOIMMUNE DISORDERS- CASE REPORT AND LITERATURE REVIEW O ASOCIERE RARĂ ÎNTRE SINDROAMELE LAUGIER-HUNZIKER, SJOGREN ȘI ALTE AFECȚIUNI AUTOIMUNE- PREZENTARE DE CAZ ȘI REVIZUIRE A LITERATURII Cristiana Voicu¹, Ana-Livia Cărbunaru², Mihaela Berevoescu², Oana Mihalcea², Victor Gabriel Clătici2 ¹ Dermatology Department, Polisano Clinic, Bucharest, Romania ² Dermatology Department, Elias Emergency Hospital, Bucharest, Romania Corresponding author: Cristiana Voicu, MD Dermatology Department, Polisano Clinic, Str. Cuza-Vodӑ nr. 53, sector 4, Bucharest, Romania; E-mail: cristianavoicu84@yahoo.com

Conflict of interest: The authors do not have any conflict of interest to declare.

Open Access Article

Abstract Keywords:

Cite this article: Cristiana Voicu, Ana-Livia Cărbunaru, Mihaela Berevoescu, Oana Mihalcea, Victor Gabriel Clătici. A rare association between Laugier-Hunziker, Sjogren syndromes and other autoimmune disorders - case report and literature review. RoJCED 2016; 3(2):136 - 142

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Laugier-Hunziker syndrome, Sjogren syndrome, autoimmune disorders, longitudinal melanonychia, oral hyperpigmentation.

Laugier-Hunziker-Baran syndrome is an aquired hypermelanosis of the oral mucosa, nails and other cutaneous sites of unknown etiology that affects middle aged individuals of all races. Up to date, less than 200 cases have been reported in the literature. So far, no association has been found between Laugier-Hunziker and genetic predisposition, malignancies, connective tissue and autoimmune disorders, even though these comorbidities have been mentionned in the literature over the years. We present the case of a 58 years old caucasian female diagnosed with Laugier-Hunziker, Sjogren syndrome and autoimmune thyroid disease, completed with a literature review. To our knowledge, this is the second case report regarding the association between Laugier-Hunziker and Sjogren syndrome presented in the literature and the first report regarding the association with autoimmune thyroid disease. The informations available so far do not conclude whether these are coincidental associations, therefore we reccomend screening patients with Laugier-Hunziker syndrome for autoimmune disorders in order to facilitate a better understanting of this relative recently described condition.

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Cristiana Voicu, Ana-Livia Cărbunaru, Mihaela Berevoescu, Oana Mihalcea, Victor Gabriel Clătici

Rezumat Cuvinte-cheie: sindrom Laugier-Hunziker, sindrom Sjogren, afecțiuni autoimune, melanonichie longitudinală, hiperpigmentări orale.

Sindromul Laugier-Hunziker-Baran este o hipermelanoză dobândită a mucoasei bucale, unghiilor și a altor regiuni, a cărei etiologie este necunoscută și care afectează indivizi de vârstă medie și orice rasă. Mai puțin de 200 de cazuri au fost raportate în literatura de specialitate. Până în prezent, nu a fost stabilită nicio asociere între sindromul Laugier-Hunziker și predispoziția genetică, malignități, boli de țesut conjunctiv sau autoimune, deși aceste comorbidități au fost menționate în ultimii ani. Autorii prezintă cazul unei paciente caucaziene în vârsta de 58 ani, diagnosticată cu sindroamele Laugier-Hunziker, Sjogren și tiroidită autoimună, precum și o revizuire a literaturii. Din informațiile noastre, acesta este al doilea caz de asociere între sindroamele Laugier-Hunziker și Sjogren raportat in literatură și primul privind asocierea cu afecțiuni tiroidiene autoimune. Informațiile disponibile până în prezent nu stabilesc cu certitudine faptul că aceste asocieri sunt fortuite, motiv pentru care autorii recomandă ca toți pacienții cu sindrom Laugier-Hunziker să beneficieze de screening pentru boli autoimune, pentru a facilita o mai bună înțelegere a acestei afecțiuni relativ recent descrise.

Introduction Laugier-Hunziker disease is a rare, aquired condition whose main features are represented by oral/ mucosal hyperpigmentation and, sometimes, longitudinal melanonychia. This syndrome was first described in 1970 by Laugier and Hunziker who reported five cases of adult-onset macular pigmentation of the oral mucosa(1), followed nine years later by Baran who noted that, in some patients, longitudinal melanonychia is associated with the mucosal lesions(2). Later on, lesions with similar histopathological aspect have been described in other areas of the body and the term „idiopatic lenticular mucocutaneous pigmentation“ has been proposed for them(3). Up to date, less then 200 cases have been reported in the literature, but the syndrome seems to be more frequent(3). Laugier-Hunziker syndrome is a diagnosis of exclusion, confirmed only after other diseases associated with hiperpigmentation, mainly Adisson’s disease and Peutz-Jeghers syndrome, have been ruled out(4). It’s etiology still remains unknown and scientists have failled to find any familial predisposition, malignant and connective tissue or autoimmune association linked to it(5).

toxic chemicals in the work environment for about 10 years (but not to any known substances that might induce hyperpigmentations) and a smoking habit suspended for 5 years. She had also been diagnosed with chronic lymphocytic thyroiditis having oral substitution (50 μg levothyroxine/day), Sjogren syndrome, for which she has been treated with hydroxychloroquine (400 mg/day), and osteoporosis treated with cholecalciferol (1000 UI/day). Sjogren syndrome was diagnosed based on clinical signs (xerostomia and xerophthalmia), positive Schirmer’s test and specific positive serology (anti SSa antibody > 2000 U/ml and anti SSb antibody > 2000 U/ml). Physical examination revealed an alert, orientated, overweight white female (Fitzpatrick III skin type), with no acute distress and stable vital signs, xerostomia and xerophthalmia. Dermatological exam showed brownish, well defined, homogenous pigmentation in longitudinal stripes on the nails of the first finger of her right hand and the second and third fingers of her left hand (fig.1).

Case report A 58 years old Caucasian woman was referred to our dermatology clinic for the evaluation of asymptomatic nail hyperpigmentations, condition which had been present for at least 4 years. She denied any local trauma, hemorrhage, topical or systemic medication prior to the appearance of the lesions. The family history revealed neurological and metabolic disorders (Alzheimer’s disease, Parkinson disease and type II diabetes mellitus) without any history of abnormal muco-cutaneous pigmentation. The patient reported previous exposure to

Figure 1. Homogenous pigmentation in longitudinal stripes on the nails

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A rare association between Laugier-Hunziker, Sjogren syndromes and other autoimmune disorders - case report and literature review

Figure 2. Longitudinal melanonychia of the toes

This longitudinal melanonychia was associated with poorly defined pigmentation of the periungual skin (Hutchinson sign). Similar hyperpigmentated bands were also present on the nails of the first, second and fourth right toes and first and second left toes (fig. 2). No nail dystrophy was found. Brown, ovoid shaped, well defined, asymptomatic macules (7 millimeters), in a lentiginous pattern, were symmetrically disposed on the hard palate mucosa (fig. 3). There were no other hyperpigmentated macules in the conjunctiva or genital mucosa and the rest of the skin was normal except the hands, which showed typical signes of phytophotodermatitis. Laboratory tests revealed mild leucopenia and neutrophilia, a positive rheumatoid factor and an elevated ESR (21 mm/hour). Other blood tests values were all within the normal limits. They included complete blood count, biochemistry, coagulogram, ionogram, urine analysis, lipid status, renal and hepatic function, nasal and tonsillar exudate. Additional biochemical assessment did not show

Figure 3. Bilateral hyperpigmented macules on the hard palate

any abnormalities regarding the levels of cortisol, ACTH, sodium, potassium, magnesium, thereby excluding Addison disease. Several other blood tests (anti double stranded DNA antibody, anti Sm antibody, C3 and C4 complement levels, LKM1 antibody, ASMA, Ig M and IgG antiphospholipid antibody, lupic cells) have also been performed in order to exclude potential autoimmune diseases and their results were negative. Dermoscopic examination of the nail unit revealed pseudo Hutchinson sign with homogenous brownish and grayish longitudinal band and lines, with ill-defined margins on the nail plate (fig. 4). The mucosal lesions on the hard palate were not accessible for dermoscopy due to their localization. Nail fold capillaroscopy revealed a normal pattern, but described the presence of pigment deposits similar to those of hemosiderin, without capillary involvement. Chest X-ray showed discrete pulmonary fibrosis and no pathological changes were found in the abdominal ultrasound.

Figure 4. Pseudo Hutchinson sign with homogenous brownish and grayish longitudinal band and lines

Figure 5. Longitudinal melanonychia with poorly defined margins on the toe

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Cristiana Voicu, Ana-Livia Cărbunaru, Mihaela Berevoescu, Oana Mihalcea, Victor Gabriel Clătici

Upper gastrointestinal endoscopy and colonoscopy were also considered but the patient refused these investigations. In addition, she did not have any suggestive family history, nor clinical manifestations of a gastro-intestinal disorder, which made the diagnosis of Peutz-Jeghers syndrome very unlikely. Considering the clinical manifestations, laboratory findings, the lack of systemic involvement, and by excluding other disorders with similar muco-cutaneous lesions, a final diagnosis of Laugier-Hunziker syndrome was made.

Dermoscopy The dermoscopic features of Laugier-Hunziker syndrome have recently been described and they include the following criteria depending on localization: parallel pattern with light to dark brown streaks and, occasionaly, globules for mucosal lesions (oral, genital); longitudinal, bandlike pigmentation with poorly definded margins and micro-Hutchinson sign on the nails; parralel, furrowed pigmented lesions on acral lesions (palmoplantar)(5,12,13).

Histopathology The main histopathological features of Laugier-Hunziker syndrome have been studied using biopsy specimens from mucosal lesions or keratinized skin. Nail changes have not been described histopathologically because nail biopsies are rarely necessary and difficult to perform in the context of multiple nail involvement. The hiperpigmented macules of LaugierHunziker usually disclose dense hypermelanosis with melanin deposits in the basal layer with no cell atypia, accumulation of melanophages in the papillary dermis, intact basement membrane and occasionaly, incontinentia pigmenti. Recently, immunohistochemichal studies using S100 and L-3,4 have documented an icrease of non-nested melanocytes in some areas of hyperpigmentation (5).

Differential diagnosis Laugier-Hunziker syndrome is a diagnosis of exclusion. Other pathologies similar in respect of clinical presentation are listed in table 1(14,15,16,17).

Table1. Differential diagnosis of Laugier-Hunziker syndrome Disease Peutz Jeghers Syndrome

Characteristics - family history – autosomal dominant transmission - hamartomatous gastro-intestinal polyposis - onset age usually in infancy or early childhood - pigmentary macules over perioral region, the oral mucosa, eyes, nose, hands; rarely on nails

Addison Disease

- endocrine disease - hyperpigmentations on the pressure exposed areas, but pigmentation of the oral mucosa may be the first sign - decreased pubic and axillary hair in women

McCune Albright Syndrome

- café-au-lait macules - onset age usually in infancy - bony modifications

Posttraumatic melanosis

- history of trauma - leukomichotic area over the hematoma - gradually fading with nail growing

Smoker melanosis

- hyperpigmentation over the anterior attached gingiva - no other pigmentation of the body

Racial pigmentation

- the principal cause of longitudinal melanonychia - usually occurs in 2 to 5 nails

Leopard Syndrome

- lentigines present in early infancy/childhood - EKG modifications, ocular hypertelorism, abnormal genitalia, growth retardation, deafness

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Carney Syndrome (NAME/LAMB)

- nevi, ephelides, lentigines, blue nevi - atrial myxoma

Cronkhite Canada Syndrome

- lentigines of buccal mucosa, hands, feet - typically older men - alopecia, nail dystrophy, intestinal polyposis

Neurofibromatosis type I

- multiple cafĂŠ-au-lait macules - axillary and inguinal freckling - usually precede the apparition of neurofibromas

Fungal melanonychia (candida, tinea)

- white, yellow, green, black changes on the nail plate - onychauxis, onychorrhexis, onycholysis, longitudinal splitting

Bacterial nail pigmentation (Pseudomonas aeruginosa, Proteus)

- greenish or greyish hue and discoloration on the lateral edge of the nail

Nutritional longitudinal melanonychia

- vitamin B12 or folate deficiency

Drugs

- one or multiple brownish-black longitudinal or transverse bands - diffuse oral pigmentation - tetracycline, minocycline, antimalarials, phenothiazines, chemotherapeutic agents, oral contraceptives, amiodarone, ketoconazole

Neoplastic diseases â&#x20AC;&#x201C; melanoma, Kaposi sarcoma

- localized mucosal pigmentation

Discussion Laugier-Hunziker syndrome is an aquired benign condition of unknown etiology that affects mainly middle-aged patients with no rasial predilection and a slightly predominance in women(3), characterized by asymptomatic hyperpigmented brown macules located on the oral mucosa (lips, tongue, gingiva, soft and hard palate). The macules can be round, lenticular, linear in shape, solitary or multiple, with distinct or poorly definded borders, they appear gradualy and are considered to be permanent(5). Longitudinal melanonychia occurs in more than 60% of cases, it is present in more than one nail, affecting both the fingers and the toes, but it is not associeted with distrophic changes. PseudoHutchinson sign has been described in patients with Laugier-Hunziker syndrome, often present in multiple nails on the same patient(5), which is a very useful criteria in separating this condition from nail malignant melanoma. Lately, similar pigmentary changes have been reported in other areas of the body, such as fingers,

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thorax, abdomen, arms, eyebrows and legs but also on other mucosal surfaces, like the genitalia, conjuctiva and esophagus (3,5). While most authors consider that there is no genetic predisposition associated with the syndrome, Makhoul et all reported the presence of Laugier-Hunziker syndrome in 3 members of the same family (a mother and two daughters) (6) . The condition is caused by a melanocytic functional alteration with increased synthesis of melanosomes, which are subsequently transported to the basel cell layer (3). The exact etiologic mechanism that induces all these changes still remains unknown. Laugier-Hunziker sydrome is a diagnosis of exclusion, stated only after other serious pathologies, mainly Addisonâ&#x20AC;&#x2122;s disease and PeutzJegers syndrome have been ruled out. In order to achieve that, the following tests should be performed: complete physical examination and history, corticotropin level, morning corti-

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A rare association between Laugier-Hunziker, Sjogren syndromes and other autoimmune disorders - case report and literature review

sol level, electrolytes, liver function tests, ANA and radiographic barium contrast studies(5). Other diseases, such as lupus erythematosus, Sjogren syndrome, hemolytic anemia and inflammatory arthritis have been described in some patients with Laugier-Hunziker syndrome, but the exact significance of their association is currently unknown(5). The literature reports one case of Laugier-Hunziker associated with actinic lichen planus(11). So far, there is no known association between Laugier-Hunziker syndrome and malignancies, but there has been one report of ovarian cancer and another one of pancreatic carcinoma and Laugier-Hunziker syndrome. While in the first case, the pigmentary lesions appeared during chemotherapy, in the latter the onset of mucosal lesions was contemporary with the first symptoms of carcinoma. Therefore, Wondratsch et all belive that the possibility of an underlying malignancy should be considered in Laugier-Hunziker syndrome(8). Laugier-Hunziker syndrome does not require treatment, unles esthetic concerns bother the patients, in which case Q-switched Nd:Yag, Q-switched alexandrite laser therapy or cryosurgery seem to be good alternatives, even though recurrences after treatment are frequent(9,10).

Our patient has also been diagnosed with Sjogren syndrome and autoimmune thyroiditis. To our knowledge, only one case regarding the association between Laugier-Hunziker and Sjogren syndrome has been presented in the literature(7) and we could not find any report regarding the association with autoimmune thyroid disease. In the absence of compelling evidence that link LaugierHunziker syndrome with autoimmune diseases, these associations might be regarded as coincidental. Nevertheless, we reccomend screening the patients with Laugier-Hunziker syndrome for connective tissue and other autoimmune disorders with subsequent reports in the literature. This conduct might stimulate researchers to develop new prospective randomised sudies, which might shade a light on this subject.

Bibliography 1. Laugier P, Hunziker N. Pigmentation mélanique lenticulaire, essentielle, de la muqueuse jugale et des lèvres. Arch Belg Dermatol Syphiligr. 1970;26:391-9. 2. Baran R. Longitudinal melanotic streaks as a clue to Laugier-Hunziker syndrome. Arch Dermatol. 1979;115:1448-9. 3. Vijayalakshmi S Kotrashetti, Jagadish V Hosmani . Laugier–Hunziker syndrome.J Oral Maxillofac Pathol. 2012 MayRamakant S Nayak-Aug; 16(2): 245–250. 4. Lalosevic J, Zivanovic D, Skiljevic D, Medenica L. Laugier-Hunziker syndrome--Case report. An Bras Dermatol. 2015 May-Jun;90(3 Suppl 1):223-5. 5. www.emedicine.medscape.com/article/1069034-overview (accesed online 31.04.2016) 6. Gencoglan G, Gerceker-Turk B, Kilinc-Karaarslan I, Akalin T, Ozdemir F. Dermoscopic findings in Laugier-Hunziker syndrome. Arch Dermatol. 2007 May;143(5):631-3. 7. Nida Kaçar, Ceren C. Yildiz, Nese Demirkan . Dermoscopic features of conjunctival, mucosal, and nail pigmentations in a case of Laugier-Hunziker syndrome. Dermatol Pract Concept. 2016 Jan; 6(1): 23–24. 8. A K Lampe, P J Hampton, K Woodford-Richens, I Tomlinson, C M Lawrence, .F S Douglas . Laugier-Hunziker syndrome: an important differential diagnosis for Peutz-Jeghers syndrome. J Med Genet 2003;40:e77 9. Silonie Sachdeva, Shabina Sachdeva, Pranav Kapoor. Laugier–Hunziker Syndrome: A Rare Cause of Oral and Acral Pigmentation. J Cutan Aesthet Surg. 2011 Jan-Apr; 4(1): 58–60. 10. Wen-Mei Wang, Xiang Wang, Ning Duan, Hong-Liu Jiang, and Xiao-Feng Huang . Laugier–

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Hunziker syndrome: a report of three cases and literature review. Int J Oral Sci. 2012 Dec; 4(4): 226–230. 11. Vijayalakshmi S Kotrashetti, Jagadish V Hosmani . Laugier–Hunziker syndrome.J Oral Maxillofac Pathol. 2012 MayRamakant S Nayak-Aug; 16(2): 245–250. 12. Makhoul EN1, Ayoub NM, Helou JF, Abadjian GA. Familial Laugier-Hunziker syndrome. J Am Acad Dermatol. 2003 Aug;49(2 Suppl Case Reports):S143-5. 13. S. Aytekin, S. Alp. Laugier–Hunziker syndrome associatedwith actinic lichen planus . JEADV. 2004; 18: 221–242. 14. Hannes Wondratsch, Robert Feldmann, Andreas Steiner, Friedrich Breier . Laugier-Hunziker Syndrome in a Patient with Pancreatic Cancer. Case Rep Dermatol. 2012 May-Aug; 4(2): 174–176. 15. Sertan Ergun, Alp Saruhanoğlu, Dante-Antonio Migliari, Ilay Maden, Hakkı Tanyeri. Refractory Pigmentation Associated with Laugier-Hunziker Syndrome following Er:YAG Laser Treatment. Case Rep Dent. 2013; 2013: 561040. Published online 2013 Dec 3. 16. Sheridan AT, Dawber RP. Laugier–Hunziker syndrome: Treatment with cryosurgery. J Eur Acad Dermatol Venereol. 1999;13:146–8. 17. Aspillaga S., Fajre X., Benedetto J., Navarrete J., McNab M.E et all. Sindrome de Laugier-Hunziker en una paciente con sindrome de Sjogren: Reporte de un caso y revision de la literatura. www.radlalima2015.org/posters (accesed online 06.04.2016)

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Case Presentations

Angieolymphoid hyperplasia with eosinophilia with later onset - case report

ANGIOLYMPHOID HYPERPLASIA WITH EOSINOPHILIA WITH LATER ONSET - CASE REPORT HIPERPLAZIE ANGIOLIMFOIDĂ CU EOZINOFILE CU DEBUT TARDIV - CAZ CLINIC Virgil Pătraşcu1, Raluca Ciurea2, Marius Eugen Ciurea3, Andreea - Oana Enache1 1 Dermatology Department, University of Medicine and Pharmacy of Craiova, Romania 2 Pathology Department, University of Medicine and Pharmacy of Craiova, Romania 3 Plastic and Reconstructive Surgery Department, University of Medicine and Pharmacy of Craiova, Romania Corresponding author: Virgil Pătrașcu, Professor, MD, PhD, University of Medicine and Pharmacy, Petru Rareș Street, No 2-4, 200345, Craiova, Romania, phone: 004-0724273676, e-mail: vm.patrascu@gmail.com

Conflict of interest: The authors do not have any conflict of interest to declare.

Open Access Article

Abstract Keywords: angiolymphoid hyperplasia with eosinophilia, pathogenesis, treatment.

Angiolymphoid hyperplasia with eosinophilia is a benign vasculo-proliferative disease, predominantly found in middle-aged women (20-50 years old) and with exceptionally cases reported in children or elderly. We report the case of a male patient who developed multiple lesions of angiolymphoid hyperplasia with eosinophilia in the seventh decade of life. A 63-year-old man, without pathological antecedents presents with 6 nodular reddish lesions, 2-4 mm in size, moderately itchy, located in the left retroauricular region. Based on anamnesis, clinical examination, histopathological exam and other laboratory tests, we established the diagnosis of Angiolymphoid hyperplasia with eosinophilia. After complete excision, immediate repair of the defect was performed using advancement flaps from the declive aria. After a 9-months follow-up there was no evidence of recurrence. Considering the possible internal organ involvement, we recommend a quarterly follow-up of the patient for an early diagnosis of other pathological conditions that can lead to a poor vital prognosis.

Cite this article: Virgil Pătraşcu, Raluca Ciurea, Marius Eugen Ciurea, Andreea - Oana Enache. Angieolymphoid hyperplasia with eosinophilia with later onset - case report. RoJCED 2016; 3(2):144-147

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Virgil Pătraşcu, Raluca Ciurea, Marius Eugen Ciurea, Andreea - Oana Enache

Rezumat Cuvinte-cheie: hiperplazia angiolimfoidă cu eozinofile, patogenie, tratament.

Hiperplazia angiolimfoidă cu eozinofile este o afecțiune vasculoproliferativă benignă, întâlnită cu precădere la femei de vârstă medie (20-50 ani) şi în mod excepţional la copii sau vârstnici. Noi prezentăm cazul unui bărbat la care boala a debutat în decada a VII-a de viață cu leziuni multiple. Pacient în vârstă de 63 ani, fără antecedente patologice, se spitalizează pentru 6 formațiuni nodulare de culoare roșietică, cu dimensiuni cuprinse între 2 și 4 mm, însoțite de prurit moderat, localizate retroauricular stâng. În urma anamnezei, examenului clinic, examenului histopatologic și a celorlalte investigații paraclinice am stabilit diagnosticul de Hiperplazie angiolimfoidă cu eozinofile. Am efectuat excizie completă și acoperirea lipsei de substanță prin lambouri cutanate avansate din partea declivă. Nu au existat semne de recidivă la 9 de luni de la intervenție. Având în vedere posibila afectare organică, considerăm necesară supravegherea trimestrială a bolnavului pentru a depista din timp alte condiții patologice care pot întuneca prognosticul vital al acestuia.

Introduction Angiolymphoid hyperplasia with eosinophilia (ALHE) was first described in 1969 by Wells and Whimster(1). ALHE is a benign vasoproliferative disease, being predominantly encountered in middle-aged women (20-50 years old) and, exceptionally, in children or elderly(2,3). We report the case of an elderly man who developed multiple lesions of ALHE in the seventh decade of life.

Case report A 63-year-old man, without significant pathological history, presents with 6 itchy reddish lesions, 2-4 mm in size, located in the left retroauricular region. Lesions had appeared 12 months earlier without a history of trauma to the affected area (figs 1, 2). The regional lymph-nodes were not enlarged. No abnormality was detected in general physical examination.

All routine laboratory investigations including complete blood count, renal and liver function tests, peripheral blood eosinophils count and total serum Ig E level were within normal limits. Magnetic resonance imaging (MRI) excluded an underlying organic cause. Histopathological examination of the skin lesions showed marked dermal vascular proliferation, lined by endothelial cells and perivascular infiltration with eosinophils and lymphocytes (figs 3, 4). Based on anamnesis, clinical examination, histopathology and other laboratory tests we established the diagnosis of ,,Angiolymphoid hyperplasia with eosinophilia". After complete excision, immediate repair of the defect was performed using advancement flaps from the declive part. At 9-months follow-up there was no evidence of recurrence.

Figures 1, 2. Angiolymphoid hyperplasia with eosinophilia showing multiple lesions in the left retroauricular region

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Case Presentations

Angieolymphoid hyperplasia with eosinophilia with later onset - case report

Figure 3. Acanthosis of the epidermis and

proliferation of vascular channels in the deep dermis (HE stain, x40)

Discussion ALHE has been described with different names including: epithelioid hemangioma, atypical pyogenic granuloma, pseudopyogenic granuloma, histiocytoid hemangioma(4). Most people who develop ALHE are aged between 20 and 50, with an average age of 30-33 at the time of diagnosis(5). Rare cases have been described in children and elderly patients. The disease is more common in women than in men. The pathogenesis of ALHE is complex and not fully understood. Some authors consider ALHE as a vascular reaction secondary to some complex immunologic mechanisms(6). Olsen and Helwig consider that arteriovenous shunt is the main etiopathogenetic mechanism observed in 46 % of the cases(7). Kempf et al. showed the predominance of T lymphocytes and the rearrangement of TCR (T -cell receptor) in 5 patients with ALHE, leading to the supposition that ALHE is a low-grade neoplastic disease(8). A variety of factors have been incriminated in ALHE appearance such as: insect bites, local trauma (onset of the lesions ranges from 7 months to 20 years), infections (HIV, HTLV and HHV8), hyperestrogenism (in pregnancy or with oral contraceptive use), after vaccination(9). The disease is clinically characterized by single or multiple purplish red or brownish papules and subcutaneous nodules, with a range of 0.2-8 cm. The surface of the lesion may be smooth, ulcerated or crusted secondary to scratching(10). ALHE appears as a single lesion in 80% of patients but multiple disseminated cutaneous lesions were reported(11). ALHE is most commonly found on the cephalic extremity, particularly on the auricular pavilions and periauricular regions, situation also present in our case. Extracutaneous involvement is rare and has been reported in salivary glands, bone, colon, liver, orbit, spleen, lung, cardiovascular system(12). According to published studies, systemic eosino-

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Figure 4. Dense, chronic, inflammatory infiltrate rich in eosinophils in dermis (HE stain, ×100)

philia of 6-34% and regional lymphadenopathy may be found in 20% of patients. Serum levels of IgE are usually normal(13). Follicular mucinosis occurring along with ALHE has been described but without a clear association with mycosis fungoides(14). Also, peripheral T-cell lymphoma has been reported in patients with AHLE, thus it is hypothesized that AHLE might represent an early stage of T-cell lymphoma(15). The diagnosis is based on histopathology, which highlights the proliferation of small blood vessels and the presence of inflammatory infiltrate containing predominantly lymphocytes and eosinophils. Blood vessels are lined by enlarged endothelial cells with eosinophilic cytoplasm and large round nuclei. The cells are mostly cuboidal, with occasional “hobnail cells” appearance. In early stages of ALHE, the vascular component predominates, whereas in late stages of the disease lymphocytes become more prominent(16). Immunohistochemistry typically reveals a predominance of T lymphocytes and occasionally B cells that usually form the lymphoid follicles(17). ALHE should be distinguished from Kimura disease, initially thought to represent the same disease spectrum. They are now known to represent separate entities. Kimura disease is characterized by deep soft tissue and subcutaneous lesions, lymphadenopathy, eosinophilia and elevated serum Immunoglobulin E(18). ALHE must also be differentiated from: bacillary angiomatosis, Kaposi sarcoma, eruptive keratoacanthomas, molluscum contagiosum, eruptive xanthomas, multiple trichoepitheliomas, cutaneous lymphomas/ pseudolymphomas, cutaneous metastases. ALHE is a chronic disease, with a strong tendency to relapse after various medical therapies or surgery. Exceptionally, ALHE has shown spontaneous resolution(19). Complete surgical excision is the treatment of choice in ALHE with fewer lesions. In most cases,

R O M A N I A N J O U R N A L o f C L I N I CA L a n d E X P E R I M E N TA L D E R M ATO LO GY

Virgil Pătraşcu, Raluca Ciurea, Marius Eugen Ciurea, Andreea - Oana Enache

relapse occurs as a result of incomplete surgical excision, being observed in 33% -50% of the cases. Better aesthetic results were obtained using Mohs surgery(20). In a recent article, Wang et al. reported a case of ALHE treated with tacrolimus 0.1% ointment with the disappearance of lesions after 14 weeks of treatment(21). Other treatments that have been reported include: curettage and cautery, irradiation, laser therapy, corticosteroids (systemic, topical or intralesional preparation), topical tacrolimus 0,1%, topical imiquimod, indomethacin farnesil, intralesional interferon alfa-2a, treatment with oral retinoids and pentoxifylline, chemotherapeutic agents (vinblastine, bleomycin, fluorouracil)(22,23).

Conclusion Considering the possible organic involvement, we recommend as necessary a quarterly follow-up of the patient for an early diagnosis of other pathological conditions that can lead to a poor vital prognosis.

Bibliography 1. Karabudak O, Taskapan O, Bozdogan O, Dogan B. Angiolymphoid hyperplasia with eosinophilia: atypical appeareance in an older patient. Indian Journal of Dermatology. 2008;53(3):144-145. 2. Zaraa I; Mlika M; Chouk S; Chelly I; Mokni M; Zitouna M et al. Angiolymphoid hyperplasia with eosinophilia: A study of 7 cases. Dermatology Online Journal, 2011:17(2). 3. Kim SM, Yoon J, Yoon T-J. Angiolymphoid Hyperplasia with Eosinophilia on the Palm. Annals of Dermatology. 2010;22(3):358-361. 4. P. Doloi and S. Khanna. Angiolymphoid Hyperplasia with Eosinophilia—A Case Report. International Journal of Otolaryngology and Head & Neck Surgery, Vol. 1 No. 2, 2012, pp. 44-47. 5.C. A. Moran and S. Suster. Angiolymphoid Hyperplasiawith Eosinophilia (Epithelioid Hemangioma) of the Lung:A Clinicopathologic and Immunohistochemical Study of Two Cases. American Journal of Clinical Pathology,Vol. 123, No. 5, 2005, pp. 762765. 6. Devi B, Jena S, Kar D, Patro S, Behera B. Epitheloid Hemangioma: A Report of Two Cases. Indian Journal of Dermatology. 2014;59(5):510-512. 7. Olsen TG, Helwig EB.Angiolymphoid hyperplasia with eosinophilia. A clinicopathologic study of 116 patients.J Am Acad Dermatol. 1985 May;12(5 Pt 1):781-96. 8. Kempf W, Haeffner AC, Zepter K, Sander CA, Flaig MJ, Mueller B, et al. Angiolymphoid hyperplasia with eosinophilia: Evidencefor a T-cell lymphoproliferative origin. Hum Pathol 2002;33:1023-9. 9. Zarrin-Khameh N, Spoden JE, Tran RM. Angiolymphoid hyperplasia with eosinophilia associated with pregnancy: A case report and review of the literature. Arch Pathol Lab Med. 2005;129:1168–71. 10. Trindade F, Haro R, Requena L. Giant angiolymphoid hyperplasia with eosinophilia on the chest. J CutanPathol. 2009 Apr;36(4):493-6. 11. Farhadian, Joshua A; Shvartsbeyn, Marianna; Meehan, Shane A; &Urbanek, Richard W. (2015). Angiolymphoid hyperplasia with eosinophilia. Dermatology Online Journal, 21(12). doj_29531.

12. Moran CA, Suster S. Angiolymphoid hyperplasia with eosinophilia (epithelioid hemangioma) of the lung: A clinicopathologic and immunohistochemical study of two cases. Am J ClinPathol. 2005;123:762–5. 13. Aggarwal A, Keluskar V. Epithelioid hemangioma (angiolymphoidhyperplasia with eosinophilia) in the oral mucosa. Indian J Dent Res 2012;23:271-4 14. Joshi R. Angiolymphoid hyperplasia with follicular mucinosis. Indian J Dermatol VenereolLeprol. 2007;73(5):346–347. 15. Andreae J, Galle C, Magdorf K, et al. Severe atherosclerosis of the aorta and development of peripheral T-cell lymphoma in an adolescent with angiolymphoid hyperplasia with eosinophilia. Br J Dermatol. 2005;152(5): 1033–1038 16. R Guo, A C P. Gavino. Angiolymphoid Hyperplasia With Eosinophilia. Archives of Pathology & Laboratory MedicineMay 2015, Vol. 139, No. 5, pp. 683-686. 17. Mukherjee B, Kadaskar J, Priyadarshini O, Krishnakumar S, Biswas J, Angiolymphoid Hyperplasia with Eosinophilia of the Orbit and Adnexa. OculOncolPathol 2016;2:40-47 18. Sah P, Kamath A, Aramanadka C, Radhakrishnan R. Kimura’s disease - An unusual presentation involving subcutaneous tissue, parotid gland and lymph node. Journal of Oral and Maxillofacial Pathology : JOMFP. 2013;17(3):455-459. 19. Satpathy A, Moss C, Raafat F, Slator R. Spontaneous regression of a rare tumour in a child: angiolymphoid hyperplasia with eosinophilia of the hand: case report and review of the literature. Br J Plast Surg. 2005 Sep; 58(6):865-8. 20. Miller CJ, Ioffreda MD, Ammirati CT.Mohs micrographic surgery for angiolymphoid hyperplasia with eosinophilia.Dermatol Surg. 2004 Aug;30(8):1169-73. 21. Wang S, Li W. Angiolymphoid hyperplasia with eosinophilia successfully treated with tacrolimus ointment. J EurAcad Dermatol Venereol. 2010 Feb;24(2):237. 22. Baghestani S, Firooz A, Ghazisaidi MR. A refractory case of angiolymphoid hyperplasia with eosinophilia successfully treated by surgery. J Dermatolog Treat. 2011;22:49–51. 23. Lembo S, Balato A, Cirillo T, Balato N. A Long-Term Follow-Up of Angiolymphoid Hyperplasia with Eosinophilia Treated by Corticosteroids: When a Traditional Therapy is Still Up-to-Date. Case Reports in Dermatology. 2011;3(1):64-67.

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INTERNATIONAL EVENTS CALENDAR CALENDAR EVENIMENTE INTERNAŢIONALE mIULIE 2016 5-7: 96th Annual Meeting of the British Association of Dermatologists.Birmingham – UK www.bad.org.uk 7-9: 5th Congress of the Psoriasis International Network-Psoriasis 2016. Paris, France. www.pso2016.com 27-31: Summer meeting of the American Academy of Dermatology (AAD). Boston, MA – USA www.aad.org mAUGUST 2016 11-14: International Congress of Tropical Dermatology. Colombo, Srilanka. http://www.ictd2016.org/ 31 aug-3 sept: 16th World Congress on Cancers of the Skin; 12th Congress of the EADO. Vienna, Austria. www.wccs2016.com mSEPTEMBRIE 2016 8-10: 23rd Biennal Conference on Diseases of the Vulva & Vagina. Chicago, USA.

http://issvd.org/event/23rd-biennial-confeence-on-diseases-of-the-vulva-vagina/ 14-17: 13th ESCD ( European Society of Contact Dermatitis) Congress, Manchester, United Kingdom.www.escd2016.com 16-17: 4th Aesthetic & Anti-aging Medicine World Congress Eastern Europe AMWC Eastern Europe. Moscow, Russia. www.euromedicom.com 28-sept-2 oct: 25th CONGRESS OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VEN REOLOGY (EADV) , Vienna – Austria. www.eadv.org mOCTOMBRIE 2016 20-22: 2nd International Conference of dermatology. Kathmandu, Nepal. www.icderm2016.com mNOIEMBRIE 2016 24-26: International Congress of Aesthetic Dermatology ICAD 2016. Bankok, Thailand. www.euromedicom.com

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