GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA … · Mario PIPPIONE Andrea PESERICO Dennis LINDER - Nicola PIMPINELLI Pietro QuAgLINO Honorary Members and Editorial Committee M

This journal is peer reviewed and is indexed by: embase/excerpta medica, index medicus/medline/pubmed, science Citation index expanded (sCie, Thomson reuters - isi)The “Giornale Italiano di Dermatologia e Venereologia”, Bi-monthly Journal of Dermatology and Venereology, was founded in 1866 by G.B. Soresina, formerly “Giornale di Dermatologia e Sifilologia”, “Minerva Dermatologica”, “Giornale Italiano di Dermatologia”, “Il Dermosifilografo”, “Dermatologia”, “Cosmetologia”.Editorial, business, graphic and advertising address - Edizioni Minerva Medica - Corso Bramante 83-85 - I-10126 Torino (Italy) - Tel. +39 011 678282 - Fax +39 011 674502 - E-mail: [email protected] - Web Site: www.minervamedica.itTypesetting and printed - Edizioni Minerva Medica - Tipografia di Saluzzo - Corso IV Novembre 29-31 - I-12037 Saluzzo (Italy) - Tel. +39 0175 249405 - Fax +39 0175 249407Annual subscription:Italy: Individual: Online € 100.00, Print € 105.00, Print+Online € 110.00; Institutional: Print € 140.00, Online (Small € 262.00, Medium € 300.00, Large € 346.00, Extra-Large € 362.00), Print+Online (Small € 270.00, Medium € 315.00, Large € 360.00, Extra-Large € 375.00).European Union: Individual: Online € 175.00, Print € 180.00, Print+Online € 190.00; Institutional: Print € 250.00, Online (Small € 262.00, Medium € 300.00, Large € 346.00, Extra-Large € 362.00), Print+Online (Small € 270.00, Medium € 315.00, Large € 360.00, Extra-Large € 375.00).Outside the European Union: Individual: Online € 195.00, Print € 205.00, Print+Online € 215.00; Institutional: Print € 275.00, Online (Small € 280.00, Medium € 315.00, Large € 365.00, Extra-Large € 380.00), Print+Online (Small € 290.00, Medium € 330.00, Large € 380.00, Extra-Large € 395.00).Subscribers: Payment to be made in Italy: a) by check; b) by bank transfer to: Edizioni Minerva Medica, INTESA SANPAOLO Branch no. 18 Torino. IBAN: IT45 K030 6909 2191 0000 0002 917 c) through postal account no. 00279109 in the name of Edizioni Minerva Medica, Corso Bramante 83-85, 10126 Torino; d) by credit card Diners Club International, Master Card, VISA, American Express. Foreign countries: a) by check; b) by bank transfer to: Edizioni Minerva Medica, INTESA SANPAOLO Branch no. 18 Torino. IBAN: IT45 K030 6909 2191 0000 0002 917; BIC: BCITITMM c) by credit card Diners Club International, Master Card, VISA, American Express.Notification of changes to mailing addresses, e-mail addresses or any other subscription information must be received in good time. Notification can be made by sending the new and old information by mail, fax or e-mail or directly through the website www.minervamedica.it at the section “Your subscriptions - Contact subscriptions department”. Complaints regarding mis-sing issues must be made within six months of the issue’s publication date. Prices for back issues and years are available upon request.© Edizioni Minerva Medica - Torino 2012All rights reserved. No part of this publication may be reproduced, stored or transmitted in any form or by any means, without the prior permis-sion of the copyright ownerBi-monthly publication. Authorized by Turin Court no. 277 of July 2, 1948.Registered in the national press register as per law no. 416 art. 11 dated 5-8-1981 with number 00 148 vol. 2 sheet 377 dated 18-8-1982. Bi-monthly publication - Poste Italiane S.p.A. - Shipped on a subscription basis - Decree Law 353/2003 (converted in Law 27/02/2004 n° 46)art. 1, para 1, DCB/CN.

GIORNALE ITALIANO DIDERMATOLOGIA E VENEREOLOGIA

Official Journal of the “Società Italiana di Dermatologia Medica, Chirurgica,Estetica e delle Malattie Sessualmente Trasmesse (SIDeMaST)”

Honorary Editor Editor in Chief Assistant Editors Mario PIPPIONE Andrea PESERICO Dennis LINDER - Nicola PIMPINELLI Pietro QuAgLINO

Honorary Members and Editorial Committee

M. Bagot (Paris, France) - L. Borradori (Bern, Switzerland) - R. Cerio (London, uK) - K. D. Cooper (Cleveland, uSA)P. M. Elias (San Francisco, uSA) - J. Hercogova (Prague, Czech Republic) - F. Kerdel (Miami, uSA) - C. Paul (Tolouse, France)

M. R. Pittelkow (Rochester, uSA) - W. Sterry (Berlin, germany) - E. Tschachler (Vienna, Austria)

Editorial Board

P. Amerio (Chieti) - g. Argenziano (Reggio Emilia) - A. Belloni Fortina (Padova) - N. Cassano (Bari) - A. Costanzo (Roma)E. Cozzani (genova) - M. C. Fargnoli (L’Aquila) - I. Neri (Bologna) - F. Rongioletti (genova)F. Sampogna (Roma) - C. Tomasini (Torino) - M. Venturini (Brescia) - g. Zambruno (Roma)

SOCIETà ITALIANA DI DERMATOLOGIA MEDICA, CHIRuRGICA, ESTETICAE DELLE MALATTIE SESSuALMENTE TRASMESSE (SIDeMaST)

Board of Directors

Andrea Peserico (President) - Federico Bardazzi - Piergiacomo Calzavara-Pinton - Santo DattolaPasquale Frascione - giampiero girolomoni - Silvano Menni - Aurora Parodi

Ketty Peris - Anna Virgili - giovanni Fabio Zagni

Managing EditorAlberto OLIARO

Vol. 147 - No. 6 GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA XIX

Vol. 147 Dicembre 2012 N. 6


INDICE

513PREFAZIONE

LINFOMI CUTANEI: COSA C’È DI NUOVO515Trent’anni di progressi nella ricerca sui linfomi cuta-neiWillemze R.

523Micosi fungoide: evoluzione clinica delle lesioni cuta-neeQuagl ino P. , Pimpinel l i N. , Bert i E. , Calzavara-Pinton P., Lombardo G. A., Rupoli S., Alaibac M., Arcaini L., Bagnato S., Baldo A., Bottoni U., Carbone A., Cestari R., Clerico R., De Renzo A., Fava P., Fierro M. T., Filotico R., Fimiani M., Frontani M.,Girgenti V., Goteri G., Leali C., Mamusa A. M., Mariotti G., Mastrandrea V., Pellegrini C., Pennese E., Pileri A., Savoia P., Stelitano C., Titli S., Virgili A., Zichichi L., Zinzani P. L., Bernengo M. G.

533Diagnosi e terapia dei CTCL eritrodermici: un aggior-namentoBernengo M. G., Quaglino P.

545Linfomi cutanei a cellule CD30+: una questione anco-ra apertaAlaibac M., Zarian H., Russo I., Peserico A.

553Linfomi cutanei a cellule T periferiche, sottotipi non altrimenti specificati e rari: un gruppo eterogeneo di linfomi cutanei impegnativiKempf W., Rozati S., Kerl K., French L. E., Dummer R.

563Linfomi cutanei a cellule T avanzati/aggressivi: come migliorare l’efficacia del trttamentoZinzani P. L.

INDICE

XX GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA December 2012

573Terapia combinata per i CTCL: ruolo attuale del bexa-roteneDelfino C., Grandi V., Pileri A., Rupoli S., Quaglino P., Alterini R., Goteri G., Canafoglia L., Pimpinelli N. per Il Gruppo Italiano Linfomi Cutanei

581Linfomi cutanei a cellule B indolenti: diagnosi e tera-pia 2012Santucci M., Grandi V., Maio V., Delfino C., Alterini R., Pimpinelli N.

589Linfomi cutanei diffusi a grandi cellule B: un aggior-namento su morfologia e trattamentoPaulli M., Lucioni M., Maffi A., Croci G. A., Nicola M., Berti E.

603Neoplasia a cellule dendritiche plasmocitoidi blasti-che: il santuario cutaneoPileri A., Delfino C., Grandi V., Agostinelli C., Pileri S. A., Pimpinelli N.

CONSENSUS609Consenso sull’uso dell’associazione fissa calcipotriolo / betametasone dipropionato nel trattamento della psoriasi in placcheGirolomoni G., Vena G. A., Ayala F., Cannavò S. P., De Pità O., Chimenti S., Peserico A.

625ARTICOLI ORIGINALIEfficacia dello shampoo Iralfaris nel trattamento della psoriasi del cuoio capelluto: uno studio prospettico con valutazione videodermatoscopica in 70 pazientiRossi A., Pranteda G., Iorio A., Mari E., Milani M.

631Malattie cutanee nei pazienti geriatrici: la nostra esperienza maturata in un ambulatorio di Dermatologia a loro dedicato a SienaRubegni P., Poggiali S., Nami N., Rubegni M., Fimiani M.

637REVIEWVitiligine: recenti conoscenze e nuovi approcci tera-peuticiLotti T. M., Berti S. F., Hercogova J., Huggins R. H., Lee B. W., Janniger C. K., Schwartz R. A.

649CASI CLINICIComparsa di un serbatoio di larva migrans cutanea in Bretagna?Veraldi S., Persico M. C., Francia C., La Vela V.

653LETTERELupus cutaneo neonatale: due casi cliniciBassi E., Bagot M., Cosnes A.

654Pemfigoide bolloso di Lever e malattia celiaca: occor-renza casuale o associazione insolita?Marconi B., Campanati A., Marzioni M., Cataldi I., Brandozzi G., Giuliodori K., Santinelli A., Pisa E., Ganzetti G., Offidani A.,

Vol. 147 - No. 6 GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA XXIII

Vol. 147 December 2012 No. 6


CONTENTS

513PREFACE

CUTANEOUS LYMPHOMA: WHERE ARE WE MOVING?515Thirty years of progress in cutaneous lymphoma researchWillemze R.

523Mycosis fungoides: disease evolution of the “lion queen” revisitedQuagl ino P. , Pimpinel l i N. , Bert i E. , Calzavara-Pinton P., Lombardo G. A., Rupoli S., Alaibac M., Arcaini L., Bagnato S., Baldo A., Bottoni U., Carbone A., Cestari R., Clerico R., De Renzo A., Fava P., Fierro M. T., Filotico R., Fimiani M., Frontani M.,Girgenti V., Goteri G., Leali C., Mamusa A. M., Mariotti G., Mastrandrea V., Pellegrini C., Pennese E., Pileri A., Savoia P., Stelitano C., Titli S., Virgili A., Zichichi L., Zinzani P. L., Bernengo M. G.

533Erythrodermic CTCL: updated clues to diagnosis and treatmentBernengo M. G., Quaglino P.

545CD30+ lymphoproliferative disorders of the skin: still an open questionAlaibac M., Zarian H., Russo I., Peserico A.

553Cutaneous peripheral T-cell lymphomas, unspecified/NOS and rare subtypes: a heterogeneous group of challenging cutaneous lymphomasKempf W., Rozati S., Kerl K., French L. E., Dummer R.

563Advanced/aggressive CTCL: improving the efficacy of treatmentZinzani P. L.

CONTENTS

XXIV GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA December 2012

573Combination treatment in CTCL: the current role of bexaroteneDelfino C., Grandi V., Pileri A., Rupoli S., Quaglino P., Alterini R., Goteri G., Canafoglia L., Pimpinelli N. for the Gruppo Italiano Linfomi Cutanei

581Indolent cutaneous B-cell lymphoma: diagnosis and treatment 2012Santucci M., Grandi V., Maio V., Delfino C., Alterini R., Pimpinelli N.

589Primary cutaneous diffuse large B-cell lymphoma (PCDLBCL), leg-type and other: an update on mor-phology and treatmentPaulli M., Lucioni M., Maffi A., Croci G. A., Nicola M., Berti E.

603Blastic plasmacytoid dendritic cell neoplasm (BPDCN): the cutaneous sanctuaryPileri A., Delfino C., Grandi V., Agostinelli C., Pileri S. A., Pimpinelli N.

CONSENSUS PAPER609Consensus on the use of the fixed combination cal-cipotriol/betamethasone dipropionate in the treat-ment of plaque psoriasisGirolomoni G., Vena G. A., Ayala F., Cannavò S. P., De Pità O., Chimenti S., Peserico A.

625ORIGINAL ARTICLESEfficacy of Iralfaris shampoo in the treatment of scalp psoriasis: a videodermoscopy evaluation pro-spective study in 70 patientsRossi A., Pranteda G., Iorio A., Mari E., Milani M.

631Skin diseases in geriatric patients: our experience from a public skin outpatient clinic in SienaRubegni P., Poggiali S., Nami N., Rubegni M., Fimiani M.

637REVIEWSVitiligo: recent insights and new therapeutic appro-achesLotti T. M., Berti S. F., Hercogova J., Huggins R. H., Lee B. W., Janniger C. K., Schwartz R. A.

649CASE REPORTSAppearance of a reservoir of hookworm-related cuta-neous larva migrans in Brittany?Veraldi S., Persico M. C., Francia C., La Vela V.

653CORRESPONDENCECutaneous neonatal lupus: two casesBassi E., Bagot M., Cosnes A.

654Bullous pemphigoid of Lever and celiac disease: a coincidental occurrence or an unusual association?Marconi B., Campanati A., Marzioni M., Cataldi I., Brandozzi G., Giuliodori K., Santinelli A., Pisa E., Ganzetti G., Offidani A.,

Vol. 147 - No. 6 GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA 513

PREFACEG ITAL DERMATOL VENEREOL 2012;147:513

Dear Friends and Colleagues,

We are very happy and proud of this monographic issue of the Giornale Italiano di Dermatologia e Venereologia, prepared with the invaluable, enthusiastic assistance of several reknown experts in the

challenging field of lymphoproliferative disorders of the skin. We sincerely trust and hope that this issue will be of great help in updating Italian dermatologists, and

hopefully others from abroad, about this difficult, continuously developing and fascinating topic in oncol-ogy.

Warmest regards and wishes to the Journal’s readers.

Maria Grazia Bernengo, MDMarco Santucci, MD

Pier Luigi Zinzani, MD

Anno: 2012Mese: DecemberVolume: 147No: 6Rivista: GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIACod Rivista: G ITAL DERMATOL VENEREOL

Lavoro: 4425-MDtitolo breve: History of cutaneous lymphoma researchprimo autore: WILLEMZEpagine: 513


lymphomas (CBCL), and the development of con-sensus classifications for primary cutaneous lympho-mas. In the last decade collaborative efforts shifted to the development of guidelines for staging, manage-ment and treatment of different types of cutaneous lymphomas, new therapies facilitated the design of randomized clinical trials, and new technologies pro-vided the opportunity to study genetic abnormalities in different types of primary cutaneous lymphoma. This review provides a historic overview of the re-sults of cutaneous lymphoma research during the last three decades. The importance of a multidisciplinary approach and continued international collaboration not only in clinical trials and guideline development, but also in basic research is emphasized.

New types of CTCL and CBCL

In the early 1970s mycosis fungoides (MF), Se-zary syndrome (SS) and some related conditions, such as pagetoid reticulosis and lymphomatoid pa-pulosis, were the only types of cutaneous lymphoma that had been rather well described. Reports on cuta-neous lymphomas other than MF/SS were few, and these conditions were often still designated as malig-nant reticulosis or reticulum cell sarcoma. They were firmly believed to represent skin manifestations of a systemic lymphoma, and treated consistently.

Department of DermatologyLeiden University Medical Center

Leiden, the Netherlands

R. WILLEMZE

Thirty years of progress in cutaneous lymphoma research

Primary cutaneous lymphomas are a heterogeneous group of T-cell and B-cell neoplasms that present in the skin without any evidence of extracutaneous disease at the time of diagnosis. In 1980 primary cutaneous lymphomas other than mycosis fun-goides, Sezary syndrome and some related disorders, collec-tively termed cutaneous T-cell lymphoma had not yet been rec-ognized. This historic review describes the history of cutaneous lymphoma research in Europe over the last thirty years. Euro-pean collaborative studies by dermatologists and pathologists, often coordinated by the European Organization for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Group, resulted in the definition of new types of cutaneous T-cell lymphomas (CTCL) and cutaneous B-cell lymphomas (CBCL), and the development of consensus classifications for primary cutaneous lymphomas (EORTC classification; WHO-EORTC classification; WHO classification 2008), which resulted in bet-ter diagnosis and treatment of these diseases. More recent ac-tivities described herein are the development of guidelines for staging, treatment and the design of clinical trials, often in close collaboration with the International Society for Cutaneous Lymphomas, the formation of an EORTC CTCL trials plat-form and attempts to translate the results of molecular genetic studies into clinical practise. In this review the importance of a multidisciplinary approach and continued international col-laboration not only in clinical trials and guideline development, but also in basic research is emphasized.Key words: Lymphoma - Skin diseases - Guidelines as topic.

In the last 30 years there has been an enormous progress in our understanding of cutaneous lym-

phomas. European collaborative studies contributed significantly to the definition of new types of cutane-ous T-cell lymphomas (CTCL) and cutaneous B-cell

Corresponding author: R. Willemze, MD, Department of Dermatol-ogy, B1-Q-93, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands. E-mail: [email protected]


Lavoro: 4425-MDtitolo breve: History of cutaneous lymphoma researchprimo autore: WILLEMZEpagine: 515-21

G ITAL DERMATOL VENEREOL 2012;147:515-21

CUTANEOUS LYMPHOMA: WHERE ARE WE MOVING?

WILLEMZE HISTORy OF CUTANEOUS LyMPHOMA RESEARCH

516 GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA December 2012

In 1975, based on the observation that the neoplas-tic cells in MF, SS and related conditions did not only have the same morphology (cerebriform nuclei), but also a common T-cell phenotype, the term CTCL was introduced for this group of diseases.1 Within a short time this term gained wide acceptance, particularly in the USA. The introduction of the CTCL concept can be considered as a landmark in the history of this group of diseases. However, a major disadvantage has been that in many subsequent studies no distinc-tion was made anymore between MF, SS and other T-cell neoplasms, which may vary considerably in clinical presentation and clinical behavior.

The development of monoclonal antibodies that could detect T-cell and B-cell associated antigens on tissue sections had a major impact on the diag-nosis and classification of cutaneous lymphomas. It allowed distinction between CTCL and CBCL, and demonstration of monotypic light chain expression became the most important criterion to differentiate between CBCL and cutaneous lymphoid hyperplasia.

In the 1980s several European groups, using these new immunohistochemical methods, started to clas-sify cutaneous lymphomas according to the criteria of the Kiel classification, a classification system used by hematopathologist for the classification of nodal lymphomas. In contrast to former belief, these stud-ies demonstrated that malignant lymphoma other than MF/SS can present in the skin without any evi-dence of extracutaneous disease at the time of diag-nosis. To better define these primary cutaneous lym-phomas, the European Organization for Research and Treatment of Cancer (EORTC) Cutaneous Lym-phoma Pathology Group started to study selected groups of patients at their annual meetings. The first meeting organized in this way resulted in a publica-tion on primary cutaneous immunocytomas (Figure 1), and many other publications would follow.

Studies by the EORTC group as well as by na-tional collaborative cutaneous lymphoma groups showed that primary cutaneous lymphomas have highly characteristic clinical and histological fea-tures, another clinical behavior, often a much better prognosis than histologically similar nodal lympho-mas involving the skin secondarily, and therefore require a different type of treatment. Subsequent studies demonstrating differences in the presence of specific translocations, and the expression of on-cogenes and adhesion receptors between primary cutaneous lymphomas and their nodal counterparts

provided further support for the view that these pri-mary cutaneous should be considered as distinct dis-ease entities. These studies on well-defined groups of primary cutaneous lymphomas resulted not only in the delineation of several new types of CTCL and CBCL, but also in the awareness that the classifica-tion systems used by hematopathologists for nodal lymphomas at that time (Kiel classification; Working Formulation) were inadequate to categorize primary cutaneous lymphomas in a clinically meaningful way. First, these classifications were based on his-tologic criteria, while studies in primary cutaneous lymphomas had clearly shown that a definite diagno-sis cannot always be made on the basis of histologic criteria alone, but should always be based on a con-stellation of morphological, immunological, genetic and clinical criteria. Second, these classifications did not distinguish between nodal and extranodal (e.g., primary cutaneous) lymphomas. As a result, primary cutaneous lymphomas were often treated inappro-priately as systemic lymphomas with unnecessarily aggressive treatment regimens. These observations prompted the EORTC Cutaneous Lymphoma Group to formulate a separate classification for primary cu-taneous lymphomas: the EORTC classification.2

New classifications

The EORTC classification was the first classifica-tion designed specifically for the group of primary

Figure 1.—Participants at the 1991 EORTC Cutaneous Lympho-ma Pathology Group meeting on primary cutaneous immunocyto-mas in Amsterdam, the Netherlands.

HISTORy OF CUTANEOUS LyMPHOMA RESEARCH WILLEMZE


classification 2001) included most types of CTCL, but remaining differences between the EORTC and WHO 2001 classification systems, in particular on the definition and terminology of the different types of CBCL resulted in considerable debate and confu-sion. These controversies came to an end with the publication of the WHO-EORTC classification for cutaneous lymphomas, which combined the best of the preceding EORTC and WHO systems (Table I).5 Several large studies have validated the clinical significance of this new classification and confirmed that it can be considered as a major step forward.5-8 In 2008 the fourth edition of the WHO classifica-tion for Tumours of Haematopoietic and Lymphoid Tissues was published.9 With respect to the primary cutaneous lymphomas, it is highly fortunate that the WHO classification 2008 adopted the terminol-ogy and definitions of the WHO-EORTC classifi-cation with only minor modifications. The publica-tion of the WHO classification 2008 may therefore be considered as another milestone, since – for the first time – a classification for malignant lymphomas used by pathologists and hematologists/oncologists worldwide contains all types of CTCL and CBCL

cutaneous lymphomas. This classification simply listed the different types of CTCL and CBCL, that had been defined as separate entities in the decade before. It contained a limited number of well-defined types of CTCL and CBCL, and some provisional en-tities. Distinction was made between cutaneous lym-phomas with an indolent, intermediate or aggressive clinical behavior. The clinical validity of this clas-sification has been validated by several large studies including follow-up data of more than 1300 patients with a primary cutaneous lymphoma.2-4 By including well-defined and recognizable disease entities, this classification provided the clinician with detailed in-formation on staging, preferred mode of treatment, clinical behavior and prognosis, and served as a use-ful guide to optimal management and treatment. The publication of a separate organ-based classification was not applauded by hematopathologists, but was essential, since primary cutaneous lymphomas other than MF/SS were not recognized in other classifica-tion systems used at that time. The third edition of the World Health Organization (WHO) classification for tumours of haematopoietic and lymphoid tissues published in 2001 (further referred to as the WHO

Table I.—WHO-EORTC classification for primary cutaneous lymphomas.

Frequency (%)# 5-year DSS (%)

Cutaneous T-cell and NK-cell lymphomasMycosis fungoidesMycosis fungoides variants and subtypes – Folliculotropic MF – Pagetoid reticulosis – Granulomatous slack skin

Sézary syndromeAdult T-cell leukemia/lymphomaPrimary cutaneous CD30-positive lymphoproliferative disorders – Primary cutaneous anaplastic large cell lymphoma – Lymphomatoid papulosis

Subcutaneous panniculitis-like T-cell lymphomaExtranodal NK/T-cell lymphoma, nasal typePrimary cutaneous peripheral T-cell lymphoma, rare subtypes

– Primary cutaneous γ/δ T-cell lymphoma – Primary cutaneous aggressive epidermotropic CD8-positive T-cell lymphoma (provisional) – Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma (provisional)

Primary cutaneous peripheral T-cell lymphoma, not otherwise specifiedCutaneous B-cell lymphomasPrimary cutaneous marginal zone B-cell lymphomaPrimary cutaneous follicle center lymphomaPrimary cutaneous diffuse large B-cell lymphoma, leg typePrimary cutaneous intravascular large B-cell lymphomaPrecursor hematologic neoplasmBlastic plasmacytoid dendritic cell neoplasm@

395

<1

<12

<110

151

<1<1

<123

7124

<1

<1

8979

100

10022

NDA95

10087NRNR

129115

99955264

NR# Relative frequency and disease-specific 5-year-survival based on 1780 patients with a primary cutaneous lymphoma registered at the Dutch Cutaneous Lymphoma Group between 1986 and 2008@ Term used in the WHO 2008 classification. This entity was formerly designated as blastic NK cell lymphoma (WHO 2001) or CD4+/CD56+ hemato-dermic neoplasm (WHO-EORTC).; DSS: disease-specfic survival; NDA: no data available; NR: not reached.



be obtained in multicenter studies. Until recently, clinical trials in cutaneous lymphomas suffered from a lack of standardization in evaluation, staging, end-points and response criteria. In 2007, the ISCL and EORTC published guidelines for the standard evalu-ation, classification and staging of MF and SS, and in a separate article for cutaneous lymphomas other than MF/SS.21, 22 These guidelines offer the potential for uniform staging of patients enrolled in clinical trials. More recently, the ISCL, EORTC and USCLC published guidelines for the study design, endpoints and response criteria in clinical trials for patients with MF or SS.23 Publication of similar guidelines for patients with cutaneous lymphomas other than MF/SS is in preparation. These recently published guidelines should facilitate the performance of coop-erative trials and comparison of the efficacy of thera-peutic agents tested at different sites.

EORTC clinical trials

In the last decade many new therapeutic agents have become available for the treatment of CTCL. These include new retinoids, monoclonal antibod-ies, immunotoxins, histone deacetylase inhibitors and many others.24, 25 Before 2000 the EORTC Cu-taneous Lymphoma Group had no track record in clinical trials, and also in the last decade only few studies have been conducted by the EORTC group. A study comparing the safety and efficacy of PUVA combined with bexarotene versus PUVA alone in patients with stage IB-IIA MF (EORTC 21011) was closed prematurely because of poor accrual. Unfor-tunately, a much more interesting study comparing PUVA plus bexarotene and PUVA plus acitretin has never been performed. The results of a phase II study of liposomal doxorubicin monochemotherapy in pa-tients with advanced stage MF (stage IIB, IVA and IVB) with or without previous chemotherapy will soon be published. It is fortunate that the EORTC Cutaneous Lymphoma Group has recently designed an EORTC CTCL Trials Platform including three successive clinical trials for patients with advanced CTCL that allow the enrollment of patients through the evolution of their disease.26 The first clinical trial (EORTC 21081) is a phase III study of lenolidomide maintenance therapy after debulking with gemcit-abine or liposomal doxorubicin with or without ra-diotherapy in patients with advanced CTCL not pre-

most relevant for dermatologists and included in pre-ceding classification systems for primary cutaneous lymphomas. The WHO classification 2008 reflects the international consensus on the classification of cutaneous lymphomas, and is therefore expected to contribute significantly to a more uniform diagnosis and more appropriate treatment of these diseases.

Activities in the third millennium

In the first decade of the third millennium the EORTC Cutaneous Lymphoma Pathology Group continued to study selected groups of cutaneous lymphomas resulting in publications on primary cutaneous diffuse large B-cell lymphomas,10 cuta-neous cytotoxic/NK cell lymphomas,11 CD56 posi-tive cutaneous lymphomas,12 granulomatous MF and granulomatous slack skin 13 and subcutaneous panniculitis-like T-cell lymphoma.14 New activities in the last decade were the formulation of consen-sus recommendations for staging, management and treatment of different types of cutaneous lymphoma, the design of clinical trials by the EORTC Cutane-ous Lymphoma Group and the introduction of high throughput molecular studies.

Consensus guidelines

While the definition of new types of CTCL and CBCL and the development of separate classifica-tions for primary cutaneous lymphomas had mainly been based on European studies, most consensus recommendations published in the last ten years re-sulted from close collaboration between the EORTC group, the International Society for Cutaneous Lym-phomas (ISCL) and more recently the United States Cutaneous Lymphoma Consortium (USCLC). These collaborative studies resulted in consensus recom-mendations for the diagnosis of early stage MF,15 the definitions and terminology of erythrodermic CTCL including SS,16 the usage of total skin electron beam irradiation in MF,17 and the management and treat-ment of MF and SS,18 CBCL 19 and the group of pri-mary cutaneous CD30-positive lymphoproliferative disorders (primary cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis).20

Because of the rarity of cutaneous lymphomas, meaningful data on therapeutic outcomes can only



limited numbers of patients lacking statistical power and not validated by independent studies. Since cu-taneous lymphomas are rare diseases, real progress can only be made by international collaborative studies ensuring sufficient numbers of patients, and using uniform selection criteria and standardized protocols. This is illustrated by a recent EORTC multicenter study on skin biopsies of 64 patients with a PCLBCL, LT, which demonstrated that inac-tivation of the CDKN2A gene is associated with an unfavourable prognosis.28 Another EORTC study fo-cusing on SS has just started. The aim of this study, in which six European cutaneous lymphoma centres participate, is to validate the diagnostic and prognos-tic value of a large number of potential biomarkers, both at the protein and mRNA level, which originate from single center studies and many of which have not been confirmed by independent studies.

Conclusions

In the last 30 years we have witnessed an enor-mous growth in our understanding of cutaneous lym-phomas. Collaborative studies by dermatologists and pathologists have been able to define distinct types of CTCL and CBCL and to establish new consen-sus classifications for cutaneous lymphomas used by dermatologists, pathologists and oncologists world-wide. These classifications are not only expected to contribute significantly to a more uniform diagnosis and more appropriate treatment of these diseases. They also form the basis for both clinical research and therapeutic trials, and basic research attempting to elucidate the molecular basis of the different types of cutaneous lymphoma. In recent years awareness has grown that randomized clinical trials are a pre-requisite for further progress in the treatment of cu-taneous lymphomas. The EORTC Cutaneous Lym-phoma Group is in a unique position to coordinate such international multicenter studies. The recently published consensus guidelines regarding staging, new endpoints and response criteria may facilitate collaborative trials with non-European cutaneous lymphoma groups. Regarding basic research, new technologies, such as exome, whole genome and mRNA deep sequencing are expected to further in-crease our understanding of the molecular pathways involved in the pathogenesis of these lymphomas, and to contribute to the definition of new molecu-

viously treated with intravenous chemotherapy has just started recruiting patients. The second trial in the CTCL platform (EORTC 21082) will compare pro-gression free survival between suberoylanilide hy-doxamic acid (SAHA) and the combination of SAHA and bortezomib in refractory and recurrent advanced CTCL. A third trial aimed to evaluate reduced inten-sity allogeneic stem cell transplantation in patients with advanced refractory CTCL is currently under discussion. This EORTC CTCL Trials Platform will be accompanied by a series of translational studies aimed to identify potential mechanisms of action of these therapies and to predict responders.

Molecular studies

In the last decade classical cytogenetic studies have been replaced by a rapidly increasing number of high throughput techniques to study (epi)genet-ic abnormalities in cancer. Regarding CTCL and CBCL studies have mainly been performed in cu-taneous lymphomas from which rather pure tumor cell populations could be obtained, such as periph-eral blood samples from patients with SS and tissue samples from patients with tumor stage MF, primary cutaneous follicle center lymphoma (PCFCL) and primary cutaneous diffuse large B-cell lymphoma (PCLBCL), leg type. Some of these studies provid-ed important diagnostic or prognostic information, which could be translated into clinical practise. For instance, demonstration of a germinal center B-cell gene expression profile in PCFCL and an activated B-cell gene expression profile in PCLBCL, leg type contributed to a better definition of these two types of CBCL and facilitated their inclusion as separate entities in the WHO-EORTC and WHO 2008 clas-sification systems.27 In addition, this study showed that apart from BCL2, MUM1/IRF4 and IgM may serve as important markers to differentiate between PCFCL and PCLBCL, leg type. However, published reports often contain impressive lists of chromo-somal abnormalities or deregulated genes, which are completely different from similar lists reported by other groups, leaving behind the interested clinician in despair. Such discrepancies may result from dif-ferences in experimental design using different pro-tocols and platforms and different selection criteria for both patients and controls. Notably, most stud-ies published thus far are single center studies with



al from the Cutaneous Lymphoma Study Group of the European Or-ganization for Research and Treatment of Cancer (EORTC). Blood 1997;90:354-71.

3. Grange F, Hedelin G, Joly P, Beylot-Barry M, D’Incan M, Delau-nay M et al. Prognostic factors in primary cutaneous lymphomas other than mycosis fungoides and the Sezary syndrome. The French Study Group on Cutaneous Lymphomas. Blood 1999;93:3637-42.

4. Fink-Puches R, Zenahlik P, Bäck B, Smolle J, Kerl H, Cerroni L. Primary cutaneous lymphomas: applicability of current classifica-tion schemes (EORTC, WHO) based on clinicopathologic features observed in a large group of patients. Blood 2002;99:800-5.

5. Willemze R, Jaffe ES, Burg G, Cerroni L, Berti E, Swerdlow SH et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005;105:3768-85.

6. Zinzani PL, Quaglino P, Pimpinelli N, Berti E, Baliva G, Rupoli S et al. Prognostic factors in primary cutaneous B-cell lymphoma: the Italian Study Group for Cutaneous Lymphomas. J Clin Oncol 2006;24:1376-82.

7. Senff NJ, Hoefnagel JJ, Jansen PM, Vermeer MH, van Baarlen J, Blokx WA et al. Reclassification of 300 primary cutaneous B-Cell lymphomas according to the new WHO-EORTC classification for cutaneous lymphomas: comparison with previous classifications and identification of prognostic markers. J Clin Oncol 2007;25:1581-7.

8. Khamaysi Z, Ben-Arieh y, Izhak OB, Epelbaum R, Dann EJ, Berg-man R. The applicability of the new WHO-EORTC classification of primary cutaneous lymphomas to a single referral center. Am J Dermatopathol 2008;30:37-44.

9. Swerdlow A, Campo E, Harris NL, Jaffe ES, Pileri S, Stein H et al. World Health Organization Classification of Tumours of Hemat-opoietic and Lymphoid Tissue. Lyon: IARC Press; 2008.

10. Grange F, Bekkenk MW, Wechsler J, Meijer CJ, Cerroni L, Ber-nengo M et al. Prognostic factors in primary cutaneous large B-cell lymphomas: a European multicentre study. J Clin Oncol 2001;19:3602-1610.

11. Santucci M, Pimpinelli N, Massi D, Kadin ME, Meijer CJ, Muller-Hermelink HK et al. Cytotoxic/natural killer cell cutaneous lym-phomas. Report of EORTC Cutaneous Lymphoma Task Force Workshop. Cancer 2003;97:610-27.

12. Assaf C, Gellrich S, Whittaker S, Robson A, Cerroni L, Massone C et al. CD56-positive haematological neoplasms of the skin: a multi-centre study of the Cutaneous Lymphoma Project Group of the Eu-ropean Organisation for Research and Treatment of Cancer. J Clin Pathol 2007;60:981-9.

13. Kempf W, Ostheeren-Michaelis S, Paulli M, Lucioni M, Wechsler J, Audring H et al. Granulomatous mycosis fungoides and granulo-matous slack skin: a multicenter study of thr Cutaneous Lymphoma Histopathology Task Force Group of the European Organization for Research and Treatment of Cancer (EORTC). Arch Dermatol 2008;144:1609-17.

14. Willemze R, Jansen PM, Cerroni L, Berti E, Santucci M, Assaf C et al. Subcutaneous panniculitis-like T-cell lymphoma: definition, classification, and prognostic factors: an EORTC Cutaneous Lym-phoma Group Study of 83 cases. Blood 2008;111:838-45.

15. Pimpinelli N, Olsen EA, Santucci M, Vonderheid E, Haeffner AC, Stevens S et al. Defining early mycosis fungoides. J Am Acad Der-matol 2005;53:1053-63.

16. Vonderheid EC, Bernengo MG, Burg G, Duvic M, Heald P, Laro-che L et al. Update on erythrodermic cutaneous T-cell lymphoma: report of the International Society for Cutaneous Lymphomas. J Am Acad Dermatol 2002;46:95-106.

17. Jones GW, Kacinski BM, Wilson LD, Willemze R, Spittle M, Ho-henberg G et al. Total skin electron beam irradiation in the manage-ment of mycosis fungoides: consensus of the EORTC Cutaneous Lymphoma Project Group. J Am Acad Dermatol 2002;47:364-70.

18. Trautinger F, Knobler R, Willemze R, Peris K, Stadler R, Laroche L et al. EORTC consensus recommendations for the treatment of my-cosis fungoides/Sezary syndrome. Eur J Cancer 2006;42:1014-30.

lar targets for diagnosis and therapeutic intervention. Collaboration between dermatologists, pathologists and oncologists has been essential for defining new entities and classifications. Such an international multidisciplinary approach, which should include clinicians, basic scientists and biostatisticians, is also indispensable for optimal translation of results from basic science into clinical practice, and is the best guarantee for further advances in the diagnosis and treatment of patients with a cutaneous lymphoma.

Riassunto

Trent’anni di progressi nella ricerca sui linfomi cutaneiI linfomi cutanei primari costituiscono un gruppo etero-

geneo di neoplasie a cellule B e a cellule T che insorgono nella cute senza alcun segno di malattia extracutanea al momento della diagnosi. Nel 1980, i linfomi cutanei pri-mari, all‘infuori della micosi fungoide, della sindrome di Sezary e di alcune patologie correlate, collettivamente de-nominate linfomi a cellule T, non erano ancora stati ricono-sciuti. La presente review ripercorre la storia della ricerca sui linfomi cutanei in Europa negli ultimi trent‘anni. Studi collaborativi europei condotti da dermatologi e patologi, spesso coordinati dal Gruppo per lo studio dei linfomi cu-tanei dell‘Organizzazione europea per la ricerca e il tratta-mento del cancro (EORTC) hanno favorito la definizione di nuovi tipi di linfomi cutanei a cellule T (cutaneous T-cell lymphomas, CTCL) e a cellule B (cutaneous B-cell lym-phomas, CBCL), oltre allo sviluppo di classificazioni dei linfomi cutanei primari (classificazione WHO-EORTC; classificazione WHO 2008) che si sono tradotte in una migliore diagnosi e in un miglior trattamento di tali ma-lattie. Attività più recenti riguardano lo sviluppo di linee guida per la stadiazione, il trattamento e il disegno degli studi clinici, spesso in stretta collaborazione con la Società internazionale sui linfomi cutanei (ISCL), la creazione da parte della EORTC di una piattaforma per gli studi clinici sui CTCL e i tentativi di tradurre i risultati degli studi sul-la genetica molecolare nella pratica clinica. Nella presen-te review, viene evidenziata l’importanza di un approccio multidisciplinare e di una collaborazione internazionale continua, non solo negli studi clinici e nello sviluppo delle linee guida ma anche nella ricerca basica.Parole chiave: Linforma - Cute, malattie - Linee guida.

References

1. Lutzner M, Edelson R, Schein P, Green I, Kirkpatrick C, Ahmed A. Cutaneous T-cell lymphomas: the Sézary syndrome, mycosis fun-goides, and related disorders. Ann Intern Med 1975;83:534-52.

2. Willemze R, Kerl H, Sterry W, Berti E, Cerroni L, Chimenti S et al. EORTC classification for primary cutaneous lymphomas. A propos-



States Cutaneous Lymphoma Consortium; Cutaneous Lymphoma Task Force of the European Organisation for Research and Treat-ment of Cancer. Clinical end points and response criteria in mycosis fungoides and Sézary syndrome: a consensus statement of the In-ternational Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treat-ment of Cancer. J Clin Oncol 2011;29:2598-607.

24. Li Jy, Horwitz S, Moskowitz A, Myskowski P, Pulitzer M, Querfeld C. Management of cutaneous T cell lymphoma: new and emerging targets and treatment options. Cancer Manag Res 2012;4:75-89.

25. Belloni B, Johansen N, Glass LF, Dummer R. Recent advances in the management of cutaneous lymphomas. Semin Oncol 2012;39:150-62.

26. Whittaker S. A cutaneous T-cell lymphoma EORTC trials platform. Clinical Lymphoma Myeloma and Leukemia 2010;10(Suppl)2:S90-S2.

27. Hoefnagel JJ, Dijkman R, Basso K, Jansen PM, Hallermann C, Willemze R et al. Distinct types of primary cutaneous large B-cell lymphoma identified by gene expression profiling. Blood 2005;105:3671-8.

28. Senff NJ, Zoutman WH, Vermeer MH, Assaf C, Berti E, Cerroni L et al. Fine-mapping chromosomal loss at 9p21: correlation with prognosis in primary cutaneous diffuse large B-cell lymphoma, leg type. J Invest Dermatol 2009;129:1149-55.

19. Senff NJ, Noordijk EM, Kim yH, Bagot M, Berti E, Cerroni L et al. European Organization for Research and Treatment of Cancer (EORTC) and International Society for Cutaneous Lymphoma (ISCL) consensus recommendations for the management of cutane-ous B-cell lymphomas. Blood 2008;112:1600-9.

20. Kempf W, Pfaltz K, Vermeer MH, Cozzio A, Ortiz-Romero PL, Bagot M et al. EORTC, ISCL, and USCLC consensus recommen-dations for the treatment of primary cutaneous CD30-positive lym-phoproliferative disorders: lymphomatoid papulosis and primary cu-taneous anaplastic large-cell lymphoma. Blood 2011;118:4024-35.

21. Olsen EA, Vonderheid E, Pimpinelli N, Willemze R, Kim y, Kno-bler R et al. Revisions to the staging and classification of mycosis fungoides and Sézary Syndrome: a proposal of the International So-ciety for Cutaneous Lymphomas (ISCL) and the Cutaneous Lym-phoma Study Group of the European Organization of Research and Treatment of Cancer (EORTC). Blood 2007;110:1713-22.

22. Kim yH, Willemze R, Pimpinelli N, Whittaker S, Olsen EA, Ranki A et al. TNM Classification System for Primary Cutaneous Lym-phomas Other Than Mycosis Fungoides and Sézary Syndrome. A Proposal of the International Society for Cutaneous Lymphomas (ISCL) and The Cutaneous Lymphoma Study Group of the Euro-pean Organization of Research and Treatment of Cancer (EORTC). Blood 2007;110:479-484

23. Olsen EA, Whittaker S, Kim yH, Duvic M, Prince HM, Lessin SR et al. International Society for Cutaneous Lymphomas; United


18Unit of DermatologyDepartment of Anesthesiology

Intensive Therapy and Dermatologic Sciences IRCCS Foundation Cà Granda

University of Milan, Milan, Italy 19Institute of Pathology

University of Ancona, Ancona, Italy 20Hematology and Stem Cell Transplant Unit, Oncology

Hospital “A. Businco”, Cagliari, Italy 212nd Dermatologic Clinic, University of Bari, Bari, Italy

22Institute of Hematology and Medical Oncology “L. e A. Seràgnoli, Sant’Orsola-Malpighi Policlinic,

University of Bologna, Bologna, Italy 23Hematology and Stem Cell Transplant Unit

Hospital “Vito Fazzi”, Lecce, Italy 24Division of Dermatology, Department of Internal

Medicine, Geriatrics and Nephrology University of Bologna, Bologna, Italy

25Hematology UnitHospital of Reggio Calabria, Reggio Calabria, Italy

26Section of DermatologyDepartment of Clinical and Experimental Medicine

University of Ferrara, Ferrara, Italy 27Dermatology Unit, Hospital of Trapani, Trapani, Italy


P. QUAGLINO 1, N. PIMPINELLI 2, E. BERTI 3, P. CALZAVARA-PINTON 4, G. A. LOMBARDO 5S. RUPOLI 6

M. ALAIBAC 7, L. ARCAINI 8, S. BAGNATO 9, A. BALDO 10, U. BOTTONI 11, A. CARBONE 12, R. CESTARI 13

R. CLERICO 14, A. DE RENZO 15, P. FAVA 1, M. T. FIERRO 1, R. FILOTICO 16, M. FIMIANI 17, M. FRONTANI 5

V. GIRGENTI 18, G. GOTERI 19, C. LEALI 4, A. M. MAMUSA 20, G. MARIOTTI 2, V. MASTRANDREA 21

C. PELLEGRINI 22, E. PENNESE 23, A. PILERI 24, P. SAVOIA 1, C. STELITANO 25, S. TITLI 1

A. VIRGILI 26, L. ZICHICHI 27, P. L. ZINZANI 22, M. G. BERNENGO 1

Mycosis fungoides: disease evolution of the “lion queen” revisited

1Department of Biomedical Sciences and Human Oncology, Dermatologic Clinic University of Turin, Turin, Italy

2Section of Dermatology, Department of Critical Care, Medicine, and Surgery

University of Florence, Florence, Italy 3Dermatologic Clinic

University of Milano-Bicocca, Milan, Italy 4Institute of Dermatology

University of Brescia, Brescia, Italy 53rd Division of Dermatology, Istituto Dermopatico

dell’Immacolata (IDI-IRCCS), Rome, Italy 6Institute of Hematology, University of Ancona

7Unit of Dermatology, University of Padua8Division of Hematology, Department of

Oncohematology, University of Pavia Medical School Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy

9Hematology & Oncology UnitHospital of Catania, Catania, Italy

10Dermatologic ClinicFederico II University, Naples, Italy

11Dermatology UnitDepartment of Experimental and Clinical Medicine

University Magna Græcia of Catanzaro Catanzaro, Italy

12Department of DermatologySacro Cuore Catholic University, Rome, Italy

13Unit of Dermatology, La Spezia Hospital, Rome, Italy14Department of Dermatology

La Sapienza University of Rome, Rome, Italy 15Hematologic Division

Federico II University, Naples, Italy 16Dermatology Unit

Hospital “A.Perrino”, Brindisi, Italy 17Institute of Dermatology

University of Siena, Siena, Italy

Corresponding author: P. Quaglino, Dermatologic Clinic, Department of Biomedical Sciences and Human Oncology, University of Turin, Tu-rin, Italy. E-mail: [email protected]


Lavoro: 4421-MDtitolo breve: MF DISEASE COURSE AND PROGRESSIONprimo autore: QUAGLINOpagine: 523-31

Mycosis fungoides (MF), which represents the most common subtype of primary cutaneous T-cell lymphoma (CTCL), is an epidermotropic lymphoma included as an indolent form in the recent WHO/EORTC classification. From a clinical point of view, the classic disease progression usually is slow and takes over years or even decades, and characterized by the evolution from patches to more infiltrated plaques and eventually to tumours or erythroderma. However, the analy-sis of the MF disease course has been greatly impaired by the rarity of the disease, thus data about the time course of disease progression and pattern of relapse during time are not well known. In this review, a summary of published data on MF large patients cohorts will be presented, together with

QUAGLINO MF DISEASE COURSE AND PROGRESSION


the results obtained by a retrospective analysis of clinical fea-tures and follow-up data of 1,422 MF patients diagnosed and followed-up from 1975 to 2010 in 27 Italian Centres (Italian Study Group for Cutaneous Lymphoma). From a clinical perspective, the amount of data support the relevance of a stage-tailored, differentiated follow-up strategy, in as much as the TNMB staging appears not only to be associated with different progression rates, but also shows as a new finding a relationship with different patterns of disease progression. From a biological point of view, there is the need to under-stand the molecular basis of the different clinical pathways of disease progression, to be able to potentially identify at an earlier phase of disease evolution, the patients who are more likely to develop erythroderma or tumour-stage progression. In conclusion, if MF is indeed a true “lion queen”, as der-matologists we need to be expert and wise tamers to keep it under control.

Key words: Mycosis fungoides - Lymphoma, T-cell, cutaneous - Prognosis - Dermatitis, exfoliative.

Primary cutaneous T-cell lymphomas (CTCL) encompass a broad spectrum of disease entities

with specific clinicopathologic, phenotypic and mo-lecular features, characterized by the primary cutane-ous origin of the lymphoproliferative disorder with-out evidence of extracutaneous disease at the time of diagnosis.1-3 CTCLs are the second most common form of extranodal non-Hodgkin lymphoma, with an estimated incidence rate of 4.5 per million person-years.4, 5

The most common subtype is mycosis fungoides (MF), an epidermotropic CTCL included as an in-dolent form in the recent WHO/EORTC classifica-tion,2, 3 characterized by a proliferation of small- to medium sized T lymphocytes with cerebriform nu-clei,1-3 firstly described at the beginning of the XIXth century by the French physician Jean Louis Alibert. In a population-based study from 2001 to 2005 in-cluding more than 3 thousands CTCL cases, the age adjusted incidence rates for MF was 4.1 cases per million.4 Recent epidemiological data show that, considering all the subtypes of CTCL, MF consti-tutes from 53.7% 4 up to 72% of cases,5 according to different series. The incidence of MF increases with age with an average age at diagnosis of 50 years; males are generally more likely to develop MF than females.1-3, 6-9

From a clinical point of view, MF is characterized by long-standing scaly patch lesions preferentially involving the buttocks and body areas infrequently exposed to sunlight (“bathing trunk”). The classic

progression described since the first reports usually is slow and takes over years or even decades, and is characterized by the evolution from patches to more infiltrated plaques and eventually to tumours or erythroderma (Figure 1).1, 3, 6-9 In MF patients, com-pared with other non-MF CTCL subtypes, tumours are found in association with previously developed patches and plaques. From an histological point of view, tumour lesions are frequently characterized by a loss of epidermotropism and extension of the infiltrate within the deep dermis. Nodal invasion is usually developed in the later stages of disease, as well as visceral involvement which is much more rare. A large cell transformation occurs more fre-quently in advanced stage disease (11% to 23% of cases), preferentially in tumour lesions.10, 11 More-over, patients with classic MF can develop typical manifestations of Sézary syndrome (SS) consisting in erythroderma, palpable adenopathies and cerebri-

Figure 1.—Clinical pictures showing the distinctive clinical fea-tures of mycosis fungoides (patches, plaques, tumours and eryth-roderma).

Patches Plaques

Tumours Erythroderma

MF DISEASE COURSE AND PROGRESSION QUAGLINO


years analysing numerically representative patient series (Table I).23-30 The study by Kim et al.24 on 525 patients showed as independent prognostic fac-tors patient age, T classification and extracutaneous involvement. Indeed, incidence of disease progres-sion at 5 years ranged from 10% in patients with T1 disease up to 58% in T3 and 48% in T4 patients, and increased steadily for each group also after 10 and 20 years from initial diagnosis. The retrospec-tive multicenter Dutch study analyzed 309 MF pa-tients with a median follow-up of 62 months. Mul-tivariate analysis of survival showed that type and extent of cutaneous involvement, presence of extra-cutaneous involvement, response to initial treatment and presence of follicular mucinosis were adverse independent prognostic factors. A disease progres-sion occurred in 4% of patients with stage Ia at ini-tial diagnosis, in 10% of Ib and in 39% of patients with nodular T3 lesions. Lymph node and visceral involvement were observed respectively in 12% and 6% of patients, with a significantly higher risk for patients with nodular lesions. Skin tumors occurred respectively in 3% of IB and 21% of IB patients.27 Zackheim et al.25 reported a stage disease progres-sion in only 2 out of 174 T1 patients (one devel-oped nodular lesions and the other plaque lesion with nodal involvement) and in 9/199 T2 patients (8 nodular lesions and one erythroderma). The larg-est study was recently conducted on an impressive single-centre cohort of 1,502 MF/SS patients by the UK group.23 Multivariate analyses showed that ad-vanced T-stage, peripheral blood clonality, elevat-ed LDH and folliculotropic MF were independent prognostic predictors of poor survival and increased risk of disease progression, large-cell transforma-tion and tumour distribution (solitary, regional, dis-seminated) were associated with an increased risk of disease progressions whilst TNMB stage, age, male gender and poikilodermatous MF were significant for overall survival.

These studies allowed to highlight relevant clin-ico-pathologic and prognostic features of MF, but nevertheless a number of clinical questions remains still open, concerning the evolution of cutaneous le-sions and the pathways leading to advanced-stage disease and extracutaneous involvement, as well as the risk trends during years of developing specific pathways of disease progression (such as tumour-stage, or erythroderma, or blood/nodal/visceral in-volvement).

form circulating atypical cells;12 these cases have been designated as “SS preceded by MF” and also as “secondary” SS.13

The treatment options depend on the stage of clini-cal presentation. In patients with early phase disease, “skin-directed” therapies including topical steroids and phototherapy are mainly used and many patients never require systemic therapy. In patients with re-fractory disease, biologic therapies such as interfer-on or bexarotene represent the treatment of choice, together with electron-beam radiotherapy either lo-calised or total-skin. Chemotherapies are usually de-served for patients with advanced-phase disease and extracutaneous involvement.14-18

The prognostic relevance of the extent of skin in-volvement and extracutaneous localizations has been known since the 70’s. In 1979, indeed, an interna-tional committee, the Mycosis Fungoides Coopera-tive Group, proposed a staging system based on the international tumour-node-metastasis (TNM) sys-tem.7, 19 A recent revision by the International Soci-ety for Cutaneous Lymphoma (ISCL) and Cutaneous Lymphoma Task Force of the European Organization for the Research and Treatment of Cancer (EORTC) 6 brought significant changes with respect to the pre-vious classification,7 among whom the prognostic relevance of the B (blood) score. Indeed a series of studies have demonstrated that a B2 rating,20 like-wise an hematologic staging of 3 or more according to the suggested British Classification,21, 22 are asso-ciated to a poor prognosis. The significant changes brought by the revised staging system 6 compared to the 1979 version, underline the need of a reappraisal of the disease outcome and prognostic parameters for each subgroup of patients, to build-up the clini-cal bases upon which a rational follow-up strategy can be developed.

However, the analysis of the MF disease course in terms of risk of relapse or stage progression, as well as incidence of extracutaneous involvement, large cell transformation, or SS development, has been greatly impaired by the rarity of the disease and the need of a long term follow-up. As a consequence, even if the slow evolution from patches to plaques and nodules is the representative and accepted clini-cal feature of MF, data about the time course of dis-ease progression and pattern of relapse during time, including the risk of SS evolution, or large cell lym-phoma transformation are not well known.

Only a few papers have been published in the past



Cutanei) referral Centres. 31 The inclusion criteria were: 1) pathologic diagnosis of MF; 2) complete clinical information and imaging at initial diagno-sis (chest X-rays, abdomen ultrasound, computed tomography or positron emission tomography);

Classical MF: the Italian experience

In the last years we performed a retrospective re-view of clinical data of MF patients collected from 1975 to 2010 in 27 GILC (Gruppo Italiano Linfomi

Table I.—Results of the most representative series of MF patients reporting data on disease progression and survival stratified by clinical stage.

ParametersToro,

1997 26Diamandidou

1999 28Van Doorn,

2000 23Zackheim,

1999 25Kim,

2003 24Anadolu, 2004 29

Suzuki, 2010 30

Agar, 2010 23

No. of MF pts 101 115 309 489 525 113 100 1,502Male/female ratio NR 1.3 1.73 1.57 1.69 0.95 1.94 1.64Age at diagnosis (median; yrs)

NR <60g 61 59 57 46e 60 54

Stagea (diagnosis):IAIBIIIIBIIIIV

24%22%13%21%6%15%

31%12%7%24%23%18%

29%44%

--15%

0--

35%

41%10%14%

30%25%11%16%11%7 %

28%52%9%5%1%5%

21%38%19%8%6%8%

29%39%3%

11%10%8%

Overall disease progression (%)

NR 30%h 25% NR NR 9% 20% 34%

Disease progression (per stagea;%):

IAIBIIIIBIIIIV

NRNRNRNRNRNR

NRNRNRNRNRNR

4%24%

--39%

0--

NRNRNRNRNRNR

10b%22%56%48%

03%0

50%100%80%

NRNRNRNRNRNR

8b%

21%17%48%

53%-82%f

62%-82% f

Overall survival (per stagea; 5-yrs;%):

IAIBIIIIBIIIIV

100%100%NR71%8%

88%i

36%78%21%

99%86%

65%0

95%

76%45%51%

96%

75c%

44c%27%

NRNRNRNRNRNR

100%89%87%73%100%

0 – 33% l

94%84%78%47%

47%-40% f

37%-18% f

Follow-up (median; yrs) NR NR 5.2 4.7 5.5 2.97 4.9 5.9Prognostic factors (multivariate):

stage at diagnosis$

agegendertreatment responsefolliculotropismLDHLarge-cell transf.

X XX

X

X

XX

X XXd

NRNRNRNR

XX

X

XXX

XXX

NR: Not Reported$: includes T score and presence of extracutaneous involvement (nodes, viscera, blood)aas to the paper by Van Doorn et al.22 patients staging was made according to the classification system adopted by the Dutch Group for Cutaneous Lymphoma; translation into actual TNM was not possible for stage II and IV; no patient in that series had erythroderma at diagnosis. As to the paper by Zackheim et al.,20 all the values reported refer only to the T-score (T1, T2, T3, T4).b5-yr disease progressioncgrouped together stage IB and II and stage IIb and IIIdconfirmed for both overall survival and disease-specific survivalemeanfvalues are respectively for IIIA and IIIB, and for IVA1, IVA2, IVBgmedian values not reported; age <60 years was shown in 60 out of 115 patientshdeaths for disease progressionigrouped together IA-IB-IIAl5-year survival was 0 for patients with IVA1 and IVB and 33% for patients with IVA2



stage IA to 40.1% for stage IIA. The risk of disease progression was calculated for patients with initial di-agnosis stage IA,IB, IIA and differentiated into nod-ular-stage, erythroderma or extracutaneous involve-ment. Five-, ten- and twenty-year time-to-progression rate were 89%, 84% and 78% for the progression to stage IIB, and 96%, 94% and 87% for the progression to stage III (erythroderma); among extracutaneous progression, occurrence of blood involvement was the most frequent event, with 5-, 10- and 20-years time-to-progression rate of 97%, 96% and 90%. Nodal and visceral involvement time-to-progression ranged from 98% at 5-years to 93% at 20 years (Figure 2), but were characterized by a progressive decrease more evident even after 20 years from diagnosis.

A second relevant point is to analyse the evolu-tion of cutaneous lesions during the follow-up. The classic MF disease scheme is historically thought to be from patches to plaques, tumours and eventually erythroderma (Figure 3). In our experience,31 we analysed separately patients with T1 score and T2 score at first diagnosis. Among the 553 patients with T1 score at diagnosis, a cutaneous progression oc-curred in 115 patients (21%). Among them, the ma-jority showed the classic evolution from patches to

3) clinical and radiological follow-up of at least 1 year.

MF diagnosis was confirmed according to ISCL/EORTC criteria 2, 3 and, if necessary, on the proposed algorithm for early-phase disease.32 All the patients were re-classified according to the new ISCL/EORTC classification.6, 33

The aims were to ascertain the time course and pathways of cutaneous and extracutaneous disease progression and trends of associated hazard rates dur-ing time; to evaluate whether different TNMB stages have not only different risk of disease progression but also different pathways of disease progression; to analyse the differences between tumour-stage and erythrodermic MF in terms of clinical onset, path-ways of disease evolution and prognosis.

The clinical evolution of cutaneous lesions: what can we learn?

A total of 1422 cases were consistent with the inclusion criteria. There was a prevalence of males with respect to females (male/female ratio: 1.72); the median age at first diagnosis was 59 years (range: 8-97). The median time from onset of cutaneous le-sions and diagnosis was 2 years. At diagnosis, nearly half the patients (47.7%) had patches and/or plaques on >10% of their body surface; patches/plaques on <10% body surface were found in 38.9% of cases, whilst a minority of patients showed tumour lesions or erythroderma. The median follow-up was 14.5 years (range: 1-35 years).31

From a dermatological point of view, in an attempt to both ascertain follow-up guidelines and improve patients counselling, an important question is to know which is the percentage of patients with MF diagnosed at early phase who will develop a progression to ad-vanced stage disease (i.e. tumour lesion and/or eryth-roderma with or without extracutaneous involvement). In the GILC study,31 a stage progression occurred in 422 patients (29.7%). Tumour-stage disease represent-ed the maximum stage in 6.7% up to 11.3% of patients with IA-IB-IIA initial stage, whereas erythroderma was less frequent. A small percentage of patients (3.7%) developed erythroderma and blood involvement, ful-filling the criteria for secondary SS.15 The cumulative percentage of progressions to advanced stage disease (IIB-III-IV) in patients diagnosed as early-phase MF (stage IA-IB-IIA) was 21.5%, ranging from 14.5% for

Figure 2.—Time-to-progression (TTP) from early-stage disease (stage IA-IB-IIA) to advanced phases. Each curve represents the TTP towards the reported advanced stage disease (from IIB to IVB).

0

3

2

1

0

To stage III

To stage IIB

To stage IV

Years from initial diagnosis

Haz

ard

rate

of

prog

ress

ion

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15



in the orderly progression of MF but rather two dif-ferent pathways of disease evolution.

Tumour-stage vs. erythrodermic MF: distinctive clinical features

Conflicting data are reported in literature as to the different survival expectancies between tumour-stage and erythrodermic MF. We decided therefore to analyse our data to evaluate the differences be-tween these two groups of patients not only in terms of survival, but also taking into account a series of clinical characteristics (Table II).

As to the demographic characteristics, T4 patients were found to be significant elderly (median age at first diagnosis: 67 years; 25th-75th percentile: 54-73) (Mann-Whitney test: P<0.0001) and with a male prevalence (73.7%) (Fisher exact test: P=0.027). Similar age differences between MF stages have al-ready been reported.24, 25 Even if these two groups showed similar features as to the total percentages of disease progression as well as to the percentages of patients developing extracutaneous involvement, nevertheless significant differences could be found on the basis of the type of extracutaneous involve-ment. Indeed, tumour-stage MF shows more fre-quently nodal and particularly visceral involvement as extracutaneous progression, whilst erythroder-mic MF mainly develop hematological involvement and thus transformation into SS. Half the patients with nodal/visceral involvement showed indeed a tumour-stage disease at time of extracutaneous pro-gression, whereas 45% of patients with blood in-volvement had erythroderma. The present data are in agreement with other previously published ex-periences. For example, the Dutch study 27 demon-strated a significantly higher risk of nodal/visceral

plaques (29%) or from patches/plaques and tumours (53%). Only 3.5% underwent the complete disease evolution from patches to plaques, tumours and at the end, erythroderma. Interestingly, 14% of pro-gressed patients developed erythroderma as a direct evolution of the patches present at diagnosis. So, it becomes quite evident that erythroderma occurred more frequently in T1 patients as a direct evolu-tion from patches than as a final stage from patches/plaques and tumours (P=0.028). The same results were obtained when analysing the cutaneous evolu-tion of lesions in patients diagnosed as T2. The most common pathway of cutaneous evolution in T2 pa-tients was the development of tumour lesions (72% of progressed patients); however, only 9% of these patients developed erythroderma after tumours. On the other hand, 28% of T2 progressed patients de-veloped directly erythroderma not preceded by tu-mour lesions (P=0.013). The hypothesis that can be drawn by these data is therefore that tumour-stage and erythroderma do not represent sequential event

Figure 3.—Old and new potential disease evolution pathway in-terpretations.

The classic progression pathway

T1 T2 T3 T4

The proposed progression pathway

T1 T2

T3

T4

Table II.—Tumour-stage (T3, stage IIB) and erythrodermic (T4) MF vis à vis.

Tumour-stage MF Erythrodermic MF

Median age (at first diagnosis) 59 (25-75 years) 67 (54-73 years)Male prevalence 58% 74%% stage progression 44% 41%% extracutaneous involvement 36% 33%% PBL involvement 13% 21%% nodal/visceral involvement 23% 13%5-year survival 69% 72%10-year survival 51% 59%



course could constitute the “targets” for the devel-opment of new drug approaches.35 From a clinical perspective, the amount of data support the relevance of a stage-tailored, differentiated follow-up strategy. The TNMB staging appears not only to be associated with different progression rates, but also shows as a new finding a relationship with different patterns of disease progression. In conclusion, if MF is indeed a true “lion queen”, as dermatologists we need to be expert and wise tamers to keep it under control.

Riassunto

Micosi fungoide: evoluzione clinica delle lesioni cutaneeLa micosi fungoide (MF) è classificata nello spettro dei

linfomi primitivi cutanei a cellule T, ed è una patologia a decorso cronico indolente, con caratteristica evoluzione da lesioni a chiazza e placca a lesioni nodulo-tumorali o eri-trodermia. Nonostante rappresenti la forma più comune di linfoma primitivo cutaneo, è una patologia rara, per cui sono relativamente pochi gli studi pubblicati su ampie casistiche di pazienti. Recentemente sono state apportate significati-ve modificazioni alla classificazione EORTC/ISCL, tra cui l’individuazione all’interno dello stadio IV, di tre differenti gruppi caratterizzati rispettivamente da interessamento del sangue periferico, linfonodale e viscerale. Nella presente review saranno analizzati i dati riportati in letteratura circa il decorso clinico, rischio di progressione e fattori progno-stici, correlandoli con i risultati emersi da un recente studio multicentrico retrospettivo italiano condotto nell’ambito del Gruppo Italiano Linfomi Cutanei (GILC). Nel loro insieme, i dati che emergono sono i seguenti: i fattori prognostici prin-cipali la stadiazione TNMB alla diagnosi e la progressione di stadio durante il follow-up; la stadiazione è correlata non solo ad una differente incidenza ma anche ad una diversa ti-pologia di progressioni; la micosi fungoide in fase tumorale e quella eritrodermica presentano rilevanti differenze in base alle modalità di insorgenza e tipologia di progressioni, ma non presentano significative differenze di sopravvivenza. La conoscenza di questi dati costituisce la base per la pianifica-zione di adeguate linee guida di follow-up.

Parole chiave: Micosi fungoide - Linfoma a cellule T - Prognosi - Dermatite esfoliativa.

References


2. Willemze R, Kerl H, Sterry W, Berti E, Cerroni L, Chimenti S et al. EORTC classification for primary cutaneous lymphomas: a proposal from the Cutaneous Lymphoma Study Group of the Eu-

involvement for T3 patients; similarly 78% of T4 patients reported by Diamandidou et al.28 devel-oped peripheral blood involvement. These findings carry relevant clinical consequences in the clinical management and follow-up of these patients. On the basis of these data, in fact, radiological procedures aimed to ascertain the presence of nodal and/or vis-ceral involvement (such as CT scan or PET) should be performed more frequently in tumour-stage pa-tients. On the other hand, erythrodermic patients should be more carefully tested for blood involve-ment, sparing them from the execution of close ra-diological procedures.

In spite of the different pathway of extracutane-ous involvement, no significant differences in the overall survival could be demonstrated from our data between tumour-stage and erythrodermic MF. Conflicting results are reported in literature. A series of papers did not find survival differences between these two groups (Table 1). Kim et al.24 found a sim-ilar risk of disease progression for T3 and T4 pa-tients. As to survival, Agar et al.23 reported a 5-year survival of 40% for stage IIB and ranging from 47% for IIIA and 40% for IIIB. Similarly, a nearly simi-lar relative survival was reported by Zackheim et al. (10-years: 39.2% for T3 and 41% for T4).25 Also in Japanese patients, no differences in both risk for disease progression and overall survival between patients with tumour-stage and erythroderma were demonstrated.30 Other studies demonstrated on the other hand a worse prognosis for T3. Diamandi-dou et al.28 reported a 5-year survival of 36% for tumour-stage and 78% for erythrodermic patients. On the other hand, Toro et al.26 obtained opposite results, demonstrating a clear survival benefit for tumour-stage patients.

Take-home messages

The evidences coming through the data collected in the retrospective GILC study as well as from the analysis of literature data underline the need, from a biological point of view, to understand the molecu-lar basis of the different clinical pathways of disease progression,34 to be able to potentially identify at an earlier phase of disease evolution, the patients who are more likely to develop erythroderma or tumour-stage progression. Moreover, the identification of molecular events associated to a different disease



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23. Agar NS, Wedgeworth E, Crichton S, Mitchell TJ, Cox M, Fer-reira S et al. Survival outcomes and prognostic factors in mycosis fungoides/Sézary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal. J Clin Oncol 2010;28:4730-9.

24. Kim YH, Liu HL, Mraz-Gernhard S, Varghese A, Hoppe RT. Long-term outcome of 525 patients with mycosis fungoides and Sézary syndrome:Clinical prognostic factors and risk for disease progres-sion. Arch Dermatol 2003;139:857-66.

25. Zackheim HS, Amin S, Kashani-Sabet M, McMillan A. Prognosis in cutaneous T-cell lymphoma by skin stage:Long-term survival in 489 patients. J Am Acad Dermatol 1999;40:418-25.

26. Toro JR, Stoll HL Jr, Stomper PC, Oseroff AR. Prognostic factors and evaluation of mycosis fungoides and Sézary syndrome. J Am Acad Dermatol 1997;37:58-67.

27. van Doorn R, Van Haselen CW, van Voorst Vader PC, Geerts ML, Heule F, de Rie M et al. Mycosis fungoides:Disease evolution and prognosis of 309 Dutch patients. Arch Dermatol 2000;136:504- 10.

28. Diamandidou E, Colome M, Fayad L, Duvic M, Kurzrock R. Prog-nostic factor analysis in mycosis fungoides/Sézary syndrome. J Am Acad Dermatol 1999;40:914-24.

29. Anadolu RY, Birol A, Sanli H, Erdem C, Türsen U. Mycosis fun-goides and Sezary syndrome: therapeutic approach and outcome in 113 patients. Int J Dermatol 2005;44:559-65.

30. Suzuki SY, Ito K, Ito M, Kawai K. Prognosis of 100 Japanese pa-tients with mycosis fungoides and Sézary syndrome. J Dermatol Sci 2010;57:37-43.

31. Quaglino P, Pimpinelli N, Berti E, Calzavara-Pinton P, Lombardo AG, Rupoli S et al. Gruppo Italiano Linfomi Cutanei (GILC). Time course, clinical pathways, and long-term hazards risk trends of disease progression in patients with classic mycosis fungoides:A multicenter, retrospective follow-up study from the Italian Group of Cutaneous Lymphomas. Cancer 2012 (in press).

32. Pimpinelli N, Olsen EA, Santucci M, Vonderheid E, Heffner AC, Stevens S et al. International Society for Cutaneous Lym-phoma. Defining early mycosis fungoides. J Am Acad Dermatol 2005;53:1053-63.

33. Olsen EA, Whittaker S, Kim YH, Duvic M, Prince HM, Lessin SR et al. Clinical end points and response criteria in Mycosis fungoides and Sézary syndrome:a consensus statement of the international so-ciety for cutaneous lymphomas, the United States cutaneous lym-phoma consortium, and the cutaneous lymphoma task force of the European organisation for research and treatment of cancer. J Clin Oncol 2011;29:2598-607.

34. van Kester MS, Borg MK, Zoutman WH, Out-Luiting JJ, Jansen PM, Dreef EJ et al. A Meta-Analysis of Gene Expression Data Iden-tifies a Molecular Signature Characteristic for Tumor-Stage Myco-sis Fungoides. J Invest Dermatol 2012;132:2050-9.

35. Dummer R, Goldinger SM, Cozzio A, French LE, Karpova MB. Cutaneous lymphomas: molecular pathways leading to new drugs. J Invest Dermatol 2011;132:517-25.

Acknowledgments.—The authors wish to thank the following collabo-rators who participated to data collections, and the institutions in which patients were diagnosed, treated and followed-up (centres in alpha-betical order): Argnani Lisa, Valenti Vanessa, Institute of Hematology and Medical Oncology “L. e A. Seràgnoli,” Policlinico “Sant’Orsola-Malpighi,” University of Bologna, Bologna, Italy; Neri Iria, Sisti An-drea, Patrizi Annalisa, Division of Dermatology, Department of Internal Medicine, Geriatrics and Nephrology, University of Bologna, Bologna, Italy; Pinna Annalisa, Dermatology Department, University of Cagliari, Cagliari, Italy; Borghi Alessandro, Minghetti Sara. Section of Derma-

ropean Organization for Research and Treatment of Cancer. Blood 1997;90:354-71.

3. Willemze R, Jaffe ES, Burg G, Cerroni L, Berti E, Swerdlow SH et al. WHO/EORTC classification for cutaneous lymphomas. Blood 2005;105:3768-85.

4. Bradford PT, Devesa SS, Anderson WF, Toro JR. Cutaneous lym-phoma incidence patterns in the United States: A population-based study of 3884 cases. Blood 2009;113:5064-73.

5. Criscione VD, Weinstock MA. Incidence of cutaneous T-cell lymphoma in the United States, 1973-2002. Arch Dermatol 2007;143:854-9.

6. Olsen E, Vonderheid E, Pimpinelli N, Willemze R, Kim Y, Knobler R et al. Revisions to the staging and classification of mycosis fun-goides and Sézary syndrome: A proposal of the International Socie-ty for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood 2007;110:1713-22.

7. Bunn PA, Lamberg SI. Report of the committee on staging and classification of cutaneous T-cell lymphomas. Cancer Treat Rep 1979;63:725-8.

8. Hwang ST, Janik JE, Jaffe ES, Wilson WH. Mycosis fungoides and Sézary syndrome. Lancet 2008;371:945-57.

9. Parker SR, Bethaney JV. Cutaneous T cell lymphoma-mycosis fun-goides and Sezary syndrome: an update. G Ital Dermatol Venereol 2009;144:467-85.

10. Diamandidou E, Colome-Grimmer M, Fayad L, Duvic M, Kurzrock R. Transformation of mycosis fungoides/Sezary syndrome: clinical characteristics and prognosis. Blood 1998;92:1150-9.

11. Vergier B, de Muret A, Beylot-Barry M, Vaillant L, Ekouevi D, Chene G et al. Transformation of mycosis fungoides: clinicopatho-logical and prognostic features of 45 cases. French Study Group of Cutaneous Lymphomas. Blood 2000;95:2212-8.

12. Bernengo MG, Quaglino P, Novelli M, Cappello N, Doveil GC, Lisa F et al. Prognostic factors in Sézary syndrome: a multivariate analysis of clinical, hematological and immunological features. Ann Oncol 1998;9:857-63.

13. Diwan AH, Prieto VG, Herling M, Duvic M, Jones D. Primary Sé-zary syndrome commonly shows low-grade cytologic atypia and an absence of epidermotropism. Am J Clin Pathol 2005;123:510-5.

14. Prince HM, Whittaker S, Hoppe RT. How I treat Mycosis Fungoides and Sézary syndrome. Blood 2009;114:4337-53.

15. Trautinger F, Knobler R, Willemze R, Peris K, Stadler R, Laroche L et al. EORTC consensus recommendations for the treatment of Mycosis Fungoides/Sézary syndrome. Eur J Cancer 2006;42:1014-30.

16. Foss FM. Enhancing existing approaches to Peripheral T-cell lym-phoma. Semin Hematol 2010;47:S8-10.

17. Fierro MT, Doveil GC, Quaglino P, Savoia P, Verrone A, Bernengo MG. Combination of etoposide, idarubicin, cyclophosphamide, vinc-ristine, prednisone and bleomycin (VICOP-B) in the treatment of ad-vanced cutaneous T-cell lymphoma. Dermatology 1997;194:268-72.

18. Dummer R, Assaf C, Bagot M, Gniadecki R, Hauschild A, Knobler R et al. Maintenance therapy in cutaneous T-cell lymphoma: Who, when, what? Eur J Cancer 2007;43:2321-9.

19. Lamberg SI, Green SB, Byar DP, Block JB, Clendenning WE, Ep-stein EH et al. Status report of 376 mycosis fungoides patients at 4 years: Mycosis Fungoides Cooperative Group. Cancer Treat Rep 1979;63:701-7.

20. Vonderheid EC, Bernengo MG, Burg G, Duvic M, Heald P, Laro-che L et al. Update on erythrodermic cutaneous T-cell lymphoma: report of the International Society for Cutaneous Lymphomas. J Am Acad Dermatol 2002;46:95-106.

21. Vidulich KA, Talpur R, Bassett RL, Duvic M. Overall survival in erythrodermic cutaneous T-cell lymphoma: an analysis of prognos-tic factors in a cohort of patients with erythrodermic cutaneous T-cell lymphoma. Int J Dermatol 2009;48:243-52.

22. Scarisbrick JJ, Whittaker S, Evans AV, Fraser-Andrews EA, Child



matology, Department of Oncohematology, University of Pavia Medical School, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy; Valen-zano Francesco, Department of Dermatology, Sacro Cuore Catholic University, Rome, Italy; De Luca G, Dermatology Unit, Hospital of Trapani, Trapani, Italy; Ribero Simone, Zingoni Adele, Dermatologic Clinic, Department of Biomedical Sciences and Human Oncology, Uni-versity of Turin, Turin, Italy.

tology, Department of Clinical and Experimental Medicine, University of Ferrara, Ferrara, Italy; Delfino Chiara, Fortunato Sara, Department of Critical Care, Medicine, and Suregry, Section of Dermatology, Uni-versity of Florence, Florence, Italy; Nazzari Guido, Dermatology Unit, Hospital of La Spezia, Rome, Italy; Fazzipo V, Hematology and Stem Cell Transplant Unit, Hospital “Vito Fazzi”, Lecce, Italy; Gruppo Co-operatore Marchigiano Linfomi Cutanei, Rizzi Silvia, Division of He-


represented by scaling, palmo-plantar hyperkerato-sis, ectropion, nail alterations (Figure 1). The skin can appear edematous, infiltrated and frequently the occurrence of exudation represents a common risk factor for the development of bacterial infections. Erythroderma is associated with a frequent worsen-ing of the health general conditions of the patient; a part from itching and pain, the involvement of the entire body surface induces the occurrence of even severe alterations of the hydro-electrolyte balance, with protein loss from the damaged skin barriers resulting in reduction of blood onchotic pressure, oedema accumulation in the lower limbs, alterations in the normal regulation of body temperature, fre-quent development of bacterial as well as viral infec-tions. Erythroderma can occur as an acute disease (less than one month of onset) or more frequently as a long-term evolution of a previous dermatological disease which in the course of months or even years, can diffuse on the body skin surface in spite of the treatments. Even if it is a rare condition, neverthe-less it represents a severe condition, often requiring hospitalization and nursing patient care. Because most patients are elderly and skin involvement is widespread, the disease implies an important risk for the life of the patient. Hasan and Jansen estimated the annual incidence of erythroderma to be 1 to 2 per 100,000 patients.1 Sehgal and Strivasta recorded

Dermatologic Clinic, Department of Medical Sciences University of Turin, Italy


M. G. BERNENGO, P. QUAGLINO

Erythrodermic CTCL: updated clues to diagnosis and treatment

Erythroderma is a rare but severe cutaneous condition char-acterized from a clinical point of view by a complete involve-ment (as per definition more than 80% body surface) of the skin surface. Pre-existing dermatoses account for about 70% of erythroderma cases, drug reactions are responsible for erythroderma in about 20%, whilst primary cutaneous T-cell lymphoma (CTCL) constitute less than 10% of and are represented by erythrodermic mycosis fungoides and Sézary syndrome. The challenge in these patients is represented by the identification of the etiological agents or conditions, which is clearly of overwhelming relevance in the clinical management and treatment strategies. In recent years, the development of multiparameter flow-cytometry, which al-lows to identify specific antigens expressed or not expressed on the surface of atypical lymphoid T-cells, and T-cell mo-lecular biology techniques, which are aimed to identify the presence of a clonal T-cell population in the skin and blood on the basis of the finding of rearrangement of the T-cell recep-tor, have represented relevant useful tool in the differential diagnosis between benign and lymphomatous erythroderma. Moreover, a better understanding of the immunological and molecular pathways in CTCL disease evolution provided the identification of specific therapeutical targets, as well as the constant improvement in the laboratory techniques lead to the development of new and promising agents in CTCL.Key words: Lymphoma, T-cell, cutaneous - Dermatitis, exfo-liative - Phenotype.

Erythroderma is a rare but severe cutaneous con-dition characterized from a clinical point of view

by a complete involvement (as per definition more than 80% body surface) of the skin surface by a dif-fuse erythema. Associated clinical signs are usually

Corresponding author: M. G. Bernengo, Dermatologic Clinic, Depart-ment of Department of Medical Sciences, University of Turin, Italy.


Lavoro: 4436-MDtitolo breve: Erythrodermic CTCLprimo autore: BERNENGOpagine: 533-44

BERNENGO ERyTHRODERMIC CTCL


the incidence of erythroderma in a large prospective study from the Indian subcontinent as 35 per 100,000 dermatologic outpatients.2

Erythroderma in adult patients can occur due to different causative factors, which can be grouped as previous dermatoses, drug reactions, malignant sys-temic diseases, infections and idiopathic disorders. Erythroderma can also occur in newborn babies and children as a result of genetically-related alterations (hictyosiform bullous or non bullous erythroderma), or seborrheic dermatosis (Leiner-Moussous syn-drome).1-6

On the basis of recent papers, in adult patients, pre-existing dermatoses account for about 70% of erythroderma cases; drug reactions are responsible for erythroderma in about 20% of patients, whilst other causes are less common.3-6 Pre-existing derma-toses that can originate erythroderma are mainly rep-

resented by psoriasis and atopic eczema, but include also lichen planus pilaris, pemphigus foliaceus, pity-riasis rubra pilaris, subacute lupus erythematous or dermatomyositis. The four more common causes of idiopathic protracted erythroderma are prob-ably atopic dermatitis of the elderly, intake of drugs overlooked by the patient, pre-lymphomatous erup-tions and occult malignancies. Malignancies that can originate erythroderma are mainly represented by primary cutaneous T-cell lymphoma, however it should not be forgotten that erythroderma can show also a para-neoplastic significance and thus occur as a manifestion of an occult solid neoplasm. Primary cutaneous T-cell lymphomas (CTCL) encompass a broad spectrum of disease entities with specific clin-icopathologic, phenotypic and molecular features, characterized by the primary cutaneous origin of the lymphoproliferative disorder without evidence

Figure 1.—The clinical picture of Sézary syndrome. A, B) Des-quamative erythroderma with diffusely infiltrated skin; C) the so-called “facies leonina” deriving from edema and infiltration by the lymphoproliferative disease; D) superficial adenopathies; E) ectropion.

ERyTHRODERMIC CTCL BERNENGO


Histopathology can help identify the cause of eryth-roderma in less than 50% of cases, particularly by multiple skin biopsies but many chronic dermatoses may be histologically indistinguishable in erythro-dermic patients. Indeed, the histopathology of SS can often be non-specific.17-23 From a histological standpoint, in the early stages, the differential diag-nosis with chronic dermatitis may be difficult. Often the picture of SS is indistinguishable from that of an erythrodermic or early-stage MF; however, in SS, lower epidermotropism, reduced incidence of Pau-trier’s microabscesses, and lower amount of inflam-matory cells have been reported. In the early phases, the infiltrate in SS may be very mild, predominantly perivascular and periadnexal; the histology is strik-ing for its marked superficial vascular component. Pautrier’s microabscesses, although characteristic, are rarely seen. Moreover, aspects of chronic der-matitis are often prevalent also in SS. In fact, Trot-ter et al. have recently reported the finding of a pre-dominant picture of chronic dermatitis in 33% of 41 patients with diagnosis of SS confirmed by a circu-lating T-cell clone; furthermore, in 11 additional pa-tients, there was no histological evidence of CTCL.21 A recent retrospective French study analysed mor-phological and immunohistochemical findings in 47 skin biopsies from erythrodermic patients with the aim to ascertain significant diagnostic parameters able to correctly identify CTCL cases.24 On the basis of exclusively morphological findings, a correct di-agnosis of the underlying cause of erythroderma was made only in 31% of cases, and a correct differential diagnosis between CTCL and other causes in 57% of cases. The morphologic parameters which were found to be specific of CTCL were the presence of atypical lymphocytes, the moderate to high density of dermal infiltrates and Pautrier microabscesses. A low (<10%) CD8:CD3 ratio in the epidermal lym-phocytic infiltrate and dermal CD30+ lymphocytes were significantly more frequent in CTCL. Interest-ingly, the authors reported the expression of JunB only in CTCL, even if it was restricted to a minority of cases.

In recent years, the development of multiparame-ter flow-cytometry, which allows to identify specific antigens expressed or not expressed on the surface of atypical lymphoid T-cells, and T-cell molecular biology techniques, aimed to identify the presence of a clonal T-cell population in the skin and blood on the basis of the finding of rearrangement of the T-

of extracutaneous disease at the time of diagnosis. CTCLs are the second most common form of extra-nodal non-Hodgkin lymphoma,7-9 even if are rare diseases with an estimated incidence rate of 0.45 per 100,000 person-years.10, 11 According to the WHO-EORTC classification,7-9 the most representative forms of CTCL are: mycosis fungoides (MF) and its variants, Sézary syndrome (SS) and primary cutane-ous CD30+ lymphoproliferative disorders. MF is an epidermotropic CTCL characterized by an indolent clinical course and histo-pathologically by a prolif-eration of small- to medium sized T-lymphocytes with cerebriform nuclei. The clinical features of MF are represented by long-standing, scaly, patch lesions preferentially involving the buttocks and body areas infrequently exposed to sunlight and by a progres-sive slow evolution over years or even decades from patches to more infiltrated plaques and eventually to tumours or erythroderma.12, 13 SS is characterized by a pruritic exfoliative erythroderma, peripheral adenopathies and atypical mononuclear cells with cerebriform nuclei (Sézary cells [SC]) in the skin, peripheral blood and lymph nodes. SS has a poor prognosis and is included in the aggressive CTCL subtypes under the recent WHO-EORTC classifica-tion, with a five-year survival of 24%.14, 15 The pres-ence of such extensive cutaneous inflammatory-re-active phenomena produces considerable effects on the general conditions of the body, especially from a metabolic and hemodynamic standpoint. Recurrent bacterial and viral infections (particularly herpes), often difficult to resolve, should be attributed on the one hand to the immunosuppression and on the other to an inefficient skin protective barrier in terms of physical and immunologic defenses. The most fre-quent cause of death are infections, either bacterial (Staphylococcus aureus or Pseudomonas aerugi-nosa) or viral (herpes, cytomegalovirus). Immune suppression may be considered also one of the main causes of the reported high incidence of other ma-lignant neoplasms in these patients.16 On the other hand, visceral localizations of SS have been reported mainly in autopsy series.

The challenge in these patients is therefore repre-sented by the identification of the etiological agents or conditions, which is clearly of overwhelming rel-evance in the clinical management and treatment strategies. Clinically, the complete involvement of the skin surface usually makes it difficult to identify the clinical signs specific of a previous dermatoses.



ent prognosis: in fact, patients with CD7+ SC tend to have longer survival than those with CD7-SC.14

A relevant immunophenotypic feature of SC is the constant loss of CD26 firstly described by our group in both the skin and peripheral blood 14, 37-39, 43 and after confirmed by several authors.44-48 CD26 iden-tifies the ectoenzyme dipeptidyl-aminopeptidase IV, a protease that cleaves N-terminal dipeptides when alanine or, more frequently, proline, are in the posi-tion before last. The percentages and absolute values of the CD4+CD26- subpopulation in the peripheral blood are significantly higher in patients with SS or MF with circulating SC, compared to MF patients without peripheral involvement, and compared to patients with benign inflammatory erythroderma, and correlate with the amount of circulating atypical cells. In healthy subjects, the CD4+CD26-subpop-ulation represent 7% of total lymphocytes (range: 3-14%). Using as threshold a value for CD4+CD26- of 30% of circulating lymphocytes, the resulting parameter has a sensitivity of 97%, a specificity of 97%, and a positive predictive value of 100% in the diagnosis of peripheral blood involvement.

Our up-dated results on a casistic of 90 patients with SS confirm that the lack of CD26 is a spe-cific feature of circulating SC. Indeed, 86 patients (95.6%) showed at first diagnosis a complete lack of CD26 expression, whilst the remaining 4 showed a mixed positive/negative CD26 expression. In the same group of patients, only 66 patients (73.3%) were CD7 negative. When considering the classic threshold value of 10 for the CD4/CD8 ratio, values higher than 10 were identified in 40 cases (44%), and the expression of a single variable region of the TCR beta-chain in a similar number of patients (54%). Flow cytometry determination of CD4+CD26- cells appears, at present, the most valid laboratory param-eter that allows a quantitative evaluation of SC.

Flow cytometry provides therefore valuable infor-mation for diagnosis, prognosis, and therapeutic ef-ficacy,49 as demonstrated also in recent papers show-ing that quantitative abnormalities (“dim” expression of T-cell lineage markers) were more frequent than phenotypic abnormalities, and that CD4+/CD26- T cells were more frequent and correlated better with disease extent than CD4+/CD7- T cells.

In addition to the loss of CD26, recent reports showed that SC express in an aberrant manner T-plastin 50 and CD158k molecule,51 which belongs to the family of immunoglobulin-like receptors and is

cell receptor (TCR), have represented relevant useful tool in the differential diagnosis between benign and lymphomatous erythroderma.

Phenotypic characteristics

Atypical lymphoid T-cells (Sézary cells) in both the skin and the blood, present a characteristic post-thymic phenotype, helper (CD4+, CD8-), with fea-tures of “memory” cells (CD45RO+, CD45RA-), and increased CD4/CD8 ratio 14, 25-30 (Figure 2). The presence of aberrant phenotypes (CD8+ CD4-, CD8+ CD4+, CD4+ CD57+) as well as the loss of T-cell markers (particularly CD2) is described in the lit-erature, usually associated with a worse prognosis.14,

25-31 The identification of a single variable region of the beta chain of the T-cell receptor (TCR) using monoclonal antibodies, usually occurs in a reduced proportion of patients.32, 33

The loss of CD7 has been described as a specific feature.14, 28, 29, 34, 35 However, in the last years, accu-mulating evidences coming from our as well as other laboratories, support the view that a percentage of pa-tients ranging from 10% up to 40% of cases present CD7+ circulating SC.14, 36-41 Dummer et al.42 found the presence of a clonal rearrangement of TCR genes in both CD7+ and CD7- cells. In our experience, the expression of CD7 is also associated with a differ-

Figure 2.—The phenotype of the Sézary cell showing at electron microscopy the characteristic hyperconvoluted cerebriform nu-cleus. For each antigen, it is reported the name of the author who firstly identified this feature and the year of publication. In blue are reported the more recent data.



1% in polyclonal background) sensitivity, even if the high instrumental costs limit its routinely application (Figure 3).

However, it is important to stress the concept that the demonstration of TCR clonal rearrangement does not constitute a criterion able to by itself to allow a correct diagnosis. Indeed, the percentage of clonal-ity demonstration in early MF cases ranges between 60% and 100%.53-57 Moreover, the demonstration of dominant T-cell clones in a small percentage of chronic dermatoses, with a still unknown biologic and clinical significance, partially impairs the diag-nostic relevance of the PCR analyses, particularly in those cases of early phase disease, in which also clinical and immunopathological features can be less useful. Therefore, clonal rearrangement has to be analysed “vis a vis” with the other diagnostic param-eters, clinical, histological and immunohistochemi-cal, and only in an appropriate context can give rel-evant information.

We firstly published our experience on TCR anal-ysis using a multiplex PCR/heteroduplex (HD) anal-ysis on polyacrylamide gel electrophoresis in 547 cutaneous biopsies 61 performed for the clinical sus-picion of CTCL (MF/SS). The final diagnosis was benign inflammatory disease (BID) in 353 samples (64.5%) and CTCL in 194 (35.5%). Our objectives were to determine the sensitivity and specificity of the multiplex PCR/HD and to identify which are the clinical, histopathological or immunophenotypical features significantly associated to the finding of a T-cell clonality. We demonstrated a clonality in 83.5% of CTCL and in 2.3% of BID (P<0.001). A signifi-

normally present in a proportion of circulating NK cells and CD8+; the functional significance linked to this expression is not yet known.

Recent data showed also that clonal circulating SC are characterized by a phenotype consistent with central memory T cells, expressing the lymph node homing molecules CCR7 and L-selectin as well as the differentiation marker CD27. On the other hand, T-cells isolated from MF skin lesions lacked CCR7/L-selectin and CD27 but strongly expressed CCR4 and CLA, a phenotype suggestive of skin resident effector memory T cells. These results suggest a dif-ferent origin of malignant T cells between SS (cen-tral memory T cells) and MF (skin resident effector memory T cells).52

TCR-gamma gene rearrangement analysis: diagnostic and prognostic relevance

The analysis of the rearrangement of T-cell recep-tor beta and gamma-chain genes has now become a cornerstone for a correct and early diagnosis of CTCL.

However, literature studies utilised different PCR protocols, in terms of both number and types of prim-ers, and amplification analysis methods, meaning that standardised and comparable data are now not available. Even if the majority of studies utilised a multiple primer set assay, there are several possibili-ties to separate and visualize the PCR amplification products such as polyacrylamide gel electrophoresis, single-strand conformation polymorphism analysis (SSCP), denaturing (DGGE) or temperature gradient electrophoresis (TGGE), and heteroduplex analysis (HD).53-60 The multiple primer set technique associ-ated to the HD analysis seems to be the most easily reproducible method, with a sensitivity and specifi-city comparable to that of the techniques (such as SSCP and DGGE) in which the PCR products are separated by nucleotide sequence and not by length as in the polyacrylamide gel, even if it does not allow to demonstrate the presence of identical rearrange-ments in the blood and skin, or in repeated skin bi-opsies from the same patient. In the recent years, the introduction of methods based on capillary electro-phoresis with automated fluorescent DNA (GeneS-can) has been associated with a significant increase in both the qualitative (90-100% of clonal rearrange-ment in pathological samples) and analytical (0.1%-

Figure 3.—An example of the results given by the Gene Scan based on capillary electrophoresis with automated fluorescent DNA. A patient with a clinical picture of erythroderma with a suspicion of erythrodermic CTCL has been shown to demosntrate the same clonal rearrangement in the skin, nodes and blood.



ance of new oligoclones was observed in 10 patients; all of them achieved a clinical response to treatment with extracorporeal photochemotherapy (ECP). The TCRgamma pattern (homogeneity or heterogeneity) in the skin at diagnosis showed a relevant prognostic value, and patients with an oligoclonal pattern were characterised by a less pronounced peripheral blood involvement and hopefully showed a significantly longer survival than those with a homogeneous pat-tern. Therefore, it can be concluded that the analysis of clonal heterogeneity by multiple-sample approach GS analysis could be a helpful clinical tool in iden-tifying SS patients with a potential higher response to therapy.

Therapeutic options: an update

The EORTC – Cutaneous Lymphoma Task Force (CLTF) provided in 2006 a consensus statement on guidelines for the treatment of CTCL on the ba-sis of the quality of supporting data, as defined by the Oxford Centre for Evidence-Based Medicine.64 First line recommendations for the treatment of SS patients are represented by extracorporeal photo-pheresis and low-dose interferon. Other treatments included as first-line options are represented by de-nileukin diftitox (not available in Europe) and chlo-rambucil plus prednisone, these two latter however, with a significantly lower level of evidence. Second line treatments are represented by bexarotene, poli-chemotherapy and methotrexate. In recent years, consensus recommendations from ISCL, EORTC and USCLC have been developed as to the general conduct of clinical trials in MF/SS as well as meth-ods for response evaluation.65

Extracorporeal photochemotherapy (or photo-pheresis, ECP), described for the first time by Edel-son et al. in 1987 66-72 associates the administration of 8-methoxypsoralen with the extracorporeal UVA irradiation of circulating blood, merging therefore into one treatment PUVA-therapy and leukapheresis. ECP can be performed alone or in combination with other drug agents (particularly interferon, bexaro-tene) or preceded by debulking agents (chemother-apy or alemtuzumab) in patients with a high tumour burden. In our experience, a clinical response was ob-tained in 32 out of 51 erythrodermic CTCL patients (63%), with a complete response rate of 16%. The median time for response induction was 8 months

cantly higher percentage of clonal cases was associ-ated to the cutaneous T-score (71.4% in T1, 76.1% in T2 and 100% in nodular and erythrodermic MF samples) and to the presence of a T-cell lineage an-tigen loss (93.9% vs. 77.4%). The multivariate lo-gistic regression showed that the density and extent of the cell infiltrate, the degree of epidermotropism and the presence of cytological atypia share an inde-pendent predictive value with respect to clonality in T1/T2 samples, even if the highest odds ratios (3.55) were associated to the density of the cell infiltrate. The disease course of T1-T2 patients was analysed according to the PCR findings. All the PCR nega-tive patients showed a long standing stable disease course; on the other hand, a disease progression oc-curred in 12/87 (13.8%) positive patients.

As a second step,62 we focused our attention on the comparison of the diagnostic accuracy of the multiplex/heteroDuplex (HD) PCR with that of the GeneScan (GS) capillary electrophoresis, particular-ly in the early diagnosis of MF/SS, using a multiple sample approach. Indeed, GS demonstrated TCR-gamma gene rearrangement (GR) in all the 57 SS (100%) and in 123/146 (84%) of the MF samples, whereas the multiplex/HD PCR was less sensitive. An increase in clonality was observed in connec-tion with both a worsening of the cutaneous disease (79% T1/T2; 100% T3/T4) and an increase in the histopathological score (HS <5, 76%; HS ≥5, 94%). Clonal heterogeneity with adjunctive reproducible skin TCRgamma-GRs was also observed. “Clonal instability”, with different GRs, was present in a small percentage of patients.

The GS approach was then used to analyse clon-al heterogeneity (defined as the coexistence of two or more different T-cell clones in multiple samples from the same patients) and its correlation with the clinico-pathologic features and potentially the dis-ease course of SS. In this study,63 we have analyzed by GS the incidence and the significance of long-lived oligoclonal expansions in multiple skin and blood samples from 24 SS patients, in an attempt to correlate these figures with the clinical outcome. A skin clonal heterogeneity with additional reproduc-ible TCRgamma-gene rearrangements (TCRgamma-GRs) was detected at diagnosis in 19/24 patients, 13 of whom had a constant prevalence of pathological TCRgamma-GRs in both skin and blood (dominant clonal pattern). During follow-up, an increase in oli-goclones that were present at diagnosis or the appear-



crease up to more than 2000/mm3. Preliminary re-ports on 14 patients documented an overall response rate of 85%, with a median decrease of circulating SC by 95%. The maintenance of clinical activity was coupled with a significant decrease in the incidence and severity of infectious complications, which oc-curred in a minority of cases.75 Our up-dated data include 24 SS patients treated with this schedule. Overall, 20 patients (83.3%) achieved a clinical re-sponse, with five patients achieving a complete re-sponse. The median time-to-treatment failure is 24 months, the median survival 35 months. Infectious complications occurred in less than 20% of patients and consisted mainly of cytomegalovirus reactiva-tion or bacterial infections, easily manageable by antibiotic treatments. Therefore, subcutaneous alem-tuzumab at very low doses (10 mg maximum per ad-ministration) and performed for a short time period based on SC levels, shows a good toxicity profile, high response rate and durable remission durations in SS patients with high tumour burden in the pe-ripheral blood.

On the basis of the literature evidences as well as on the clinical experience, we recently developed an algohorythm for the treatment of SS patients, which takes into account different therapeutic strategies on the basis of the peripheral blood tumour burden. In patients with a low tumour burden in the periph-eral blood (SC less or equal than 1000/mm3), the first-line treatment is represented by photopheresis, which is prolonged also for long periods of time in the presence of clinical response or favourable dis-ease stabilisation with good quality of life. In case of progression, ECP can be associated with interferon, or interferon plus bexarotene. On the other hand, in patients with a high tumour burden in the peripheral blood, the first line treatment is represented by a de-bulking agent (mainly alemtuzumab) followed by a maintenance treatment with ECP alone or in associa-tion with immune-modulators.

During the recent years, a better understanding of the immunological and molecular pathways in CTCL disease evolution provided the identification of specific therapeutical targets, as well as the con-stant improvement in the laboratory techniques lead to the development of new and promising agents in CTCL 76-88 (Table I).

Histone deacetylase inhibitors (HDAC) consti-tute a broad group of molecules which regulate gene transcription by inducing epigenetic physical altera-

(range: 1-23). The median response duration was 22.4 months (range: 6 months-11 years). The treat-ment was generally well tolerated also in this cohort of elderly patients, and no systemic toxicities grade III-IV were observed. The pre-treatment parameters significantly associated with a higher likelihood to obtain a clinical response were the B-score in the pe-ripheral blood, the CD4/CD8 ratio and the amount of circulating CD3+CD8+ cells before treatment.

In patients with a high tumour burden in the pe-ripheral blood it is, therefore, of potential clinical interest the use of a debulking agent to reduce the number of circulating atypical cells before the begin-ning of ECP. Data from our group have documented a potential synergy of action between fludarabine and extracorporeal photochemotherapy; in fact, the response rate was significantly higher (58%) in patients treated with a sequential scheme of fluda-rabine followed by photopheresis compared to that obtained in patients treated with fludarabine alone (40%).73 More recently, we analysed the clinical ac-tivity and tolerability of a treatment foreseeing low doses of the monoclonal antibody alemtuzumab di-rected against the CD52 molecule expressed on the T-cell surface. Lundin et al.74 treated 22 CTCL pa-tients heavily pre-treated with the classic therapeutic regimen, foreseeing an alemtuzumab dosage of 30 mg on alternating days for 12 weeks by i.v. admin-istration. A response rate of 55% was achieved, with 32% of complete responses and a median duration of remissions of 12 months. This treatment regimen, however, is weighted by severe side effects (hyper-thermia, osteo-arthralgias, hypotension, urticaria), in particular with an high incidence of serious bacterial or viral infections (particularly cytomegalovirus). The high incidence of infections is clearly dependent from the significant immune-suppression induced by the drug, and limits its use to patients with multi-relapsing disease and high proportion of circulating leukemic cells. Based on these data, we designed a low-dose patient-tailored alemtuzumab schedule for the treatment of patients with SS who were refracto-ry to or had relapsed after chemotherapy, and/or with a high peripheral blood tumour burden. Our regimen foresees subcutaneous instead of i.v. administration of alemtuzumab 3 mg on day 1, then 10 mg as maxi-mum dosage (instead of 30 mg) on alternating days until a SC count reduction to values of <1000/mm3. Thereafter, patients were monitored and treatment repeated only when the values of circulating SC in-



duced by this drug include fatigue, thrombocytope-nia, diarrhea and anorexia. Romidepsin is another pan HDAC inhibitor (inhibits class I, II and IV of HDACs), but administered intravenously. According to two multicenter phase II trials in patients with pre-treated CTCL, responses were obtained in 34% of patients in each study, with 6-7% complete respons-es. One of the more relevant features of both studies was the long duration of responses (median time to progression from 8 to 15 months).81, 82

Pralatrexate is a novel antifolate compound poten-tially more active than its homologue methotrexate due to its higher intracellular accumulation. A multi-center trial which enrolled 31 patients with relapsed/refractory MF, SS and primary cutaneous anaplas-tic large–cell, reported an overall response rate of 43%.83 The side effects were manageable and mainly consisted of grade I and II fatigue, mucositis, nausea and epistaxis.

tions of DNA or structural components of chromatin, resulting in the intra-cellular accumulation of acety-lated histones as well as non-histone proteins. This event induces a cascade of several alterations, among which transcriptional modifications and altered functions of proteins regulating cell proliferation, cell cycle progression, differentiation and apoptosis. Two agents of this class, vorinostat and romidepsin have been approved for the treatment of relapsed or refractory CTCL in the United States. Vorinostat (su-beroylanilide hydroxamic acid), is an oral pan HDAC inhibitor (inhibits class I, II and IV of HDACs). A response rate of 24.4% was obtained using this drug in a group of 33 advanced, heavily pre-treated CTCL patients, among whom 11 SS cases.79 The optimal dosage was 400 mg daily. These results were con-firmed by a subsequent multicenter trial conducted on 74 patients 80 with relapsed CTCL, which showed an overall response rate of 29.5%. The toxicities in-

Table I.—Summary of the results obtained by new investigational drugs in CTCL patients.

Drug Ref. Mechanism of action No. pts

Clinical characteristics of patients included

Route of administration

% response

rateSide effects

Alemtuzumab 75 Monoclonal antibody anti-CD52

14 Sèzary syndrome Subcutaneous 85% Infections

Vorinostat 79 HDAC 33 Advanced, heavily pretreated CTCL including SS

Oral 400 mg per day

24,4% Fatigue, anorexia, diarrhoea, thrombocytopenia, QT alterations

Vorinostat 80 HDAC 74 Relapsed CTCL Oral 400 mg per day

29,5% Fatigue, anorexia, diarrhoea, thrombocytopenia, QT alterations

Romidepsin 81, 82

HDAC 96 Pre-treated CTCL Intravenous 34% Fatigue, anorexia, diarrhoea, thrombocytopenia, QT alterations

Pralatrexate 83 Anti-folate compound

31 Relapsed/refractory MF, SS, and anaplastic large-cell lymphoma

Intravenous30 mg/m2

every week

43% Fatigue, mucositis, nausea, epistaxis

Bortezomib 84 Proteasome inhibitor

12 MF, peripheral CTCL Intravenous1.3 mg/m2 days 1,4,8,11 every 21 days

67% Myelosuppression, neuropathy

Forodesine 85 Inhibitor of purine nucleoside phosphorylase

9 Advanced CTCL Oral 5/9 Nausea, fatigue, edema, dyspnea and urinary casts

Zanolimumab 86 Monoclonal antibody anti-CD4

47 Early and advanced stage CTCL

Intravenous 56% Skin reactions, infections of skin and upper respiratory tract

Mogamulizumab 87 Monoclonal antibody anti-CCR-4

42 Relapsed, refractory CTCL including SS

Intravenous 1 mg/kg

42% Lymphopenia, neutropenia, thrombocytopenia, acute infusion reaction and skin eruptions

Brentuximab vedotin

88 Monoclonal antibody anti-CD30

58 Relapsed, refractory systemic CD30 anaplastic large cell lymphoma

Intravenous 1.8 mg/kg

86% Neutropenia, thrombocytopenia and peripheral neuropathy

CCR4: chemokine receptor 4; HDAC: histone deacetylase inhibitor; MF: mycosis fungoides; SS: Sézary syndrome.



peripheral blood involvement, with 87% of patients achieving a significant reduction of circulating SC. The main toxicities include hematologic side effects (neutropenia, thrombocytopenia) infusion-related effects and skin reactions.87

Another monoclonal antibody recently utilized is the antibody-drug conjugate brentuximab vedo-tin, which delivers the potent antimicrotubule agent monomethylauristatin E to CD30-positive malignant cells. A series of phase II multicenter trials were con-ducted to evaluate the efficacy and safety of brentux-imab vedotin in patients with relapsed or refractory systemic anaplastic large-cell lymphomas as well as Hodgkin lymphoma. Even if no specific data have been reported until now in CTCL patients, one phase II trial performed in 58 patients with systemic ana-plastic-large cell lymphoma with recurrent disease showed an impressive response rate (86%), with a complete response rate of 57%. The median dura-tions of overall response were approximately one year. Toxicities included neutropenia, thrombocyto-penia and peripheral sensory neuropathy (12%).88

Conclusions

In conclusion, a better understanding of the biologic mechanisms leading to the natural disease evolution of erythrodermic CTCL patients, coupled with a more precise knowledge of the with effective clinical activi-ty of these drugs as well as the identification of patients more likely to respond to each different compound, could hopefully significantly increase our therapeutic strategies and thus potentially improve the clinical out-comes and quality of life of these patients.

Riassunto

Diagnosi e terapia dei CTCL eritrodermici: un aggiorna-mento

L’eritrodermia è una rara (incidenza annua stimata 1-2 casi su 100.000) ma purtroppo severa manifestazione cuta-nea clinicamente caratterizzata da un interessamento pres-sochè completo della superficie cutanea. L’eritrodermia nei pazienti adulti può essere conseguente a differenti condizio-ni, tra cui le più frequenti sono costituite da precedenti der-matosi (70% dei casi) e reazioni cutanee avverse da farmaci (20%). I linfomi cutanei a cellule T (CTCL) rappresentano meno del 10% dei casi di eritrodermia (micosi fungoide eri-trodermica e sindrome di Sézary). Da un punto di vista cli-

Bortezomib is a proteasome inhibitor specifically targeting the catalytic core of the proteosome. The binding of the drug to its ligand induces a series of ef-fects including inhibition of cellular proteosome, ac-cumulation of the cell-cycle dependent kinase inhibi-tors p27/p21, activation of p53, inhibition of NF-kB and accumulation of pro-apoptotic proteins. The first trial on CTCL was conducted in a small series of pa-tients (10 MF, 2 peripheral T-cell lymphoma), with a reported response rate of 67% and response duration ranging from 7 to 14 months.84 Myelosuppression and neuropathy are the most common side effects.

Forodesine is an inhibitor of the enzyme purine nucleoside phosphorylase; the action mechanism of this drug is represented by the inhibition of this en-zyme which determines an intracellular accumula-tion of GTP, causing in turn apoptosis and cell cycle arrest. The drug is given orally for long-time periods (more than 12 months), and despite a small group of patients has been reported as available for evaluation (n=9), a response was obtained in 5 and a disease stabilization in the remaining.85 The side effects of the drug include nausea, fatigue, peripheral edema, dyspnea and urinary casts

Zanolimumab is a fully humanized monoclonal antibody directed against the CD4 surface molecule. Two different prospective multicenter trial are re-ported, one in “early-stage” the other in “advanced-stage” CTCL. Responses were shown to be obtained in both MF and SS patients, more frequently in pa-tients treated with high doses and in early phase dis-ease. Inflammatory skin reactions and infections of the skin and upper respiratory tract constituted the most common toxicities.86

Mogamulizumab is a defucosylated, humanized monoclonal antibody directed against the CC chem-okine receptor 4 (CCR4) which has shown promis-ing clinical activity in refractory or relapsed periph-eral T-cell lymphoma (PTCL) including adult T-cell leukemia-lymphoma (ATL). In CTCL, a phase I/II study was conducted in US in 42 patients with re-fractory or relapsed disease. The drug is performed intravenously at a dosage of 1 mg/kg. Among 38 evaluable patients, an overall response rate of 42% was achieved, even if CCR4 expression on lympho-ma cells was not mandatory for patient enrolment. As to the subtypes of CTCL, SS patients showed a response rate of 50% and MF patients 36%. An im-portant point for the clinical use of this drug is that it shows a relevant activity in the management of



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27. Worner I, Matutes E, Beverley PC, Catovsky D. The distribution of CD45, CD29 and CD45RO (UCHL-1) antigens in mature CD4 positive T-cell leukemias. Br J Haematol 1990;74:439-44.

28. Vonderheid EC, Kantor GR, Pequignot EC. Analysis of clinical, his-topathologic and immunopathologic parameters in erythrodermic variants of cutaneous T-cell lymphoma with implications for stag-ing. In: Lamberts WC, ed. Basic mechanisms of physiologic and aberrant lymphoproliferation in the skin. New york, Ny: Plenum Press; 1994. p. 275.

29. Harmon CB, Witzig TE, Katzmann JA, Pittelkow MR. Detection of circulating T cells with CD4+CD7- immunophenotype in patients with benign and malignant lymphoproliferative dermatoses. J Am Acad Dermatol 1996;35:404-10.

30. Bogen SA, Pelley D, Charif M, McCusker M, Koh H, Foss F et al. Immunophenotypic identification of Sezary cells in peripheral blood. Am J Clin Pathol 1996;106:739-48.

31. Van der Putte SCJ, Toonstra J, Van Wichen DF, van Unnik JA, van Vloten WA. Aberrant immnophenotypes in mycosis fungoides. Arch Dermatol 1988;124:373-80.

32. Finn DT, Jaworsky C, Chooback L, Jensen PJ, Lessin SR. Correla-tion between clonotypic T-cell receptor beta chain variable region

nico, la strategia fondamentale è costituita dalla possibilità di effettuare una diagnosi corretta già dalle fasi iniziali di malattia. Negli anni più recenti, lo sviluppo delle tecniche di citometria a flusso e biologia molecolare, in particolare la possibilità di identificare la presenza di un riarrangiamento clonale del T-cell receptor (TCR), ha rappresentato un utile strumento nella diagnosi differenziale tra eritrodermie “be-nigne” e forme invece conseguenti ad un disordine linfopro-liferativo a cellule T. L’individuazione di specifici meccani-smi immuno-patogenetici di sviluppo delle differenti forme di eritrodermia, se da una lato rappresenta un utile strumento per la diagnostica differenziale tra le varie forme, dall’altro ha consentito l’individuazione di nuove strategie terapeuti-che basate sull’impiego di anticorpi monoclonali diretti con-tro specifici “targets” molecolari. Parole chiave: Linfoma cutaneo a cellule T - Dermam-tite esfoliativa - Fenotipo.

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63. Fierro MT, Ponti R, Titli S, Bonello L, Comessatti A, Novelli M et al. TCRgamma-chain gene rearrangement by GeneScan: incidence and significance of clonal heterogeneity in Sézary syndrome. J In-vest Dermatol 2010;130:2312-9.

64. Trautinger F, Knobler R, Willemze R, Peris K, Stadler R, Laroche L et al. EORTC consensus recommendations for the treatment of my-cosis fungoides/Sézary syndrome. Eur J Cancer 2006;42:1014-30.

65. Olsen EA, Whittaker S, Kim yH, Duvic M, Prince HM, Lessin SR et al.; International Society for Cutaneous Lymphomas; United

(TCR-V beta) gene expression and aberrant T-cell antigen expres-sion in cutaneous T-cell lymphoma. J Cutan Pathol 1996;23:306-11.

33. Potoczna N, Boehncke WH, Nestle FO, Küenzlen C, Sterry W, Burg G et al. T-cell receptor beta variable region (V beta) usage in cutane-ous T-cell lymphomas (CTCL) in comparison to normal and ecze-matous skin. J Cutan Pathol 1996;23:298-305.

34. Haynes BF, Metzgart RS, Minna JD, Bunn PA. Phenotype charac-terization of cutaneous T-cell lymphoma. Use of monoclonal an-tibodies to compare with other malignant T cells. N Engl J Med 1981;304:1319-29.

35. Wood GS, Hong SR, Sasaki DT, Abel EA, Hoppe RT, Warnke RA et al. Leu8/CD7 antigen expression by CD3+ T cells: comparative analysis of skin and blood in Mycosis fungoides/Sézary syndrome relative to normal blood values. J Am Acad Dermatol 1990;22:602-7.

36. Laetsch B, Haffner AC, Dobbeling U, Seifert B, Ludwig E, Burg G et al. CD4+/CD7– T cell frequency and polymerase chain reaction-based clonality assay correlate with stage in cutaneous T cell lym-phomas. J Invest Dermatol 2000;114:107-11.

37. Novelli M, Fierro MT, Quaglino P, Bernengo MG. CD26 (DPP-IV): a useful marker in Sézary syndrome. J Invest Dermatol 1994;103:448 (abstr).

38. Bernengo MG, Novelli M, Quaglino P, Lisa F, De Matteis A, Savoia P et al. The relevance of the CD4+CD26- subset in the identification of circulating Sézary cells. Br J Dermatol 2001;144:125-35.

39. Savoia P, Novelli M, Fierro MT, Cremona O, Marchisio PC, Bernengo MG. Expression and role of integrin receptors in Sézary syndrome. J Invest Dermatol 1992;99:151-9.

40. Foss FM, Koc y, Stetler-Stevenson MA, Nguyen DT, O’Brien MC, Turner R et al. Costimulation of cutaneous T-cell lymphoma cells by Interleukin-7 and Interleukin-2: potential autocrine or paracrine effectors in the Sézary syndrome. J Clin Oncol 1994;2:326-35.

41. yagi H, Tokura y, Furukawa F, Takigawa M. CD7-positive Sé-zary syndrome with a Th1 cytokine profile. J Am Acad Dermatol 1996;34:368-74.

42. Dummer R, Nestle FO, Niederer E, Ludwig E, Laine E, Grund-mann H et al. Genotypic, phenotypic and functional analysis of CD4+CD7+ and CD4+CD7- T lymphocyte subsets in Sézary syn-drome. Arch Dermatol Res 1999;291:307-11.

43. Novelli M, Comessati A, Quaglino P, Savoia P, Fierro MT, Bernen-go MG. CD26 expression on cutaneous infiltrates from patients with cutaneous T-cell lymphoma (CTCL) CD26 in cutaneous T-cell lymphoma patients. Adv Exp Med Biol 2003;524:223-34.

44. Jones D, Dang NH, Duvic M, Washington LT, Huh yO. Absence of CD26 expression is a useful marker for diagnosis of T-cell lym-phoma in peripheral blood. Am J Clin Pathol 2001;115:885-92.

45. Narducci MG, Scala E, Bresin A, Caprini E, Picchio MC, Remotti D et al. Skin-homing of Sezary cells involves SDF-1-CXCR4 sig-naling and downregulation of CD26/dipeptidylpeptidase IV. Blood 2006;107:1108-15.

46. Sokolowska-Wojdylo M, Wenzel J, Gaffal E, Steitz J, Roszkiewicz J, Bieber T et al. Absence of CD26 expression on skin-homing CLA+ CD4+ T lymphocytes in peripheral blood is a highly sensi-tive marker for early diagnosis and therapeutic monitoring of pa-tients with Sezary syndrome. Clin Exp Dermatol 2005;30:702-6.

47. Hristov AC, Vonderheid EC, Borowitz MJ. Simplified flow cyto-metric assessment in mycosis fungoides and Sézary syndrome. Am J Clin Pathol 2011;136:944-53.

48. Nagler AR, Samimi S, Schaffer A, Vittorio CC, Kim EJ, Rook AH. Peripheral blood findings in erythrodermic patients: importance for the differential diagnosis of Sézary syndrome. J Am Acad Dermatol 2012;66:503-8.

49. Washington LT, Huh yO, Powers LC, Duvic M, Jones D. A stable aberrant immunophenotype characterizes nearly all cases of cutane-ous T-cell lymphoma in blood and can be used to monitor response to therapy. BMC Clin Pathol 2002;2:5.

50. Su MW, Dorocicz I, Dragowska WH, Ho V, Li G, Voss N et al.



Querfeld C. Management of cutaneous T cell lymphoma: new and emerging targets and treatment options. Cancer Manag Res 2012;4:75-89.

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79. Duvic M, Talpur R, Ni X, Zhang C, Hazarika P, Kelly C et al. Phase II trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood 2007;109:31-9.

80. Olsen EA, Kim yH, Kuzel TM, Pacheco TR, Foss FM, Parker S et al. Phase IIB multicenter trial of vorinostat in patients with per-sistent, progressive, or treatment refractory cutaneous T-cell lym-phoma. J Clin Oncol 2007;25:3109-5.

81. Piekarz R, Frye R, Turner M, Wright JJ, Allen SL, Kirschbaum MH et al. Phase II multi-institutional trial of the histone deacetylase in-hibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol 2009;27:5410-7.

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84. Zinzani PL, Musuraca G, Tani M, Stefoni V, Marchi E, Fina M et al. Phase II trial of proteasome inhibitor bortezomib in patients with relapsed or refractory cutaneous T-cell lymphoma. J Clin Oncol 2007;25:4293-7.

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77. Li Jy, Horwitz S, Moskowitz A, Myskowski PL, Pulitzer M,


new insights in the clinicopathologic features and biological behaviour of primary cutaneous and sys-temic CD30+ lymphomas resulted in the recognition of CD30+ lymphoproliferative disorders of the skin as a distinct nosologic group.4

CD30 molecule

CD30 is a member of the Tumor necrosis factor receptor superfamily member 8 (TNFRSF8). It is a cell surface receptor originally discovered on cul-tured Hodgkin/Reed–Sternberg cell line which was initially called Ki-1 and subsequently designated CD30.5, 6 In healthy individuals, CD30 is expressed on activated B and T lymphocytes. CD30 can be ex-pressed in several lymphoid malignancies, notably Hodgkin disease, systemic and cutaneous ALCL, primary mediastinal large B cell lymphoma, immu-noblastic lymphoma, adult T-cell lymphoma leuke-mia, and transformed mycosis fungoides.7, 8

CD30 ligand (CD30L) is a type II transmem-brane protein that belongs to the TNF superfamily (TNFSF8). CD30L is observed in both resting and activated B cells, activated T cells and natural killer cells, eosinophils, granulocytes, monocytes and mast cells. Moreover, CD30L protein has been detected in neoplastic cells of chronic lymphocytic leukemia, follicular B cell lymphoma, hairy cell leukemia, T-cell lymphoblastic lymphoma, and adult T cell leukemia lymphoma.9

Unit of Dermatology, University of Padua, Padua, Italy


M. ALAIBAC, H. ZARIAN, I. RUSSO, A. PESERICO

CD30+ lymphoproliferative disorders of the skin: still an open question

CD30+ lymphoproliferative disorders of the skin represent a well-defined spectrum of primary cutaneous T-cell lympho-mas. They include lymphomatoid papulosis and cutaneous anaplastic large-cell lymphoma which are characterized by the common expression of the CD30 antigen, but different clinical, histological and molecular features. Recent progress in the pathobiology and identification of therapeutic targets has contributed to our current understanding of this peculiar group of cutaneous lymphoproliferative disorders. The char-acteristic features of this group of cutaneous lymphoprolif-erative disorders are reviewed with particular emphasis to their diagnosis and treatment strategies.Key words: Lymphoproliferative disorders - Lymphomatoid papulosis - Lymphoma, primary cutaneous anaplastic large cell - Lymphoma, T-cell, cutaneous - Skin neoplasms.

CD30+ lymphoproliferative disorders of the skin represent a well-defined spectrum of primary

cutaneous T-cell lymphomas (CTCL). They include lymphomatoid papulosis (LyP) and cutaneous ana-plastic large-cell lymphoma (C-ALCL) which are characterized by the common expression of the CD30 antigen, but different clinical, histological and molecular features. They represent the second most common group of CTCL, accounting for approxi-mately 30% of CTCLs.1

CD30+ malignant lymphomas were first recog-nized as distinct lymphoma entities in 1985 2 and added to the updated Kiel classification which did not separate primary cutaneous CD30+ lymphomas from their systemic counterparts.3 Subsequently,

Corresponding author: M. Alaibac MD, PhD, Unit of Dermatology, University of Padua, Via Battisti 206 35128, Italy. E-mail: [email protected]


Lavoro: 4424-MDtitolo breve: CD30+ LYMPHOPROLIFERATIVE DISORDERS OF THE SKINprimo autore: ALAIBACpagine: 545-52

ALAIBAC CD30+ LYMPHOPROLIFERATIVE DISORDERS OF THE SKIN


The exact function of CD30 and CD30L in CD30+ lymphomatous malignancies is largely unknown. Engagement of CD30L with its cognate receptor CD30 may result in either proliferation or apoptosis. CD30 induced cell death may induce self-regression seen in LyP lesions, whereas proliferation may be responsible for C-ALCL Tumor formation.10

CD30+ lymphoproliferative disorders of the skin: clinical presentation

Lymphomatoid papulosis

LyP was first described as a chronic recurrent, self-healing papulonodular skin eruption with histologic features of a malignant lymphoma.11 LyP can last from months to years and affects all ages with a peak incidence in the fifth decade. Clinically, localized or disseminated asymptomatic red papules and small nodules are observed, which regress spontaneously (Figure 1). Involution of the lesion is characterized by scaling, crusting (Figure 2), and often ulcera-tion which may leave hypo-/hyperpigmented areas and sometimes atrophic scars. Individual lesions can take 3 weeks to several months to regress and pa-tients can show lesions at different stages at the same time. The number of lesions in LyP can range from few to hundreds and they usually involve the trunk and extremities. Ulcerated nodules or lesions more than 2.0 cm in diameter may indicate the possibility

of progression to C-ALCL.12 Rare clinical variants of LyP include regional LyP, follicular LyP and pus-tular LyP.13-15

A controversial issue concerning LyP is its asso-ciation with other types of lymphoma. This event ranges from less than 5% to 20% and the most fre-quent lymphomas reported to be associated with LyP are Hodgkin’s disease, mycosis fungoides, and C-ALCL.16, 17 Although most lymphomas occur sub-sequent to the earlier LyP lesions, sometimes they can occur simultaneous with or prior to LyP. Because in some cases, a clonal relationship between LyP and the associated lymphoma has been demonstrated, it is plausible that they share a common lymphoid precursor.18 On the other hand, the prognosis of this condition is extremely good as the disease-related survival at 10 years is 100%.19

Cutaneous anaplastic large-cell lymphoma

C-ALCL is usually characterized by an asympto-matic solitary nodule (Figure 3) which sometimes may become ulcerated (Figure 4). The tumours fre-quently occur on an extremity and can initially be mistaken for insect bites or abscesses. About 20% of the patients have multifocal cutaneous disease and several patients show a rapid Tumor growth.20 Spon-taneous partial or complete regression of individual lesions may often be observed and this biological behaviour is consistent with the initial clinicopatho-logical denomination of “regressing atypical his-

Figure 1.—Lymphomatoid papulosis: small red nodule (less than 2 cm) on the wrist.

Figure 2.—Lymphomatoid papulosis: involution of lesions on the distal part of the leg characterized by scaling and crusting.

CD30+ LYMPHOPROLIFERATIVE DISORDERS OF THE SKIN ALAIBAC


tial identification is based on anaplastic lymphoma kinase (ALK) expression in systemic ALCL and the lack of ALK in C-ALCL (see the immunophenotype section).

Histology of Lyp and C-ALCL

The histological features of LyP and C-ALCL vary considerably as the lesions evolve.

In fully developed LyP lesions, four histologic subtypes (A, B, C and D) have been identified (23, 24). LyP type A (histiocytic) is observed in 75% of patients with this condition. In LyP type A, wedge-shaped dermal infiltrate composed of medium-sized to large pleomorphic or anaplastic lymphoid cells, neutrophils, eosinophils, and histiocytes is seen. In LyP type B (mycosis fungoides-like), an epider-motropic infiltrate of small to medium-sized lym-phocytes with cerebriform nuclei is observed. This form displays the histologic features of mycosis fun-goides. In LyP type C (C-ALCL-like), a monotonous population or clusters of large atypical lymphoid cells with relatively few admixed inflammatory cells is present. This form strongly resembles C-ALCL. Type D (Berti’s lymphoma-like) can histological-ly resemble the very aggressive CD8+ lymphoma known as Berti’s lymphoma, but unlike CD8+ lym-phoma, the lesions self-regress.24

The histology of C-ALCL is characterized by cohesive sheets of large cells with an anaplastic, pleomorphic, or immunoblastic morphology infil-trating the dermis and, sometimes, the subcutis. The epidermal compartment is generally not involved in the neoplastic process (Figure 5), although in some circumstances infiltration and ulceration can be present. The Tumor cells in C-ACLC show irregular nuclei, prominent nucleoli and abundant cytoplasm (Figure 6). Tumor cells may be multinucleated and show high mitotic activity. Inflammatory cells, in-cluding small lymphocytes are observed at the pe-riphery of the neoplastic infiltrate, whereas in LyP they are generally admixed with the large atypical lymphocyets.25

Immunophenotype

The tumor cells in LyP represent a proliferation of activated T-helper cells with a CD3+, CD4+, CD8–,

tiocytosis”.21 The condition is generally observed in adult male patient with a peak incidence in age of 60 years. After treatment, primary cutaneous ALCL frequently relapses in skin, and 10% of tumours spread to regional lymph nodes. The overall survival for patients with ALCL is favourable, with a 5-year survival rate of 95%.21 Interestingly, the vast major-ity of primary cutaneous lymphomas in immunosup-pressed patients (HIV infection and transplant recipi-ents) are C-ALCL.22 C-ALCL must be distinguished from systemic ALCL in which secondary cutaneous lesions are indicative of a poor prognosis. Differen-

Figure 3.—Cutaneous anaplastic large-cell lymphoma: solitary red nodule (more than 2 cm) on the thigh.

Figure 4.—Cutaneous anaplastic large-cell lymphoma: ulcerative plaque on the penis.



In several cases, Tumor cells in LyP show cytotoxic molecules, notably TIA-1, granzyme B, and per-forin.28, 29 Antigen deletion of one or more pan-T cell antigens (CD2, CD3, and/or CD5) can sometimes be observed. Type D LyP is characterized by the pres-ence of CD8+ lymphocytes with cytotoxic TIA-1 staining.24

C-ACLC displays an activated T-cell phenotype, expressing CD30, CD4, CD25, CD71, HLA-DR with deletion of one or more pan T-cell antigens CD2, CD3, CD5. According to the WHO/EORTC classification, the large lymphoid cells must repre-sent at least 75% of the Tumor infiltrate.1 Further-more, at least one of the above-mentioned cytotoxic molecules can be expressed by the majority of Tu-mor cells.30, 31 Most systemic ALCL are character-ized by a specific chromosomal translocation t(2;5)(p23;q35) resulting in expression of ALK protein. Several studies demonstrated absence of ALK ex-pression in C- ALCL in contrast to systemic ALCL in which most cases are positive for the product of this translocation.32, 33 C-ALCL lacks expression of epithelial membrane antigen (EMA) generally ob-served in systemic ALCL, but displays the cutaneous lymphocyte antigen (CLA).34

Recent studies indicate that there are an increasing number of neoplastic, infectious and inflammatory skin disorders which contain a significant number of CD30+ cells.35 Among infectious and inflammatory skin diseases, CD30 expression has been observed in herpes simplex, molluscum contagious, scabies, arthropod bite reactions, pityriasis lichenoides et varioliformis acuta and atopic dermatitis.35-38With regard to neoplastic skin conditions, CD30 expres-sion is present in large cell transformed MF and SS where this molecule can be detected on the majority of tumor cells.39, 40

Genotype

Monoclonal rearrangement of T-cell receptor (TCR) genes is detected in a variable percentages of LyP lesions. Moreover, clonality is not generally ap-parent in LyP type A and B, but only in about 50% of LyP type C specimens.41 In particular, it has been hy-pothesized that the CD30+ cells are the results of the expansion of a monoclonal neoplastic T-cell clone, whereas the CD30– cells are polyclonal non-neo-plastic lymphoid cells.42 In contrast, Gellrich et al.

CD30+, HLA-DR+, and CD25+ phenotype.23, 26 Expression of CD15, a characteristic marker for Reed Sternberg cells in Hodgkin lymphoma, is in-frequent.27 The atypical cells generally express the leukocyte common antigen (CD45) and a memory T-cell phenotype CD45R0+. The lymphoid cells with cerebriform nuclei in LyP type B are usually nega-tive for CD30. CD30+ cells are also infrequent in type A LyP whereas are a hallmark of type C LyP.23

Figure 6.—Histology of cutaneous anaplastic large-cell lympho-ma: the Tumor cells show irregular nuclei, prominent nucleoli and abundant cytoplasm.

Figure 5.—Histology of cutaneous anaplastic large-cell lympho-ma: cohesive sheets of large cells infiltrating the dermis and spar-ing the epidermis.



Therapy of C-ACLC

A characteristic of LyP is its propensity to under-go spontaneous regression. This phenomenon is ob-served in about 30% of C-ALCL and, consequently, a 6-8 weeks “watchful waiting” approach can also be proposed for patients with mild presentation of C-AL-CL.44 Treatment choice of patients who show no ten-dency to spontaneous regression should be based on disease distribution (solitary or multifocal). Radiation therapy is the most effective form of local treatment in the management of solitary C-ALCL, although surgi-cal excision is the most frequent therapeutic approach used in this condition.44, 49 This is due to the fact that the diagnosis of C-ALCL is often made histologically after surgical removal of an undiagnosed nodular le-sion. In this case, adjuvant therapy is not indicated be-cause recurrence at the same site is highly unlikely if the lesion has been completely excised. Radiotherapy is not indicated for multifocal disease, although in se-lected cases total skin electron beam therapy can be considered as a therapeutic option. In case of multi-focal disease, a systemic therapy should be taken in consideration.50 To this regard, MTX has proven ef-ficacy in inducing remission, although weekly high-dose MTX therapy may be required.44, 50 Different therapeutic approaches have been proposed for treat-ing recalcitrant A-ALCL, notably oral etoposide, bexarotene and interferon-alpha.51-53 More recently, targeted therapies with anti-CD30 antibodies (SGN-30 and SGN-35) have been proposed as an alternative to MTX.54, 55 CD30 is considered an ideal target for monoclonal antibody therapy because it is highly re-stricted to the malignant cells and is rarely expressed by nonmalignant T-cells. In particular, the anti-CD30 biological agent SNG-35 is currently being investigat-ed in several clinical trials for the treatment of both C-ALCL and CD30+ transformed mycosis fungoides.56 SNG-35 (brentuximab vedotin) consists of an anti-CD30 monoclonal antibody attached to a potent anti-Tumor agent, monomethyl auristatin E (MMAE) and induces objective responses in patients with relapsed or refractory CD30+ lymphoproliferative disorders.57

The biological nature of CD30+ cutaneous lymphoproliferative disorders

Although included in the same group of lympho-proliferative disorders, LyP and C-ALCL, differ sig-

demonstrated that the CD30+ large atypical cells are the results of a polyclonal expansion of lymphocytes which is not consistent with a neoplastic nature of these cells.43

TCR gene rearrangement is generally present in C-ALCL but not in all cases.41 In contrast to the systemic counterpart, C-ALCL does not contain the t(2;5) translocation. The nucleophosmin (NPM)-ALK fusion protein generated by this translocation is considered a constitutively active oncoprotein, al-though patient with systemic ALCL with this trans-location have a better prognosis of patients with the systemic counterpart ALK-.18

Staging and therapy

The therapeutic approach to these disorders should be decided after careful evaluation of the clinical manifestations, pathologic findings and imaging data. In particular, overtreatment should be avoided for these conditions that are highly unlikely to be life threatening, although they are potentially malignant disorders.

In LyP, the presence of associated systemic lym-phoproliferative disorders should be assessed on the basis of clinical symptoms, physical examination and baseline laboratory investigations. If symptoms or signs are not consistent with a systemic disease no other investigations are required. In C-ALCL, addi-tional tests (positron emission tomography-CT-scan, bone-marrow biopsy) should be performed in order to exclude extracutaneous spread.44

Therapy of LyP

Therapy of LyP is not known to influence the course of the disease or to prevent the development of associated lymphoproliferative disorders. There-fore, asymptomatic patients with mild disease can be managed with a “watchful waiting” approach. More severely symptomatic patients may require treatment with low dose oral methotrexate (MTX) or photo-therapy (PUVA or UVB).44 Therapeutic decisions in these cases should be based on clinical criteria and risk profile. Other less commonly used treatments include interferon-alpha, retinoids (systemic or topi-cal), imiquimod and oral (short-course) or intral-esional steroid.45-48



un andamento cronico e nuovi elementi possono comparire per molti anni. Istologicamente vengono riconosciute tre forme denominate A, B e C in base alla tipologia dell’infil-trato neoplastico. La prognosi è eccellente e spesso non vi è necessita di alcuna terapia. Il linfoma anaplastico a gran-di cellule CD30+ è caratterizzato dalla presenza di placche e/o noduli, spesso come lesioni singole o comunque con distribuzione loco-regionale, con tendenza alla regressio-ne spontanea delle lesioni. Le recidive sono frequenti, ma la prognosi è favorevole. L’istologia è caratterizzata dal-la presenza di grandi cellule anaplastiche che esprimono in misura maggiore del 75% l’antigene CD30. Dal punto di vista terapeutico l’escissione chirurgica è spesso suffi-ciente nel caso di lesioni singole, nei casi caratterizzati da lesioni con distribuzione loco-regionale la radioterapia è generalmente risolutiva. Nei soggetti immunosoppressi il linfoma anaplastico a grandi cellule CD30+ mostra un’in-cidenza aumentata rispetto agli altri linfomi cutanei.

Nel presente articolo verranno discusse le più recenti acquisizioni in relazione alla biologia, classificazione e trattamento di tale gruppo di disordini linfoproliferativi cutanei.Parole chiave: Malattie linfoproliferative - Papulosi lin-fomatoide - Linfoma a grandi cellule anaplastico - Linfo-ma cutaneo a cellule T - Pelle, tumori.

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nificantly in several aspects. In contrast to LyP, C-ALCL may spread to extracutaneous sites in 10–20% of the patients, whereas the classical type of LyP (de-fined type A) is characterized clinically by recurrent self-healing lesions and there is no risk of spread to extracutaneous sites.18 The presence of clonality by TCR gene rearrangements is detected only in a mi-nority of LyP cases in contrast to C-ALCL where it is observed in the great majority of patients;41 in par-ticular it has been shown that CD30+ cells in type A LyP are generally polyclonal and therefore the CD30 expression in these patients is only a sign of acti-vated T-cells.43 In organ transplant patients there are several reports of patients with ALCL, but no cases of LyP have been reported;22 this is consistent with the idea that LyP is a reactive conditions and there-fore its onset is hampered by the immunosuppressive therapy, whereas ALCL is a true lymphoma and con-sequently its development is favoured by the immu-nosuppressive regimen. Type B LyP is characterized by CD30- neoplastic cells and therefore should not be included among primary CD-30 lymphoprolifera-tive disorders. Type C LyP is histologically indistin-guishable from C-ALCL and may well be included in this entity.23

In conclusion, we raise the question if most of the cases of LyP are true CD30+ cutaneous lymphpopro-liferative disorders and therefore if it is appropriate to consider this entity together with C-ALCL in or-der to assess the cumulative prognosis of this group of cutaneous lymphomas.

Riassunto

Linfomi cutanei a cellule CD30+: una questione ancora aperta

I linfomi cutanei a cellule CD30+ rappresentano un gruppo di disordini linfoproliferativi caratterizzati dall’espressione da parte delle cellule neoplastiche della molecola CD30. Sono rappresentati dalla papulosi linfo-matoide e dal linfoma anaplastico a grandi cellule CD30+. Sono linfomi a basso grado di malignità con potenzialità evolutive verso forme sistemiche non ancora ben stabilite e prognosi solitamente favorevole.

La papulosi linfomatoide si presenta con lesioni papu-lari di colorito rosso-brunastro, in numero variabile, con localizzazione preferenziale al tronco ed agli arti e tenden-za all’ulcerazione centrale. Vi è spesso un polimorfismo evolutivo con lesioni in via di guarigione e nuove lesioni subentranti. Le singole lesioni sono presenti per poche set-timane, ma il disordine linfoproliferativo ha generalmente



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nostic criteria and the classification of the rare subtypes of PTL and PTL NOS.Key words: Lymphoma, T-cell, peripheral, therapy - CD8-pos-itive T-lymphocytes - Prognosis - Skin.

Abbreviations

EORTC: European Organization for Research and Treatment of Cancer

PTL NOS: Cutaneous peripheral T-cell lympho-ma, unspecified/not otherwise specified

WHO: World Health Organization

Introduction

Cutaneous peripheral T-cell lymphoma represent a phenotypically and prognostically heterogeneous group of cutaneous T-cell lymphomas (CTCL). The terminology of PTL is confusing and underwent sev-eral changes and modifications during recent years. The category PTL, unspecified/not otherwise speci-fied (NOS) had been introduced in the Revised Eu-ropean American Lymphoma (REAL) classification and was maintained in the World Health Organization (WHO) classification (3rd edition). In the European Organization for Research and Treatment of Cancer (EORTC) classification for primary cutaneous lym-phomas, most of these lymphomas were referred to as primary cutaneous CD30-negative large T-cell

1Department of DermatologyUniversity Hospital Zürich, Zürich, Switzerland

2Histologic Diagnostics, Zürich, Switzerland


W. KEMPF 1, 2, S. ROZATI 1, K. KERL 1, L. E. FRENCH 1, R. DUMMER 1

Cutaneous peripheral T-cell lymphomas, unspecified/NOS and rare subtypes: a heterogeneous group

of challenging cutaneous lymphomas

Cutaneous peripheral T-cell lymphoma, unspecified/not otherwise specified (PTL NOS) represents a phenotypically and prognostically heterogenous group of cutaneous T-cell lymphomas (CTCL) that do not fit into any of well defined defined CTCL subtypes. In the WHO-EORTC classifica-tion as well as the WHO classification, three entities have been delineated as provisional rare subtypes of PTL based on their characteristic clinico-pathological, immunopheno-typic and prognostic features and have been separated out from PTL, NOS: Primary cutaneous CD4-positive small/medium T-cell lymphoma (CD4+ SMTL), primary cutane-ous CD8-positive aggressive epidermotropic T-cell lympho-ma (CD8+ AECTCL), and primary cutaneous gamma/delta T-cell lymphoma (CGD-TCL). CD4+ SMTL manifests in most patients with a solitary nodule in the head and neck area and nodular infiltrates of CD4+ small to medium-sized lymphocytes with nuclear pleomorphism. The prognosis of this lymphoproliferation is excellent in patients with a soli-tary lesion, but may be impaired in patients with multifocal disease. Rapidly evolving erosive or necrotic plaques and nodules with an epidermotropic infiltrate of CD8+ atypi-cal lymphocytes are the hallmark of CD8+ AECTCL, which exhibits a poor prognosis. CGD-TCL displays a broad spectrum of clinical and histological manifestations with expression of the T-cell receptor gamma/delta chain as the common denominator and diagnostic marker. As most of other forms of PTL, CGD-TCL carries a poor prognosis. Despite the rarity of PTL NOS, clinicians as well as dermat-opathologists and pathologists should be familiar with these rare CTC, especially since most of these lymphomas exhibit an unfavourable prognosis. Immediate intense treatment with multiagent chemotherapy and hematopoietic stem cell transplantation is indicated in patients with PTL NOS. This review focuses on the clinicopathological aspects, the diag-

Corresponding author: W. Kempf, MD, Department of Dermatology, University Hospital Zürich,Kempf and Pfaltz,Histologic Diagnostics, Schaffhauserplatz 3,CH-8042 Zürich, Switzerland.E -mail: [email protected]


Lavoro: 4423-MDtitolo breve: CUTANEOUS PERIPHERAL T-CELL LYMPHOMAS, UNSPECIFIED/NOS AND RARE SUBTYPESprimo autore: KEMPFpagine: 553-62

KEMPF CUTANEOUS PERIPHERAL T-CELL LYMPHOMAS, UNSPECIFIED/NOS AND RARE SUBTYPES


lymphoma or in the provisional group of primary cutaneous small/medium-sized pleomorphic CTCL. Distinction between these two categories was based on the presence of more or less than 30% large neo-plastic T cells, because these two groups exhibited different prognosis. In following years, three entities among PTL, could be delineated based on their char-acteristic clinicopathological, immunophenotypic and prognostic features: Primary cutaneous CD4-positive small/medium pleomorphic T-cell lympho-ma (CD4+ SMTL), primary cutaneous CD8-positive aggressive epidermotropic T-cell lymphoma (CD8+ AECTCL), and primary cutaneous gamma/delta T-cell lymphoma (CGD-TCL). In the WHO-EORTC classification for primary cutaneous lymphomas, these three entities were listed as provisional entities and were separated out from PTL, unspecified. In the current WHO classification (4th edition, 2008), these three entities comprise the group of primary cutaneous peripheral T-cell lymphomas, rare subty-pes. For the remaining lymphomas which did not fit into either of these provisional entities or any other well-defined CTCL, the designation PTL, unspeci-fied was maintained in both the WHO-EORTC clas-sification as well as the WHO classification (4th edi-tion, 2008) (Table I).1-3 As other forms of primary cutaneous lymphomas, cutaneous PTL NOS arise in the skin and are restricted to the skin at the time of diagnosis and staging. History, detailed clinical ex-amination, clinicopathologic correlation and staging

examinations are indispensable elements in the diag-nostic work-up, since the histological presentation of PTL NOS alone does not allow final diagnosis due to an overlap of histopathological features with other CTCL entities. Despite the rarity of PTL NOS, cli-nicians as well as dermatopathologists and patholo-gists should be familiar with these CTCL forms, especially since most of these lymphoproliferations exhibit an impaired prognosis and therefore require immediate intense treatment. This review describes the clinicopathological features of PTL NOS and their biology.

Primary cutaneous CD4+ small/medium T-cell lymphoma

This T-cell lymphroproliferation is listed as a pro-visional entity within the group of PTL, in both the WHO (2008, 4th edition) and the WHO-EORTC classifications (2005).1-3 First reports of CD4+ small/medium T-cell lymphoma (SMTL) date back to the mid nineties of the last century when Friedman and coworkers reported a series of 11 cases of primary cutaneous pleomorphic small T-cell lymphomas and the Dutch lymphoma group reporting similar cases.4,

5 Although this lymphoma entity was originally con-sidered a rare form of CTCL, it turned out that CD4+ SMTL is in fact much more common. Larger series allowed to characterize the clinicopathologic pres-

Table I.—�Primary cutaneous peripheral t-cell lymphomas — rare subtypes and PTL unspecified/NOS

Entity Clinical features Histological features Immunphenotype Course and prognosis

Primary cutaneous CD4+ small- to medium T-cell lymphoma

Solitary nodule, rarely multiple nodules

Dense infiltrate of small to medium-sized pleomor-phic lymhocytes.

No or subtle epidermotro-pism

CD3+ CD4+ CD8-CD30-, PD-1 +

Indolent5-year survival rate:solitary or localized >90

%

Primary cutaneous CD8+ aggressive epidermo-tropic T-cell lymphoma

Erosive or ulcerating papules and nodules

Occasionally hyper-keratotic plaques

Ulceration, apoptotic keratinocytes, epidermo-tropic infiltrate of small to medium-sized atypical lymphocytes,

CD3+ CD4-CD8+,TIA-1+; CD30-, EBV-

Very aggressiveMedian survival: 32

months

Primary cutaneous gamma/delta T-cell lymphoma

Plaques and nodules with necrosis and ulceration

Epidermotropic and/or dermal and/or subcutane-ous infiltrates of medium-sized to large tumor cells with pleomorphic chroma-tin dense nuclei

CD3+ CD56+, TIA-1+,CD4-CD8-, betaF1 -,TCR-delta+y-ns

Very aggressiveMedian survival: 15

months

Cutaneous peripheral T-cell lymphoma, unspecified

Solitary or general-ized nodules

Cohesive nodular infiltrate of small / medium / large tumor cells with pleomor-phic or immunoblastic morphology

CD3+ CD4+ CD8-CD30-, TIA-1-

Aggressive5-year survival rate: 20%

CUTANEOUS PERIPHERAL T-CELL LYMPHOMAS, UNSPECIFIED/NOS AND RARE SUBTYPES KEMPF


be present in aggregations. In a subset of cases a few scattered CD30+ pleomorphic, large lymphocytes (24%) are present.6, 7 The proliferation rate of the small to medium-sized lymphocytes is 5-30%.6, 7 A monoclonal rearrangement of the T-cell receptor (TCR) gamma gene is found in at least 60 percent of the cases.6 Recent studies indicate that CD4+ SMTL represents a neoplastic proliferation of follicular T helper (TFH) cells based on the expression of CXCL-13 and PD-1.8

The differential diagnosis of CD4+ SMTL includes nodular T-cell pseudolymphoma (T-PSL), mycosis fungoides and secondary cutaneous infiltrates of nod-al T-cell non-Hodgkin lymphomas. The distinction of

entation in more detail.6 Clinically, this lymphopro-liferation affects both genders equally (male:female ratio of approx. 1:1) and appears most frequently in the fifth decade with a median age of 53 years at diagnosis (range 3-90 years). The characteristic and most frequent clinical manifestation occurring in 75% of the patients is a nodule of up to 3 cm in diameter arising on the head and neck area, espe-cially on the face (Figure 1).6 Ulceration does usu-ally not occur. In a minority of the patients, multiple nodules arise at different body regions. In contrast to mycosis fungoides (MF), the nodules develop without preceding patches and plaques. Histologi-cally the dense nodular infiltrates are predominantly composed of small and medium-sized lymphocytes (Figure 2).4, 6 The small and medium-sized lym-phocytes display chromatin-dense nuclei with slight to moderate nuclear pleomorphism and a small cyto-plasmic rim (Figure 3). Epidermotropism may be fo-cally present, although not a prominent feature, but folliculotropism can occasionally be seen. There is classically an admixture of eosinophils, clusters of plasma cells and a variable number of macrophages occasionally forming small non-necrotizing granu-lomas. Phenotypical analysis reveals expression of CD3 and CD4 by nearly all small and medium-sized lymphocytes. There is no loss of CD5. Small CD8-positive lymphocytes account for 5 up to 40% of the lymphocytes. There is a remarkably high number of CD20+ B-cells, which are found in all cases and may

Figure 1.—�Primary cutaneous CD4+ small/medium-sized T-cell lymphoma: erythematous nodule on the nose.

Figure 2.—�Primary cutaneous CD4+ small/medium-sized T-cell lymphoma: dense lymphocytic infiltrate extending throughout the entire dermis.

Figure 3.—�Primary cutaneous CD4+ small/medium-sized T-cell lymphoma: small to medium-sized lymphocytes with slight nu-clear pleomorphism.



clinical and histological features with CD4+ SMTL, but express a CD8 phenotype have been reported. These lymphoproliferations occur on the ear and on the face, but also in extrafacial sites, especially on the legs.14-16 These CD8+ SMTL share biologi-cal features of CD4+ SMTL and show a favourable prognosis particularly in the solitary form.

These data suggest that there is a phenotypically (CD4+ or CD8+) heterogeneous group of small to medium-sized lymphoproliferative disorders, which share clinical and prognostic features. For this group, we propose the term primary cutaneous small to me-dium-sized lymphoproliferative disorders (CD4+ or CD8+).

Recently, primary cutaneous follicular helper T-cell lymphoma was described as a new subtype of cutaneous T-cell lymphoma based on expression of follicular helper T-cells (TFH) markers (CD10, Bcl-6, PD-1, CXCL13, and ICOS) (17). The mean age of the patients was 61 years (range, 33-78 years). The disease manifested in four of five patients with mul-tiple papules, plaques, and nodules predominating on the trunk and the head and in one patient with a nodular plaque on the face. In contrast to CD4+ SMTL, the infiltrates in primary cutaneous follicu-lar helper T-cell lymphoma are mostly composed of medium- to large-sized atypical T-cells. Whereas the patient with localized disease was successfully treated with radiotherapy, the disease was resistant to multiagent chemotherapy in patients with multifocal lesions. Further studies are needed to clarify the rela-tionship of this new CTCL subtype to CD4+ SMTL with which it shares some histologic and phenotypic features.

Primary cutaneous CD8+ aggressive epidermotropic T-cell lymphoma

In 1999 Berti et al. described a series of patients with rapidly evolving erosive and necrotic plaques and tumors and epidermotropic infiltrates of atypi-cal CD8 positive lymphocytes.18 It is a rare and ag-gressive form of CD8+ CTCL with less than 50 cases reported in the literature to date. Men are more com-monly affected (male: female ratio approximately 2:1). The age at diagnosis ranges from 19 to 83 years with most patients being in their fifth to seventh dec-ade. The disease presents with widespread erosive patches, plaques, or papules and nodules undergoing

CD4+ SMTL, particularly in its multifocal form, from mycosis fungoides is based on the presence of patches and plaques in MF.1-3 Due to an overlap in the cellular composition and the phenotype, differential diagnosis also includes secondary cutaneous infiltrates of an-gioimmunoblastic T-cell lymphoma (AITL) in which tumor cells also express PD-1 and other TFH markers.9 Staging examinations are essential, in particular in patients presenting with mutiple rapidly growing skin lesions of CD4+ SMTL, to exclude secondary cuta-neous involvement by AITL. The most challenging differential diagnosis is nodular T-PSL due to a sig-nificant overlap of clinical and histological features. In individual cases, the distinction can be impossible. Neither the composition of the infiltrate nor the cyto-morphology of the lymphocytes allow differentiating between CD4+ SMTL and nodular T-PSL. Detection of clonal T-cells has been reported in both disorders and therefore T-cell clonality does not serve as a relia-ble discriminating diagnostic marker. The data by Ro-driguez Pinilla and coworkers indicating that PD-1 is expressed by small to medium-sized T-cells in CD4+ SMTL, but to a lesser extent in nodular T-PSL was considered to be a helpful as a distinctive diagnostic marker.8 Unfortunately a recent study could not con-firm these results and reported PD-1 expression in all cases of CD4+ SMTL as well as in nodular T-PSL.7 Based on the overlap in clinical, histologic and pheno-typic markers some experts support the concept that most cases classified as CD4+ SMTL are identical to nodular T-PSL, at least when presenting as a solitary lesion.7 As a consequence, the term “cutaneous nodu-lar proliferation of pleomorphic T-lymphocytes of un-determined significance” has been proposed.6

The data on course and prognosis of CD4+ SMTL reported so far in the literature demonstrate a favour-able prognosis with 5-year-survival rates of more than 90% when presenting as solitary or localized lesions.4, 6, 10-13 There is however a subset of cases which display an impaired prognosis especially in patients with rapidly evolving large tumors or nod-ules (> 5cm in diameter), a higher proliferation rate of tumor cells, and a lower number of infiltrating CD8 positive cells.11 In patients with solitary or lo-calized lesions, surgical excision and/or radiotherapy is the first-line therapy, whereas patients with multi-focal lesions should be treated more intensively by chemotherapy.

Remarkably, nodular lymphoproliferations com-posed of small to medium-sized T-cells, which share



tures may be seen.18 The tumor cells display a CD3+, CD4- CD8+, CD45RA+, CD45RO-, TIA-1+, beta F1+ phenotype.18-20 CD30 is negative in all cases (E. Berti, personal communication). No association with Epstein-Barr virus is found. Clonal rearrangement of TCR genes can be demonstrated in most cases. A CD2- CD7+ phenotype, as well as CD15 expression, appear to be associated with a more aggressive course.21, 22 Recently diagnostic criteria for CD8+ AECTCL have been proposed including short history, widespread lesions, epidermotropism of pleomorphic T-cells, a CD8+/CD4- phenotype and an aggressive course as essential diagnostic elements.20 Differential diagnosis includes CD8+ MF which also displays a band-like and epidermotropic infiltrate, but only very few or no necrotic keratinocytes and no epidermal necrosis.23 In contrast to CD8+ AETCL, CD8+ MF manifests clinically with hyper- or hypopigmented patches and plaques, but no erosions, necroses or ulcerations, and has the same favourable prognosis as classic MF.24,

25 Pagetoid reticulosis may present with histologcal features similar or identical to CD8+ AECTCL, but is by definition characterized by a solitary lesion. The recently described LyP type D can be distinguished by clinical manifestation with self-regressing and re-current papules and small nodules.26 Moreover lym-phocytes in LyP type D express CD30 in 90% of the cases and lack expression of CD45RA.26 PLEVA with expression of CD8 and CD30 represents a further chal-lenging differential diagnosis, since numerous necrot-

necrosis and ulceration (Figure 4).18 Less commonly hyperkeratotic patches and plaques and annular le-sions are observed. Histologically, there is a promi-nent epidermotropism of small-medium or medium-large lymphocytes with pleomorphic chromatin-dense nuclei (Figures 5, 6). Apoptotic keratinocytes, epider-mal necrosis and spongiosis with blister formation are commonly found (Figure 5). Extension of the lym-phocytic infiltrates into deeper dermis and subcutis, angiocentric growth and destruction of adnexal struc-

Figure 4.—�Primary cutaneous CD8+ aggressive epidermotropic cutaneous T-cell lymphoma: partly necrotic and crusted plaques (by courtesy of Prof. Dr. D. Metze, MD, Germany).

Figure 6.—�Primary cutaneous CD8+ aggressive epidermotropic cutaneous T-cell lymphoma: epidermotropic infiltrate of small and medium-sized atypical lymphocytes.

Figure 5.—�Primary cutaneous CD8+ aggressive epidermotropic cutaneous T-cell lymphoma: epidermotropic infiltrate of small and medium-sized atypical lymphocytes. Numerous necrotic ke-ratinocytes are present.



come involved, whereas lymph nodes, spleen and bone marrow are usually spared. The patients often have B symptoms including night sweats, fever and weight loss. The disease may be accompagnied by a hemophagocytic syndrome, especially in patients with the subcutaneous form of CGD-TCL. Histolog-ically, epidermotropic (pagetoid), dermal (diffuse or nodular) and subcutaneous infiltrates can be found. In subcutaneous CGD-TCL the predominantly sub-cutaneous infiltrates are often accompanied by a dermal and an epidermotropic component.35, 36 Epi-dermal and dermal involvement, however, may also occur in predominantely subcutaneous CGD-TCL. In the subcutaneous form, a predominantely lobu-lar infiltrate is found. Tumor cells are medium-sized to large with irregular chromatin-dense or vesicu-lar nuclei (Figure 8).1 Angioinvasive infiltrates and necrosis are common.37 The tumor cells exhibit a CD2+ CD3+ CD56+ phenotype and are often CD4- CD8- double-negative. Cytotoxic molecules (TIA-1, granzyme B, perforin) are expressed. In addition, expression of CD7 may be found. As defining cri-terion, the tumor cells in CGD-TCL express TCR γ/δ (TCRd+) but lack TCR α/β (βF1). Nowadays ex-pression of TCRd can be demonstrated also on for-malin fixed, paraffin embedded tissues. Molecular studies reveal clonal rearrangement of TCR gamma or delta genes. Isochromosome 7q is a common genetic abnormality. EBV is generally negative in

ic keratinocytes may be present.27 Lack of significant nuclear atypia of the CD8+ CD30+ lymphocytes and the clinical presentation allow distinction of PLEVA from CD8+ AECTCL. Febrile ulcero-necrotic pityria-sis lichenoides et varioliformis acuta (PLEVA), how-ever, may simulate clinically as well as histologically CD8+ AECTCL, but does not express CD45RA and has no loss of T-cell antigens. Transition from febrile ulcero-necrotic PLEVA to CD8+ AECTCL, however, has been reported.28

In contrast to MF, CD8+ AECTCL shows a short history with rapidly progressing skin lesions and spread to extracutaneous sites, particularly oral mucosa, visceral organs (lung) and central nerv-ous system. The lymph nodes are usually not in-volved. The disease runs an aggressive course with a median survival of less than 32 months and a 5-year-survival rate of 18%.18, 20, 29 Only a small subset of patients appears to have a less aggressive course.30 Multiagent chemotherapy is not effec-tive and followed by rapid relapse. Combination of chemotherapy and autologous stem cell trans-plantation may be a promising strategy to control the disease.20

Primary cutaneous γ/δ+ T-cell lymphoma

Primary cutaneous γ/δ+ T-cell lymphoma (CGD-TCL) is a rare lymphoma which is characterized by a clonal proliferation of mature activated g/d T-cells expressing the γ/δ T-cell receptor and a cytotoxic phenotype.31 γ/δ T-cells represent a small subset ac-counting for less than 5% of all lymphocytes in the peripheral blood, are part of innate immunity and play an important role in immunosurveillance. When activated, γδ T cells appear large and granular, and can display one or more natural killer (NK) associ-ated surface molecules (CD56, CD16, CD57).32 In cutaneous inflammatory and neoplastic lymphocytic infiltrates, γ/δ T-cells are only exceptionally found.33 Neoplastic proliferations of γ/δ T-cells comprise hepatosplenic and primary cutaneous forms.34 Ap-proximately 50 cases of primary cutaneous CGD-TCL have been reported to date. The disease affects patients of all ages without gender predilection. The clinical manifestation includes generalized of-ten necrotic or ulcerated papules, plaques or nod-ules (Figure 7).35 Involvement of oral mucosa is common, and other extranodal sites may often be-

Figure 7.—�Primary cutaneous gamma/delta-positive T-cell lym-phoma: ulcerated nodular lesion on the right arm (by courtesy of Dr. B. Pfeiff, MD, Germany).



stem cells transplantation may provide a promising strategy.43-45 Remarkably, there are reports indicat-ing that forms of CGD-TCL with a less aggressive course exist, and that these forms of the disease can be controlled by UV-light treatment in combination with steroids, retinoids or methotrexate.46, 47

Primary cutaneous peripheral T-cell lymphoma, unspecified/NOS

There is a small number of CTCL which do not fit into any other well defined CTCL entity, as they do not fulfill clinico-pathological criteria of the above described rare subtypes of PTL or any other CTCL. Those cases have originally been referred to in the literature and in previous lymphoma classifications as cutaneous small/medium and medium/large pleo-morphic T-cell lymphoma based on the presence and number of large cells (more or less than 30%).10, 48 Only very few case series have been documented in the literature.10, 48 This form of PTL NOS or unspeci-fied affects adults and presents with solitary, grouped or disseminated nodules without preceding patches or plaques (Figure 9),10 but patients with solitary large ulceration have been reported.49 Histologically, the tumors are characterized by diffuse or nodular dense infiltrates composed of variably sized, mostly medi-um-sized to large lymphoid cells with pleomorphic nuclei and pale cytoplasm (Figure 10). Tumor cells may display an immunoblast-like morphology.10 Re-active cells such as eosinophils and plasma cells are

CGD-TCL, but isolated EBV-positive cases have been reported.38

Subcutaneous CGD-TCL has to be distinguished from subcutaneous panniculitis-like T-cell lympho-ma, which expresses a TCR α/β + phenotype and shows an indolent course with a favorable progno-sis.36 In contrast to subcutaneous CGD-TCL, the lymphocytic infiltrates in subcutaneous panniculitis-like T-cell lymphoma are almost exclusively restrict-ed to the subcutis. Differential diagnosis includes ex-tranodal NK/T-cell lymphoma, which is associated with EBV and displays a CD3ε+, CD56+ phenotype. In addition, the differential diagnosis also includes lupus panniculitis which displays lobular infiltrates of small lymphocytes lacking the nuclear atypia seen in CGD-TCL. Epidermotropic forms of CGD-TCL have to be distinguished from MF and its subtype pagetoid reticulosis by expression of TCRδ+.

The clinical course of CGD-TCL is usually ag-gressive with a median survival of 15 months and a 5-year-survival rate of 33%.39 The disease may be complicated by hemophagocytosis syndrome and production of large amounts of interferon γ.36,

40 Hemophagocytosis syndrome is defined by fe-ver, splenomegaly, cytopenia, hypertriglyceridemia and/or hypofibrinogenemia, elevated serum ferritin and CD25-positive cells and as well as evidence of hemophagocytic histiocytosis in bone marrow, spleen, or lymph nodes.41, 42 CGD-TCL responds poorly to multiagent chemotherapy. Hematopoietic

Figure 8.—�Primary cutaneous gamma/delta-positive T-cell lym-phoma: infiltrates of lymphocytes with enlarged chromatin-dense nuclei.

Figure 9.—�Cutaneous peripheral T-cell lymphoma, unspecified (NOS): nodular lesion on the trunk.



may account for the aggressive course of PTL NOS. Complete remission after chemotherapy and radio-therapy are usually of short duration and followed by relapses.10 Patients with solitary or localized skin lesions rapidly develop widedespread disease.

Conclusions

The term PTL NOS covers a group of phenoytpically and prognostically highly diverse lymphoproliferations. Therefore classification and treatment are complex and challenging. It remains a matter of debate whether the solitary form of CD4+ SMTL differs from nodular T-PSL, and whether the designation of CD4+ SMTL should be revised. From a practical point of view, cli-nicians should be aware of the impaired prognosis of multifocal CD4+ SMTL which requires more intense treatment. More detailed diagnostic criteria would fa-cilitate the diagnostic work-up of PTL NOS. Since the TNM staging system as outlined in its sixth version of the TNM Classification of Malignant Tumors (2002) did not sufficiently reflect the extent of cutaneous in-volvement (T stage),53 new TNM staging schemes for MF, SS as well as for other CL have been proposed.54, 55 The applicability and reproducibility of these new stag-ing schemes have still to be validated for PTL NOS.

Since most forms of PTL NOS are rare and have an aggressive course, early diagnosis and therapeu-tic intervention are important. Respecting the role of clinico-pathologic correlation in the diagnostic proc-ess and the steadily increasing number of new as well as emerging therapies for various forms of CL, the diagnostic work-up and the treatment of PTL NOS are recommended to be performed at specialized centers and by an expert panel including dermatolo-gists, dermatopathologists and hematopathologists.

Riassunto

Linfomi cutanei a cellule T periferiche, sottotipi non altri-menti specificati e rari: un gruppo eterogeneo di linfomi cutanei impegnativi

I linfomi cutanei a cellule T periferiche, non specificati/non altrimenti specificati (LCTP-NAS) costituiscono un gruppo di linfomi cutanei a cellule T (LCCT) eterogeneo dal punto di vista fenotipico e prognostico i quali non rientrano in nessun sottotipo di LCCT ben definito. Nella classificazio-ne WHO-EORTC, oltre che nella classificazione WHO, sono stati delineati tre sottotipi rari e provvisori di LCTP sulla base

present.50 Angiocentric infiltrates can be observed. Epidermotropism has been reported as a feature in a few cases.51 Tumor cells express CD2, CD3, CD5, but show loss of T-cell antigens such as CD7. They may be CD4 or CD8 positive or negative. A cytotoxic phenotype has been reported.48, 49, 51 By definition the tumor cells do not express CD30.1 Molecular biologic assays reveal a clonal rearrangement of TCR genes.

The differential diagnosis of PTL NOS or unspeci-fied includes transformation of MF, which is charac-terized by preceding patches and plaques. Primary or secondary cutaneous anaplastic large-cell lymphoma is defined by expression of CD30 by at least 75% of tu-mor cells whereas in PTL NOS CD30 is not expressed or only in a small subset of tumor cells (usually less than 30%). The phenotype of tumor cells allows to differentiate cases of extranodal NK/T-cell lymphoma (CD3ε+; CD56+; association with EBV) and gamma/delta T-cell lymphoma (TCRδ+). Especially in patients of Asian origin or from the Caribbean region, HTLV-1 or 2 associated adult T-cell lymphoma/leukemia has to be distinguished by serology and/or demonstration of the virus integrated into the host genome of tumor cells. Secondary cutaneous involvement by nodal PTL has to be excluded by staging examinations.

The prognosis of PTL NOS is poor with a 5-year-survival rate of less than 20 percent.1, 10, 52 Recent molecular studies revealed differences in chromo-somal alterations, expression of chemokine receptors and apoptotis regulators between PTL NOS and pri-mary cutaneous anaplastic large-cell lymphoma that

Figure 10.—�Cutaneous peripheral T-cell lymphoma, unspeci-fied (NOS): dense infiltrates of medium-sized to large cells with pleomorphic nuclei. Note: some cells have an immunoblast-like morphology.



7. Cetinozman F, Jansen PM, Willemze R. Expression of programmed death-1 in primary cutaneous CD4-positive small/medium-sized pleomorphic T-cell lymphoma, cutaneous pseudo-T-cell lymphoma, and other types of cutaneous T-cell lymphoma. Am J Surg Pathol 2012;36:109-16.

8. Rodriguez Pinilla SM, Roncador G, Rodriguez-Peralto JL, Mollejo M, Garcia JF, Montes-Moreno S et al. Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma expresses fol-licular T-cell markers. Am J Surg Pathol 2009;33:81-90.

9. Roncador G, Garcia Verdes-Montenegro JF, Tedoldi S, Paterson JC, Klapper W, Ballabio E et al. Expression of two markers of germinal center T cells (SAP and PD-1) in angioimmunoblastic T-cell lym-phoma. Haematologica 2007;92:1059-66.

10. Bekkenk MW, Vermeer MH, Jansen PM, van Marion AM, Cannin-ga-van Dijk MR, Kluin PM et al. Peripheral T-cell lymphomas un-specified presenting in the skin: analysis of prognostic factors in a group of 82 patients. Blood 2003;102(6):2213-9.

11. Garcia-Herrera A, Colomo L, Camos M, Carreras J, Balague O, Martinez A et al. Primary cutaneous small/medium CD4+ T-cell lymphomas: a heterogeneous group of tumors with different clin-icopathologic features and outcome. J Clin Oncol 2008;26:3364- 71.

12. Grogg KL, Jung S, Erickson LA, McClure RF, Dogan A. Primary cutaneous CD4-positive small/medium-sized pleomorphic T-cell lymphoma: a clonal T-cell lymphoproliferative disorder with indo-lent behavior. Mod Pathol 2008;21:708-15.

13. Williams VL, Torres-Cabala CA, Duvic M. Primary cutaneous small- to medium-sized CD4+ pleomorphic T-cell lymphoma: a retrospective case series and review of the provisional cutaneous lymphoma category. Am J Clin Dermatol 2011;12:389-401.

14. Petrella T, Maubec E, Cornillet-Lefebvre P, Willemze R, Pluot M, Durlach A et al. Indolent CD8-positive lymphoid proliferation of the ear: a distinct primary cutaneous T-cell lymphoma? Am J Surg Pathol 2007;31:1887-92.

15. Suchak R, O’Connor S, McNamara C, Robson A. Indolent CD8-positive lymphoid proliferation on the face: part of the spectrum of primary cutaneous small-/medium-sized pleomorphic T-cell lym-phoma or a distinct entity? J Cutan Pathol 2010;37:977-81.

16. Kempf W, Kazakov DV, Cozzio A, Kamarashev J, Kerl K, Plaza T et al. Primary cutaneous CD8+ small to medium-sized lymphoprolif-erative disorder in extrafacial sites–clinicopathological features and concepts on their classification. Am J Dermatopathol 2012; [Epub ahead of print].

17. Battistella M, Beylot-Barry M, Bachelez H, Rivet J, Vergier B, Ba-got M. Primary Cutaneous Follicular Helper T-cell Lymphoma: A New Subtype of Cutaneous T-cell Lymphoma Reported in a Series of 5 Cases. Arch Dermatol 2012;148:832-9.

18. Berti E, Tomasini D, Vermeer MH, Meijer CJ, Alessi E, Willemze R. Primary cutaneous CD8-positive epidermotropic cytotoxic T cell lymphomas. A distinct clinicopathological entity with an aggressive clinical behavior. Am J Pathol 1999;155:483-92.

19. Gormley RH, Hess SD, Anand D, Junkins-Hopkins J, Rook AH, Kim EJ. Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma. J Am Acad Dermatol 2010;62:300-7.

20. Nofal A, Abdel-Mawla MY, Assaf M, Salah E. Primary cutaneous aggressive epidermotropic CD8(+) T-cell lymphoma: Proposed di-agnostic criteria and therapeutic evaluation. J Am Acad Dermatol 2012;67:748-59.

21. Agnarsson BA, Vonderheid EC, Kadin ME. Cutaneous T cell lym-phoma with suppressor/cytotoxic (CD8) phenotype: identification of rapidly progressive and chronic subtypes. J Am Acad Dermatol 1990;22:569-77.

22. Yoshizawa N, Yagi H, Horibe T, Takigawa M, Sugiura M. Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma with a CD15(+)CD30(-) phenotype. Eur J Dermatol 2007;17:441-2.

23. Dummer R, Kamarashev J, Kempf W, Haffner AC, Hess-Schmid M, Burg G. Junctional CD8+ cutaneous lymphomas with nonaggres-

delle loro caratteristiche clinico-patologiche, immunofenoti-piche e prognostiche, i quali sono stati differenziati dal LCTP NAS: il linfoma cutaneo primario a cellule T medio-piccole CD4-positive (LCT-MP CD4+), il linfoma cutaneo primario aggressivo epidermotropo a cellule T CD8-positive (LCT-AE CD8+) e il linfoma cutaneo primario a cellule T gamma/delta (LCT-GD). Il LCT-MP CD4+ si manifesta nella mag-gior parte dei pazienti attraverso un nodulo solitario nell‘area di collo e testa e con infiltrati nodulari di linfociti CD4+ di di-mensioni medio-piccole con pleomorfismo nucleare. La pro-gnosi di tale linfoproliferazione è ottima in pazienti con lesio-ne solitaria ma potrebbe essere meno favorevole in pazienti con malattia multifocale. Le placche erosive o necrotiche in rapido sviluppo e i noduli con infiltrato epidermotropo di lin-fociti atipici CD8+ sono caratteristiche del LCT-AE CD8+ il quale presenta una prognosi infausta. Il LCT-GD presenta un ampio spettro di manifestazioni cliniche ed istologiche con l‘espressione della catena gamma/delta del recettore delle cellule T quale marcatore diagnostico e denominatore comune. Come la maggior parte delle altre forme di LCTP, il LCT-GD NAS presenta una prognosi infausta. Nonostante la rarità del LCTP NAS, i medici, i dermopatologi e i pato-logi dovrebbero conoscere bene tali rare forme di LCCT, dal momento che la maggior parte di tali linfomi presenta una prognosi sfavorevole. Il trattamento intensivo immediato con polichemioterapia e trapianto di cellule staminali ematopo-ietiche è indicato in pazienti con LCTP NAS. La presente review è incentrata sugli aspetti clinico-patologici, sui criteri diagnostici e sulla classificazione dei rari sottotipi di LCTP e LCTP NAS.Parole chiave: Linfoma a cellule T periferico, terapia - Linfociti T CD8 positivi - Prognosi - Pelle.

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50. Joly P, Vasseur E, Esteve E, Leibowitch M, Tilly H, Vaillant L et al. Primary cutaneous medium and large cell lymphomas other than mycosis fungoides. An immunohistological and follow-up study on 54 cases. French Study Group for Cutaneous Lymphomas. Br J Der-matol 1995;132:506-12.

51. Yamamoto M, Nakada T, Iijima M. Primary cutaneous T-cell lym-phoma, unspecified, exhibiting an aggressive clinical course and a cytotoxic phenotype. Int J Dermatol 2008;47:720-2.

52. Beljaards RC, Meijer CJ, Van der Putte SC, Hollema H, Geerts ML, Bezemer PD et al. Primary cutaneous T-cell lymphoma: clinico-pathological features and prognostic parameters of 35 cases other than mycosis fungoides and CD30-positive large cell lymphoma. J Pathol 1994;172:53-60.

53. UICC. TNM Classification of Malignant Tumors (ed sixth). New York: Wiley-Liss; 2002.

54. Kim YH, Willemze R, Pimpinelli N, Whittaker S, Olsen EA, Ranki A et al. TNM classification system for primary cutaneous lympho-mas other than mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Or-ganization of Research and Treatment of Cancer (EORTC). Blood 2007;110:479-84.

55. Olsen E, Vonderheid E, Pimpinelli N, Willemze R, Kim Y, Knobler R et al. Revisions to the staging and classification of mycosis fun-goides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood 2007;110:1713-22.

sive clinical behavior: a CD8+ variant of mycosis fungoides? Arch Dermatol 2002;138:199-203.

24. El-Shabrawi-Caelen L, Cerroni L, Medeiros LJ, McCalmont TH. Hypopigmented mycosis fungoides: frequent expression of a CD8+ T-cell phenotype. Am J Surg Pathol 2002;26:450-7.

25. Nikolaou VA, Papadavid E, Katsambas A, Stratigos AJ, Marinos L, Anagnostou D et al. Clinical characteristics and course of CD8+ cy-totoxic variant of mycosis fungoides: a case series of seven patients. Br J Dermatol 2009;161:826-30.

26. Saggini A, Gulia A, Argenyi Z, Fink-Puches R, Lissia A, Magana M et al. A variant of lymphomatoid papulosis simulating primary cuta-neous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma. Description of 9 cases. Am J Surg Pathol 2010;34:1168-75.

27. Kempf W, Kazakov DV, Palmedo G, Fraitag S, Schaerer L, Kut-zner H. Pityriasis lichenoides et varioliformis acuta with numerous CD30+ cells: a variant mimicking lymphomatoid papulosis and oth-er cutaneous lymphomas. A clinicopathologic, immunohistochemi-cal, and molecular biological study of 13 cases. Am J Surg Pathol 2012;36:1021-9.

28. Cozzio A, Hafner J, Kempf W, Haffner A, Palmedo G, Michaelis S et al. Febrile ulceronecrotic Mucha-Habermann disease with clon-ality: a cutaneous T-cell lymphoma entity? J Am Acad Dermatol 2004;51:1014-7.

29. Santucci M, Pimpinelli N, Massi D, Kadin ME, Meijer CJ, Muller-Hermelink HK et al. Cytotoxic/natural killer cell cutaneous lym-phomas. Cancer 2003;97:610-27.

30. Massone C, Chott A, Metze D, Kerl K, Citarella L, Vale E et al. Subcutaneous, blastic natural killer (NK), NK/T-cell, and other cy-totoxic lymphomas of the skin: a morphologic, immunophenotypic, and molecular study of 50 patients. Am J Surg Pathol 2004;28:719-35.

31. Gaulard P, Berti E, Willemze R, Jaffe E. Primary cutaneous periph-eral T-cell lymphomas, rare subtypes. WHO Classification of Tu-mors of the Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2008. p. 302-5.

32. Havran WL, Boismenu R. Activation and function of gamma delta T cells. Curr Opin Immunol 1994;6:442-6.

33. Hocker TL, Wada DA, El-Azhary R, Gibson LE. Expression of T-cell receptor-gammadelta in normal human skin, inflammatory der-matoses and mycosis fungoides. J Cutan Pathol 2012;39:419-24.

34. Tripodo C, Iannitto E, Florena AM, Pucillo CE, Piccaluga PP, Fran-co V et al. Gamma-delta T-cell lymphomas. Nat Rev Clin Oncol 2009;6:707-17.

35. Berti E, Cerri A, Cavicchini S, Delia D, Soligo D, Alessi E et al. Primary cutaneous gamma/delta T-cell lymphoma presenting as dis-seminated pagetoid reticulosis. J Invest Dermatol 1991;96:718-23.

36. Willemze R, Jansen PM, Cerroni L, Berti E, Santucci M, Assaf C et al. Subcutaneous panniculitis-like T-cell lymphoma: definition, classification, and prognostic factors: an EORTC Cutaneous Lym-phoma Group Study of 83 cases. Blood 2008;111:838-45.

37. Arnulf B, Copie-Bergman C, Delfau-Larue MH, Lavergne-Slove A, Bosq J, Wechsler J et al. Nonhepatosplenic gammadelta T-cell lymphoma: a subset of cytotoxic lymphomas with mucosal or skin localization. Blood 1998;91:1723-31.

38. Caudron A, Bouaziz JD, Battistella M, Sibon D, Lok C, Leclech C et al. Two atypical cases of cutaneous gamma/delta T-cell lympho-mas. Dermatology 2011;222:297-303.

39. Toro JR, Liewehr DJ, Pabby N, Sorbara L, Raffeld M, Steinberg SM et al. Gamma-delta T-cell phenotype is associated with sig-nificantly decreased survival in cutaneous T-cell lymphoma. Blood 2003;101:3407-12.

40. Burg G, Dummer R, Wilhelm M, Nestle F, Ott MM, Feller A et al.


cal nitrogen mustard or psoralen plus ultraviolet A therapy.4 Treatment of advanced stage disease includes systemic therapy with α-interferon, bex-arotene, photopheresis, denileukin diftitox, vorino-stat, cytotoxic chemotherapy, or combined modality therapies. However, in most patients, responses are seldom durable. This has led to a need to develop new therapies with targeted mechanisms of action and acceptable safety profiles. While no regimen has been proven to prolong survival in advanced stages, immunomodulatory regimens should be used initially to reduce the need for cytotoxic therapies. In more advanced stages of disease, treatment ef-forts should strive for palliation and improvement of quality of life. With many new therapies and strate-gies on the horizon, the future looks promising for CTCL patients. Unfortunately, other than allogeneic transplant, there are no potential curative therapies for CTCL. Clinical trials are currently underway to identify new therapies to improve quality of life for patients, and researchers are hard at work to iden-tify novel pathways and genes for prognostication and as targets for therapies. Importantly, collabora-tive clinical trials to enhance rates of accrual need to be conducted, and improved interpretation of data via standardizing end points and response cri-teria should be an emphasis. Recently, the Interna-tional Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous Lymphoma Consor-

“L. e A. Seràgnoli” Institute of Hematology University of Bologna, Bologna, Italy


P. L. ZINZANI

Advanced/aggressive CTCL: improving the efficacy of treatment

Treatment regimens of patients with cutaneous T-cell lym-phoma (CTCL) vary widely based on clinician preference and patient tolerance. Skin directed therapies are recom-mended for patients with early stage IA and IB MF, with combinations used in refractory cases. While no regimen has been proven to prolong survival in advanced stages, immu-nomodulatory regimens should be used initially to reduce the need for cytotoxic therapies. In more advanced stages of disease, treatment efforts should strive for palliation and improvement of quality of life. With many new therapies and strategies on the horizon, the future looks promising for CTCL patients.Key words: Lymphoma, T-cell, cutaneous - Mycosis fungoides - Drugs, investigational.

Cutaneous T-cell lymphoma (CTCL) is a rare group of mature T-cell lymphomas primarily

presenting in the skin. Between 2000 and 3000 new cases of CTCL occur in the US each year, with my-cosis fungoides (MF) being the predominant sub-type.1 Skin manifestations of MF include patches, plaques, tumors, and erythroderma. MF is catego-rized as limited stage by plaques or patches limited to the skin (IA, IB, and IIA) and advanced stage by cutaneous tumors and involvement of the blood, lymph nodes, bone marrow, or visceral organs (IIB to IVB).2 Sezary syndrome (SS), the leukemic vari-ant of MF, is characterized by generalized erythro-derma and abnormal lymphoid cells in the blood.3 Patients with limited stage disease frequently have an indolent clinical course and may be effectively treated with skin-directed therapies, including topi-

Autore di contatto: P. L. Zinzani, “L. e A. Seràgnoli” Institute of He-matology, University of Bologna, Bologna, Italy


Lavoro: 4419-MDtitolo breve: ADVANCED/AGGRESSIVE CTCLprimo autore: ZINZANIpagine: 563-71

ZINZANI ADVANCED/AGGRESSIVE CTCL


tium (USCLC), and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer (EORTC) met to develop consensus guidelines to facilitate collaboration on clinical trials.5 These proposed guidelines consist of: recommendations for standardizing general protocol design; a scoring system for assessing tumor burden in skin, lymph nodes, blood, and viscera; definition of response in skin, nodes, blood, and viscera; a com-posite global response score; and a definition of end points. Although these guidelines were generated by consensus panels, they have not been prospectively or retrospectively validated through analysis of large patient cohorts.

Current and innovative therapies

Biological treatments

Recent research has reevaluated the efficacy of oral bexarotene. Previous studies had reported re-sponse rates of 54% in early-stage CTCL and 45% in advanced-stage CTCL patients when given oral monotherapy with bexarotene.6 A recent study from the United Kingdom validated the use of bexarotene for refractory and advanced-stage MF and SS. They demonstrated an intention-to-treat response of 46% with an overall response of 65% (13 out of 20) in those who tolerated a month of therapy. Bexarotene has been used in combination with PUVA plus inter-feron alfa, with extracorporeal photopheresis (ECP) alone, with ECP and interferon, and with ECP and interferon/PUVA.7

Denilkeukin diftitox

Denileukin diftitox is a chimeric fusion protein composed of interleukin-2 (IL2) and the diphtheria toxin A chain. Upon engaging the IL2 receptor on malignant T-cells, the drug is internalized and the diphtheria toxin is cleaved from the fusion protein, released into the cytosol to inhibit protein synthesis, and causes cell death. Another potential mechanism for denileukin diftitox activity is the depletion of Tregs,8 which are typically CD25bright. Denileukin diftitox received US Food and Drug Administration (FDA) approval following completion of a pivotal phase III trial using 9 or 18 μg/kg/d in 71 patients with relapsed or refractory CTCL.9 The ORR was

30% (20% PR, 10% CR) with a median duration of 6.9 months (range, 2.7-46.1 months) without a sta-tistical difference between the two doses. A follow-up study demonstrated significant improvements in self-rated overall quality of life, skin appearance and pruritus severity.10 The toxicity of denileukin diftitox can be significant and includes fever, rigors, fatigue, peripheral oedema, diarrhoea, anorexia, myalgia, hypoalbuminemia and hepatic transaminitis.

Histone deacetylase inhibitors (HDACi)

Epigenetic modulation is an important mechanism of regulation in gene expression. Histone deacetyla-se inhibition increases acetylation of lysine residues that form the octomeric histone core of chromatin, thereby decreasing the ability of the histones to bind to DNA. This decreased binding allows chromatin expansion, permitting transcription of the tumor suppressor genes. However, HDACi affect acetyla-tion globally and may have wider effects on various cellular functions. There are currently 18 different HDACi that can be divided into four families, de-pending on the inhibitory spectrum displayed. Two of these agents, vorinostat and romidepsin, were re-cently approved by the US FDA for use in patients with CTCL;11, 12 other two agents, belinostat and panobinostat are quite active in CTCL.

Vorinostat

Vorinostat (suberoylanilide hydroxamic acid, Zolinza®) is the first HDACi approved by the US FDA in October 2006 for cutaneous manifestations of CTCL in patients with progressive, persistent, or recurrent disease on or following two systemic thera-pies. In CTCL, a Phase 2 trial of vorinostat in the set-ting of refractory disease demonstrated a PR in 8 of 33 patients.13 Pruritus relief was observed in almost 50% of patients. A larger Phase IIb trial with 74 ad-vanced stage patients showed an ORR of 29.7% and a time to progression of 4.9 months overall.11 The most common drug-related side effects observed during clinical trials included fatigue, GI symptoms (nausea, vomiting, diarrhea), hematologic (especial-ly thrombocytopenia and anemia), dysgeusia, ano-rexia, weight loss and spasms. Thromboembolism was reported in 5% of patients and corrected QT in-terval prolongation was reported albeit of no clinical relevance. The ease of schedule, route of administra-

ADVANCED/AGGRESSIVE CTCL ZINZANI


The median duration of the response was 273 days (range, 48-469+). Pruritus relief was noted in 7 out of 14 patients. Of interest median time to response and relief of pruritus was short of 16 days. Overall in both study arms the drug was well tolerated and most adverse events were only grade 1/2 (nausea, fatigue, constipation, diarrhea, and vomiting).

Panobinostat

Panobinostat (LH589) is a novel pan-HDACi un-der investigation. A Phase I study in 15 patients with primarily AML showed transient improvements in disease with a major dose-limiting toxicity of pro-longation of the QT interval.18 In a Phase I study in CTCL, panobinostat was well tolerated and 2 of 10 patients showed complete response.19 The most common adverse events include diarrhoea, thrombo-cytopenia, and fatigue.

Monoclonal antibodies

Anti-CD52 (Alemtuzumab)

Alemtuzumab (Campath-1H), is a humanized monoclonal antibody that recognizes the CD52 cell surface antigen. It is thought to mediate its effects through antibody-dependent cellular cytotoxicity and activation of complement-dependent cytolysis; however it may also cause apoptosis without comple-ment activation.20 CD52 is also variably expressed on tumour cells in MF/SS.21 Numerous studies dem-onstrate that alemtuzumab is active in CTCL.22-26 In 22 patients with advanced MF/SS treated with sin-gle agent alemtuzumab administered intravenously at 30 mg for up to 12 weeks, there was an ORR of 55% (32% CR and 23% PR). Efficacy was higher in patients with early stage MF and peripheral blood involvement.22 To reduce opportunistic infections, a trial using a lower dose of alemtuzumab (10 mg three times a week for 4 weeks) showed clinical ac-tivity in 10 pretreated T-cell lymphomas (6 PTCL-not otherwise specified and 4 MF) with an ORR of 60% and 20% of CRs (the CR rate was higher (33%) in the PTCL group).23 A favourable experience com-bining the low dose and the subcutaneous (SQ) ad-ministration of single agent alemtuzumab has been recently reported in CTCL.25 The ORR was 85.7% with a 21.4% CR and a disease-free survival (DFS) of 12 months after a median follow-up of 16 months.

tion and the low toxicity profile of vorinostat led to evaluation of combination therapies. Vorinostat is a very promising agent in the treatment of CTCL and is currently in multiple clinical trials exploring its combination with other agents such as bortezomib, lenalidomide and combination chemotherapy.

Romidespin

Romidepsin (depsipeptide, FK-228, Istodax®) is a cyclic peptide that selectively inhibits histone deacetylase isotypes 1, 2, 4 and 6. Romidepsin, like other HDACi, was shown to induce cell cycle arrest in both G1 and G2/M phases of DNA replication and to trigger apoptosis in several cell lines.14 Generally, romidepsin is well tolerated; common side-effects include fatigue, nausea, vomiting, and transient thrombocytopenia and neutropenia.15 An initial re-port demonstrated PR in three patients with CTCL and a CR in one patient with PTCL.16 These studies demonstrated the sensitivity of T-cell lymphomas to HDACi. In a multi-institutional Phase II trial of dep-sipeptide (14 mg/m2 on days 1, 8 and 15 of a 28-day cycle) in patients refractory to multiple prior thera-pies with CTCL and 62 with advanced disease, the ORR was 34%.12 The median duration of response (DOR) was 13.7 months and the maximum DOR as of data cut-off was >63 months. Adverse events were generally mild, including nausea, fatigue, thrombo-cytopenia and anemia.

Belinostat

Belinostat (PXD101) is a hydroxamate pan-his-tone deacetylase inhibitor (inhibits class I, II and IV HDACs) which demonstrates broad anti-neoplastic activity in vitro with half-maximal inhibitory con-centration IC50 in CTCL cell lines in micromolar range. A multicenter phase II trial by Pohlman et al. evaluated the activity of belinostat in patients with PTCL or CTCL who had failed 1 prior systemic therapy. Belinostat (1000 mg/m2) was administered as a 30-min IV infusion on days 1-5 of a 3 week cy-cle.17 Twenty nine patients in the CTCL arm (includ-ing 15 MF, 7 SS, 5 non-MF/SS and 2 unclassified) were enrolled with majority (55%) having stage IV disease and were treated for a median of 2 cycles (range, 1-6). Four responses were observed (14%) with 2 CR (anaplastic large cell lymphoma and MF), 2 PR (MF and SS) and 16 stable disease (SD).



with many partial responses.31-33 A phase II trial of 13 patients (eight with PTCL, five with CTCL) dem-onstrated one CR and eight PR using gemcitabine 1200 mg/m2.34 A larger prospective phase II trial in previously treated MF (30 patients) and PTCL (14 patients) demonstrated five CR and 26 PR.32 A phase II trial as frontline therapy in 32 CTCL patients with MF, PTCL or SS showed response with seven achieving CR and 17 achieving a PR (total response rate of 75%) with a very modest toxicity.33 Another Phase II trial, employing gemcitabine at 1000 mg/m2 on the same schedule as monotherapy in CTCL, demonstrated a comparable ORR (68%) in 25 pa-tients with CTCL.31

Pentostatin is a purine analog and showed promise in early, smaller studies of CTCL.35 In a Phase I/II trial, pentostatin was given intravenously for 3 days on a 21-day cycle in 24 patients with, on average, three prior therapies;36 17 patients had either a PR or CR, with an ORR of 71%. A subsequent phase I/II trial with 42 patients demonstrated an ORR 54.8%.37 The median duration of response was 4.3 months.

Pegylated doxorubicin is an anthracycline topoi-somerase inhibitor that works by altering the DNA structure within tumor cells (and other rapidly divid-ing cells) triggering apoptosis. The pegylated version consists of doxorubicin encapsulated in liposomes, which allows selective accumulation of the drug in the tumor vascular bed. The pegylation induces re-duced clearance by the mononuclear phagocyte sys-tem, and decreases the risk of cardiotoxicity while preserving the antitumor efficacy.38, 39 Pegylated li-posomal doxorubicin (Doxil) at a dose of 20 mg/m2 monthly was first studied in CTCL in a phase I/II trial with 10 patients, where the best response was CR in 6 patients and a PR in two patients with an 80% ORR.40 A subsequent multicenter phase I/II study at varying doses of Doxil at 20-40 mg/m2 in 34 patients with CTCL showed that 15 patients achieved CR and 15 patients achieved PR for an ORR 88.2%.41 Another recent phase II trial enrolled 19 patients with ad-vanced/refractory CTCL.42 Dummer et al. conducted the EORTC 21012, phase II multicenter trial of PLD in 49 steroid naive relapsed and refractory advanced MF patients that demonstrated a RR of 40.8% (20 of 29) including 6% CR (N.=3) and 34.7% PR (N.=17).43 The drug was considered safe for administration with the following ≥ grade 3 toxicity: 2% cardiac toxic-ity, allergy (2%), and 4% constitutional symptoms. No severe hematological toxicity or infections were

Furthermore, alemtuzumab was safely administered subcutaneously to five elderly patients, three with SS with durable response (18-28+ months).26

Anti-CD4 (Zanolimumab)

CD4 belongs to the immunoglobulin superfamily and acts as a co-receptor of TCR (T-cell receptor). It is normally expressed in helper T-cells, regulatory T-cells, macrophages, monocytes and dendritic cells and highly expressed by T-cell malignancies includ-ing PTCL and CTCL. Different monoclonal anti-bodies against T-cell antigens have been developed. One of the more promising anti-CD4 antibodies is zanolimumab, a human IgG1 mAb, against CD4.27 CD4 is a major histocompatibility complex class II co-receptor expressed on T cells, and less on mono-cytes, macrophages, and LC. CD4 is retained on the malignant T cells, and is an ideal antigen to target. Zanolimumab showed encouraging findings in both early-stage CTCL and late stage, treatment-refrac-tory CTCL.28 Currently, zanolimumab remains in clinical development in both CTCL and peripheral T-cell lymphoma (PTCL).

Chemotherapy

Neither single agent nor multiagent therapy is curative in MF. Additionally, single or multiagent chemotherapy results in a higher incidence of trans-formation to large cell lymphoma, which carries a worse prognosis than the original diagnosis.29 Be-cause ORR and disease free survival are generally higher after combination therapy, single agent chem-otherapy is rarely used. However, use of multiagent chemotherapy results in increased immunosuppres-sion and higher risk of serious infections, leading to death in a majority of patients who develop these complications.25 A number of single agent chemo-therapeutic agents have been reported to be effective in CTCL. For example, gemcitabine (2′, 2′-difluor-odeoxycytidine), is a pyrimidine nucleoside analog with antitumor cytotoxic activity. It is metabolized intracellularly to its active metabolites gemcitabine diphosphate and triphosphate; the triphosphate com-ponent gets incorporated into DNA, causing inhibi-tion of DNA synthesis and induction of apoptosis.30 It is widely used in the treatment of patients with MF or SS, though there are limited published data of effi-cacy. Overall response rates range from 65% to 73%,



demonstrates a higher affinity for reduced folate car-rier-1 (RFC-1) compared to other antifolates, allow-ing it to selectively accumulate in tumor cells. The polyglutamylation of the drug ensures its retention inside the cancer cell. It interferes with dihydrofolate reductase, which affects synthesis of deoxythymidine and the purine DNA nucleotides. This leads to arrest of the cell cycle and thus its cytotoxic effects.50, 51 A Phase I/II trial of pralatrexate in patients with lym-phoma 52 demonstrated efficacy in aggressive T-cell lymphomas, achieving lasting complete responses (up to 16 months). Analysis of 12 patients with re-fractory transformed MF in the PROPEL study dem-onstrated a 58% ORR using International Workshop Criteria.53 The significant activity observed in this group led to the dose finding multicenter study that initially enrolled 31 patients with relapsed/refractory MF, SS and primary cutaneous anaplastic large cell lymphoma into 6 cohorts at varying dose and sched-ule and established the optimal dose and schedule as 15 mg/m2 weekly for 3 out of 4 weeks based on grade 3 mucositis.54 Based on the mSWAT score, an ORR of 43% was observed at the above stated opti-mal dose. This highlighted promising activity of this agent and the toxicity profile suggested that it could be given for prolonged time periods to sustain re-sponses. Toxicity was mild and consisted of grade 1 and 2 adverse events included fatigue (34%), mu-cositis (28%), nausea and edema (24%), epistaxis (21%), pyrexia (17%), and anemia (14%). A phase II trial of pralatrexate in combination with bexarotene in relapsed/refractory CTCL is ongoing.

Nucleoside analogs

Forodesine (BCX-177; immucillin H) is a pu-rine nucleoside analogue that is a highly selective purine nucleoside phosphorylase (PNP) inhibitor at nanomolar levels. By blocking PNP, forodesine leads to increased levels of deoxyguanosine and de-oxyguanosine triphosphate in T cells to inhibit T cell proliferation.55, 56 In a phase I dose-ranging study, 13 CTCL (MF and SS) patients were treated with intravenous forodesine at various doses in a 3-week cycle, leading to three CR, 1 PR and six SD with an excellent safety and tolerability profile. An oral formulation of forodesine was evaluated in a Phase I/II multi-centre dose escalation study in refractory CTCL patients using 80 mg/m2 once daily.57 The objective response was 53.6% with two CR, 13 PR

seen. Temozolomide is an oral imidazotetrazine de-ritivative of dacarbazine that induces DNA damage by methylating nucleotide bases, specifically at the O6-position of guanine.44 Subsequently, base pair mismatch occurs resulting in cytotoxic and mutagen-ic DNA adducts.44 The efficacy of temozolomide is dependent on o6-methylguanine-DNA methyltrans-ferase (MGMT) activity in addition to the level of mismatch repair. High MGMT activity and defects of DNA mismatch repair have been associated with re-sistance to temozolomide treatment.45 Temozolomide shows potential in CTCL based on the observation that malignant CD4+ T lymphocytes in patients with CTCL show low levels of MGMT, rendering them particularly sensitive to this methylator. In a recent phase II multicenter trial, twenty-six patients with ad-vanced CTCL (stages IB-IVB) were given daily doses of 200 mg/m2 for 5 days, for a total dose of 1,000 mg/m2 every 28 days, which constituted one cycle. The overall response rate was 27%, including two com-plete remissions (8%) and five partial remissions (19%). Median disease-free survival was 4 months, while the median overall survival was 24 months.44 Enzastaurin is a novel oral protein kinase C (PKC) inhibitor that plays a role in cell survival, growth factor response, proliferation and angiogenesis. In vitro studies demonstrated apoptotic activity in two CTCL cell lines (HH and Hut-78) mediated via the AKT signaling and caspase pathways which led to its phase I trial in patients with advanced malignan-cies that established the MTD at 525 mg orally.46, 47 Querfeld et al. conducted the phase II multicenter trial of enzastaurin in patients with relapsed/refrac-tory MF (IB-IVB) and SS.48 Twenty-five patients were enrolled and 1 PR was observed in 1 MF patient with an ORR of 5% by composite response evalua-tion. There were no CR. Although 17 patients with MF and 4 patients with SS had SD, the median time to progression was only 78 days in MF patients and 44 days in SS patients. Accrual was terminated early due to lack of response. About 25% of the enrolled patients had meaningful pruritus relief. The authors concluded that it might be worth combining enzas-taurin with other active agents to enhance its efficacy given its favorable toxicity profile.

Antifolate antagonist

Pralatrexate is a novel targeted antifolate that af-fects the reduced folate carrier in cells.49 Pralatrexate



20S proteasome inhibitor which causes minimal neuropathy and demonstrates promising activity in both bortezomib naïve and treated myeloma patients will be soon evaluated in T-cell lymphoma patients including CTCL.63-65 Currently, a phase I study of bortezomib and five-azacitidine for relapsed/refrac-tory T-cell lymphoma patients in ongoing in US.

Other new agents

Lenalidomide

Lenalidomide, a thalidomide analogue, is an im-munomodulatory agent with antiangiogenic and an-tineoplastic properties. Querfeld et al. reported an ORR of 28% in CTCL patients who received a me-dian of nine cycles of therapy consisting of 25 mg lenalidomide daily for 21 days of a 28-day cycle. Median TTR was 6 months. However, high toxicity symptoms (i.e., anemia, fatigue/malaise, skin burn-ing, pruritus, diarrhea, and lower leg edema) resulted in discontinuation of the drug in 40% of patients.66,

67 The study was amended to initiate patients at less than the maximum tolerated dose and escalate the dose as tolerated. Results of the entire phase Ib study are anticipated in the near future. Its role as mono-therapy in relapsed/refractory CTCL is further being assessed in a larger single institution phase II study using updated and standardized clinical endpoint criteria such as the mSWAT. Given the chronicity of CTCL treatment and its established potential in multiple myeloma, its role as a maintenance regi-men following systemic chemotherapy (gemcitabine or doxil) in advanced stage CTCL patients is being explored in a pivotal EORTC initiated phase III trial.

CCR4 antibody

KW-0761, a novel defucosylated humanized mon-oclonal antibody against CCR4, enhances antibody-dependent cellular cytotoxicity against malignant CTCL cells.68 In vitro studies of KW-0761 using MF or SS cell lines, primary MF and SS cells, and MF and SS mouse models showed not only significant antibody-dependent cellular cytotoxicity-mediated antitumor activity.

Phase I-II studies in adult T cell leukemia/lym-phoma have demonstrated an ORR of 31% and 50%, respectively, with minimal adverse events, consist-ing mainly of hematologic toxicities.69, 70 In US a

and 22 SD. Forodesine was well tolerated with nau-sea, dizziness, pruritus, fatigue, peripheral oedema and headache being the most frequent side effects. No opportunistic infections or cytomegalovirus re-activation were noted. Foreodesine defnitely shows acceptable tpòerability in patients with T-cell lym-phoma, is convenient in administration (oral) and has efficacy on estende duration of therapy (>12 months). A phase II study of forodesine monothera-py is ongoing in Japan in patients with relapsed and refractory CTCL patients.

Proteosome inhibitors

Bortezomib is a selective, reversible inhibitor that affects NF-κB activity by preventing the degradation of I-κB.58 Bortezomib has shown marked growth-in-hibitory activity, most extensively in multiple myelo-ma and non-Hodgkin, but studies have shown growth inhibition and induction of apoptosis also in malig-nant T-cells.59, 60 Zinzani et al. conducted a phase II trial of bortezomib (1.3 mg/m2 on days 1,4, 8, and 11 of a 21-day cycle) in 15 patients with relapsed/refrac-tory T-cell lymphoma, including PTCL (2 patients) or CTCL (10 patients all MF, no SS) with a reported ORR of 67% (with 2 CR and 6 PR).61 Among the CTCL patients who received a median of 6 cycles, there was a RR of 70% (7 of 10) to bortezomib. One CR (10%) lasted for more than 12 months and 6 PR (60%) were observed. The responses were also dura-ble in CTCL patients, ranging from 7 to 14 months even in patients with PR. The most common dose limiting side-effects with bortezomib are myelosup-pression (neutropenia and thrombocytopenia) and sensory neuropathy that occurred in 30-40% patients with myeloma and 50% of patients with CTCL treat-ed with bortezomib. Most patients had improvement or resolution of symptoms off drug.

A phase I study evaluated the use of standard dose CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) plus bortezomib in 13 patients with advanced, aggressive T-cell or NK/T-cell lympho-ma.62 No dose limiting toxicities were observed up to the maximal dose of bortezomib of 1.6 mg/m2. The CR rate was 62%. No data were provided for progression free or overall survival. Thus while ex-perience with the use of bortezomib in patients with CTCL is limited, the responses observed are durable and toxicity was acceptable. We anticipate that car-filzomib, the new selective irreversible epoxyketone



mated overall survival of 66% at 1 year and 54% at 3 years post-transplant.79 Allogeneic HCT avoids the risk of tumor contamination of the graft that could be present in an autologous HCT, but the benefit may be offset by the higher morbidity and mortality.74

Riassunto

Linfomi cutanei a cellule T avanzati/aggressivi: come miglio-rare l’efficacia del trttamento

I regimi di trattamento dei pazienti linfoma primitivo cutaneo di derivazione T linfocitaria variano notevolmente in funzione delle condizioni cliniche del paziente e dello status della malattia. Le terapie dirette sulla cute sono rac-comandate per i pazienti con micosi fungoide in stadio IA ed IB ed eventualmente in combinazione con altri farmaci nei casi refrattari. Al momento alcun regime terapeutico ha dimostrato un allungamento della sopravvivenza negli stadi avanzati; i regimi contenenti immunomodulanti do-vrebbero essere inizialmente utilizzati per ridurre la neces-sità di terapie citotossiche. Nell’ambito della terapia della malattia avanzata vi sono diversi nuovi farmaci innovativi che stanno mostrando promettenti risultati clinici.Parole chiave: Linfoma cutaneo a cellule T - Micosi fun-goide - Farmaci investigazionali.

References

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phase II is currently ongoing in patients with CTCL and the interim results show an ORR of 33% in MF patients and 47% in SS patients.71

Brentuximab vedotin (SGN-35)

SGN-35 is a drug-antibody conjugate in which SGN-30 is linked to monomethylauristatin E (MME), a synthetic antitubulin agent to enhance antitumor ac-tivity. After binding CD30, the conjugate is rapidly internalized inside the cell through CD30 receptor mediated endocytosis where it binds to tubulin and in-itiates cell cycle arrest. its promising activity in Hodg-kin lymphoma and anaplastic large cell lymphoma 72, 73 has led to several trials exploring the use of this agent in other CD30 expressing lymphomas including CTCL. MF and SS have variable expression of CD30 and hence a phase II single arm open label exploratory study evaluating the biologic effects of brentuximab vedotin in patients with CTCL is currently ongoing where patients regardless of their levels of CD30 ex-pression (low, intermediate and high based on immu-nohistochemical studies) will be enrolled.

Transplantation

Research related to the use of stem cell transplan-tation in CTCL patients has indicated that autologous hematopoietic stem cell transplants (HSCT) achieve a transient, short response, whereas allogeneic HCT has the potential for cure due to graft versus lymphoma effect.74, 75 Autologous SCT showed very limited ef-ficacy in most patients with CTCL, since 60% of these patients experienced an early relapse (median time to relapse was 120 days).76 In another study, relapse oc-curred in 50% of patients in less than 100 days.77 The CR of 58% in the first US study by Duvic et al.78 is similar to the 60.5% reported by Duarte et al.74 The re-lapse rate was shown to be lower after allogeneic SCT (39% of patients), however, time to relapse was shorter (50 days).78 Nevertheless, SCT carries a risk of sig-nificant toxicity and fatal complications, particularly in older patients. Careful patient selection and proper timing of SCT are critical factors in successful therapy. The first large multicenter analysis of allogeneic HCT for MF/SS patients by the European Group for Blood and Marrow Transplantation was reported recently. Sixty patients with MF and SS who received an allo-geneic HCT from a matched donor between 1997 and 2007 were analyzed, and the results showed an esti-



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Apart primary cutaneous CD30+ lymphoprolifera-tive disorders, which account for approximately 30% of CTCL, the relative frequency of the other, mostly aggressive subgroups is certainly low.1, 2

The treatment choices depend on clinical entity and disease stage. Early stage MF (I-IIA) 3 are treated with skin directed therapies (SDT) as first line ther-apy, whereas advanced stage MF (IIB-IV) and most peripheral T-cell lymphoma, not otherwise specified (PTL, NOS) 1 require radiotherapy (conventional and/or total skin electron beam irradiation, TSEBI) and/or systemic therapy, including single (monoCT) or multiagent chemotherapy (polyCT) and biologic response modifiers (BRM), including alpha-interfer-on (IFN-α) and oral bexarotene. Stage III MF and Sézary Syndrome (SS) have extracorporeal pho-tochemoterapy (ECP) as main indication.4-7 CTCL

1Division of Dermatology, Department of Critical Care Medicine and Surgery; University of Florence, Italy

2Division of DermatologyDepartment of Internal Medicine

Geriatrics and NephrologyUniversity of Bologna, Bologna, Italy

3Division of HematologyUniversity of Ancona, Ancona, Italy

4Division of DermatologyDepartment of Biomedical Sciences and Human Oncology

University of Turin, Turin, Italy 5Division of Hematology, Department of Critical Care

Medicine and SurgeryUniversity of Florence, Florence, Italy

6Division of Anatomic PathologyUniversity of Ancona, Ancona, Italy


C. DELFINO 1, V. GRANDI 1, A. PILERI 2, S. RUPOLI 3, P. QUAGLINO 4, R. ALTERINI 5

G. GOTERI 6, L. CANAFOGLIA 3, N. PIMPINELLI 1; FOR THE GRUPPO ITALIANO LINFOMI CUTANEI

Combination treatment in CTCL: the current role of bexarotene

Primary cutaneous T-cell lymphomas are a heterogeneous group of extranodal NH lymphomas primarily presenting in the skin without extracutaneos involvement at diagnosis. Treatment choices closely depend on clinic-pathologic entity and disease stage. Among available choices, oral bexarotene has shown efficacy and safety both in monotherapy and in as-sociation with other treatments, by virtue of its versatility and high synergism with alpha-interferon, photochemotherapy (PUVA), and chemotherapy. Moreover, when associated with a wise management of its side effects, bexarotene is well toler-ated if used in long-term administration, and it is therefore a good candidate to maintenance treatment after different induction therapies. Recently, the Gruppo Italiano Linfomi Cutanei (GILC) has started some pilot studies, with the aim to investigate bexarotene potential in association with PUVA and single agent chemotherapy (as pegylated liposomal doxo-rubicin and gemcitabine), and as consolidation/maintenance treatment. The preliminary results of GILC pilot studies confirm the good tolerability and safety of low-intermediate dose bexarotene, and its potential synergism with PUVA and chemotherapy. In addition, its use in consolidation/mainte-nance has proven efficacy in improving overall response rate.Key words: Lymphoma, T-cell, cutaneous - Skin diseases - Photochemotherapy.

Primary cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of extranodal NH lym-

phomas primarily presenting in the skin without extracutaneous involvement at diagnosis. Mycosis fungoides (MF) and its variants by far represent the most common CTCL subgroup, accounting for almost 50% of all primary cutaneous lymphomas.

Corresponding author: N. Pimpinelli, MD, Division of Dermatology, Department of Critical Care Medicine and Surgery, University of Flo-rence, piazza Indipendenza 11, 50129 Florence, Italy. E-mail [email protected]


Lavoro: 4464-MDtitolo breve: Combination treatment in CTCLprimo autore: DELFINOpagine: 573-9

DELFINO COMBINATION TREATMENT IN CTCL


usually respond to induction therapy, but extending progression-free survival (PFS) and overall survival (OS), as well as preserving quality of life (QoL), are still hot topics in the treatment of advanced stages. Different induction/maintenance strategies have been extensively reported in literature, although most data deal with retrospective analyses.8

In recent years, an increasing number of promis-ing, novel therapies has been developed, based on emerging categories of drugs, provided with a selec-tive mechanism of action. These drugs include mon-oclonal antibodies, immunotoxins, histone deacety-lase inhibitors (HDACI), lenalidomide, bortezomib, targeted antifolate pralatrexate, and others,6, 9, 10 ex-tensively dealt with in another article of this issue.

New horizons in the management of CTC: the role of bexarotene

Among BRMs, bexarotene is the first synthetic nuclear retinoid X receptor (RXR)-selective retin-oid (“rexinoid”) tested in humans. Bexarotene has an upfront position in the outline of CTCL treat-ment, and its oral formulation has been approved by the Food and Drug Administration (FDA) for the treatment of CTCL refractory to at least one prior systemic therapy in 1999. In Europe, its approval in 2001 (2004 in Italy) is restricted to refractory, advanced-stage CTCL.11, 12

Bexarotene is a versatile drug, that is thought to work by interfering with several mechanisms: ap-optosis,13 cell adhesion and trafficking,14 cell pro-liferation, angiogenesis and drug resistance.15 The reference dosage of bexarotene in monotherapy in clinical practice is 300 mg/m2/die, as emerged from phase II clinical trials in the USA.16, 17 Bexarotene side effects, which are closely related to its mecha-nism of action 7, 18, 19 are dose-dependent and revers-ible. Among them, hyperlipidemia (mostly hyper-triglyceridaemia) and central hypothyroidism are predictable and can be prevented by home adminis-tration of fibrates, statins and levothyroxine. Further side effects are hepatotoxicity, myelotocxicity (ane-mia, leucopenia), headache, and skin peeling syn-drome, this latter preventable by low dose desam-ethasone administration (1-2 mg/die per os) (Heald P, unpublished data). Tolerability is improved when bexarotene is first administrated at low dose, with following, gradual increase.12

Bexarotene has proved to be highly synergic with other systemic treatments, such as IFN-α,20-27 chem-otherapy (CT),22 phototherapy - either PUVA 12, 29-31 or narrowband UVB,32, 33 and ECP.34, 35 As a rule, association treatment including bexarotene allows dose reduction, and therefore reduction of toxicity.

Conventional chemotherapy

Conventional systemic chemotherapy in refrac-tory/relapsed early MF, in advanced MF, and in aggressive CTCL relies on a number of cytotoxic drugs, used as monotherapy or combined together in variable degree. MonoCT includes methotrexate, pegylated liposomal doxorubicin (peg-doxo), gem-citabine, pentostatin, fludarabine, chlorambucil. PolyCT schemes are usually CHOP (cyclophospha-mide, hydroxyldaunorubicin/adriamycin, oncovin/vincristine and prednisone) CHOP-like.36

As a rule, polyCT has not shown any real advan-tage as compared to monoCT;37, 38 e. g., the median response duration to polyCT is 5.7 months,8 with the cost of a considerable toxicity. Therefore, the European Organisation for Research and Treatment of Cancer (EORTC) recommendations 4 restrict their use to advanced disease stages, with palliative intent.

Current issues in CTCL treatment: improving progression free survival and overall survival

Bexarotene showed efficacy and tolerability in in-duction therapy due to its dose-dependent toxicity, and is expected to be of help in further improving overall response rate (ORR) and, even more impor-tant, progression free survival (PFS) in refractory/advanced CTCL. In two multicenter trials, Duvic reported that the response rate was 45% at a dose of 300 mg/m2 per day in monotherapy.16, 17 Following these trials, bexarotene was approved for all stages of CTCL by the FDA.39 The versatility of bexaro-tene and its sinergism with other treatments make it the ideal candidate in association schemes. Sev-eral association treatments have been tested.12 More often, the combination treatment achieved a RR greater than the RR obtained with bexarotene alone (median response rate: 67% versus 48% (Quaglino, data not published). Nevertheless, results were not

COMBINATION TREATMENT IN CTCL DELFINO


for a long period, as requested from a maintenance treatment. The use of bexarotene as maintenance treatment seemed to be promising yet in a small number of patients in early experiences.29 Data from more recent literature confirm previous observa-tions.54 As a consequence, the role of bexarotene in maintenance deserves investigation in larger stud-ies.

Gruppo Italiano Linfomi Cutanei’s ongoing pilot trials

In recent years, GILC has investigated bexarotene potential in some pilot, multicenter trials. Particu-larly, bexarotene has been evaluated in combination with PUVA and with CT (gemcitabine, Peg-doxo) with the aim to improve OS and PFS. Moreover, a multicenter, prospective, non-randomized trial is in progress, in order to evaluate the activity and safety of bexarotene as consolidation/maintenance therapy in CTCL patients (MF stage IIB-IV, SS, and PTCL, NOS) who achieved response or at least stabiliza-tion after one previous systemic treatment.

Bexarotene plus PUVA (study coordinator: S. Rupo-li, MD Ancona)

In this study, patients affected by either early or advanced stage MF, relapsed/refractory after/to at least one systemic treatment have been treated with the association low-dose bexarotene/PUVA. Primary endpoints were ORR, including complete response (CR) and partial response (PR), while secondary endpoints were safety and event free survival (EFS).

Schedule treatment consists of an induction phase with low dose bexarotene (150 mg/die), associated with adeguate prophilaxis of the known side ef-fects (preventive fenofibrate 200 mg/die one week prior the initiation of bexarotene and levothyroxine 50 μg/die at the initiation of bexarotene). Clinical response was assessed after two months: patients who achieved CR went on to the consolidation with PUVA, with gradual reduction of the frequen-cy of PUVA sessions (two/week for two months, one/week for two months, one/two weeks for two months, one/four weeks for four months), while pa-tients in very good partial response (VGPR), PR, MR (minimal response) and stable disease (SD) got an increasing dose of bexarotene, up to 300 mg/die.

always as expected. In a series of 22 patients af-fected by CTCL, ranging from stage IB to IV and treated with bexarotene plus IFN-α, the ORR was 39%, i.e., comparable to the response rate of bex-arotene alone.21

On the other hand, the association bexarotene-PUVA seemed to be promising since the early studies performed even at low doses of bexarotene on small groups of patients.28, 29, 40-43 Indeed, the PUVA/low-dose bexarotene combination provided an ORR of 75% (complete clinical response of 63%) in a group of 8 patients affected by CTCL, ranging from stage IA to IIB, relapsed/refractory after mul-tiple single agent regimens.28 Recently, final results from EORTC trial 21011 have been published.44 This multicenter, phase III randomized clinical tri-al compared two arm of patients affected by stage IA-IIB MF. One arm was treated with PUVA alone and one with beaxarotene plus PUVA. The best OR achieved were similar (71% in PUVA arm versus 77% in combination treatment arm). Nevertheless, the use of combination treatment seemed to be use-ful in order to reduce PUVA sessions and, therefore, UVA dose.

It should be stressed that the use of bexarotene plus IFN-α or PUVA has been extensively investi-gated, and it is based on past experiences of com-bination therapy with the “historical” retinoids isotretinoin and etretinate.45-48 On the contrary, the association bexarotene/CT has been investigated only recently.39, 49

Among cytotoxic drugs, gemcitabine and Peg-doxo have demonstrated activity in monotherapy at relatively lower doses with less myelosuppres-sion in comparison with other chemoterapics.6 Following such treatments ORR and median PFS have been 70% and 15 months for gemcitabine in front line,50 and 88% and 17 months 51 and 84.2% and 19 months 52 for peg-doxo. Accordingly, these monoCT schemes are quoted in literature as suitable candidates in combined therapeutical schemes 53 in-cluding bexarotene, even though published studies are mainly phase II.

The most exacting challenge in CTCL treatment is still the maintenance of ORR and the improve-ment of PFS. Up to date, only few studies have been investigated maintenance treatment options.8 Bexar-otene is effective, safe and can be self-administered at home; its side effects are well known and could be prevented. Accordingly, it could be administered



Treatment schedule consisted of induction with low dose bexarotene (150 mg/m2/die per os) in as-sociation with Peg-doxo (20 mg/m2 i.v. every four weeks) or with gemcitabine (1200 mg/m2 i.v. days 1.8 every 21), until best response. To follow, pa-tients continued with low dose bexarotene for six months. Bexarotene treatment was associated with adeguate prophilaxis of hypertriglyceridemia one week before bexarotene start-up, and of central hy-pothyroidism at start-up. Clinical response was re-assessed during every clinical examination before infusional treatment. Fifteen patients were enrolled: 11 patients (6 MF stage IIB and 5 PTL-NOS) were treated with bexarotene plus Peg-doxo, and more recently four patients (2 MF stage IIB and 2 PTL-NOS) were treated with bexarotene plus gemcitab-ine.

Under bexarotene/Peg-doxo combination, 9/11 patients achieved response (3 CR, 4 VGPR, 2 PR), and one patient obtained SD. One patient was dropped out because of an idiosyncrasic reaction to first Peg-doxo infusion, with a severe urticarial/angioedema syndrome. Palmoplantar erythrodyses-tesia (PPE) of Grade 1-2 was the only observed AE. Its management consisted of oral administration of pyridoxine (1000 UI/die.) and folate (7.5 mg/die). To date, median PFS and median OS are 15 months and 20 months, respectively.

In bexarotene/gemcitabine group, clinical re-sponse was obtained in 3/4 patients (1 VGPR, 2 PR); one patient reached SD. To date, median PFS and median OS are 8 months and 11 months, respec-tively. No AE were observed.

Overall, ORR was 80%. Noteworthy, PFS achieved with bexarotene in consolidation after induction with Peg-doxo was the same as that ob-tained with Peg-doxo alone. Prospective data in bexarotene/gemcitabine group are lacking, due to the short follow-up. Treatment schedule was over-all well tolerated (the idiosyncrasic reaction to Peg-doxo was non predictable).

Adjuvant bexarotene trial (study coordinator: Pi-etro Quaglino, MD, Turin)

Primary endpoint of this study was to evaluate ac-tivity and toxicity of low-doxe bexarotene as adju-vant therapy in patients affected by advanced stage MF and by aggressive CTCL (Sézary Syndrome, SS; PTCL, NOS) who achieved response or at least

To follow, patients who did not achieve at least PR left the study. Starting dose of PUVA was 1-2 J/cm2, afterwards increased up to 5-9 J/cm2 (depending on patients phototype.) at every follow-up visit. The to-tal time of bexarotene treatment was 12 months.

Twenty-two patients were enrolled in the study given written informed consent. Fifteen patients were affected by early stage MF (13 in stage IB, 2 in stage IIA), 7 were affected by advanced disease (3 stage IIB, 2 stage IIIA, 1 stage IIIB, 1 stage IVA). Low dose bexarotene/PUVA association obtained positive results both in early and in advanced stage MF already at the end of induction phase: ORR was 93% in early MF and 72% in advanced disease, glo-bal ORR was 86%. At the end of maintenance, CR in early stage patients was unchanged. In advanced stage disease, maintenance improved CR (14% ver-sus 0%). Accordingly, global CR achieved at the end of maintenance was higher than global CR at the end of induction.

Median time to maximum response (TTR) was 12 weeks in early stage patients and eight weeks in ad-vanced stage; event free survival was 33 months in both groups of patients

Bexarotene was well tolerated due to SE prophi-laxis and to the progressive dose increase in induc-tion: only one patient was dropped out because of triglycerids’ elevation; AE grade was low-moderate but two CK elevation of grade 3. No grade 4 AEs were observed.

Compared to recent data on similar experiences with bexarotene plus PUVA in early stage MF,44 GILC study achieved greater ORR and CR (ORR 87% versus 77% and CR 47% versus 31.3%, re-spectively). The results of the GILC study confirm the importance of maintenance treatment to consoli-date response rate.

Bexarotene plus Peg-doxo and bexarotene plus gem-citabine (study coordinator: Nicola Pimpinelli, MD, Florence)

The aim of this study was to investigate the role of low dose bexarotene plus Peg-doxo or plus gem-citabine in induction and maintenance in advanced/aggressive CTCL relapsing after monoCT alone. Primary endpoints were ORR and PFS. Clinical response, valued as the best clinical response ever reached, and overall survival (OS) were also as-sessed.



KEY MESSAGES

— In our hands, combination treatments achieved ORR greater than ORR obtained with monotherapy (global ORR=86% with bexarotene plus PUVA, ORR=80% with bexarotene plus Peg-doxo and gem-citabine)

— Combination schemes are equally safe as than single treatments in monotherapy. Furthermore, bex-arotene plus PUVA allowed to reduce PUVA overall dose, with a lower risk of UV induced carcinogen-esis.

— Adjuvant, low-dose bexarotene improved ORR obtained with previous, first line treatments..

— Only low to moderate toxicity was observed, and only a few patients suffered grade 3 AE.

— Proper prophylaxis of bexarotene SE is useful to reduce the number and grade of AE, as well as the risk of patients discontinuation.

Riassunto

Terapia combinata per i CTCL: ruolo attuale del bexaro-tene

I linfomi primitivi cutanei a cellule T (primary cuta-neous T-cell lymphomas, CTCL) costituiscono un gruppo eterogeneo di linfomi NH extranodali a primitiva localiz-zazione cutanea senza interessamento extracutaneo al mo-mento della diagnosi. La scelta terapeutica viene operata in base alla entità clinico-patologica e allo stadio di malattia. Tra le varie opzioni terapeutiche disponibili, il bexarotene per uso orale ha dimostrato efficacia e sicurezza sia in mo-noterapia che in associazione con altri trattamenti, in virtù della sua versatilità e dell’elevato sinergismo in combina-zione con interferone alfa, fotochemioterapia (photoche-motherapy, PUVA) e chemioterapia. Inoltre, se associato a un’attenta gestione degli effetti collaterali, bexarotene è ben tollerato anche in trattamenti a lungo termine, ed è quindi un valido candidato per l’impiego come farmaco di mantenimento dopo vari regimi di induzione. Recentemen-te il Gruppo Italiano Linfomi Cutanei ha intrapreso alcuni studi clinici pilota, con lo scopo di indagare le potenzialità di bexarotene sia in associazione a PUVA terapia e mo-nochemioterapia (doxorubicina pegilata liposomiale-Peg-doxo, gemcitabina), che come farmaco di consolidamento/mantenimento. I risultati preliminari degli studi pilota del GILC confermano l’elevata tollerabilità e sicurezza di be-xarotene e il suo potenziale sinergismo in associazione a PUVA-terapia e chemioterapia. L’impiego di bexarotene in consolidamento/mantenimento ha permesso inoltre di mi-gliorare la risposta globale.Parole chiave: Linfoma primitivo cutaneo a cellule T - Cute, malattie - Fotochemioterapia.

stabilization after radiotherapy and/or a first line of systemic treatment. Secondary endpoint was to in-vestigate the possible immunomodulating effect of low-dose bexarotene on lymphocytes.

Bexarotene treatmnent was started 6 weeks after the end of previous treatment, at the intial dose of 150 mg/die for two weeks (300 mg/die if BSA >2 m2), then increased to 300 mg/die (450 mg/die if BSA >2 m2) for six months. As in previous studies, SE prophylaxis consisted of fibrate administration 1 week before bexarotene start-up and of levothyrox-ine on start-up. Clinical evaluation was done every four weeks during the six months.

Forty patients were enrolled: 30 advanced MF, 5 SS and 5 P-TCL-NOS. Previous treatments were variegated: IFN-α ± PUVA, ECP, radiotherapy (TSEBI ± Boost), chemotherapy..

Before and after adjuvant bexarotene administra-tion, ORR was 65% (CR: 8%; PR: 57%) and 75% (CR:13%; PR 62%), respectively. Progression of disease (PD) was observed in 3% of patients. Me-dian relapse-free survival (PFS) was 25 months, and 2-year-PFS was 58%. Toxicity due to bexarotene was mostly low-moderate: grade 3 hypertriglyceri-demia and grade 3 central hypothyroidism were ob-served only in 3% patients; no grade 4 toxicity was observed. Nine patients (22.5%) needed to reduce bexarotene dose.

Bexarotene enhanced the expression of CD3/CD25 and CD3/CD8 in lymphocytes and modified the ratio CD3-CD16/CD56+ (which was increased).

In summary, adjuvant bexarotene improved ORR both increasing CR and PR, was well tolerated and - as in the other GILC studies described above, its side effects could be well prevented with a proper prophylaxis. Moreover, bexarotene certainly influ-enced the expression of some surface markers in lymphocytes.

Conclusions

GILC studies preliminary confirm the key role of bexarotene in association with other treatments (PUVA, monochemotherapy), both in induction and consolidation. Moreover, it seems to be very effective and well tolerated as adjuvant treatment in patients af-fected by advanced stage MF or by aggressive CTCL who achieved response after first line radiothesapy (TSEBI +/- boost) and/or systemic treatments.



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of hematopoietic and lymphoid neoplasms.2 Most CBCL (90% of the total) have an indolent course (very limited risk of extracutaneous spread) and an excellent prognosis (>90% 5-year survival). Two main clinico-pathologic entities are recognized, i.e. marginal zone lymphoma (MZL), otherwise defined as extranodal MZL, MALT (Mucosa-Associated Lymphoid Tissue) type,2 and follicle center lympho-ma (FCL). Conversely, smaller CBCL subsets (10%) are characterized by overall worse prognosis (55% 5-year survival): diffuse large B-cell lymphomas, leg type (DLBCL, LT), due to the clearcut predilection for the presentation in the lower limbs, and DLBCL, other 1 or NOS (not otherwise specified).2 The issue of diagnosis and treatment of primary cutaneous DL-BCL is dealt with elsewhere.

Diagnosis

The typical clinical presentation of marginal zone lymphoma (MZL) consists of erythematous to cian-otic papules, plaques and/or nodules, with usually

1Divisions of Pathological AnatomyDepartment of Critical Care Medicine and Surgery

University of Florence Medical School, Florence, Italy 2Division of Dermatology

Department of Critical Care Medicine and Surgery University of Florence Medical School, Florence, Italy

3Division of HematologyDepartment of Critical Care Medicine and Surgery

University of Florence Medical School, Florence, Italy


M. SANTUCCI 1, V. GRANDI 2, V. MAIO 1, C. DELFINO 2, R. ALTERINI 3, N. PIMPINELLI 2

Indolent cutaneous B-cell lymphoma: diagnosis and treatment 2012

Among primary cutaneous B-cell lymphomas (CBCL), two main clinico-pathologic entities are recognized, i.e. margin-al zone lymphoma (MZL), otherwise defined as extranodal MZL, MALT (Mucosa-Associated Lymphoid Tissue) type, and follicle center lymphoma (FCL). They are mostly charac-terized by indolent course (very limited risk of extracutane-ous spread), very good response to non-aggressive treatment (radiotherapy is the gold standard), and excellent prognosis (>90% 5-year survival overall). The clinical presentation of MZL and FCL slightly differ concerning site predilection (trunk and upper limbs in the former, head&neck and trunk in the latter) and frequency of cases with multiple, non-con-tiguous lesions (higher in MZL). Histologically, MZL and FCL share the multiphasic evolution of lesions, while some distinctive features are clues to diagnosis and differential diagnosis: CD5-/CD10-/bcl2+ phenotype of neoplastic cells, “colonization” of reactive lymphoid follicles by neoplastic cells, lymphoplasmacytoid and plasma cells at the periph-ery of nodular infiltrates in MZL; CD5-, CD10 +/-, bcl6+, MUM-1 neg, FOX-P1 neg, IRF4 neg, IgM neg phenotype of neoplastic cells (centrocytes), and neoplastic follicles (in early lesions) in FCL.Key words: Skin - Lymphoma, B-cell - Diagnosis - Therapeu-tics.

The spectrum of primary cutaneous B-cell lym-phomas (CBCL) has been clearly established

since the consensus classification of cutaneous lym-phomas from the World Health Organization and Eu-ropean Organization for the Research and Treatment of Cancer (WHO-EORTC classification),1 and more recently acknowledged in the WHO classification

Corresponding author: N. Pimpinelli, MD, Division of Dermatology, Department of Critical Care Medicine and Surgery, University of Flor-ence Medical School, Piazza Indipendenza 11, 50129 Florence, Italy. E-mail: [email protected]


Lavoro: 4449-MDtitolo breve: INDOLENT CUTANEOUS B-CELL LYMPHOMAprimo autore: SANTUCCIpagine: 581-8

SANTUCCI INDOLENT CUTANEOUS B-CELL LYMPHOMA


regional extension and predilection for the trunk and upper limbs (Figure 1). Less frequently, multifocal lesions in non-contiguous sites are characteristically found in some patients (Figure 2). Spontaneous, par-tial regression of biopsied lesions is relatively com-mon and worth of note. The association of MZL with Borrelia burgdorferi infection is reported has been reported in a minority of cases from Europe.1, 3, 4

Histologically,1-5 MZL is characterized by a nodu-lar to diffuse dermal infiltrate, with a typical mul-tiphasic variation according to the lesions’ age (over months to years) and size (Figure 3A). The infiltrate is composed of small-medium centrocyte-like cells (marginal zone cells) (Figure 3B), lymphoplasmacy-toid cells, and plasma cells, intermingled with nu-merous small lymphocytes (mostly T-cells) and rare large centroblast- and immunoblast-like cells. Fre-quent and characteristic findings are: reactive lym-phoid follicles, often characteristically surrounded and infiltrated by centrocyte-like neoplastic cells (so called “colonization” of lymphoid follicles) (Figure 4A); plasma cells and lymphoplasmacytoid cells at the periphery of the infiltrate, especially in the super-ficial dermis. An increased number of large cells (so-called “large transformed”) is not uncommon, espe-

cially in larger and older lesions, even though very rarely these cells represent over 50% of the infiltrat-ing cells. The phenotype of neoplastic cells (CD20+, CD79a+, bcl2+, CD5-, CD10-, bcl6-) and their light chain monoclonal restriction are additional, useful tools for the differential diagnosis with FCL, espe-cially when these cells “colonize” reactive lymphoid follicles (Figure 4B). Cells with plasma cell dif-ferentiation are characteristically CD20-, CD79a+, CD138+, cIg+. Their monoclonal restriction is a clue to diagnosis (Figure 5).

From a molecular standpoint, a monoclonal rear-rangement of immunoglobulin heavy chains is fre-quently found. MZL sometimes present the t(14:18)(q32:q21) translocation, yet not other features of gastric MALT lymphomas such as t(11:18)(q21:q21) or (1:14)(p22:q32) (1-6).

The typical clinical presentation of follicle center lymphoma (FCL) is with erythematous to cianotic plaques and/or nodules or tumours, with by far most-ly regional extension and predilection for the trunk and head and neck (Figure 6). Larger and thicker le-sions (nodules and/or tumours) are often character-Figure 1.—MZL: isolated plaque of the upper limb.

Figure 2.—MZL: multifocal lesions of the trunk.

INDOLENT CUTANEOUS B-CELL LYMPHOMA SANTUCCI


show a predominantly follicular or follicular and dif-fuse pattern, and contain a mixture of centrocytes (often large and multilobated, sometimes with spin-dle-cell features), relatively few centroblasts, and many small (reactive T) cells (Figure 8). Neoplas-tic follicles are composed of bcl6+ cells (Figure 9) with low proliferative index associated with CD21+/CD35+ dendritic cells, show indistinct margins, do not have macrophages with stainable bodies, and have a reduced or absent mantle zone. Progressing towards nodular and tumoural lesions, a diffuse pat-tern is the rule (Figure 10A), neoplastic cells grow in

istically surrounded by smaller and less infiltrated, inconspicuous ones (macules, patches and/or thin plaques), these latter often preceding of months or even years the rapid growth of nodules or tumours (Figure 7). Multifocal lesions in non-contiguous sites are much less frequent than in MZL.

Histologically, FCL are characterized by a nodu-lar to diffuse dermal infiltrate, with variations clearly related multiphasically with the age and growth rate of skin lesions 1, 2, 5, 7 and also with the site of onset (the follicular pattern is by far more frequent in scalp lesions than in trunk ones).8 Small and early lesions

Figure 3.—MZL: nodular and diffuse dermal infiltrate (A), characteristically composed by small-medium centrocyte-like cells (mar-ginal zone cells) (B).

Figure 4.—MZL: Reactive follicles (A), characteristically surrounded and infiltrated by bcl2+ neoplastic cells (B).

A

A

B

B



Figure 6.—FCL: variably sized, nodular lesions of the scalp. Figure 7.—FCL: large nodules and tumours on the back, typi-cally surrounded by slightly infiltrated patches, small nodules and plaques, some of which figurate. The onset of these latter lesions preceded by >3 years the rapid growth of large nodules and tu-mours.

A BFigure 5.—MZL: lymphoplasmacytoid cells and plasmacells (A) with monoclonal restriction for cIg lambda chains (B) at the periph-ery of the dermal infiltrate.

number and size, while - in contrast - small reactive T cells clearly decrease, showing a predominant of large follicle center cells: large centrocytes, mostly multilobated and sometimes with spindle-cell fea-tures,9 associated with scattered centroblasts and

immunoblasts never in cohesive aggregates (Figure 10B); follicular structures are only found as resid-



From the molecular standpoint,1, 2, 6 monoclonal rearrangement of immunoglobulin heavy chains is commonly found, with hypersomatic mutations of genes encoding the variable region of light and heavy chains, further supporting the follicle center origin of these lymphomas, similarly to their gene expression profile.12 In the majority of studies,1, 2,

6 FCL did not show the t(14:18) translocation and/or bcl2 gene rearrangement. Using interphase FISH, no evidence for translocations involving IGH, MYC, BCL6 or MALT1 loci was found.

Staging, prognosis, and therapy

The staging classification (TNM) system of cuta-neous lymphomas other that mycosis fungoides and Sézary syndrome, including CBCL, proposed by the International Society for Cutaneous Lymphomas (ISCL) and the EORTC Cutaneous Lymphoma Task Force in 2007 13 has the aim to integrate the iden-tification of clinico-pathologic entities 1, 2, 14 with a further prognostic tool, and to facilitate the choice of proper treatment. The efficacy of this TNM clas-sification in CBCL has been recently tested and vali-dated.15, 16

In MZL, despite a fair tendency for skin relapses (>30% patients), extracutaneous dissemination is ex-ceedingly rare and the prognosis is excellent, with a 5-year survival rate close to 100%.1, 2, 14 The treat-ment of choice in MZL 17 with localized lesions is

ual clusters of CD21+/CD35+ dendritic cells, and an intense stromal reaction is frequently found. The phenotype of the neoplastic cells (1,2,5) is CD20+, CD79a+, CD5-, CD10 +/- (positive especially in lesions with follicular pattern) (8), bcl6 +, bcl2-/+ (modest positivity in a minority of neoplastic cells), and MUM-1 neg (Figure 11), FOX-P1 neg, IRF4 neg, IgM neg.6, 10, 11 It should be highlighted that a positive staining for IgM is frequently found in FCL located on the legs, and has been associated with a worse prognosis.10, 11

Figure 9.—FCL: bcl6+ neoplastic follicle.

Figure 8.—FCL: early lesions, characterized by a nodular and diffuse dermal infiltrate (A) composed by centrocytes, centroblasts, and many reactive small lymphocytes (B).

A B



advisable in patients with solitary lesions. Intral-esional rituximab (anti-CD20 immunotoxin) is an alternative second line treatment (especially in the rare evenience of relapses within irradiated fields). In cases with multifocal lesions, the treatment with oral chlorambucil, especially in old patients, is the alternative to i.v. rituximab, possibly associated with COP- or CHOP-like multiagent chemotherapy.17 The combination with antibiotic therapy is recommended in cases with demonstrated association with Borrelia burgdorferi infection, while the possible efficacy of antibiotic therapy alone is still debated.3, 4, 17 Impor-tant, in case of recurrent lesions of mild severity, the strategy of watchful waiting - typical of other indo-lent lymphomas – is definitely acceptable.1, 2, 17

In FCL, despite a fair tendency for skin relapses (> 20%), the extracutaneous dissemination is rare and the prognosis is excellent, with a 5-year survival of >95%.1, 2, 14 The treatment of choice in FCL with lo-calized lesions is radiotherapy (15-50 Gy, according to lesions’ size) (Figure 12), without any distinction related to the histological pattern. Relapses, which

radiotherapy (15-40 Gy, according to lesions’ size), also in case of limited skin relapses (mostly out-side the irradiated fields). Surgical excision is also

Figure 10.—FCL: late lesions, characterized by a diffuse dermal infiltrate (A) composed by large, multilobated centrocytes with few, scattered “round cells” (centroblasts, immunoblasts) (B).

Figure 11.—FCL: late lesions. Large, neoplastic cells are typi-cally MUM-1 negative.

A

B



cutanea), ottima risposta a trattamento non aggressivo (la radioterapia è il trattamento d’elezione) e ottima prognosi (sopravvivenza a 5 anni >90%). Le caratteristiche differen-ziali delle due forme sono cliniche (predilezione di sede per tronco e arti superiori nel MZL, testa-collo e tronco nei FC; frequenza di casi con lesion multiple in sedi non contigue, più alta nei MZL) e immuno-istologiche (fenoti-po CD5-/CD10-/bcl2+ delle cellule neoplastiche con “co-lonizzazione” dei follicoli linfatici reattivi, cellule linfo-plasmocitoidi e plasmacellule alla periferia dell’infiltrato nei MZL; fenotipo CD5-, CD10 +/-, bcl6+, MUM-1 neg, FOX-P1 neg, IRF4 neg, IgM neg delle cellule neoplastiche -centrociti - e follicoli neoplastici, soprattutto nelle lesioni inziali, nei FCL).Parole chiave: Pelle - Linfoma a cellule B - Diagnosi - Trattamento.

References

1. Willemze R, Jaffe E, Burg G, Cerroni L, Berti E, Swerdlow SH et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005;105:3768-85.

2. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, editors. World Health Organization Classifi-cation of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2008.

3. Takino H, Li C, Hu S, Kuo TT, Geissinger E, Muller-Hermelink HK et al. Primary cutaneous marginal zone B-cell lymphoma: a mo-lecular and clinico-pathological study of cases from Asia, Germany and the United States. Modern Pathology 2008;21:1517-26.

4. Dalle S, Thomas L, Balme B, Dumoment C, Thieblemont C. Pri-mary cutaneous marginal zone lymphoma. 2010. Crit Rev Oncol Hematol 2010;74:156-62.

5. Santucci M, Pimpinelli N. Primary cutaneous B-cell lymphomas. Current concepts. I. Haematologica 2004;89:1360-71.

6. Pimpinelli N. New aspects in the biology of cutaneous B-cell lym-phomas. J Cutan Pathol 2006;33(Suppl 1):6-9.

7. Gulia A, Saggini A, Wiesner T, Fink-Puches R, Argenyi Z, Ferrara G et al. Clinicopathologic features of early lesions of primary cuta-neous follicle center lymphoma, diffuse type: implications for early diagnosis and treatment. J Am Acad Dermatol 2011;65:991-1000.

8. Cerroni L, Arzberger E, Pütz B, Höfler G, Metze D, Sander CA et al. Primary cutaneous follicular center cell lymphoma with follicu-lar growth pattern. Blood 2000;95:3922-8.

9. Cerroni L, El-Shabrawi-Caelen L, Pink-Fuches R, LeBoit PE, Kerl H. Cutaneous spindle-cell lymphoma: a morphologic variant of cutane-ous large B-cell lymphoma. Am J Dermatopathol 2000;22:299-309.

10. Koens L, Vermeer MH, Willemze R, Jansen PM. IgM expression on paraffin sections distinguishes primary cutaneous large B-cell lym-phoma, leg type from primary cutaneous follicle center lymphoma. Am J Surg Pathol 2010;34:1043-8.

11. Demirkesen C, Tüzüner N, Esen T, Lebe B, Özkal S. the expres-sion of IgM is helpful in the differentiation of primary cutaneous diffuse large B-cell lymphoma and follicle center lymphoma. Leuk Res 2011;35:1269-72.

12. Hoefnagel JJ, Dijkman R, Basso K, Jansen PM, Hallermann C, Willemze R et al. Distinct types of primary cutaneous large B-cell lymphoma identified by gene expression profiling. Blood 2005;105:3671-8.

13. Kim YH, Willemze R, Pimpinelli N, Whittaker S, Olsen EA, Ranki A et al. TNM classification system for primary cutaneous lympho-mas other than mycosis fungoides and Sezary syndrome: a proposal

have no adverse prognostic significance, can be suc-cessfully treated again with radiotherapy, especially if they occur outside the limits of the irradiation field (as mostly observed). Intralesional rituximab can be used as a second line treatment, especially in the rare evenience of relapses within irradiated fields. Only in patients with multifocal lesions (multiple >3 in non-contiguous sites) and/or particularly large le-sions and/or with multiple relapses, and of course in refractory patients and in those with extracutaneous spread, treatment with systemic multiagent chemo-therapy (CHOP-like) is recommended and indicat-ed.17 The association with rituximab (R-CHOP) is increasingly used, like in nodal FCL.17 Recently, the high rate of stable remissions obtained with pegylat-ed doxorubicin monochemotherapy, alone 18 or in association with rituximab (data not published), has been claimed.

Riassunto

Linfomi cutanei a cellule B indolenti: diagnosi e terapia 2012

Tra i linfomi primitivi cutanei a cellule B (cutaneous B-cell lymphpoma, CBCL) si riconoscono due più frequen-ti forme clinico-patologiche, definite come linfoma della zona marginale (MZL, altrimenti noto come MZL extra-nodale) e linfoma a cellule del centro follicolare (FCL). Queste due entità sono caratterizzate da decorso clinico indolente (con rischio molto limitato di diffusione extra-

Figure 12.—FCL: the back of the patient shown in Figure 7 after radiotherapy (limited field electron beam, 30 Gy),



16. Gerami P, Wickless SC, Rosen S, Kuzel TM, Ciurea A, Havey et al. Applying the new TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sezary Syndrome in primary cutaneous marginal zone lymphoma. J Am Acad Dermatol 2008;59:245-54.

17. Senff NJ, Noordijk AM, Kim YH, Bagot M, Berti E, Cerroni L et al. European Organization for Research and Treatment of Cancer and International Society for Cutaneous lymphoma consensus rec-ommendations for the management of cutaneous B-cell lymphoma. Blood 2008;112:1600-9.

18. Pulini S, Rupoli S, Goteri G, Pimpinelli N, Alterini R, Bettacchi A et al. Efficacy and safety of pegylated liposomal doxorubicin in pri-mary cutaneous B-cell lymphomas and comparison with the com-monly used therapies. Eur J Haematol 2009;82:184-93.

of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Task Force of the European Organization of research and Treatment of Cancer (EORTC). Blood 2007;110:479-84.

14. Zinzani PL, Quaglino P, Pimpinelli N, Berti E, Baliva G, Rupoli S et al. Italian Study Group for Cutaneous Lymphomas. Prognostic factors in primary cutaneous B-cell lymphoma: the Italian Study Group for Cutaneous Lymphomas. J Clin Oncol 2006;24:1376- 82.

15. Senff NJ, Willemze R. The applicability and prognostic value of the new TNM classification system for primary cutaneous lympho-mas other than mycosis fungoides and Sezary Syndrome: results on a large cohort of primary cutaneous B-cell lymphomas and com-parison with the system used by the Dutch Cutaneous Lymphoma Group. Br J Dermatol 2007;157:1205-11.


Primary cutaneous B-cell lymphoma (PCBCL) comprise about 25-30% of all primary cutaneous

lymphoma and less than 1% of all non Hodgkin lym-phomas.1, 2 PCBCL are a spectrum of B-cell lym-phoproliferative disorders that, by definition, arise primarily in the skin with no sign of extracutaneous spread for a long time or for the entire course of the disease.3 As like as in T-cell cutaneous lymphomas, a series of peculiar biological and clinical-prognos-tic features marks the difference between PCBCL in respect to their nodal/systemic counterparts that may affect the skin secondarily and usually require a much more aggressive therapeutic approach.

On this basis, the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer (EORTC) proposed a clas-sification devoted to primary cutaneous lymphomas only.4 A major advantage of this scheme was that it classifies the different entities according to their clinical behaviour, making the therapeutic approach easier. Around the same years, the WHO Classifica-tion of tumours of lymphoid tissues was also pub-lished.5 Although both the schemes shared a mod-

1Anatomic Pathology SectionDepartment of Molecular Pathology

University of Pavia and IRCCS Fondazione Policlinico “San Matteo”

Pavia, Italy 2Dermatology Section, Milano-Bicocca University

Milan, Italy 3Cà Granda Ospedale Maggiore Policlinico Foundation

Milan, Italy


M. PAULLI 1, M. LUCIONI 1, A. MAFFI 1, G. A. CROCI 1, M. NICOLA 1, E. BERTI 2, 3

Primary cutaneous diffuse large B-cell lymphoma (PCDLBCL), leg-type and other: an update on morphology and treatment

Primary cutaneous B-cell lymphoma (PCBCL) is an hetero-geneous group of lymphoproliferative disorders, which ac-count for 25-30% of all primary cutaneous lymphoma and include three main histotypes: 1) primary cutaneous mar-ginal zone B-cell lymphoma (PCMZL); 2) primary cutane-ous follicular center cell lymphoma (PCFCL); 3) primary cutaneous diffuse large B-cell lymphoma (DLBCL), leg type (PCDLBCL-LT). PCMZL and PCFCL are indolent lym-phomas, with an excellent prognosis despite an high rate of cutaneous recurrences; in contrast, PCDLBCL-LT is clini-cally more aggressive and usually requires to be treated with multi-agent chemotherapy and anti-CD20 monoclonal anti-bodies. PCDLBCL-LT histologically consists of large round cells (centroblasts and immunoblasts), is characterized by strong bcl-2 expression, in the absence of t(14;18) transloca-tion, and resembles the activated B-cell type of nodal DL-BCL. Recently, the term primary cutaneous DLBCL-other (PCDLBCL-O) has been proposed to include diffuse lym-phomas composed of large transformed B-cells that lack the typical features of PCDLBCL-LT and do not conform to the definition of PCFCL. Some clinical studies suggested that such cases have an indolent clinical course and may be treated in a conservative manner; however, data regarding the actual prognosis and clinical behaviour of these peculiar cases are still too limited. The spectrum of primary cutane-ous DLBCL also encompasses some rare morphological vari-ants, such as anaplastic or plasmablastic subtypes and T-cell rich B-cell lymphoma, and some recently described, exceed-ingly rare DLBCL subtypes, such as intravascular large B-cell lymphoma and EBV-associated large B-cell lymphoma of the elderly, which often present in the skin.

Key words: Lymphoma, T-cell, cutaneous - Molecular biol-ogy - Genetics.

Corresponding author: M. Paulli, Anatomic Pathology Section, De-partment of Molecular Pathology, University of Pavia, Policlinico San Matteo IRCCS Foundation, Via Forlanini 14, 27100 Pavia, Italy. E-mail: [email protected]


Lavoro: 4431-MDtitolo breve: PCDLBCL, LEG-TYPE AND OTHERprimo autore: PAULLIpagine: 589-601

PAULLI PCDLBCL, LEG-TYPE AND OTHER


ern approach in defining each entity on the basis of clinical, histopathological and immunomolecular-cytogenetic data, some controversies arose about the classification of cutaneous lymphomas, especially of PCBCL. The main differences concerned the defini-tion of primary cutaneous follicle center cell lympho-ma and the classification of diffuse large B-cell lym-phomas. Actually, the EORTC scheme recognized a separate entity, termed large B-cell lymphoma of the leg, characterized by centroblastic/immunoblastic histology and primary presentation on the leg.6

To reconcile disputes on these issues, a consen-sus was subsequently reached between representa-tives of the original EORTC and WHO groups on a new classification of cutaneous lymphomas, termed “WHO/EORCT Consensus Classification” for cuta-neous lymphomas.1, 7, 8 This redefinition of cutane-ous lymphomas gained wide acceptance and, more recently, most of the entities revised in the consen-sus classification merged into the 2008 update of the WHO Lymphoma Classification.9, 10

The 2008 WHO lymphoma classification of cu-taneous lymphomas recognizes three main types of PCBCL, which alone represent over 90% of PCBCL: 1) primary cutaneous marginal zone B-cell lympho-ma (PCMZL); 2) primary cutaneous follicular center cell lymphoma (PCFCL); 3) primary cutaneous dif-fuse large B-cell lymphoma, leg-type (PCDLBCL-LT). PCFCL, which is the most frequent cutaneous lymphoma, is morphologically defined on the basis of cytological features (presence of centrocytes), whereas its growth pattern can be variable, from follicular to follicular and diffuse to purely diffuse. PCFCL usually lacks bcl-2 expression and t(14;18) translocation and have a very favourable prognosis (5 year survival 95%).3, 9, 11

On the other hand, the term PCDLBCL-LT de-signs the spectrum of cutaneous B-cell lymphomas, almost exclusively made of large centroblast- and immunoblast-like cells, mostly expressing an acti-vated immunphenotype (bcl-2+, MUM-1+, bcl-6+/-). Although identification of this lymphoma subtype based on primary site of presentation has been debat-ed, clinically PCDLBCL-LT differs from PCFCL for incidence, age of onset (generally more advanced), predilection for some skin districts (lower limbs, thereafter the definition of the leg type subset) and less favourable outcome.3, 9, 11

In addition, the previous WHO-EORTC Consen-sus Classification also contained a category termed

primary cutaneous DLBCL-other (PCDLBCL-O), which includes an heterogeneous group of lympho-proliferative disorders that do not belong to the group of PCDLBCL-LT nor to the group of PCFCL.1, 8 This consensus classification may include rare clin-icopathological variants of PCDLBCL, with a pecu-liar morphology such as anaplastic or plasmablas-tic subtypes, intravascular large B-cell lymphoma, T-cell rich B-cell lymphoma 1, 8 and some recently described new entities such as EBV-associated large B-cell lymphoma of the elderly.9, 10

The recent advances in the classification, diag-nosis and prognosis of the three major entities of PCBCL have contributed to a better understanding and management of this disease.11 However, some controversies still remain, especially regarding the precise classification of PCDLBCL consisting of “pure” centroblast-like cells, with altered bcl-2 ex-pression and presenting at cutaneous sites other than the leg. Although many authors suggest to classify these cases under the single heading of PCFCL, based on the presence of at least some centrocytes and of a focal nodular/follicular growth pattern, this feeling does not appear to be adequately supported by clinico-pathologic studies, comparing these cases with PCFCL and PCDLBCL-LT.1, 8, 12, 13

Recent molecular genetic advances, mainly based on techniques of gene expression profiling (GEP), comparative genomic hybridization (CGH) and ar-ray-CGH provided a biological background to the current classification of PCBCL, revealing different molecular signatures and chromosomal imbalances in PCFCL and PCDLBCL-LT, the latter resembling the activated B-cell type of nodal DLBCL;14-17 at present, no definitive data are available regarding the molecular features of PCDLBCL-O that do not fit in the LT category.

Diagnostics

The diagnosis of cutaneous PCDLBCL requires the integration of pathologic and clinical data. The skin is often involved as a secondary site by aggressive nod-al/systemic B-cell lymphomas that are histologically and immunophenotypically indistinguishable from primary cutaneous forms. Accurate differentiation of primary PCDLBCL from secondary localizations of systemic large B cell lymphomas (usually bcl-2+) is only possible by means of staging procedures, which

PCDLBCL, LEG-TYPE AND OTHER PAULLI


ognized in the eighties as a subgroup of cutaneous follicular lymphoma with a somewhat different his-tology and a more aggressive clinical behaviour.22,

23 The term of primary cutaneous large B-cell lym-phoma of the leg was proposed in 1996 by Vermeer et al. and based on cytomorphologic features of lymphoma cells (centroblasts and immunoblasts), their phenotype (bcl-2 overexpression) and unusual predilection for lower limbs localization.24, 25 Under this name, it was included as a distinct subtype in the EORTC classification.4 Although delineation of this entity based on the site of presentation has been questioned, some recent clinicopathologic and ge-netic studies supported the idea that PCDLBCL of the leg represents a distinct entity from PCFCL.12-17 However, as it has been acknowledged by most au-thors that cases with similar morphology, immu-nophenotype and prognosis may arise at sites other than the leg and other types of PCBCL may present on the leg, EORTC/WHO Consensus Classification preferred the term of PCDLBCL, leg type, to encom-pass both lesions presenting on the leg and at other skin sites.1

PCDLBCL-LT represents about 1% of all primary cutaneous lymphomas and 5-10% of all primary cu-taneous B-cell lymphomas.1, 12, 26 It usually affects elderly patients with a peak in the 7th decade of life (average age: 78 years).24 Women are affected more often than males (M:F 1:3- 4).24 Some cases with clinicopathologic features consistent with PCDLB-CL-LT have been reported in immunodeficient pa-tients, following solid organ transplantation.27

In the vast majority of patients, lesions are located on the legs but presentation at other locations such as the trunk, the head-neck, and the upper extremities has been reported in 10-15% of cases.12,13,26 Usu-ally patients present with solitary or multiple, rap-idly growing red to violaceous nodular tumours of firm consistency, that can ulcerate or may show lym-phoedematous-sarcomatous appearance (Figure 1). Multiple disseminated or aggregated dome shaped tumours may be seen.13, 26, 28-31

Histologically, PCDLBCL-LT is characterized by a diffuse, non epidermotrophic, monomorphic, dense infiltrate, with a grenz zone, which involves the entire dermis, effaces adnexal structures and often extends to the subcutaneous tissue (Figure 2). The infiltrate usually consists almost exclusively of a monotonous population of large round cells, arranged in confluent sheets. Tumour cells have most commonly an im-

should include patient’s medical history in search of B symptoms (fever, night sweats, weight loss), physi-cal examination, blood-cell count, LDH level meas-urement, serum electrophoresis and radiologic stud-ies such as chest radiograph, computed tomographic scan with contrast enhancement, total body PET-CT and ultrasound sonography of enlarged superficial lymphnodes. At our centers, bone marrow biopsy is also included in staging procedures of PCBCL. When involvement of loco-regional lymph nodes is clini-cally suspected at disease onset or during its clinical course, surgical excision and histologic examination of the lymph node are recommended.

Pathologic diagnosis of PCDLBCL is based on growth pattern (follicular vs diffuse) and on cyto-morphologic, immunophenotypic and genotypic fea-tures of the neoplastic population.

A basic panel comprises antibodies against pan-B (CD19, CD20, CD22, CD79a, PAX5/BSAP) and pan-T (CD2, CD3, CD5, CD7) epitopes. Im-munophenotypic analysis of large B cell infiltrates should include bcl-2, B-cell histogenetic markers (CD10, bcl-6, MUM1 and CD138), CD30 and pro-liferation markers such as Mib1/Ki-67. Markers for dendritic cells (CD21, CD23 and CD35) are useful to highlight a residual follicular/nodular growth pat-tern, in order to differentiate PCDLBCL and PCFCL with predominance of large cells.18 In selected cases expression of heavy (IGM-IGA) and light chains im-munoglobulins must be also analysed.19 Cyclin D1 immunostaining may be useful to exclude the pos-sibility of a secondary localization of mantle cell lymphoma with blastic or pleomorphic morphology, mimicking PCDLBCL.20 In B-cell infiltrates with plasmacellular, plasmablastic and immunoblastic differentiation, in situ hybridization to detect Ep-stein-Barr Virus (EBV) RNA (EBERs) and immu-nostainings for HHV-8 related antigens are recom-mended.9 The search of t(14;18)(q32;q21) involving BCL-2 and IGH genes may be useful in the differen-tial diagnosis between a primary cutaneous lympho-ma and a secondary skin involvement by a nodal fol-licular lymphoma mainly consisting of large cells.21

Primary cutaneous diffuse large B-cell lymphoma, leg type

Within the group of primary PCDLBCL, this is the best defined category. This lymphoma was rec-



sponsible for bcl-2 overexpression in PCDLBCL-LT are still partially unknown. The t(14;18)(q32;q21) translocation, which causes bcl-2 protein overex-pression by fusion of the BCL-2 gene on chromo-some 18 and the immunoglobulin heavy chain IGH gene locus on chromosome 14, does not occur in PCDLBCL-LT.33 In some cases bcl-2 overexpres-sion may result from chromosomal amplification of the BCL-2 gene.34

B-cell histogenetic markers were investigated in PCDLBCL-LT in a previous study by Paulli et al., in which was observed that bcl-6 is expressed in most tumours, usually showing a weaker staining than the tumour cells in PCFCL.35 CD10 is usually absent whereas, in contrast to PCFCL, MUM1/IRF4 is strongly expressed.36-38 These features have been shown in nodal DLBCL to correlate with an activat-ed B-cell gene expression profile, which is usually predictive of a more aggressive clinical course.39-42 The expression of FOXP1 protein, a member of the FOX-P subfamily of transcription factors normally found in activated B-cells, was documented in the vast majority (82%) of PCDLBCL-LT, independent of gene alterations.38, 43

munoblastic appearance with large, round vesicular nuclei and a prominent centrally placed nucleolus. In some cases tumour cells resemble centroblasts, with large non-cleaved nuclei and nucleoli attached to the nuclear membrane; occasionally, anaplastic cells (bizarre, irregularly configured, usually with a broad cytoplasm) are seen. Mitotic figures as well as apoptotic tumour cells are frequently observed. A little stromal reaction and a minimal inflammatory component are usually found, the latter consisting of a few reactive T-cells, often confined to perivascular area. Follicular structures are lacking, as well as an identifiable CD21+ and/or CD35+ dendritic mesh-work.12, 13, 24-32

Tumour cells express B-cell associated markers (CD19, CD20, CD22 and CD79a). The over-expres-sion of bcl-2 is detected in about 90% of PCDLBCL-LT, independent of localization (leg vs non leg) and morphology (centroblastic vs immunoblastic).13 In the clinico-pathologic practice, the strong reactivity for bcl-2 is useful in the differential diagnosis be-tween PCDLBCL and PCFCL with prevalence of large cells, the latter usually lacking bcl-2 expres-sion.1, 3, 7, 9 However, the molecular mechanisms re-

Figure 1.—Primary cutaneous B cell lymphoma, leg type, clinical presentation: A) typical leg distribution of red-violaceous nodules; B) nodules present a confluent grow pattern; C) skin ulceration can be found.



Figure 2.—Primary cutaneous diffuse large B-cell lymphoma, leg type: A) diffuse dermal infiltrate sparing the epidermis (HE 10x); B) yumor cell exhibiting immunoblastic features (Giemsa 40X); C) lymphoma population comprises sometimes centroblastic cells; the mitotic index is usually high (HE 40x); D) tumor cells show strong expression of bcl-2 (SABC method, 20X); E) bcl-6 (SABC method, 20X); F) MUM-1 (SABC method, 20X); G) Mib1/Ki67 (SABC method, 20X).



deletion or promoter hypermethylation, has been re-tained as an unfavourable prognostic factor.54

Primary cutaneous diffuse large B-cell lymphoma, other

The category of “primary cutaneous DLBCL, other” (PCDLBCL-O) is an heterogeneous category encompassing rare, different entities. The term was introduced by EORTC/WHO Consensus Classifi-cation, to include diffuse lymphomas composed of large transformed B-cells lacking the typical features of PCDLBCL-LT and did not conform to the defi-nition of PCFCL.1 Such cases usually present with solid nodules or tumours located on the leg in one-half of the patients, on the head, trunk and arms in the remaining (Figure 3). Histologically, these tu-mours usually consist of a monomorphic population of centroblast-like cells (Figure 4); an intermingled mixed inflammatory background may be frequently observed. In addition to B-cell markers expression, lymphoma cells express bcl-6 (100%), MUM1 (67%) and FOXP1 (72%), while bcl-2 is usually negative.13

The precise diagnosis and classification of these cases is still a matter of debate, especially with re-spect to their differentiation from PCFCL with dif-fuse growth pattern. Some cases of PCFCL lym-phoma which are mainly composed of centroblasts (often showing multilobated or centrocytoid appear-ance) have been regarded in the past as PCDLBCL mostly by pathologists, with an overtreatment as a consequence.28, 21, 52 Conversely, some cases of PCDLBCL-O have probably been underestimated by most dermatopathologists and diagnosed as PCF-

PCDLBCL-LT usually lacks expression of CD5, CD30, CD138, and cyclin D1. An high proliferation rate (usually more than 70%) is frequently observed. Recently, the expression of IgM has been advocated as a useful additional tool in differentiating PCDLB-CL-LT, which usually expresses IgM, from PCFCL, more often negative for IgM.19 Search for EBV as well as for Borrelia burgdorferi were negative in PCDLBCL-LT, whereas PCR for HHV8 has been reported to be positive in a single case only.13, 35, 44

Clonal rearrangements of IGH genes are detected in most cases.35 According to a post-germinal center derivation,45, 46 rearranged IGH genes usually carry somatic hypermutation, often with concurrent BCL-6 mutations.35, 47-49

The prognosis of PCDLBCL-LT is poor, with fre-quent relapses and dissemination to extracutaneous sites during the course of disease.28 The 5-year sur-vival rate of 78 cases included in the Dutch and Aus-trian registries resulted to be 55% on average (range 20-60%).12, 13 The 5-year disease specific survival rates ranged from 43% to 63% in other two large studies.50, 51

The prognostic significance of leg involvement has been debated for a long time. Some studies, includ-ing more than 100 patients, suggested that PCDL-BCL presenting on the lower extremities has a worse prognosis than PCDLBCL arising at other cutaneous sites.24, 25, 28, 31 However, a few series did not support this conclusion.29, 35 Even though in a recent study it has been shown that PCFCL involving the leg had a significantly worse prognosis than PCFCL present-ing at other skin sites,12 it is likely that biologic pa-rameters rather than the anatomic location may influ-ence the clinical behaviour.

Some studies suggested that multiple tumours at presentation, location on the leg and bcl-2 expres-sion are associated with an increased risk of recur-rence and reduced survival.28, 52 However, these se-ries included all the PCBCL composed of large B cells, some of which would be probably considered PCFCL today. Actually, it does not seem that bcl-2 expression has any prognostic role if the cases are appropriately classified according to EORTC/WHO criteria.13

Recently, Kodama et al. suggested that strong ex-pression of MUM1 and FOXP1 might be linked to a worse prognosis.13 A low content of FOXP3+ Treg cells also has been correlated to a reduced survival.53 Similarly, inactivation of CDKN2A gene, either by

Figure 3.—Primary cutaneous B cell lymphoma, other, clini-cal presentation: A) diffuse solid nodular pattern on the back; inset:magnification of nodules; B) leg presentation.



In addition, the authors reported a few cases with overlapping clinicopathologic features, hampering a precise subclassification. Three patients with PCFCL morphology and diffuse pattern had lesions located solely on the leg and were bcl-2+/MUM1- or bcl-2-/MUM1+. On the other hand, three patients with PCDLBCL-LT morphology presented with lesions located at sites other than the legs and were MUM1-, showing similarities to PCFCL.13

The definition of the category of PCDLBCL-O, characterized by predominance of centroblasts and lack of bcl-2 expression, requires further stud-ies, based also on molecular and genetic investiga-tions to clarify whether these cases represent a dis-tinct entity, or a morphologic (centroblastic) variant of PCFCL or a or a phenotypic (bcl-2-) variant of PCDLBCL-LT. In this respect, PCDLBCL-O could correspond to the germinal center B-cell subgroup of nodal DLBCL, as shown by molecular signature and immunophenotype.39-42

Diffuse large B cell lymphoma, rare subtypes

T-cell/histiocyte rich diffuse large B-cell lym-phoma (TCHRBCL) is a lately recognized subtype of nodal DLBCL 55 which very rarely occurs pri-marily in the skin.56-62 In this lymphoma subtype a small number of large neoplastic B-cells (<10%) are scattered within a predominant background of small reactive T-lymphocytes and, often, histiocytes. Large binucleated, Reed Sternberg like B-cells may be observed but they are CD30- and CD15-. Only sporadic cases of primary cutaneous TCHRBCL have been reported.56-62 Patients usually present with plaques and/or nodules on the head and neck area or on the trunk. The information about prognosis is conflicting; however, its clinical course seems to be less aggressive than in nodal forms and cases with spontaneous resolution were also reported.56, 58, 59, 61,

62 It cannot be ruled out that at least some cases of cutaneous TCHRBCL actually represent a form of FCL with a strikingly abundant reactive background.

Primary cutaneous lymphomas with plasmablastic features are exceedingly rare. Most of these cases oc-cur in settings of immunodeficiency (HIV-associated or iatrogenic) or during the course of systemic T-cell lymphoma, such as angioimmunoblastic T-cell lym-phoma.63-65 The tumour cells range in morphology from immunoblasts to cells with more obvious plas-

CL with an high content of centroblasts. According to some authors and to 2005 WHO/EORTC criteria, these cases should be classified within the PCFCL subtype, when a significative population of large centrocytes is still recognizable.1, 8 Some clinical studies suggested that such cases have an indolent clinical course and may be treated in a conservative manner, in spite of the predominance of centrob-lasts.1, 2, 8 However, data regarding the actual prog-nosis and clinical behaviour of these peculiar cases are still too limited.

A recent study compared the clinical behaviour of PCFCL diffuse type, PCDLBCL-LT and PCDLB-CL-O. PCFCL, diffuse type, was defined as a tumour with a predominance of large cleaved cells, irrespec-tive of bcl-2 expression; PCDLBCL-LT was defined as a tumour with predominance of large round cell, positive for bcl-2; PCDLBCL-O, was defined as a tumour with predomimance of bcl-2 negative round cells. According to this study, PCDLBCL-O showed more similarities to PCDLBCL-LT than to PCFCL, diffuse type, also in terms of prognosis, with a dis-ease-specific 5-year survival of 50% in PCDLBCL-O vs 61,7% in PCDLBCL-LT and 86,7% in PCFCL.

Figure 4.—Primary cutaneous diffuse large B-cell lymphoma, other: a monomorphic centroblastic-like population (HE, 40x).



tral nervous system and skin but also lungs, adre-nal glands, thyroid, gastrointestinal system, kidneys, genitourinary tract and eye. 8,68

EBV positive DLBCL of the elderly has only re-cently been described and is listed as a subtype of DLBCL in the 2008 edition of the WHO lymphoma classification.9 This rare lymphoma is an EBV+ clon-al B-cell lymphoid proliferation, that occurs in pa-tients above 50 years of age and without any known immunodeficiency or prior lymphoma history. It has been hypothesized that EBV-driven transformation of B-cells may be related to immunological dete-rioration or senescence in immunity that is part of the aging process. In Asian countries EBV+ DLBCL of the elderly accounts for 8-10% of DLBCL, but it seems to be much rarer in Western countries. Ex-tranodal presentation is found in 70% of patients, with or without lymph node involvement. The most frequently involved extranodal sites are skin, lung, tonsil and stomach. Skin lesions consist of rapidly growing ulcerated nodules. Histologically, the lym-phoma infiltrate consists of large transformed cells with centroblastic, immunoblastic and plasmablastic features. Giant cells with Hodgkin and Reed-Stern-berg-like appearance are often found. Cases showing a broad range of B-cell maturation and an intense reactive background comprising small lymphocytes, plasma cells, histiocytes and epithelioid cells were termed polymorphous subtype. The lymphoma cells express CD20 and/or CD79a, as well as bcl-2 and MUM1. CD10 and bcl-6 are usually negative. The large cells are variably reactive for CD30 but are CD15-negative. The detection of EBV-related pro-tein LMP1 and/or EBV transcripts (EBERs) in tu-mour cells is mandatory for diagnosis. EBV+ DL-BCL of the elderly is an aggressive disease, with a median survival of about two years.73-76

The morphologic spectrum of PCDLBCL-O also include sporadic cases exhibiting peculiar cytologic (i.e. anaplastic vs multilobated vs spindle cell) or ar-chitectural features (sclerosis, epidermotropism).32 Due to their rarity, the putative prognostic signifi-cance of such cytomorphological variants is largely unknown. Cases with anaplastic cytology must be differentiated from CD30+/CD30- anaplastic large T-cell lymphoma and non-lymphoid large cells neo-plasms. The spindle cell variant is characterized by an interstitial and diffuse infiltrate of medium to large size cells showing spindle cell cytology, due to the presence of a fibrous dermal reaction secondary

macytic differentiation. The lymphoma cells pheno-type is consistent with terminal stages of B-cell dif-ferentiation (CD20-, MUM1+, CD138+, EMA+). In most cases tumour cells are EBV positive.63

Intravascular B-cell lymphoma (IVBL) and EBV positive DLBCL of the elderly are two exceedingly rare DLBCL subtypes which may present in the skin or localize to the skin during the course of the dis-ease.9, 66

IVBL is characterized by the presence of large lymphoid cells within the lumina of small to me-dium sized blood vessels, particularly capillaries and postcapillary venules (Figure 5). This peculiar intravascular growth pattern has been attributed to a defect in homing receptors and adhesion molecules on the tumour cells, such as the lack of CD29 (b1 integrin) and CD54 (ICAM1).67 Lymphoma cells ex-press B-cell associated antigens and may be positive for CD5 (38%) and CD10 (13%);9, 68, 69 most cases show overexpression of bcl-2, in absence of BCL2 rearrangements.69

Skin is a common site of presentation of IVBL but most patients have systemic disease at time of di-agnosis.68 The cutaneous form of IVBL has a better prognosis as opposed to the systemic form (5-year survival rate 56% vs. 33%). IVBL may occur at any age, with predilection for 6th to 9th decade of life.68 Dermatologic manifestations are present in one third of patients and encompass a wide range of skin le-sions, including livedo-like reticulate erythema, panniculitis like lesions, painful telangiectasies and nodular lesions.71 Clinical symptoms include fever and focal neurologic defects.72 The systemic form is a multi-organ disease that frequently involves cen-

Figure 5.—Primary cutaneous diffuse large B cell lymphoma, rare variants: A) intravascular B-cell lymphoma (HE, 20x), inset: detail of intravascular lymphocytes (HE, 40x); B) cutaneous dif-fuse large B-cell lymphoma, spindle cell variant (HE, 40x).



thus providing a possible explanation to the resist-ance to chemotherapy and poorer outcome of acti-vated DLBCL.85

Another study based on GEP analysis showed that cases with diffuse histology not presenting on the leg and consisting mainly of centroblasts share a “ger-minal center” signature with primary cutaneous and secondary FCL, thus supporting their classification under the heading of FCL.81

In various, different studies by CGH, chromo-somal imbalances were detected in up to 85% of primary cutaneous DLBCL, with higher frequencies in PCDLBCL-LT.16, 17 FISH investigations demon-strated that translocations involving MYC, BCL6, and IGH genes are found only in PCDLBCL-LT.86,

87 In their study on 31 cases of PCBCL by array-CGH, Dijkman et al observed different chromosom-al anomalies in PCFCL and PCDLBCL-LT.15 They documented that the most recurrent chromosomal alterations in PCFCL were amplifications at 2p16.1, containing c-REl/BCL11A oncogenes (63%) and de-letion of chromosome 14q32.33 (68%), whereas in PCDLBCL-LT the most prominent aberrations were a high-level DNA amplification of 18q21.31-q21.33 (67%), including the BCL-2 and MALT1 genes, and deletions of a small region within 9p21.3 region, containing the CDKN2A, CDKN2B and NSG-x genes; in both groups, recurrent chromosomal altera-tions included gains at 12q, 10q, and 7q and losses at 6q. FISH analysis confirmed amplification of BCL-2 gene, thus providing an explanation to overexpres-sion of bcl-2 protein in PCDLBCL-LT in absence of t(14;18) translocation. Complete genetic inactivation of CDKN2A, by either FISH-confirmed biallelic de-letion of 9p21.3 locus and/or promoter hypermeth-ylation, was found to correlate with a worse prog-nosis.16

Based on such observation, the pathogenetic and prognostic relevance of alterations at 9p21 locus was more comprehensively investigated in a larger, mul-ticentric series of 64 PCDLBCL-LT cases by Senff et al., using the more sensitive fine chromosomal mapping by means of multiplex ligation-dependent probe amplification.54 These investigations demon-strated homozygous and heterozygous loss of one or multiple probes within the 9p21.3 locus, encompass-ing oncosuppressor genes CDKN2A (coding for p16 and p14ARF), CDKN2B (coding for p15) and MTAP, in up to 90% cases. Although no minimal common region of deletion was identified, the CDKN2A gene

to the host response, with oval nuclei and prominent nucleoli (Figure 5). Mitotic activity is often high in these cases. Differential diagnosis includes spindle cell melanoma, spindle squamous cell carcinoma and spindle cell mesenchymal tumours, such as der-matofibrosarcoma, atypical fibroxanthoma, fibrosar-coma etc.77-80

Primary cutaneous DLBCL, molecular genetics advances

The molecular histogenetic relationship between primary cutaneous FCL e DLBCL has been a contro-versial issue. Recent, comprehensive studies of gene expression profile gave interesting insights into this issue, providing further evidence to the current PCB-CL classification.14, 81 Hoefnagel et al. compared the gene expression profile of PCFCL and PCDLBCL-LT demonstrating that they cluster, respectively, in the “germinal center” and “activated post germinal center B-cell like” groups. PCDLBCL-LT showed increased expression of genes associated with cell-proliferation and the transcription factors MUM1/IRF4 and OCT-2, whereas in the group of PCFCL high expression of SPINK2 was observed.14 MUM1/IRF4 and SPINK2 emerged as the single, most spe-cific predictors of histogenesis.82 These data were subsequently enhanced by the characterization of apoptosis-related genes expression profile. A clus-ter analysis, carried out using 169 genes involved in apoptosis on a group of 21 cases of PCBCL, re-sulted in two separate groups, namely of the cellu-lar cytotoxic response (CCR) and of the activated apoptotic cascade (AAC) type, which showed large overlap, respectively, with PCFCL and PCDLBCL-LT. CCR-type group included all eight cases of pri-mary cutaneous PCFCL, but also two PCDLBCL-LT, and was characterized by high expression levels of apoptosis-inducing cytotoxic effector genes and a favourable prognosis. AAC-type group comprised only PCDLBCL-LT, was characterized by high ex-pression levels of both pro-apoptotic genes and anti-apoptotic genes (including BCL2) and retained a sig-nificance of poorer prognosis.83 These observations are consistent with what was previously described in nodal DLBCL 84 and support the notion that ABC-like phenotype is associated with constitutive activa-tion of the NFκB pathway, resulting in up-regulation of many genes, including apoptosis-inhibiting genes,



therapy was successfully evaluated. In addition other regimens evaluated were: R-ACVBP or EPOCH-R or autologous stem cells transplantation (ASCT). In case of relapse ASCT with R-ICE or R-DHAP fol-lowed by different conditioning regimens remain the standard of care. New monoclonal antibodies, len-alinomide and tyrosine kinase inhibitors are under evaluation. 11, 90, 91

Few note about PCFCL: in early stages (T1) may be successfully treated by skin directed therapy such as excisional biopsy and/or radiotherapy (used also in T2a-c lesions) and, in case of patients present-ing several cutaneous relapse s or in T3, an immu-nomodulatory therapy using IFN-alpha or an anti CD20 local and systemic treatment may be used, avoiding polychemotherapy. Obviously, if during the follow-up the staging procedures will show a systemic involvement, polychemotherapy must be used as in the case of PCDLBCL-LT. However, in our opinion, in several cases of PCFCL with clin-icopathologic signs of progression to PCDLBCL, forming nodulo-tumoral lesions and large ulcerated plaques (T2c-T3), histologically showing a deep dif-fuse centroblastic infiltrate, with a high proliferation index and a nodular/interstitial pattern and particu-larly in case of sarcomatous-like infiltrative and scle-rotic clinical features, where radiotherapy might be complicated from local tissue damage and relapses, polychemotherapy associated to anti CD20 must be used instead of radiotherapy.

Conclusions

Primary cutaneous DLBCL is a heterogeneous group of lymphoproliferative disorders, with dis-tinct clinico-pathologic features with respect to their nodal counterparts. In less than a decade, significant progress has been made in our understanding of clin-ical, genetic and prognostical features.

The histological diagnosis of primary cutane-ous DLBCL usually poses little difficulties; how-ever some cases may present with unfamiliar clini-cal appearance or special cytological features. This group of cases has been termed DLBCL, other, not otherwise specified type, encompassing rare cases of PCBCL not belonging to either the leg-type or the PCFCL group. Further studies are requested to clarify whether the category of PCDLBCL-O shows indeed peculiar clinico-pathologic features or repre-

resulted to be the most commonly involved, with homozygous deletion being detected in 67% of the cases. Analysis of p16 and p14ARF promoter meth-ylation status was also performed, with methylation detected only at p16 promoter. In the whole mount of cases, whether with an allelic loss or promoter hy-permethylation, inactivation of CDKN2A was con-firmed to carry an adverse prognostic significance.

A heterozygous mutation of exon 5 (c.794T>C) in MYD88 gene has been recently identified in a sub-stantial proportion of activated B-cell-like subtype (ABC) of nodal/systemic DLBCL. The correspond-ing single amino acid substitution (L265P) affects the Toll/IL-1 receptor (TIR) domain of adaptor pro-tein MYD88, and favors tumour cell survival through IRAK1 (interleukin-1 receptor associated kinase)/IRAK4 and NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling.88 Re-cently, the presence of L265P was investigated by means of Sanger sequencing in a series of PCBCL and found in a high proportion of PCDLBCL-LT cases, in contrast with the absence of such abnormal-ity among other primary cutaneous lymphoma cases. No correlation was found with prognosis.89

Primary cutaneous DLBCL, treatment

The EORTC/ISCL International Recommenda-tion for the management of CBCL were published in 2008.2

Staging procedures, as cited above, include clini-cal examination, laboratory studies and bone mar-row biopsy and aspirate. Therapy is usually based on staging, histology, anatomic location, size and number of tumor lesions.

In case of PCDLBCL-LT and of PCDLBCL-O, depending from the performance status ECOG of patients (median age 78), multiagent chemotherapy, better with an antracycline dependent regimen with rituximab (anti-CD20) (R-CHOP) every 21 days, and/or radiotherapy (all lesions, 40 gray) must be considered as the first line of therapy.

In case of patients over 70 years of age radiother-apy and multiagent chemotherapy (CVP, modified R-CHOP) or Chlorambucil must be considered. In the last 4 years the R-CHOP immunochemotherapy has become the standard of care for DLBCL,¸the du-ration (dose intensification) of the cycle has varied from 14 to 21 days and the anti-CD20 maintenance



3. Kempf W, Denisjuk N, Kerl K, Cozzio A, Sander C. Primary cuta-neous B-cell lymphomas. J Dtsch Dermatol Ges 2012;10:12-22.

4. Willemze R, Kerl H, Starry W, Berti E, Cerroni L, Chimenti et al. EORTC classification for primary cutaneous lymphomas: a pro-posal from the Cutanesous Lymphoma Study Group of the Euro-pean Organization for Research and Treatment of Cancer. Blood 1997;90:354-371.

5. Jaffe ES, Harris NL, Stein H, Vardiman JW, editors. Pathology and Genetics. Tumours of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2001.

6. Santucci M, Pimpinelli N. Primary cutaneous B-cell lymphomas. Current concepts. I. Haematologica 2004;89:1360-71.

7. Burg G, Kempf W, Cozzio A, Feit J, Willemze R, S Jaffe E et al. WHO/EORTC classification of cutaneous lymphomas 2005: histo-logical and molecular aspects. J Cutan Pathol 2005;32:647-74.

8. LeBoit P, Burg G, Weedon D and Sarasin A eds. Pathology and Ge-netics. Skin Tumours. Lyon: IARC Press; 2006.

9. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H et al., editors. WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2008.

10. Kempf W, Sander CA. Classification of cutaneous lymphomas - an update. Histopathology 2010;56:57-70.

11. Sokol L, Naghashpour M, Glass LF. Primary cutaneous B-cell lym-phomas: recent advances in diagnosis and management. Cancer Control 2012;19:236-44.

12. Senff NJ, Hoefnagel JJ, Jansen PM, Vermeer MH, van Baarlen J, Blokx WA et al. Reclassification of 300 primary cutaneous B-cell lymphomas according to the new WHO-EORTC classification for cutaneous lymphomas: comparison with previous classifications and identiofication of prognostic markers. J Clin Oncol 2007;25:1581-7.

13. Kodama K, Massone C, Chott A, Metze D, Kerl H, Cerroni L. Pri-mary cutaneous large B-cell lymphomas: clinicopathologic fea-tures, classification, and prognostic factors in a large series of pa-tients. Blood 2005;106:2491-7.

14. Hoefnagel JJ, Dijkman R, Basso K, Jansen PM, Hallermann C, Willemze R et al. Distinct types of primary cutaneous large B-cell lymphoma identified by gene expression profiling. Blood 2005;105:3671-8

15. Dijkman R, Tensen CP, Jordanova ES, Knijnenburg J, Hoefnagel JJ, Mulder AA et al. Array-based comparative genomic hybridization analysis reveals recurrent chromosomal alterations and prognostic parameters in primary cutaneous large B-cell lymphoma. J Clin On-col 2006;24:296-305.

16. Giménez S, Costa C, Espinet B, Solé F, Pujol RM, Puigdecanet E et al. Comparative genomic hybridization analysis of cutaneous large B-cell lymphomas. Exp Dermatol 2005;14:883-90.

17. Hallermann C, Kaune KM, Siebert R, Vermeer MH, Tensen CP, Willemze R et al. Chromosomal aberration patterns differ in sub-types of primary cutaneous B cell lymphomas. J Invest Dermatol 2004;122:1495-502.

18. De Leval L, Harris NL, Longtine J, Ferry JA, Duncan LM. Cutane-ous B-cell lymphomas of follicular and marginal zone types: use of Bcl-6, CD10, Bcl-2, and CD21 in differential diagnosis and clas-sification. Am J Surg Pathol 2001;25:732-41.

19. Koens L, Vermeer MH, Willemze R, Jansen PM. IgM expression on paraffin sections distinguishes primary cutaneous large B-cell lym-phoma, leg type from primary cutaneous follicle center lymphoma. Am J Surg Pathol. 2010;34:1043-8.

20. Sen F, Medeiros LJ, Lu D, Jones D, Lai R, Katz R, Abruzzo LV. Mantle cell lymphoma involving skin: cutaneous lesions may be the first manifestation of disease and tumors often have blastoid cyto-logic features. Am J Surg Pathol 2002;26:1312-8.

21. Kim BK, Surti U, Pandya AG, Swerdlow SH. Primary and second-ary cutaneous diffuse large B-cell lymphomas: a multiparameter analysis of 25 cases including fluorescence in situ hybridization for t(14;18) translocation. Am J Surg Pathol 2003;27:356-64.

22. Willemze R, Meijer CM, Sentis HJ, Scheffer E, van Vloten WA,

sents only a morphologic or phenotypic variant of PCFCL or PCDLBCL-LT.

Riassunto

Linfomi cutanei diffusi a grandi cellule B: aggiornamento su morfologia e trattamento

I linfomi a cellule B primitive della cute sono un grup-po eterogeneo di disordini linfoproliferaitivi, che rappre-sentano il 25-30% di tutti i linfomi primitivi cutanei e si suddividono in tre principali istotipi: 1) linfoma B della zona marginale primitivo cutaneo; 2) linfoma B follicola-re primitivo cutaneo; 3) linfoma B diffuso a grandi cellule primitivo cutaneo, “leg type”. Mentre le prime due enti-tà sono linfomi indolenti, caratterizzati da una progno-si eccellente nonostante le frequenti recidive, il linfoma B diffuso a grandi cellule “leg type” è clinicamente più aggressivo e richiede solitamente un approccio terapeu-tico comprendente poli-chemioterapia ed immunoterapia anti-CD20. Dal punto di vista istopatologico, il linfoma B diffuso “leg type” appare costituito da elementi cellulari tondeggianti, di grandi dimensioni (centroblasti ed im-munoblasti), è caratterizzato dall’intensa espressione del-la proteina bcl-2, in assenza della traslocazione t(14;18), e presenta un profilo immunofenotipico di tipo “attivato”. In tempi recenti, è stata proposta la definizione di linfoma B diffuso a grandi cellule primitivo cutaneo “other”, ad individuare quei casi costituiti da elementi B-cellulari di grandi dimensioni che non presentano gli aspetti morfofe-notipici caratteristici dei “leg type” né risultano coerenti con una diagnosi di linfoma follicolare primitivo cutaneo. Alcuni studi clinici, invero basati su casistiche molto li-mitate, suggeriscono un comportamento clinico indolente nella maggior parte dei casi ed una strategia terapeutica di tipo conservativo. Lo spettro dei linfomi B diffusi a grandi cellule comprende infine alcune rare varianti mor-fologiche, quali i sottotipi anaplastico, plasmablastico e ricco in linfociti T, ed alcuni sottotipi particolari, solo re-centemente descritti, quali il linfoma B a grandi cellule intravascolare ed il linfoma B a grandi cellule associato al virus EBV dell’anziano, spesso caratterizzati da pre-sentazione cutanea.Parole chiave: Linfoma cutaneo a cellule T - Biologia molecolare - Genetica.

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44. Goteri G, Ranaldi R, Simonetti O, Capretti R, Menzo S, Stramaz-zotti D et al. Clinicopathological features of primary cutaneous B-cell lymphomas from an academic regional hospital in central Italy: no evidence of Borrelia burgdorferi association. Leuk Lymphoma 2007;48:2184-8.

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47. Franco R, Camacho FI, Fernández-Vázquez A, Algara P, Rodríguez-Peralto JL, De Rosa G et al. IgV(H) and bcl6 somatic mutation anal-ysis reveals the heterogeneity of cutaneous B-cell lymphoma, and indicates the presence of undisclosed local antigens. Mod Pathol 2004;17:623-30.

48. Gellrich S, Rutz S, Golembowski S, Jacobs C, von Zimmermann M, Lorenz P et al. Primary cutaneous follicle center cell lymphomas and large B cell lymphomas of the leg descend from germinal center cells. A single cell polymerase chain reaction analysis. J Invest Der-matol 2001;117:1512-20.

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50. Grange F, Beylot-Barry M, Courville P, Maubec E, Bagot M, Ver-gier B et al. Primary cutaneous diffuse large B-cell lymphoma, leg type: clinicopathologic features and prognostic analysis in 60 cases. Arch Dermatol 2007;143:1144-50.

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53. Felcht M, Heck M, Weiss C, Becker JC, Dippel E, Müller CS et al. Expression of the T-cell regulatory marker FOXP3 in primary cutaneous large B-cell lymphoma tumour cells. Br J Dermatol. 2012;167:348-58.

54. Senff NJ, Zoutman WH, Vermeer MH, Assaf C, Berti E, Cerroni L et al. Fine-mapping chromosomal loss at 9p21: correlation with prognosis in primary cutaneous diffuse large B-cell lymphoma, leg type. J Invest Dermatol 2009;129:1149-55.

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26. Zinzani PL, Quaglino P, Pimpinelli N, Berti E, Baliva G, Rupoli S et al. Italian Study Group for Cutaneous Lymphomas. Prognostic factors in primary cutaneous B-cell lymphoma: the Italian Study Group for Cutaneous Lymphomas. J Clin Oncol. 2006;24:1376-82.

27. Zhao J, Han B, Shen T, Zhao Y, Wang T, Liu Y et al. Primary cutane-ous diffuse large B-cell lymphoma (leg type) after renal allograft: case report and review of the literature. Int J Hematol 2009;89:113-7.

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32. Plaza JA, Kacerovska D, Stockman DL, Buonaccorsi JN, Baillar-geon P, Suster S et al. The histomorphologic spectrum of primary cutaneous diffuse large B-cell lymphoma: a study of 79 cases. Am J Dermatopathol 2011;33:649-55.

33. Child FJ, Russell-Jones R, Woolford AJ, Calonje E, Photiou A, Or-chard G et al. Absence of the t(14;18) chromosomal translocation in primary cutaneous B-cell lymphoma. Br J Dermatol 2001;144:735-44.

34. Mao X, Lillington D, Child F, Russell-Jones R, Young B, Whit-taker S. Comparative genomic hybridization analysis of primary cutaneous B-cell lymphomas: identification of common genomic alterations in disease pathogenesis. Genes Chromosomes Cancer 2002;35:144-55.

35. Paulli M, Viglio A, Vivenza D, Capello D, Rossi D, Riboni R et al. Primary cutaneous large B-cell lymphoma of the leg: histogenetic analysis of a controversial clinicopathologic entity. Hum Pathol 2002;33:937-43.

36. Hoefnagel JJ, Vermeer MH, Jansen PM, Fleuren GJ, Meijer CJ, Willemze R. Bcl-2, Bcl-6 and CD10 expression in cutaneous B-cell lymphoma: further support for a follicle centre cell origin and dif-ferential diagnostic significance. Br J Dermatol 2003;149:1183-91.

37. Pham-Ledard A, Prochazkova-Carlotti M, Vergier B, Petrella T, Grange F, Beylot-Barry M et al. IRF4 expression without IRF4 re-arrangement is a general feature of primary cutaneous diffuse large B-cell lymphoma, leg type. J Invest Dermatol 2010;130:1470-2.

38. Hoefnagel JJ, Mulder MM, Dreef E, Jansen PM, Pals ST, Meijer CJ et al. Expression of B-cell transcription factors in primary cutane-ous B-cell lymphoma. Mod Pathol 2006;19:1270-6.

39. Alizadeh AA, Eisen MB, Davis RE, Ma C, Losso IS, Rosenwald et al. Distinct types of diffuse lage B-cell lymphoma identified by gene expression profiling. Nature 2000;403:503-11.



et al. Senile Epstein-Barr virus-associated B-cell lymphoprolifera-tive disorders:a mini review. J Clin Exp Hematop 2006;46:1-4.

75. Oyama T, Yamamoto K, Asano N, Oshiro A, Suzuki R, Kagami Y et al. Age-related EBV-associated B-cell lymphoproliferative dis-orders constitute a distinct clinicopathologic group:a study of 96 patients. Clin Cancer Res 2007;13:5124-32.

76. Shimoyama Y, Asano N, Kojima M, Morishima S, Yamamoto K, Oyama T et al. Age-related EBV-associated B-cell lymphoprolif-erative disorders: diagnostic approach to a newly recognized clini-copathological entity. Pathol Int 2009;59:835-43.

77. Cerroni L, El-Shabrawi-Caelen L, Fink-Puches R, LeBoit PE, Kerl H. Cutaneous spindle-cell B-cell lymphoma:a morphologic variant of cutaneous large B-cell lymphoma. Am J Dermatopathol 2000;22:299-304.

78. Goodlad JR. Spindle-cell B-cell lymphoma presenting in the skin. Br J Dermatol 2001;145:313-7.

79. Ferrara G, Bevilacqua M, Argenziano G. Cutaneous spindle B-cell lymphoma:a reappraisal. Am J Dermatopathol 2002;24:526-7.

80. Ries S, Barr R, LeBoit P, McCalmont T, Waldman J. Cutaneous sar-comatoid B-cell lymphoma. Am J Dermatopathol 2007;29:96-8.

81. Storz MN, van de Rijn M, Kim YH, Mraz-Gernhard S, Hoppe RT, Kohler S. Gene expression profiles of cutaneous B cell lymphoma. J Invest Dermatol 2003;120:865-70.

82. Wright G, Tan B, Rosenwald A, Hurt EH, Wiestner A, Staudt LM. A gene expression-based method to diagnose clinically distinct sub-groups of diffuse large B cell lymphoma. Proc Natl Acad Sci U S A 2003;100:9991-6.

83. van Galen JC, Hoefnagel JJ, Vermeer MH, Willemze R, Dijkman R, Tensen CP et al. Profiling of apoptosis genes identifies dis-tinct types of primary cutaneous large B cell lymphoma. J Pathol 2008;215:340-6.

84. Muris JJ, Ylstra B, Cillessen SA, Ossenkoppele GJ, Kluin-Nele-mans JC, Eijk PP et al. Profiling of apoptosis genes allows for clini-cal stratification of primary nodal diffuse large B-cell lymphomas. Br J Haematol 2007;136:38-47.

85. Davis RE, Brown KD, Siebenlist U, Staudt LM. Constitutive nucle-ar factor kappa B activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J Exp Med 2001;194:1861-74.

86. Hallermann C, Kaune KM, Gesk S, Martin-Subero JI, Gunawan B, Griesinger F et al. Molecular cytogenetic analysis of chromo-somal breakpoints in the IGH, MYC, BCL6, and MALT1 gene loci in primary cutaneous B-cell lymphomas. J Invest Dermatol 2004;123:213-9.

87. Wiesner T, Streubel B, Huber D, Kerl H, Chott A, Cerroni L. Genet-ic aberrations in primary cutaneous large B-cell lymphoma:a fluo-rescence in situ hybridization study of 25 cases. Am J Surg Pathol 2005;29:666-73.

88. Ngo VN, Young RM, Schmitz R, Jhavar S, Xiao W, Lim KH et al. Oncogenically active MYD88 mutations in human lymphoma. Na-ture 2011;470:115-9.

89. Pham-Ledard A, Cappellen D, Martinez F, Vergier B, Beylot-Barry M, Merlio JP. MYD88 somatic mutation is a genetic feature of pri-mary cutaneous diffuse large b-cell lymphoma, leg type. J Invest Dermatol 2012;132:2118-20.

90. Habermann TM. New developments in the management of diffuse large B-cell lymphoma. Hematology 2012;17(Suppl 1):S93-7.

91. Nastoupil LJ, Rose AC, Flowers CR. Diffuse large B-cell lym-phoma: current treatment approaches. Oncology (Williston Park) 2012;26:488-95.

B-cell lymphoma of the skin: report of a case. Am J Hematol 1996;52:221-3.

58. Dommann SN, Dommann-Scherrer CC, Zimmerman D, Dours-Zimmermann MT, Hassam S, Burg G. Primary cutaneous T-cell-rich B-cell lymphoma. A case report with a 13-year follow-up. Am J Dermatopathol 1995;17:618-24.

59. Wollina U. Complete response of a primary cutaneous T-cell-rich B cell lymphoma treated with interferon alpha2a. J Cancer Res Clin Oncol 1998;124:127-9.

60. Dunphy CH, Nahass GT. Primary cutaneous T-cell-rich B-cell lymphomas with flow cytometric immunophenotypic findings. Re-port of 3 cases and review of the literature. Arch Pathol Lab Med 1999;123:1236-40.

61. Li S, Griffin CA, Mann RB, Borowitz MJ. Primary cutaneous T-cell-rich B-cell lymphoma: clinically distinct from its nodal coun-terpart? Mod Pathol 2001;14:10-3.

62. Vezzoli P, Fiorani R, Girgenti V, Fanoni D, Tavecchio S, Balice Y et al. Cutaneous T-cell/histiocyte-rich B-cell lymphoma:a case report and review of the literature. Dermatology 2011;222:225-30.

63. Colomo L, Loong F, Rives S, Pittaluga S, Martínez A, López-Guill-ermo A et al. Diffuse large B-cell lymphomas with plasmablastic differentiation represent a heterogeneous group of disease enti-ties. Am J Surg Pathol 2004;28:736-47.

64. Hausermann P, Khanna N, Buess M, Itin PH, Battegay M, Dirn-hofer et al. Cutaneous plasmablastic lymphoma in an HIV-positive male: an unrecognized cutaneous manifestation. Dermatology 2004;208:287-90.

65. Yang QX, Pei XJ, Tian XY, Li Y, Li Z. Secondary cutaneous Ep-stein-Barr virus-associated diffuse large B-cell lymphoma in a pa-tient with angioimmunoblastic T-cell lymphoma:a case report and review of literature. Diagn Pathol 2012;7:7.

66. Ferreri AJ, Campo E, Seymour JF, Willemze R, Ilariucci F, Ambro-setti A et al. Intravascular lymphoma: clinical presentation, natural history, management and prognostic factors in a series of 38 cases, with special emphasis on the “cutaneous variant.”. Br J Haematol 2004;127:173-83.

67. Ferry JA, Harris NL, Picker LJ, Weinberg DS, Rosales RK, Tapia J et al. Intravascular lymphomatosis (malignant angioendotheli-omatosis). A B-cell neoplasm expressing surface homing recep-tors. Mod Pathol 1988;1:444-52.

68. Ponzoni M, Arrigoni G, Gould VE, Del Curto B, Maggioni M, Scap-inello A et al. Lack of CD 29 (beta1 integrin) and CD 54 (ICAM-1) adhesion molecules in intravascular lymphomatosis. Hum Pathol 2000;31:220-6.

69. Khalidi HS, Brynes RK, Browne P, Koo CH, Battifora H, Medeiros LJ. Intravascular large B-cell lymphoma: the CD5 antigen is ex-pressed by a subset of cases. Mod Pathol 1998;11:983-8.

70. Yegappan S, Coupland R, Arber DA, Wang N, Miocinovic R, Tubbs RR et al. Angiotropic lymphoma: an immunophenotypically and clinically heterogeneous lymphoma. Mod Pathol 2001;14:1147-56.

71. DiGiuseppe JA, Nelson WG, Seifter EJ, Boitnott JK, Mann RB. Intravascular lymphomatosis:a clinicopathologic study of 10 cases and assessment of response to chemotherapy. J Clin Oncol 1994;12:2573-9.

72. Beristain X, Azzarelli B. The neurological masquerade of intravas-cular lymphomatosis. Arch Neurol 2002;59:439-43.

73. Oyama T, Ichimura K, Suzuki R, Suzumiya J, Ohshima K, Yatabe Y et al. Senile EBV+ B-cell lymphoproliferative disorders:a clinico-pathologic study of 22 patients. Am J Surg Pathol 2003;27:16-26.

74. Shimoyama Y, Oyama T, Asano N, Oshiro A, Suzuki R, Kagami Y


Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare tumour, which stems from

plasmacytoid dendritic cells (PDC), and is charac-terised by an aggressive course (median survival 14 months). The disease was originally described by Adachi et al.1 in 1994 as “blastic NK cell lymphoma/leukemia”. Since then, according to the expanding knowledge, the disease has changed several times its name and nomenclature. The original definition was sustained by both the cytology and possible NK ori-gin, as suggested by CD56 expression. However the French Study Group on Cuteneous Lymphoma 2 bas-ing on the CD4 positivity and the lack of expression of others NK-lineage markers proposed the defini-tion of “agranular CD4+/CD56+ he matodermic ne-oplasm”. The Word Health Organisation-European Organisation for research and Treatment of Cancer (WHO-EORTC) consensus classification 3 accepted this proposal. Further studies about the lineage of disease postulated PDC as the normal counterpart of the disease.4-6 Finally in the last WHO Classification of tumours of the matopoietic and lymphoid tissues,7 BPDCN has been listed among “acute myeloid

1Division of Dermatology, Department of Internal Medicine, Geriatrics and Nephrology University of Bologna, Bologna, Italy

2Section of Dermatology, Department of Critical Care, Medicine and Surgery

University of Florence Medical School, Florence, Italy 3He matopathology Unit, Department of Hematology

and Oncology “L. and A. Seragnoli” S. Orsola-Malpighi Hospital

University of Bologna, Bologna, Italy


A. PILERI 1, C. DELFINO 2, V. GRANDI 2, C. AGOSTINELLI 3, S. A. PILERI 3, N. PIMPINELLI 2

Blastic plasmacytoid dendritic cell neoplasm (BPDCN): the cutaneous sanctuary

Aim. Blastic plasmacytoid dendritic cell neoplasm (BPDNC) is a rare tumour, which stems from plasmacytoid dendritic cells. Although the aetiology is still unclear, in the last few years various reports suggested a potential role of chromo-somal aberrations in the oncogenesis. The disease is currently enclosed among “acute myeloid leukemia (AML) and related precursor neoplasms” in the last WHO classification. BPD-CN has an aggressive course, however, it has been suggested that an exclusive cutaneous involvement at presentation is re-lated to a better clinical outcome.Methods. We review the literature about BPDCN, and we present a series of 11 cases, all characterised by disease lim-ited to the skin at presentation. Furthermore, we examined all cases of the last 10 years stored in the database of the multidisciplinary study group on cutaneous lymphomas of the University of Florence.Results. Basing on the clinical features, patient were classi-fied into two groups: with a single-lesion or multiple erup-tive-lesions presentation. The former were treated with ra-diotherapy (limited field, electron beam therapy). The latter were treated with different therapeutic options, depending on age and co-morbidities. All patients with a single lesion achieved complete response. Five of 6 patients with eruptive lesions achieved a clinical response (2 complete and 3 partial response). Notably, the progression free survival was higher in the single-lesion than in the eruptive-lesion group (23 vs. 9 months). However all patients relapsed and 8 of 11 died.Conclusion. Although the small number of selected patients, we could speculate that the concept of “cutaneous sanctuary” is particularly true in patients with a single lesion-presenta-tion. In these patients, especially if >70 year-old aged, radio-therapy should be encouraged as the treatment of choice.Key words: Dendritic cells - Immunohistochemestry - Gene expression profiling.

Corresponding author: A. Pileri MD, Division of Dermatology, De-partment of Internal Medicine, Geriatrics and Nephrology, University of Bologna, Via Massarenti 1, 40138 Bologna, Italy. E-mail: [email protected]


Lavoro: 4420-MDtitolo breve: Blastic plasmacytoid dendritic cell neoplasm (BPDCN)primo autore: PILERIpagine: 603-8

PILERI BLASTIC PLASMACyTOID DENDRITIC CELL NEOPLASM (BPDCN)


leukemia (AML) and related precursor neoplasms”. Although the disease can involve multiple organs (skin, lymph nodes, bone marrow and other extra-nodal sites), in most instances it presents in the skin, either as a solitary tumour or as a papulo-nodular eruption. In more advanced stages, a fatal leukemic dissemination can be observed. Although the disease has an aggressive course, with a mean survival of 14 months, Suzuki et al.8 in 2005 suggested that an exclusive cutaneous involvement at presentation is related to a better prognosis. Interestingly, Lucioni et al.,9 analysing 21 of BPDCN with array-based com-parative genomic hybridisation, corroborated this finding. Furthermore they observed that cases char-acterized by diffuse skin lesions had 2-fold higher 9p21.3 locus losses compared with those with local-ised disease suggesting that 9p21.3 deletion could delineate a specific oncogenic pathway for BPDCN.

The aim of this paper was to discuss a series of 11 BPDCN cases, all characterized by disease limited to the skin at presentation and to review the literature in this regard.

Materials and methods

All cases of BPDCN of the last 10 years stored in the database of the multidisciplinary study group on cutaneous lymphomas of the University of Florence were examined and reviewed. Only cases with his-tological and immunohistochemical confirmation, minimum follow-up of 6 months, as well as absence of extra-cutaneous dissemination (after complete staging procedures, including total body CT scans and bone marrow biopsy) at the time of diagnosis were considered eligible.

Eleven patients were retrieved (8 males and 3 fe-males), with a median age 67 years (range 42-81 years): 5 of them presented with a solitary tumour (4 on the trunk, 1 on the thigh), the remaining 6 pre-sented with multiple, erythemato-cianotic, eruptive lesions. All sections of the selected cases were evalu-ated by experienced pathologists who confirmed the diagnosis of BPDCN based on the criteria of the fourth edition of the WHO Classification of He mat-opoietic and Lymphoid Tumours (Figure 1).7 Stag-

Figure 1.—Microscopic characteristics of blastic plasmocytoid dendritic cell neoplasm. a) At conventional microscopy, the tumour infiltrates the dermis showing a monotonous appearance (H&E, x200). In the inset, the cytological details of neoplastic cells, which are provided with irregularly-shaped, often eccentric nuclei, finely dispersed chromatin, small nucleoli, and a variable rim of acidophilic cytoplasm (H&E, x400). On immunohistochemestry the tumoural elements express: b) TCL1 (x 200), c) CD56 (x600) and d) CD123 (x600) (Immuno-alkaline phosphatase technique; Gill’s he matoxylin nuclear counterstining).

BLASTIC PLASMACyTOID DENDRITIC CELL NEOPLASM (BPDCN) PILERI


ing procedures were negative in all these patients. The mean follow-up duration was 16.5 months (me-dian: 16 months).

The response to treatment was evaluated as: com-plete response (CR) in cases with documentable re-gression of all lesions (100%), partial response (PR) in cases with regression of ≥50% of the tumour load, stable disease (SD) in cases with <50% reduction up to ≤20% increase of the tumour load, and progres-sive disease (PD) in cases with >20% increase of the tumour load.

Results

Basing on the presenting clinical features, patient were classified into two groups: with a single-lesion (Figure 2) or multiple eruptive-lesions presentation (Figures 3, 4). The former were treated with differ-ent therapeutic options, depending on age and co-morbidities. In particular, an ARA-C-based proto-col was administered to one of them, a 58 year-old otherwise, healthy male. The remaining ones were treated with radiotherapy (limited field, electron beam therapy), because of their age (>75 years) and comorbidities contraindicating multiagent chemo-therapy. The six patients with eruptive lesions were treated with multiagent chemotherapy: CHOP (cy-clophosphamide, hydroxydaunorubicin, vincristine and prednisone) in three cases, and ARA-C (arab-inofuranosyl and cytidine) in the remaining ones.

Notably, all 5 patients with a single lesion achieved CR. Five of 6 patients of the second group (multiple,

Figure 2.—Erythematous plaque on the trunk: paradigmatic ex-ample of BPDCN in single lesion presentation.

Figure 4.—Violaceous to purplish papules and plaques on the head in a patient with eruptive presentation.

Figure 3.—Erythematous-cyanotic nodules and plaques on the trunk in a patient with eruptive presentation.



and can be reasonably defined as the “sanctuary” of the disease. In fact, BPDCN frequently continues to be clinically confined to the skin till the rapid, second step of progression, i.e. leukemic spread and multior-gan involvement. Histology shows a diffuse, mono-morphous infiltrate of medium-sized blast cells with irregular nuclei, fine chromatin and small nucleoli. Angioinvasion and coagulative necrosis are absent. In skin lesions the neoplastic cells predominantly infiltrates the dermis, sparing the epidermis, eventu-ally extending to subcutaneous fat. On immunohis-tochemistry, neoplastic cells are characterized by the expression of the PDC-associated antigens CD123 and TCL1 molecule. As previously mentioned, in few instances staining for CD4 or CD56 can turn out negative. Furthermore, CD43, CD45RA, BDCA-2/CD303, the cutaneous lymphocyte associated anti-gen CLA and the interferon-α dependent molecule MxA are usually expressed. Interestingly, Cota et al11 reviewed 33 cases with a previous diagnosis of BPDCN, and observed that the histological picture could be quite variable ranging from a nodular to dif-fuse infiltrate in the dermis to a modest perivascular or interstitial aggregate of neoplastic cells. The lat-ter can simulate a cutaneous inflammatory disorder as lupus erythematosus.16 BPDCN e thiology is still unclear, although in the last few years various report suggested a potential role of chromosomal aberra-tions in the oncogenesis of the disease, as losses on 5q, 6q, 12p, 13q, chromosomes 9 and 15 as well as deletions on 4q34, 9p13-p11, pq12-q34 and 13q12-q31.16 Wiesner et al.17 found losses of chromosomes 9, 12, 13 and 15. These results strength the concept that alteration of cell-cycle checkpoint controlling proteins p27 (KIP1), p16 (INK4a) and RB1 may play a potential role in malignant transformation. More-over Lucioni et al.9 analysing 21 cases of BPDCN with aCGH found 4 most common deleted regions (9p21.3, 13q13.1-q14.3, 12p13.2-p13.1 and 13q11-q12) containing several genes controlling G1/S tran-sition of cell cycle, as CDKN2A/CDKN2B, RB1, CDKN1B and LATS and suggested that these genet-ic abnormalities might delineate a specific oncogenic pathway for BPDCN. Although clinicians have been empowered their efforts to a better understanding of the disease, unfortunately it has a rapid course with a progression to death within 12-14 months, despite an initial response to chemotherapy.

In this paper, we present a series of 11 patients af-fected by BPDCN characterised by exclusive clinical

eruptive lesions) achieved a clinical response (2 CR and 3 PR). One patient initially experienced a SD, yet died of disease after a new progression (leuke-mization) 5 months later. All responding patients in both groups experienced relapse/progression, with a significantly different progression-free-survival (PFS): median 23 months (single-lesion-presenta-tion) versus 9 months (multiple, eruptive lesion-presentation). Eight of 11 patients died, with a medi-an overall survival of 18 months. One patient with a single-lesion-presentation is currently a long-lasting survivor (37 months). One with a multiple, eruptive lesion-presentation, after having achieved CR with 6-CHOP courses, has been treated with allogeneic stem cell transplantation from related donor (sister), and is now in stable CR since 10 months.

Discussion and conclusions

The term “blastic plasmacytoid dendritic cell neo-plasm” (BPDCN) has been coined during the 2008 WHO classification drafting.7 In fact, the pathologic condition had variously been named in both the 2001 edition of the same classification and the EORTC classification: blastic NK/T cell lymphoma and agranular CD4+ CD56+ he matodermic neoplasm/tumour, respectively.7 The former expression did rep-resent a misnomer, the tumour having nothing to do with T and NK-cells. The latter was fairly imprecise, since the involvement of the peripheral blood and the expression of CD4 and CD56 are not invariable.10, 11 In particular, BPDCN is thought to derive from the precursors of a special subset of dendritic cells, the plasmacytoid dendritic cells (PDC).4-6 These cells are distinguished by the production of high amounts of α-interferon in humans;12 in the past, they have been defined with many different terms, such as lym-phoblast, T-associated plasma cell, plasmacytoid T-cell, and plasmacytoid monocyte.7

BPDCN is a rare neoplasm usually occurring in the 6th decade, although pe diatric cases had been reported.13 According to a Spanish study,14 the over-all incidence of BPDCN among all acute myeloid leukemia and non Hodgkin’s lymphoma is under 1% in both group. Males are more frequently affected (M:F ratio 3:1). The disease can have both a single- or a multiorgan involvement. Skin is by far the most commonly affected site, although Rauh 15 has recent-ly described a series lacking cutaneous involvement,

BLASTIC PLASMACyTOID DENDRITIC CELL NEOPLASM (BPDCN) PILERI


stati divisi in due categorie: pazienti con lesione singola e pazienti con lesioni eruttive. Il primo gruppo è stato tratta-to con approccio radioterapico (la cosiddetta “limited field, electron beam therapy”), il secondo con differenti schemi terapeutici in base ad età e comorbilità. Tutti i pazienti con lesione singola hanno avuto una remissione completa, mentre 5/6 casi con presentazione eruttiva hanno risposto alle terapie (2 risposte complete e 3 parziali). Sebbene tutti i pazienti abbiano avuto una recidiva ed 8/11 siano morti, è interessante notare come chi presentava una lesione singo-la abbia avuto una “progression free survival” maggiore di chi aveva lesioni multiple (23 vs. 9 mesi).

Conclusioni. Sebbene il numero di pazienti studiato sia esiguo, la cute per i BPDCN potrebbe fungere da organo “santuario”, in special modo per pazienti con lesione sin-gola. Per questi, specie se l’età è maggiore di 70 anni, la radioterapia può rappresentare un’opzione di cui tenere conto.Parole chiave: Cellule dendritiche - Immunistochimica - Profilo di espressione genetica.

References

1. Adachi M, Maeda K, Takekawa M, Hinoda y, Imai K, Sugiyama S et al. High expression of CD56 (N-CAM) in a patient with cutane-ous CD4-positive lymphoma. Am J Hematol 1994;47:278-82.

2. Petrella T, Dalac S, Maynadié M, Mugneret F, Thomine E, Cour-ville P et al. CD4+ CD56+ cutaneous neoplasms: a distinct hema-tological entity? Groupe Français d’Etude des Lymphomes Cutanés (GFELC). Am J Surg Pathol 1999;23:137-46.


4. Cella M, Facchetti F, Lanzavecchia A, Colonna M. Plasmacytoid dendritic cells activated by influenza virus and CD40L drive a po-tent TH1 polarization. Nat Immunol 2000;1:305-10.

5. Soumelis V, Liu yJ. From plasmacytoid to dendritic cell: morpho-logical and functional switches during plasmacytoid pre-dendritic cell differentiation. Eur J Immunol 2006;36:2286-92.

6. Petrella T, Meijer CJ, Dalac S, Willemze R, Maynadié M, Machet L et al. TCL1 and CLA expression in agranular CD4/CD56 hemato-dermic neoplasms (blastic NK-cell lymphomas) and leukemia cutis. Am J Clin Pathol 2004;122:307-13.

7. Facchetti F, Jones DM, Petrella T. Blastic plasmocytoid dendritic cell neoplasm (Acute myeloid leukaemia and related precursor neo-plasms) In: Swerdlow S, Campo E, Harris N, Jaffe E, Pileri S, Stein H et al., editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC; 2008 p. 145-7.

8. Suzuki R, Nakamura S, Suzumiya J, Ichimura K, Ichikawa M, Oga-ta K et al. NK-cell Tumor Study Group. Blastic natural killer cell lymphoma/leukemia (CD56-positive blastic tumor): prognostica-tion and categorization according to anatomic sites of involvement. Cancer 2005;104:1022-31.

9. Lucioni M, Novara F, Fiandrino G, Riboni R, Fanoni D, Arra M et al. Twenty-one cases of blastic plasmacytoid dendritic cell neoplasm: focus on biallelic locus 9p21.3 deletion. Blood 2011;118:4591-4.

10. Ascani S, Massone C, Ferrara G, Rongioletti F, Papini M, Pileri S et al. CD4-negative variant of CD4+/CD56+ hematodermic neoplasm: description of three cases. J Cutan Pathol 2008;35:911-5.

11. Cota C, Vale E, Viana I, Requena L, Ferrara G, Anemona L et al. Cutaneous manifestations of blastic plasmacytoid dendritic cell

involvement of the skin at presentation. Interestingly, 5 of them presented with a solitary lesion, while the remaining ones had multiple, eruptive papulo-nod-ular lesions, currently thought to be the commonest clinical appearance.18 Our data confirm that aggres-sive treatment strategy as suggested by Dalle et al.19 should be considered the best choice for patients with an eruptive presentation, in order to produce a signifi-cant impact on the tumour load. Furthermore, alloge-neic stem cell transplantation should be considered the protocol of choice whenever possible (even in elderly patients up to 70 years old, if reduced inten-sity regimens are used).20 Among our patients, only one (42 year old), was treated with allogeneic stem cell transplantation after having achieved CR with multiagent chemotherapy (6 CHOP courses). Note-worthy, despite multiagent chemotherapy was ad-ministered in only one patient, PFS was significantly higher in the group with a single lesion presentation than in patients with an eruptive appearance (23 vs. 9 months respectively, with a long lasting remission of 37 months in the first group), suggesting that sin-gle lesion-presentation can be a prognostic marker of lower severity - or at least more indolent course - of the disease. Basing on our data, although with the obvious limitation given the small dimension of the studied group, we could speculate that the concept of “cutaneous sanctuary” is particularly true in patients with a single lesion-presentation. In these patients, especially if >70 year-old aged, radiotherapy should be encouraged as the treatment of choice.

Riassunto

Neoplasia a cellule dendritiche plasmocitoidi blastiche: il santuario cutaneo

Obiettivo. Con il termine “blastic plasmacytoid dendri-tic cell neoplasm” (BPDNC) viene indicata una neoplasia maligna che deriva dalle cellule dendritiche plasmacitoidi. Tale patologia, attualmente collocata nell’ultima classifi-cazione WHO nel capitolo delle “acute myeloid leukemia (AML) and related precursor neoplasms”, ha un’eziopato-genesi ignota, sebbene negli ultimi anni siano stati condot-ti vari studi molecolari allo scopo di identificare anomalie geniche ricorrenti.

Metodi. In questo lavoro viene rivisitata e discussa la letteratura relativa ai BPDCN e sono presentati 11 casi con esclusivo interessamento cutaneo, selezionati dagli archivi del Gruppo multidisciplinare sui linfomi cutanei dell’Uni-versità di Firenze.

Risultati. In base alla presentazione clinica i casi sono



Alterations of the cell-cycle inhibitors p27(KIP1) and p16(INK4a) are frequent in blastic plasmacytoid dendritic cell neoplasms. J In-vest Dermatol 2010;130:1152-7.

18. Herling M, Jones D. CD4+/CD56+ hematodermic tumor: the fea-tures of an evolving entity and its relationship to dendritic cells. Am J Clin Pathol 2007;127:687-700.

19. Dalle S, Beylot-Barry M, Bagot M, Lipsker D, Machet L, Joly P et al. Blastic plasmacytoid dendritic cell neoplasm: is transplantation the treatment of choice? Br J Dermatol 2010;162:74-9.

20. Dietrich S, Andrulis M, Hegenbart U, Schmitt T, Bellos F, Martens UM et al. Blastic plasmacytoid dendritic cell neoplasia (BPDC) in elderly patients: results of a treatment algorithm employing alloge-neic stem cell transplantation with moderately reduced conditioning intensity. Biol Blood Marrow Transplant 2011;17:1250-4.

Notes.—The content of this manuscript has never been published or presented elsewhere.

Conflicts of interest.—None.Funding.—None.

neoplasm-morphologic and phenotypic variability in a series of 33 patients. Am J Surg Pathol 2010;34:75-87.

12. Cella M, Jarrossay D, Facchetti F, Alebardi O, Nakajima H, Lan-zavecchia A et al. Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon. Nat Med 1999;5:919-23.

13. Nizza D, Simoneaux SF. Blastic plasmacytoid dendritic cell neo-plasm presenting as a subcutaneous mass in an 8-year-old boy. Pedi-atr Radiol 2010;40(Suppl. 1):S40-2.

14. Bueno C, Almeida J, Lucio P, Marco J, Garcia R, de Pablos JM et al. Incidence and characteristics of CD4(+)/HLA DRhi dendritic cell malignancies. Haematologica 2004;89:58-69.

15. Rauh MJ, Rahman F, Good D, Silverman J, Brennan MK, Dimov N et al. Blastic plasmacytoid dendritic cell neoplasm with leukemic presentation, lacking cutaneous involvement: Case series and litera-ture review. Leuk Res 2012;36:81-6.

16. Chang HJ, Lee MD, yi HG, Lim JH, Lee MH, Shin JH et al. A case of blastic plasmacytoid dendritic cell neoplasm initially mimicking cutaneous lupus erythematosus. Cancer Res Treat 2010;42:239-43.

17. Wiesner T, Obenauf AC, Cota C, Fried I, Speicher MR, Cerroni L.


inhibiting the recruitment and migration of inflam-matory cells, as well as cytokine modulation and re-lease. It should also include treatment designed to reduce the hyperproliferation and normalize the dif-ferentiation of keratinocytes, biological effects that are offered to some extent by steroid therapy, but that are achieved to a greater extent with calcipotriol (or calcipotriene), a synthetic vitamin D analogue that acts by binding to the vitamin D receptor. This is the rationale whereby betamethasone and calcipotriol have both been widely used for psoriatic patients for more than two decades. Before the introduction of the fixed combination, the two therapies had to be applied separately, because calcipotriol requires an alkaline environment for stability whereas betam-ethasone requires acidic conditions. The fixed com-bination of calcipotriol (50 mcg/g) and betametha-

G. GIROLOMONI 1, G. A. VENA 2, F. AYALA 3,S. P. CANNAVÒ 4, O. DE PITÀ 5, S. CHIMENTI 6, A. PESERICO 7

Consensus on the use of the fixed combination calcipotriol/betamethasone dipropionate

in the treatment of plaque psoriasis

Calcipotriol, a vitamin D analogue, and betamethasone di-propionate, a high potency corticosteroid, are complementary agents for the topical treatment of psoriasis vulgaris. Robust evidence on the efficacy and safety of their fixed combina-tion has been provided by randomized, double-blind, con-trolled clinical trials involving more than 7000 patients with the ointment formulation in psoriasis of the body and more than 4000 patients with the gel formulation in scalp psoriasis. These trials have shown that the fixed combination ointment is more effective and better tolerated, not only than placebo, but also than calcipotriol and tacalcitol monotherapies. In addition, it has proved, in most instances, to be more effective than betamethasone and at least as well tolerated. The same applies to the gel for scalp and body psoriasis. Safety stud-ies have excluded that repeated courses of treatment with the fixed combination for up to one year produce systemic effects. Studies have also shown that the fixed combination treatment improves quality of life to a significantly greater extent than calcipotriol, with the once daily regimen most ap-preciated by patients, in both active disease and recurrency. Because of the extensive evidence, American and European guidelines recommend the calcipotriol/betamethasone dipro-pionate fixed combination as first line topical treatment for mild to moderate plaque psoriasis of the body and scalp.Key words: Psoriasis - Therapeutics - Betamethasone - Skin diseases.

Treatment of mild to moderate psoriasis should ensure rapid onset of control of the disease,

which may be achieved by potent topical steroid therapy, such as betamethasone, which suppresses erythema, edema and the inflammatory infiltrate by

Corresponding author: G. Girolomoni, Section of Dermatology and Venereology, Department of Medicine, University of Verona, Piazzale A. Stefani 1, 37126 Verona, Italy.E-mail: [email protected]


Lavoro: 4414-MD INGtitolo breve: Calcipotriol/betamethasone dipropionate in psoriasisprimo autore: Girolomonipagine: 609-24

1Department of MedicineSection of Dermatology and Venereology

University of Verona, Verona, Italy2Unit of Dermatology and Venereology

Department of Biomedical Sciences and Human Oncology, University of Bari, Bari, Italy

3Department of Dermatology and VenereologyMedical School of Naples Federico II University, Naples, Italy

4Section of Dermatology, Department of Social MedicineUniversity of Messina, Messina, Italy

5Department of Immunology and AllergologyIstituto Dermopatico dell’Immacolata, IRCSS, Rome, Italy

6Department of DermatologyUniversity of Rome “Tor Vergata”, Rome, Italy7Unit of Dermatology, Department of Medicine

University of Padoa, Padoa, Italy

CONSENSUS PAPERG ITAL DERMATOL VENEREOL 2012;147:609-24

GIROLOMONI CALCIPOTRIOL/BETAMETHASONE DIPROPIONATE IN PSORIASIS


sone (0.5 mg/g) therefore offered a convenient and rational therapeutic option.1, 2

This paper reviews the key efficacy evidence supporting the usage of the fixed combination in an ointment for psoriasis of the body and a gel for psoriasis of both the body and the scalp, the safety profile of the product based on the information that has accumulated in this decade and the recommen-dations made by American and European guidelines for the management of the disease. The objective is to provide a general consensus document, under the endorsement of the Italian Society of Dermatology (SIDeMaST), on the role of the fixed combination of calcipotriol and betamethasone dipropionate in the correct management of mild to moderate plaque psoriasis.

Therapeutic efficacy and quality of life in patients with plaque psoriasis of the body

Four key efficacy randomized, controlled trials (RCTs) have been conducted comparing the fixed combination ointment to both of its components separately or to alternative active monotherapy in patients with psoriasis vulgaris: two four-armed, double-blind trials comparing the combination to its single components and to vehicle (placebo);3, 4 one three-armed, double-blind trial comparing it to its single components;5 and one two-armed, double-blind trial comparing sequential treatment (four-week fixed combination treatment followed by four-week calcipotriol monotherapy) with tacalcitol 4 mcg/g for eight weeks 6 (Table I).

As shown in Table I, more than 4000 patients were included in these trials: 1412 patients were randomized to treatment with the combination or to sequential treatment first with the combination and then with calcipotriol; 1157 patients to treatment with calcipotriol monotherapy; 1153 to treatment with betamethasone monotherapy; 264 to treatment with vehicle (i.e., placebo) and 252 to treatment with active reference therapy (tacalcitol monotherapy). The duration of treatment ranged from 4 to 8 weeks. Eligible patients were aged ≥18 years and had pso-riasis involving at least 10% of one or more body regions (trunk and/or limbs) in all studies. The main exclusion criteria were unstable forms of psoriasis, other confounding inflammatory diseases, systemic antipsoriatic treatment including PUVA and UVB in

the last four to six weeks or during the trial, other topical treatment during the trial or in the last two weeks, hypercalcemia, contraindications to topical steroid therapy, pregnancy or breast feeding. The patient population generally included middle-aged subjects (mean age ranged from to 46.0 to 51.6 years), but subjects of all ages were included (range: 18-89 years). Men were slightly more numerous than women (range: 53.8-62.9%). Mean baseline psoriasis area severity index (PASI) ranged from 9.5 to 10.8. Mean disease duration in the different studies ranged from 17.7 to 20.3 years. Important reductions in the PASI score were consistently ob-tained in all studies, with a mean reduction of 65% to 74% achieved with the combination at four weeks. This reduction was always significantly greater than the reduction achieved with the single components (betamethasone 57-64%; calcipotriol 46-55%) and than the reduction achieved by the active control (tacalcitol 33%), as well as by the placebo (approx 23-31%). The mean differences between the sin-gle components and active treatment were consist-ent and always clinically important. In the studies by Kaufmann et al.,3 Papp et al.4 and Douglas et al.,5 the difference versus calcipotriol was -25.2%, (95%CI -21.9, -28.7), -24.4% (95%CI -20.0, -28.9) and -19.1% (95%CI -15.2, -22.8), versus betametha-sone -14.1% (95%CI -10.8, -17.6), -10.3% (95%CI -5.8, -14.7) and -13.1% (95%CI -9.3, -16.9), respec-tively. The difference versus vehicle was always con-siderable: Kaufmann et al.:3 -48.6%, (95%CI -43.4, -53.2): Papp et al.:4 -44.6% (95%CI -38.4, -50.8); in the study by Ortonne et al.6 the difference versus active reference treatment (tacalcitol) was -31.7% at the end of the four weeks with the combination and -20.6% at the end of treatment, at week eight after another four weeks of treatment with calcipotriol (all P<0.001).

Important differences were evident already after one week of treatment (Figure 1) indicating that the combination enables not only a greater disease con-trol, but also a more rapid onset of disease improve-ment, which is crucial to capture and maintain pa-tient adherence to therapy. For instance, in the study by Kaufmann et al.,3 after one week, the difference was -5.9% (95%CI -8.4, -3.5; P<0.001) between the combination group and the betamethasone group, -15.8% (95%CI -18.1, -13.2; P<0.001) between the combination group and the calcipotriol group and -21.1% (95%CI -24.3, -17.3; P<0.001) between the

CALCIPOTRIOL/BETAMETHASONE DIPROPIONATE IN PSORIASIS GIROLOMONI


Table I.—Main efficacy clinical trials conducted with the fixed combination calcipotriol / betamethasone dipropionate.

Author(Year) Design Patients population

(N. – inclusion criteria) Treatment Endpoint

Efficacy of the fixed combination ointment

Kaufmann R et al.(2002)Rif. 3

Randomized 3:3.3:1Double-blind4 parallel groups:Combination (Co)Betamethasone (B)Calcipotriol (Ca)Vehicle placebo (P)

Entered no 1605Eligible for efficacy (ITT) 1603 (Co 490, B 476, Ca 480, P 157)Age ≥ 18 yrsPsoriasis ≥10% of body regions (trunk and/or limbs)

Co calcipotriol 50 mcg/g + betamethasone 0.5 mg/gB 0.5 mg/gCa 50 mcg/gVehicle placeboOnce daily application x 4 weeks

Primary: Psoriasis Area and Severity Index (PASI)6-point investigators’ global assessment of disease severity6-point patient global assessment of disease severityChanges after 1, 2 and 4 weeks

Papp KA et al.(2003)Rif. 4


Entered no 1043Eligible for efficacy (ITT) 1028 (Co 301, B 312, Ca 308, P 107)Age ≥ 18 yrsPsoriasis ≥10% of body regions (trunk and/or limbs)

Co calcipotriol 50 mcg/g + betamethasone 0.5 mg/gB 0.5 mg/gCa 50 mcg/gVehicle placeboTwice daily applications x 4 weeks

Primary: Psoriasis Area and Severity Index (PASI), based on reference color photographs defining different grades of redness, thickness and scaliness6-point investigators’ global assessment of disease severity6-point patient global assessment of disease severity9-point target lesion severity scale Changes after 1, 2 and 4 weeks

Douglas et al.(2002)Rif. 5

Randomized 1:1.1Double-blind3 parallel groupsCombination (Co)Betamethasone (B)Calcipotriol (Ca)Open-labelExtension with Ca

Randomized no 1106Co 372 B 365 Ca 369Age ≥ 18 yrsPsoriasis vulgaris

Co calcipotriol 50 mcg/g + betamethasone 0.5 mg/gB 0.5 mg/gCa 50 mcg/gTwice daily appl x 4 weeksextens Ca same dosex 4 weeks

Primary: Psoriasis Area and Severity Index (PASI)6-point investigators’ global assessment of disease severityChanges after 1 and 4 weeks

Ortonne JP et al.(2004)Rif. 6

Randomized 1:1 double-blind2 parallel groups:Sequential treatment combination – calcipotriolOrtacalcitol

Entered no 501Eligible for efficacy (ITT) 501 (sequential 249, tacalcitol 252)

Age ≥ 18 yrsPsoriasis ≥10% of body regions (trunk and/or limbs)

Sequential treatment4 weeks with Fixed Co calcipotriol 50 mcg/g + betamethas 0.5 mg/g4 weeks calcipotriol 50 mcg/g aloneOr8 weeks with tacalcitol 4 mcg/g One application daily

Primary: Psoriasis Area and Severity Index (PASI)6-point investigators’ global assessment of disease severity6-point patient global assessment of disease severityChanges after 2, 4, 6 and 8 weeks of treatment

Quality of life

Saraceno R et al.(2007)Rif. 7

Randomized 1:1Open-label2 parallel groups:Sequential treatment Combination - calcipotriolOrCalcipotriol alone

Randomized 150 (Co. 75, calcipotriol alone 75)Age ≥ 18 yrsPsoriasis ≥10% of body regions (trunk and/or limbs)

Sequential treatment:calcipotriol 50 mcg/g + betamethasone 0.5 mg/g for 4 weeks + calcipotriol 50 mcg/g x 8 weeksorcalcipotriol 50 mcg&g x 12 weekstwice daily applications

Primary: Psoriasis Area and Severity Index (PASI) after 4 weeksSkindex-29 quality of life scale

Change after 2, 4, 8 and 12 weeks

Clareus BW et al.(2009)Rif. 8

Open-label. Observational Non-interventionalPatients followed x 6 months

Enrolled 1224Out-patients prescribed the combination for plaque psoriasis on trunk and/or limbs

Combination at discretion of physician

6-point investigator’s global assessment of disease severityPatient treatment satisfaction on 4-point scaleIf second course Reason for 2nd prescription and check if any change in satisfaction

(Continued)



the study by Ortonne et al.6 the response rate was 57.6% with the combination vs. 17% with tacalci-tol (P<0.001) and continued to be high after another four weeks of treatment with calcipotriol (50.8% vs. 23.5% with tacalcitol, P<0.001). The self-assessment of the patients was consistent with the measurements of the investigators. In the study by Kaufmann et al.3

combination group and the placebo group. The re-sponse rate, i.e. the proportion of patients in whom a marked improvement was achieved, was always sig-nificantly higher with the combination (range 56.3-76.1%) compared to betamethasone (37-55.8%) or calcipotriol (22.3-38.9%) alone, the active reference treatment (17%) and the placebo (7.5-10.2%). In

Table I.—Main efficacy clinical trials conducted with the fixed combination calcipotriol / betamethasone dipropionate.

Author(Year) Design Patients population

(No. – inclusion criteria) Treatment Endpoint

Ortonne JP et al.(2009)Ref. 9

Randomized 2:1 investigator-blind, two-arm,parallel-group

Enrolled 312 (Co. 207, calcipotriol solution 105)Age ≥ 18 yrsPsoriasis ≥ 10% or more of the total scalp area

The two-compound scalp formulation once daily for 8 weeks orcalcipotriol scalp solution twice daily for 8 weeks

SF-36 questionnaireSkindex-16 quality of life scaleChange after 2, 4, 8 weeks

Efficacy of fixed combination gelJemec JBE et al.(2008)Rif. 10


Enrolled 1506Randomized 1505Co541, B 556 Ca 272 pl 136Age ≥ 18 yrsScalp psoriasis ≥10% of total scalp area, at least moderate in severity, and signs or earlier diagnosis of psoriasis of body regions (trunk and/or limbs)

Co calcipotriol 50 mcg/g + betamethasone 0.5 mg/gB 0.5 mg/gCa 50 mcg/gVehicle placeboOne daily application x 8 weeks

Investigator’s global assessment of disease severity0-4-point severity scale for 3 signs (redness, thickness, scaliness) total score 0-12Patient’s global assessment of response

SafetyKragballe K et al.(2006)Rif. 11

RandomizedDouble-blind3 parallel groupsCombination – continuous therapyAlternating therapy with combination and calcipotriolSequential therapy with combination and calcipotriol

Enrolled 636Randomized 634 (continuous 212, alternating 213, sequential 209)Age ≥ 18 yrsAt least moderate psoriasis of trunk and/or limbs

Continous therapy:Co. x 52 weeksAlternating therapy4-week periodsCo. / calcipotriol 50 mcg/gSequential therapyCo. x 4 weeks then 48 weeks with calcipotriol 50 mcg/gOnce daily when required

Primary: incidence of ADRs assessed by independent Adjudication Panel assessments every 4 weeks in subgroup adrenal function tests(0, 4, 12 and 52 weeks)

Luger TA et al.(2008)Rif. 12

Randomized 1:1Double-blind2 parallel groupsCombinationOrcalcipotriol 50 mcg/g

Enrolled 873Randomized 869 (Co.429, calcipotriol 440)Age ≥ 18 yrsScalp psoriasis ≥10% of total scalp area, at least moderate in severity, and signs or earlier diagnosis of psoriasis of body regions (trunk and/or limbs)

Co. calcipotriol 50 mcg/g + betamethasone 0.5 mg/gorcalcipotriol 50 mcg/gonce daily when requiredx 52 weeks

Primary: incidence of ADRs and AE related to long-term use of steroids6-point Investigator’s global assessment od fisease severityChanges every 4 weeks up to 52 weeks

Fleming C et al.(2010)Rif. 13

Single-center, randomized, Double-blind, 2 parallel groupsCombinationBetamethasoneWith 2-week

Psoriasis of the body involving 15-30% of body surface

Co. calcipotriol 50 mcg/g + betamethasone 0.5 mg/gor bethametasone 0.5 mg/gOnce daily x 4 weeks

ACTH stimulation test (HPA axis function): Primary: maximum serum cortisol concentrationSecondary: maximum rise versus baseline



lesion. Combination treatment produced a 79% re-duction in both studies versus 61.7% and 67.1% in the betamethasone group, 63% and 53.8% in the calcipotriol group, respectively, and 26.8% with pla-cebo (all differences vs. combination P<0.001). Also these differences were clinically important, provid-ing further support to the superiority of the combi-nation. In the study by Ortonne et al.6 clearance of the lesions was the reason for early withdrawal in 6.4% of patients in the combination group vs. 1.2% in the tacalcitol group. Efficacy is supported also by the reduction in capillary bush diameter and capil-lary loop density assessed by videocapillaroscopy in 30 patients with psoriatic plaques on the elbows

64.9% of patients believed that the treatment had been a success in the combination group, 45.7% in the betamethasone group, 29.0% in the calcipotriol group and 9.7% in the placebo group. Results were similar in the study by Papp et al.4 and by Douglas et al.5 In the study by Ortonne et al.6 58.4% of patients believed that they had markedly improved after four weeks of treatment with the combination vs. 17.4% in the tacalcitol group; the corresponding propor-tions were 52.4% and 27% at week 8, after another four weeks of treatment with calcipotriol after the combination and with tacalcitol, respectively (both P<0.001). Papp et al.4 and Douglas et al.5 measured the additional parameter of thickness of the target

Figure 1.—Percent reduction in PASI score after 1 and 4 weeks of treatment with the fixed combination of betamethasone and calci-potriol, its single components and vehicle (Placebo) in 3 RCTs.3-5

% P

ASI

red

uctio

n

-80A

-70

-60

-50

-40

-30

-20

-10

0Week 1 Week 4

Kaufmann

Douglas

Papp

Ortonne

-39,2

-47,4 -48,1

-71,3-74,4 -74

-65

% P

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red

uctio

n

-70B

-60

-50

-40

-30

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0Week 1 Week 4

Kaufmann

Douglas

Papp

-33,2

-39,8 -41,4

-57,2

-61,3-64

% P

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uctio

n

-60C

-50

-40

-30

-20

-10

0Week 1 Week 4

KaufmannDouglas

Papp

-23,4

-31-28,4

-46,1

-55,3

-51

% P

ASI

red

uctio

n

-35D

-30

-25

-20

-15

-10

-5

0Week 1 Week 4

Kaufmann

Papp

-18,1

-21,5-22,7

-31



terms of Skindex-29 in both groups at weeks two and four as compared to baseline, but results were signif-icantly superior in the combination group compared with calcipotriol group (P<0.001). Patient satisfac-tion was recorded in the DESIRE study by Clareus et al.,8 an international multicenter, observational study, in which 1124 out-patients (mean age 49.4 years, 52% male), with psoriasis of the body (mostly mild to moderate disease 85%; mean duration 183 months) were enrolled and 997 (81.5%) completed a six-month study period. Patients could be prescribed a four-week course of treatment with the fixed com-bination repeatedly. Most of the patients received only one course of therapy (88%); 22.9% received two courses and 4.6% three or more. Nearly all pa-tients were prescribed the drug once daily (92.4%). The satisfaction rate with the drug was high and did not change after repeated courses (Figure 3). The most commonly mentioned reason for being very satisfied with treatment with the fixed combination was efficacy (94.9%); other less common reasons were easy of use (32.5%), tolerability (28.5%) and cosmetic acceptability (27.8%). Cost was not an issue (3.8%). Indeed, 59.6% of patients were will-ing to provide co-payment after the first course and 78.6% after the third course.9

assigned either to treatment of one elbow with the fixed combination and the other with betamethasone or to treatment of one elbow with the fixed combina-tion and the other with calcipotriol for four weeks.14 The reduction was significantly more marked with the combination than with the two monotherapies.

Quality of life was measured by means of the Skindex-29 scale in the randomized, open-label study by Saraceno et al.7 comparing sequential treat-ment (fixed combination for four weeks followed by calcipotriol monotherapy for another eight weeks) with calcipotriol monotherapy for 12 weeks in 150 patients aged 18-83 years with psoriasis of the body. The Skindex-29 scale is a validated instrument con-sisting of three scales rating burden of symptoms, social functioning and emotional state. Quality of life improved to a significantly greater degree with the combination than with calcipotriol monotherapy (Figure 2). Also in this study, in which medication was applied twice daily, the mean PASI score improved to a significantly greater degree with the combination than with calcipotriol monotherapy after four weeks: from 9.5±5.4 to 2.5±2.5 in the combination group versus from 9.1±4.1 to 4.1±3.3 in the calcipotriol monotherapy group (P<0.001). Similarly the quality of life assessment showed a marked improvement in

Figure 3.—High satisfaction rate with the combination that did not change with the increase in the number of courses of treat-ment.9

Figure 2.—Quality of life expressed as Skindex-29 scale score af-ter treatment for 2 and 4 weeks with calcipotriol monotherapy or the fixed combination in 150 patients with psoriasis of the body.8

Skin

dex-

29 s

core

-70

-60

-50

-40

-30

-20

-10

0Week 2Baseline Week 4

Combination Calcipotriol

% p

at

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80

70

60

50

40

30

20

10

0

73,6

78,9 80

2019,5

14,4

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most cleared was 68.6%, 62.5%, 38.3% and 20.7%, respectively. So the two compound scalp formulation was significantly more effective than calcipotriene and vehicle alone. Quality of life was measured by the Skindex-16 scale in the randomized, investiga-tor-blind trial by Ortonne et al.,9 comparing the once daily two compound formulation with twice daily calcipotriol scalp solution. There were treatment dif-ferences significantly in favor of calcipotriol/betam-ethasone dipropionate over calcipotriol. These dif-ferences included the total score at weeks 2 and 4 (P<0.001) and 8 (P=0.008); symptoms at weeks 2 and 4 (P<0.001) and 8 (P=0.004); emotions at weeks 2 and 4 (P<0.001) and 8 (P=0.005).

Use of calcipotriol – betamethasone dipropionate gel in psoriasis of the body

Three studies were conducted on the use of cal-cipotriol-betamethasone dipropionate gel in psoria-

Therapeutic efficacy and quality of life in patients with plaque psoriasis of the scalp

The key trial 10 assessing the efficacy of the fixed combination in psoriasis of the scalp was a rand-omized, double-blind four-armed trial comparing the fixed combination in a gel formulation, devel-oped specifically for use on the scalp, to its single components and to vehicle (placebo) in 1505 adult patients with psoriasis involving at least 10% of the scalp area (Table I). Exclusion criteria included sys-temic therapy (PUVA, steroids, vitamin D analogues and retinoids in the last four weeks, UVB or topical treatment in the last two weeks, biological therapy in the last six months), planned exposure to the sun, diagnosis of erythrodermic, exfoliative or pustular psoriasis, viral, fungal, bacterial or parasitic infec-tions of the skin, hypercalcemia, severe renal or he-patic disease. The gel was to be applied once daily for up to eight weeks. The primary endpoint was the proportion of patients in whom manifestations of the disease disappeared completely or who had very mild disease according to the Investigator’s Global Assessment (IGA) at the end of the eight-week treat-ment period. The patient population included all ages (range 18 to 91 years), with a mean age of 49.1 years. 55.2% were women and 96.3% were Cauca-sian. The mean duration of scalp psoriasis was 16.5 years. The fixed combination gel was significantly more effective, in terms of proportion of patients in whom absence of disease or very mild disease had been achieved, not only than placebo, but also than its two components starting from week 2 through-out the eight-week period. The differences were both highly significant (at least P<0.01) and clinically im-portant (at week 4 the difference was statistically sig-nificant vs. betamethasone dipropionate [P=0.0005] and vs. calcipotriene [P<0.0001]) (Figure 4). Sec-ondary efficacy assessment was the total sign score (5-item semiquantitative severity score with scores ranging from 0 to 4 for three signs, namely red-ness, thickness and scaliness) and the patient’s as-sessment of treatment response. At all on-treatment visits, the total sign score was lower in the combina-tion group compared with the other treatment group and diminished by -70.8% in the combination group, by -67.7% with betamethasone (P=0.12), by -49% with calcipotriene (P<0.0001) and by -35.6% with placebo (P<0.0001). The proportion of patients who claimed that their scalp psoriasis had cleared or al-

Figure 4.—Efficacy of fixed combination gel treatment (once dai-ly application for up to 8 weeks) in terms of proportion of 1505 patients in whom scalp psoriasis disappeared or became very mild.10

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riol 50 µg/g gel; gel vehicle. The randomization ratio among groups was 4:2:2:1. The primary efficacy pa-rameter was the responder rate at week 4 and week 8 according to IGA. The secondary efficacy param-eter was the change in the “Psoriasis Area and Se-verity Index” (PASI) score, expressed as a percent-age, at week 4 and at week 8, whereas the tertiary endpoint was the proportion of patients who experi-enced ≥75% improvement of PASI (PASI 75) score as compared to baseline. Assessments of IGA, PASI score and tolerability (reporting of systemic adverse events and events involving the lesions and the area surrounding them) were performed at week 0 and af-ter 1, 2, 4, 6 and 8 weeks of treatment. A total of 364 patients were randomized: 162 to the combination group, 83 to the betamethasone group, 79 to the cal-cipotriol group and 40 to the vehicle placebo group. Overall, 90% of randomized patients were examined at week 8. At week 4 the proportion of patients who achieved disease control was 16% in the combina-tion gel group versus 9.6% in the betamethasone gel group, 3.8% in the calcipotriol gel group and e 2.5% in the vehicle group. At week 8 the corresponding proportions were 27.2%, 16.9%, 11.4% and 0%. So the combination calcipotriol/betamethasone dipro-pionate gel was significantly more effective than all the three other treatments. The mean change in PASI index at week 4 as compared to baseline amounted to −48.1% in the combination gel group, −40.9% in the betamethasone gel group, −32.7% in the calcipo-triol gel group and −16.9% in the placebo group. The combination in gel formulation was significantly more effective than betamethasone gel (difference −7.2%; 95% CI −15.2 to −0.5; P=0.04), calcipot-riol gel (difference −15.4%; 95% CI −22.8 to −7.9; P<0.001) and placebo (difference −31.2%; 95% CI −40.4 to −21.2; P<0.001). The changes in PASI in-dex over time, expressed as percentages, are shown in Figure 5. The safety population included 362 out of the 364 randomized patients. The proportion of patients with at least one adverse event was 42.5% in the combination group, 48.2% in the betamethasone gel group, 35.4% in the calcipotriol gel group and 55% in the placebo group. There were no statistical-ly significant differences in the frequency of adverse events among the 4 groups of treatment. Most of the adverse events was considered not to be related to treatment and were judged to be of mild to moderate intensity. No serious adverse events related to study treatment were reported. Adverse events involving

sis of the body.11-14 The first was the study by Flem-ing et al.15 Its objective was to compare the clinical efficacy and safety of psoriasis treatment with cal-cipotriol and betamethasone dipropionate gel ap-plied once daily versus betamethasone dipropionate in the gel vehicle, calcipotriol in the gel vehicle and vehicle alone (placebo). The study was a prospec-tive, randomized, controlled, double-blind, four-armed international, multicenter trial. Treatment lasted eight weeks in patients suffering from at least mild plaque psoriasis, defined according to the IGA rating scale. The study was conducted at 19 centers located in Canada, Germany, Ireland, UK and Swe-den. A total of 364 adult patients were recruited, who were suffering from at least mild plaque psoriasis (IGA criterion) involving the trunk and limbs to an extent requiring no more than 100 g topical drug per week. The exclusion criteria were: guttate, erythro-dermic, exfoliative or pustular psoriasis; use of po-tentially active biological therapy for psoriasis in the six months before randomization, other systemic therapy for psoriasis, treatment with other drugs, PUVA or Grenz ray therapy in the last four weeks and topical therapy or UVB in the last two weeks be-fore randomization. The patients were treated once daily for up to a maximum of eight weeks with: com-bination in gel formulation (containing calcipotriol 50 µg/g and betamethasone diproprionate 0.5 mg/g); betamethasone dipropionate 0.5 mg/g gel; calcipot-

Figure 5.—Mean percentage changes in PASI index over time by treatment in 364 patients with plaque psoriasis.15

Two-compound gel Betamethasone

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after 1-16 weeks. The primary parameter selected to measure the efficacy of treatment was a 6-item IGA score (1= complete remission; 2=nearly complete remission; 3=mild disease; 4=moderate disease; 5=severe disease; 6=very severe disease), analyzing the proportion of patients who achieved complete or almost complete disappearance of disease at week 8. The secondary efficacy parameter was the change in the modified PASI score, expressed as a percentage. The head was excluded from the assessment (thus, the maximum score was 64.8 instead of 72, as set for the standard PASI score). At each visit patients were asked to self-assess the severity of their dis-ease, using a five-item rating scale ranging from no disease to severe disease. IGA regarded the objec-tive severity of the disease, so the patient’s assess-ment was to focus on subjective symptoms and the impact of the disease on quality of life. Also the proportions of patients who achieved at least 50% and 75% improvement in PASI index (PASI 50 and PASI 75, respectively) as compared to baseline were recorded. The recurrence (reduction in the improve-ment in PASI ≥50% in patients with a complete or almost complete response according to IGA criteria) rate was measured among responders to treatment after its discontinuation and so was the appearance of rebound (worsening of psoriasis, with PASI score >125% of baseline value). Furthermore, also compli-ance to treatment was assessed and adverse events, adverse reactions related to treatment and reasons for discontinuation of the study were recorded. A to-tal of 458 patients were randomized: 183 to the com-bination gel group, 184 to the tacalcitol group and 91 to the placebo group. 86.9% of the randomized patients completed eight weeks of treatment. During treatment, 60 patients stopped participating: 12 in the combination group, 21 in the tacalcitol group and 27 in the placebo group. The efficacy of calcipotriol/betamethasone dipropionate gel was noticeable early on. At each visit the proportion of patients in whom the disease had disappeared or had almost disap-peared was higher in the combination group than in the other two. At week 4 the proportion in the combi-nation gel group was 18.6% versus 6.5% in the tacal-citol group and 1.1% in the placebo group (P<0.001 for both comparisons). The proportion of patients with complete or almost complete remission at week 8 (primary objective) was 39.9% in the combina-tion group, 17.9% in the tacalcitol group and 5.5% in the placebo group (P<0.001 for the comparison

the skin lesions or the area surrounding them oc-curred in 7.5% of patients in the combination group, in 8.4% in the betamethasone gel group, in 10.1% in the calcipotriol group and in 25% in the placebo group. Thus, the combination calcipotriol/betameth-asone dipropionate gel was superior to all compa-rators in terms of efficacy. There was no significant difference among treatments in terms of frequency and type of adverse events.

The second study was performed by Langley et al.16 The objective of this study was to compare cal-cipotriol/betamethasone dipropionate gel applied once daily with tacalcitol ointment and placebo gel in the treatment of plaque psoriasis in terms of clinical efficacy and tolerability. It was a phase III, multicenter, prospective, randomized, controlled, single-blind (the investigator was blind) trial, with three arms and parallel groups treated for 8 weeks, in patients suffering from at least moderate plaque pso-riasis, defined according to the IGA. Eighteen Ca-nadian centers took part in the study. A total of 458 patients were randomized. They were suffering from plaque psoriasis involving the trunk and limbs (area equivalent to ≥10% of the upper limbs and/or ≥10% of the trunk and/or ≥10% of the lower limbs). The main exclusion criteria were: systemic biotechnolog-ical therapy for psoriasis in the three months before randomization, systemic therapy with retinoids, cor-ticosteroids or other immunosuppressants or therapy with UVA or Grenz ray therapy in the last four weeks before randomization. Concomitant systemic admin-istration of vitamin D preparations with daily doses exceeding 500 IU was forbidden. Patients were treat-ed once daily up to a maximum of eight weeks with: the combination gel (containing calcipotriol 50 µg/g and betamethasone dipropionate 0.5 mg/g); tacalci-tol monohydrate 4 mg/g ointment; placebo. The ratio among groups was 2:2:1. The maximum quantity of product that could be applied every week was 100 g of the combination gel or placebo gel and 70 g of ta-calcitol ointment. In the event that clinical remission was achieved, according to IGA criteria, treatment was stopped before eight weeks had elapsed, but the patients continued the study entering the follow-up period and was instructed to resume treatment if the disease reappeared. Patients who were judged to have achieved “complete or almost complete remission” at week 8 entered the follow-up period without treat-ment, which lasted up to eight weeks. Clinical re-sponse and tolerability were assessed at baseline and



treatment was significantly lower in the combination gel group (8.8% versus 15.8% in the tacalcitol group [P=0.042] and 17.6% in the placebo group P=0.033). No serious adverse events related to treatment oc-curred. Early discontinuation due to adverse events rarely occurred in all three groups (1.6% in the com-bination gel group, 2.2% in the tacalcitol group and 4.4% in the placebo group). This study shows that the efficacy of calcipotriol/betamethasone dipropi-onate gel, applied once daily up to a maximum of eight weeks on circumscribed plaques on the trunk and/or limbs, is high and that its tolerability is excel-lent. The gel is superior not only to placebo, but also to tacalcitol ointment.

The third study was the one by Queille-Roussel.17

The objective of this study was to assess the use of a standard method (sonography) for the study of pso-riatic plaques, comparing the therapeutic efficacy of six topical products: the combination of calcipotriol 50 µg/g and betamethasone dipropionate 0.5 mg/g in a gel or ointment formulation, calcipotriol 50 µg/g in a cream or ointment formulation, an investigational product containing calcipotriol 25 µg/g and hydro-cortisone 10 mg/g and an inert topical preparation (control). The study was a single-center, randomized, controlled, single-blind (blinded investigator) trial that assessed the therapeutic efficacy and tolerabil-ity of five topical products for plaque psoriasis and a placebo control. Twenty-four adult patients were included. They were suffering from plaque psoriasis with skin lesions involving the upper or lower limbs or the trunk, which were assessed according to the Total Clinical Score (TCS) at baseline ranging from 4 to 9. The exclusion criteria were: presence of gut-tate, erythrodermic, exfoliative or pustular psoria-sis; use of topical therapy in the last 2 or 4 weeks, UVB rays in the last two weeks or PUVA therapy in the last four weeks before randomization; use of systemic treatment (corticosteroids, retinoids, im-munosuppressants and antiproliferative drugs) in the last 12 weeks. Patients were treated simultaneously once daily for six days a week for 21 days with: cal-cipotriol 50 mg/g and betamethasone dipropionate 0.5 mg/g in gel formulation; calcipotriol 50 µg/g and betamethasone dipropionate 0.5 mg/g in ointment formulation; calcipotriol 50 µg/g cream; calcipotriol 50 µg/g ointment; investigational product containing calcipotriol 25 mg/g and hydrocortisone 10 mg/g; placebo ointment. The primary efficacy parameter was the clinical response, assessed by TCS (result-

between the combination group and each of the other two groups). The mean change in PASI index versus baseline at week 8 (LOCF approach) was -57% in the calcipotriol/betamethasone gel group, -41.9% in the tacalcitol group and -17.9% in the placebo group (P<0.001 for both differences). Statistically signifi-cant differences in the change in PASI score in favor of the combination gel group were recorded also at week 4 and at other visits, as can be seen in Figure 6. Furthermore, the judgment expressed by the patient about the severity of disease was consistent with the objective assessment of the clinical response. In par-ticular, at week 4, 29.7% of the subjects treated with the combination gel believed that their disease had resolved or was very mild as compared to 12% in the tacalcitol group and 8.6% in the placebo group; the corresponding rates at week 8 were 40.4% ver-sus 21.5% and 21.9%). Compliance was high in all three groups (94% in the combination arm, 92.9% in the tacalcitol group and 87.9% in the placebo group). The mean weekly quantity of drug used amounted to about 27.5 g in the combination group, 33.2 g in the tacalcitol group and to 26.2 g in the placebo group. The proportion of patients who reported at least one adverse event was similar in the three groups: 39.6% in the calcipotriol/betamethasone gel group, 45.1% in the tacalcitol group (P=0.28) and 38.5% in the placebo group (P=0.86). The proportion of patients with at least one adverse reaction related to

Figure 6.—Mean percentage changes in PASI index over time by treatment in 458 patients with plaque psoriasis.16

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ment of plaque thickness, which improved to a sig-nificantly greater degree with the combination in gel or ointment as compared to the other topical refer-ence therapies. There were no significant differences between the combination gel and the combination ointment. A reduction in TCS was recorded with all the six products, but the combination of calcipotriol and betamethasone dipropionate, in its formulation in gel or ointment proved to be more effective than other preparations (Table II and Figure 7). The ul-trasound assessment showed that the fixed combina-tion of calcipotriol and betamethasone dipropionate in gel or ointment was more effective than the other therapies, as it produced an important reduction in plaque skin thickness. There were no statistically significant differences between the two formulations of the combination. This is consistent with the re-sults related to the TCS (Table II). The combination of the two active ingredients produced a significant-ly greater reduction in skin thickness than the other therapies used, also in terms of reduction in the his-tological score (P<0.005) as compared to placebo. Furthermore, the combination of calcipotriol and betamethasone produced also a significant reduction in CD3, CD4, CD8, CD45RO, Ki-67 and cytokera-tin 16, as compared to calcipotriol monotherapy and placebo. The data collected showed, therefore, that the combination was more effective on morphol-ogy, infiltration and differentiation of the epidermis than monotherapy. During the treatment period 12 adverse events occurred in nine subjects. The most common event was itching, with seven episodes in six patients; three episodes occurred after the appli-cation of vehicle, two after the application of cal-cipotriol cream, one after application of calcipotriol ointment and one after application of the investiga-tional ointment. The adverse events were classified as events that were probably related to treatment; the remaining adverse events were not related. No seri-ous adverse events were reported. Ultrasound assess-

ing from the sum of the scores related to the severity of erythema, infiltration and scaliness), using a 0 to 3 rating scale for each parameter. Patients attended the centre for check-ups twice a week. Also an analy-sis of plaque thickness was performed through ul-trasound assessment of lesion skin on days 1, 8, 15 and 22 using a B scanner equipped with a 20 MHz transducer. A separate study assessed the morphol-ogy of the epidermis, the degree of proliferation and the differentiation biomarkers by means of skin bi-opsies with 4 mm punch. Biopsies were collected at the final visit, after a physician not involved in the clinical score recording had calculated the clinical score related to the psoriatic plaques in selected ar-eas; no more than two biopsies were collected for each subject. Biopsies were randomized to ensure that an equal number of biopsies was collected for each of the three treatments undergoing evaluation (calcipotriol ointment, the combination of calcipot-riol and betamethasone and placebo). The histologi-cal and immunohistochemical examination of the biopsies was designed to assess the morphology of the epidermis and biomarker levels, including CD3, CD4, CD8 and CD45RO, as parameters measur-ing T cell infiltration; and Ki-67 as an indicator of epidermal proliferation. The histological score was calculated as the sum of the values of: the thickness of the epidermis, the thickness of the stratum cor-neum and granulosum, the degree of parakeratosis, infiltration by inflammatory cells and frequency of neutrophil microabscesses. The results of this study have shown that the combination of calcipotriol and betamethasone dipropionate in gel is as effective as the same combination in ointment formulation. Both these products have proved to be more effective than calcipotriol ointment and than the investigational ointment; calcipotriol cream and placebo were the least effective treatments. The clinical results, based on the primary efficacy endpoint, i.e. the change in TCS, were confirmed by the sonographic assess-

Table II.—Change in the single parameters of total clinical score (TCS) versus baseline at the end of treatment.

Erythema Scaling Infiltration

Dovobet® ointment -1,69 ± 0,79 -2,27 ± 0,49 -2,23 ± 0,55Dovobet® gel -1,60 ± 0,72 -2,08 ± 0,43 -2,04 ± 0,62Calcipotriol ointment -1,08 ± 0,60 -1,71 ± 0,74 -1,69 ± 0,76Calcipotriol cream -1,08 ± 0,72 -1,06 ± 0,70 -1,23 ± 0,57Investigational ointment -1,10 ± 0,75 -1,77 ± 0,87 -1,38 ±0,76Vehicle (placebo control) -0,67 ± 0,64 -1,13 ± 0,78 -0,92 ± 0,72



most common adverse reactions were local cutane-ous events, reported in 2.9-9.9% of patients treated with the fixed combination, 4.7-8.6% of patients treated with betamethasone, 11.4-17.2 % of patients treated with calcipotriol, 11.8% of patients treated with tacalcitol and 13.6-15.7% of patients in the placebo group. The most common local event was pruritus; in the study by Papp et al.4 its incidence was 14.3% with calcipotriol, 9.3% with placebo, 5.4% with betamethasone and 4.9% with the fixed combination. Regarding the gel, withdrawals due to intolerance were also more common with calcipo-triol monotherapy (7.4%) and with vehicle (5.1%) than with the fixed combination (1.5%) and with betamethasone (1.1%).12 The same was true for the proportion of patients reporting at least one adverse event: calcipotriol 46.2%, vehicle 40%, fixed com-bination 34.5%, betamethasone 34.9%. Once again the most common event was pruritus (calcipotriol 6%, vehicle 6.7%, fixed combination 2.8%, beta-methasone 1.8%). Thus, the fixed combination and betamethasone were the best tolerated products. This was expected, as they both contain a potent steroid that controls local symptoms in the short-term, but that may cause well-known cushingoid untoward ef-fects in the long-term. This issue was addressed by

ment was very useful for the assessment of response to treatment of psoriatic plaques. It showed that treat-ment with calcipotriol/betamethasone dipropionate gel or ointment is more effective than monotherapy, but that there are no significant differences between the two formulations of the combination.

Short-term and long-term tolerability

The fixed combination was very well tolerated in the short-term efficacy trials both in body and scalp psoriasis. Out of the 1412 patients treated with the fixed combination ointment, only 11 (0.8%) with-drew because of adverse events. The withdrawal rates due to adverse events in the other treatment groups were higher - 4.8% with tacalcitol, 4.5% with placebo, 1.3% with calcipotriol - with the only ex-ception of betamethasone (0.4%). The proportions of patients reporting adverse events were similar to the withdrawal rates due to intolerance, as fewer patients on treatment with the fixed combination reported adverse events (range: 16.3-29.6%) than those on treatment with calcipotriol (33.1-38.3%), betameth-asone (24.7-32.1%) or tacalcitol (26.8%), and even than those in the placebo group (31.5-34.4%). The

Figure 7.—Absolute change in TCS from baseline. p-values assessed by a pair-wise t-test.17

TC

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patients (2.8%) in the alternating therapy group and six reactions in six patients (2.9%) in the sequential therapy group. ADRs with an incidence ≥1% were: skin atrophy (1.9%, 0.5% 1%, respectively), follicu-litis (1.4%, 0.5% and none, respectively) and skin depigmentation (1% only with continuous therapy). In the long-term study with the gel by Luger et al.12 the fixed combination was much better tolerated than calcipotriol monotherapy: the proportion of patients who reported ADRs was 17.2% vs. 29.5%; 2.1% of patients withdrew because of unacceptable ADRs vs. 10%. Once again the most common adverse event was pruritus (10% of patients on calcipotriol, 3.6% on the fixed combination). Also in this study ADRs considered to be due to the long-term use of corticos-teroids occurred in few patients: 11 patients (2.6%) in the fixed combination group vs. 13 (3%) in the cal-cipotriol group; the only single event that occurred in ≥1% of patients was rosacea (1.2% in the calcipotriol group vs. 0.7% in the fixed combination group). In both studies the tachyphylaxis phenomenon is not mentioned, because the authors did not remark it in all patients, that have been treated with combination therapy for up to 52 weeks. Additional reassurance has been provided by two studies that addressed the issue of whether treatment with the fixed combina-

two long-term studies, in which psoriatic patients were treated, when required, for up to one year: the randomized, double-blind trial by Kragballe et al.11 comparing continuous therapy with the fixed com-bination ointment, alternating therapy (fixed combi-nation and calcipotriol monotherapy, when required) and sequential therapy (four weeks with fixed com-bination, then 48 weeks with calcipotriol mono-therapy) in 634 patients with psoriasis of the body, and the randomized, double-blind trial by Luger et al.12 comparing the two compound formulation in gel with calcipotriol solution monotherapy in 869 patients with scalp psoriasis. In both trials long-term treatment with the fixed combination was the best tolerated treatment. In the study by Kragballe et al.11 patients in the continuous treatment group reported fewer adverse drug reactions (ADRs) than patients in the alternating group and in the sequen-tial group (21.7% vs. 29.6% and 37.9%, respec-tively); adverse events led to withdrawal in 6.8% during continuous therapy, in 5.2% during alternat-ing therapy and in 7.8% during sequential therapy. Few events considered to be corticosteroid adverse reactions by the Adjudication Panel occurred in all three groups: 11 reactions in 10 patients (4.8%) in the continuous therapy group, seven reactions in six

Figure 8.—Absolute change in skin thickness from baseline. p-values assessed by a pair-wise t-test.17

Ointment vehicle control

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focusing on compliance to anti-psoriatic therapy showed that the once daily application was much more preferable than the twice daily (on average 82.3% versus 44%); also compliance to topical ther-apy was much higher than that to oral therapy (on average 71.9% vs. 46.1%).19 To our knowledge, only the fixed combination of betamethasone and calcipo-triol is approved for once daily application, due to the superiority of the fixed combination given once daily compared to placebo and to both components (betamethasone and calcipotriol) alone in plaque-type psoriasis (involving the body) 3 and to calcipot-riol in scalp psoriasis.10

Place of the fixed combination of calcipotriol and betamethasone dipropionate

in the treatment of psoriasis

Topical therapy alone is usually used for the treat-ment of mild to moderate psoriasis of the body and scalp. Patients with severe psoriasis are treated with systemic drugs, as are some of the patients with moderate psoriasis, together with topical treatment, as appropriate. In this case, the treatment is usu-ally divided into two steps: initial therapy to clear plaques and then long-term maintenance therapy to prevent recurrence.

Most patients have mild psoriasis and are treated exclusively with topical therapies. American and European guidelines 20, 21 list a number of agents for topical treatment. Among these drugs, potent and very potent corticosteroids are effective, but they should be used in short-duration courses, since they are associated with well known adverse effects. Combining corticosteroids with vitamin D3 ana-logues increases efficacy and accelerates the onset of clinical response, compared with monotherapy, and permits, therefore, to spare the use of corticoster-oids in the long term. Guidelines point out that really good evidence of efficacy and safety (level A or level 1) is available only for corticosteroids and vitamin D analogues.20, 21 They both single out the fixed combi-nation of betamethasone and calcipotriol in view of the excellent evidence supporting long-term efficacy and safety. Calcipotriol/betamethasone dipropion-ate formulation is composed of two agents that act synergically through different and complementary mechanisms of action. RCTs involving more than 7000 patients have shown that the fixed combination

tion suppresses the hypothalamus-pituitary-adrenal axis (HPA) by assessing adrenal function by means of a rapid standard dose synthetic adrenocortico-trophic hormone (ACTH) stimulation test, measur-ing serum cortisol before and 30 and 60 minutes af-ter stimulation. The first study was a single center, prospective randomized, double-blind trial in 27 psoriatic patients comparing the fixed combination to betamethasone monotherapy, both applied once daily for four weeks.13 No significant differences were found between the two treatments or between the rise in serum cortisol before and after treatment. Nine patients had abnormal cortisol values after four weeks of treatment; eight of these had abnormal or unquantifiable values at baseline; the ninth patient was in the betamethasone group. The second study was the long-term trial by Kragballe et al.;11 HPA suppression was tested in a subgroup of 19 patients and no cases of suppression related to treatment were found.

Dosage and administration

The fixed combination gel and ointment cal-cipotriol 50 µg/g and betamethasone dipropion-ate 0.5 mg/g is approved in Europe for the treat-ment of stable plaque psoriasis once daily for four weeks. The recommended treatment duration is four weeks, however application may be restarted after a medical examination and four-week courses may be continued or repeated for up to 52 weeks. The maximum daily dose should not exceed 15 g and the maximum weekly dose is 100 g; the treated body surface area should not exceed 30%. The fin-ger tip unit (FTU), defined as the amount of oint-ment applied from the distal skin-crease to the tip of the index finger of an adult,18 should be the measure used to optimize the clinical results and to encourage adherence to therapy. According to this method, two FTUs are approximately equivalent to treat the 4% of cutaneous surface (BSA score). The fixed combination gel is approved for therapeutic use once daily for recommended treatment duration of four weeks in scalp psoriasis and eight weeks in body psoriasis; courses of the gel may be repeated with the same limitations as described above for the ointment.

Once daily application of topical treatment is cru-cial for patients’ adherence to treatment. A survey



dose their topical medications. As 1 FTU is sufficient to treat two palms, including fingers, (corresponding to about 2% of the skin surface according to the BSA score), it becomes easy to calculate the appropriate amount of topical agents to be applied to affected skin. Moreover, topical therapy with the combination offers important advantages also with regard to pa-tient’s compliance, as shown by the numerous studies on the quality of life and the degree of satisfaction in relation to the treatments, with which more than 80% of patients were satisfied.8, 23 In this regard recent studies indicate that the gel formulation is preferred by the patients and lead to greater treatment’s compli-ance.24 Treatment should be individualized to match the patients’ needs and expectations regarding the success of therapy. The two-compound gel is a new topical treatment option for body psoriasis and it is more effective than the single components and tacal-citol, with fewer adverse events, as showed in scien-tific evidences.15, 16 Furthermore, the combination gel efficacy is comparable to ointment, as demonstrated in a recent study, where the authors have evaluated the clinical response to both formulation through TCS score, ultrasound assessment and lesion biopsies.17

Conclusions

In conclusion, the calcipotriol/betamethasone di-propionate fixed combination is an effective and well tolerated medicinal product for once daily usage for the treatment of mild to moderate psoriasis of the body and scalp. It can be used in combination with systemic therapies in more severe cases, possibly acting as a systemic drug-sparing tool.25 It plays an important role in the management of the disease and both American and European guidelines associate treatment with the two-compound preparation to a high strength of recommendation20,21.

Riassunto

Consenso sull’uso dell’associazione fissa calcipotriolo / betametasone dipropionato nel trattamento della psoriasi in placche

Il calcipotriolo, un analogo della vitamina D, e il beta-metasone dipropionato, un corticosteroide di alta potenza, sono farmaci complementari per il trattamento topico del-la psoriasi. Sono state fornite ampie prove dell’efficacia e

ointment is more effective and better tolerated, not only than placebo, but also than calcipotriol and ta-calcitol monotherapies; in addition, it has proved, in most instances, to be more effective than betametha-sone dipropionate and at least as well tolerated. The same applies to the gel formulation in both body and scalp psoriasis. What is more, videocapillaroscopic observations have documented that the fixed combi-nation calcipotriol/betamethasone dipropionate pro-duces significantly greater improvements in capillary structure derangement than its components alone.

The synergistic effect of the combination with the single monotherapies was also confirmed by im-mmunohistochemical studies.22 Greater efficacy of calcipotriol/betamethasone dipropionate compared with the monotherapies was demonstrated for both the ointment and gel formulation, given once daily for the recommended a four-week treatment period. The response to the two compound product is rapid, but it is generally necessary to continue treatment up to four weeks to achieve an optimal clinical response. Safety studies have demonstrated the good tolerabil-ity of repeated courses of treatment, with the fixed combination, as needed under medical supervision for up to 52 weeks. During long-term treatment, with repeated courses for up to 52 weeks, in patients who had satisfactory responses at all visits during treat-ment, there was a trend in favor of the continuous use of calcipotriol/betamethasone dipropionate over switching or alternating therapies. Evidence suggests that two compound formulations may be used con-tinuously for up to one year with improved efficacy, without any significant increase in corticosteroid-related adverse events and with fewer adverse events than calcipotriol. Moreover, the fixed combination treatment improves quality of life to a significantly greater extent than calcipotriol; the once daily regi-men of the fixed combination, to date a unique feature of the fixed combination calcipotriol/betamethasone, contributes to this improvement and is an important premise to increase adherence to therapy. Finally, at the light of these data, the usage of calcipotriol is suggested in combination with betamethasone di-propionate for the first four weeks only. Its usage as monotherapy, in the relapses, is not justified.

In clinical practice patients may often encounter difficulties in using the correct dosage of topical ther-apy with important implications in terms of clinical response and economic aspects. The usage of the con-cept of finger tip unit (FTU) may help patients better



garis: a randomized, multicentre, clinical trial. J Dermatol Treat 2007;18:361-5.

9. Clareus BW, Houwing R, Sindrup JH, Wigchert S. The DESIRE study – psoriasis patients’ satisfaction with topical treatment using a fixed combination of calcipotriol and betamethasone dipropionate in daily clinical practice. Eur J Dermatol 2009;19:581-5.

10. Jemec JBE, Ganslandt C, Ortonne JP et al. A new scalp formula-tion of calcipotriene plus betamethasone compared with its active ingredients and the vehicle in the treatment of scalp psoriasis: a randomized, double-blind, controlled trial. J Am Acad Dermatol 2008;59:455-63.

11. Ortonne JP, Ganslandt C, Tan J et al. Quality of life in patients with scalp psoriasis treated with calcipotriol/betamethasone dipropionate scalp formulation: a randomized controlled trial. J Eur Acad Derma-tol Venereol 2009;23:919-26.

12. Kragballe K, Austad J, Barnes L et al. A 52-week randomized safety study of a calcipotriol/betamethasone dipropionate two-compound product (Dovobet®/Daivobet®/Taclonex®) in the treatment of pso-riasis vulgaris. Br J Dermatol 2006;154:1155-60.

13. Luger TA, Cambazard F, Larsen FG et al. A study of the safety and efficacy of calcipotriol and betamethasone dipropionate scalp formulation in the long-term management of scalp psoriasis. Der-matology 2008;217:321-8.

14. Fleming C, Ganslandt C, Leese GP. Short- and long-term safety assessment of a two-compound ointment containing calcipotriene/betamethasone dipropionate (Taclonex®/ Daivobet®/ Dovobet® ointment): hypothalamic-pituitary-adrenal axis function in patients with psoriasis vulgaris. J Drugs Dermatol 2010;9:969-74.

15. Fleming C, Ganslandi C, Guenther L et al. Calcipotriol plus beta-methasone dipropionate gel compared with its active components in the same vehicle and the vehicle alone in the treatment of psoriasis vulgaris: a randomised, parallel group, double-blind, exploratory study. Eur J Dermatol 2010;20:1-7.

16. Langley RGB, Gupta A, Papp K et al. Calcipotriol plus betametha-sone dipropionate gel compared with tacalcitol ointment and the gel vehicle alone in patients with psoriasis vulgaris: a randomized, controlled clinical trial. Dermatology 2011;222:148-56.

17. Queille-Roussel C, Hoffmann V, Ganslandt C, Hansen KK. Com-parison of the antipsoriatic effect and tolerability of calcipotriol-containing products in the treatment of psoriasis vulgaris using a modified psoriasis plaque test. Clin Drug Investig 2012;32:613-9.

18. Zaghloul SS, Goodfield MJD. Objective assessment of compliance with psoriasis treatment. Arch Dermatol 2004;140:408-14.

19. Finlay AY, Edwards PH, Harding KG. “Fingertip unit” in dermato-logy. Lancet 1989;2:155.

20. Menter A, Korman NJ, Elmets CA et al. Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 3. Guide-lines of care for the management and treatment of psoriasis with topical therapies. J Am Acad Dermatol 2009;60:643-59.

21. Nast A, Boehncke WH, Mrowietz U et al. German S3-guidelines on the treatment of psoriasis vulgaris (short version). Arch Dermatol Res 2012;304:87-113.

22. Van der Velden HMJ, Pasch MC, Van Herp PEJ et al. Treatment of plaque psoriasis with the two-compound product calcipotriol/beta-methasone dipropionate versus both monotherapies: an immunohi-stochemical study. J Dermatol Treat 2010;21:13-22.

23. Vena GA, Cassano N, Agnusdei CP et al. Treatment of psoriasis vulgaris with calcipotriol betamethasone dipropionate combination followed by calcipotriol and assessment of the adjuvant basic use of urea-based emollients. Eur J Inflamm 2005;3:37-41.

24. Reich K, Bewley A. What is new in topical therapy for psoriasis? JEADV 2011;25:15-20.

25. Vena GA, Galluccio A, Pezza M et al. Combined treatment with low-dose cyclosporine and calcipotriol/betamethasone dipropiona-te ointment for moderate-to-severe plaque psoriasis: a randomized controlled open-label study. J Dermatol Treat 2011 [Epub ahead of print].

della sicurezza della loro associazione fissa in più di 7,000 pazienti con la formulazione in unguento nella psoriasi del tronco e/ o degli arti ed in più di 4,000 pazienti con la formulazione in gel per la psoriasi del cuoio capelluto nell’ambito di studi randomizzati e controllati in doppio cieco. Tali studi hanno dimostrato che l’associazione fis-sa è più efficace e meglio tollerata, non solo del placebo, ma anche della monoterapia a base di calcipotriolo o tacal-citolo; inoltre, si è dimostrato, in molti casi, più efficace del betametasone ed altrettanto bene tollerato. Lo stesso vale per il gel nella psoriasi del cuoio capelluto e del cor-po. Studi sulla sicurezza hanno escluso che cicli di terapia con l’associazione fissa, ripetuti fino ad un anno, causino la comparsa di effetti sistemici. Altri studi hanno mostrato che l’associazione fissa migliora la qualità di vita significa-tivamente di più della monoterapia a base di calcipotriolo; la posologia che prevede una sola somministrazione gior-naliera, finora una peculiarità esclusiva dell’associazione fissa calcipotriolo/betametasone dipropionato, contribuisce a questo miglioramento, sia nella fase acuta di malattia sia nelle sue riesacerbazioni. In seguito alla vastità delle evi-denze cliniche a favore dell’associazione fissa calcipotriolo / betametasone dipropionato, le linee guida Americane ed Europee consigliano specificamente il prodotto per il trat-tamento topico di prima linea della psoriasi da lieve a mo-derata a carico del tronco, degli arti e del cuoio capelluto.Parole chiave: Psoriasi - Terapia - Betametasone - Cute, malattie.

References

1. Saraceno R, Gramiccia T, Frascione P, Chimenti S. Calcipotriene/betamethasone in the treatment of psoriasis: a review article. Expert Opin Pharmacother 2009;10: 2357-65.

2. McCormack PL. Calcipotriol/betamethasone dipropionate. A re-view of its use in the treatment of psoriasis vulgaris of the trunk, limbs and scalp. Drugs 2011;71:709-30.

3. Kaufmann R, Bibby AJ, Bissonnette R et al. A new calcipotriol/betamethasone dipropionate formulation (Daivobet®) is an ef-fective once-daily treatment for psoriasis vulgaris. Dermatology 2002;205:389-93.

4. Papp KA, Guenther L, Boyden B et al. Early onset of action and efficacy of a combination of calcipotriene and betamethasone di-propionate in the treatment of psoriasis. J Am Acad Dermatol 2003;48:48-54.

5. Douglas WS, Poulin Y, Decroix J et al. A new calcipotriol/beta-methasone formulation with rapid onset of action was superior to monotherapy with betamethasone dipropionate or calcipotriol in psoriasis vulgaris. Acta Derm Venereol 2002;82:131-5.

6. Ortonne JP, Kaufmann R, Lecha M, Goodfield M. Efficacy of tre-atment with calcipotriol/betamethasone dipropionate followed by calcipotriol alone compared with tacalcitol for the treatment of psoriasis vulgaris: a randomised, double-blind trial. Dermatology 2004;209:308-13.

7. Rosina P, Giovannini A, Gisondi P, Girolomoni G. Microcirculatory modifications of psoriatic lesions during topical therapy. Skin Res Technol 2009;15:135-8.

8. Saraceno R, Andreassi L, Ayala F et al. Efficacy, safety and qua-lity of life of calcipotriol /betamethasone dipropionate (Dovobet® versus calcipotriol (Daivonex®) in the treatment of psoriasis vul-


score, performed at baseline, after 45 and 90 days. Patients were evaluated for itching. Results. VSCAPSI score at baseline was 8.5. Ir-S induced a significant reduction of VSCAPSI score in comparison with baseline value both after 45 and 90 days of treatment. The use of shampoo lead to a progressive reduction of VSCAPSI score having (getting) a score of 4.2 at T45 and a score of 4.0 at T90 (P=0.001 vs. baseline). The use of Ir-S has significantly re-duced the percentage of patients reporting itching sensation. Conclusion. The treatment was safe and well‐tolerated with an high cosmetic acceptance. Ir-S is a good alternative to other medicated shampoo in the treatment of mild to moder-ate scalp psoriasis. Moreover, in the treatment of severe scalp psoriasis, it can lead to an improvement if associated with topical medications. Key words: Scalp - Psoriasis - Urea.

Scalp involvement is a common clinical feature of psoriasis. It is present at the time of the initial

manifestation of the disease in at least one third of patients; about three quarters of patients experience scalp involvement at some point in time, and it is the sole site of involvement in 25% of the patients.1 Psoriasis is a chronic inflammatory skin disease his-tologically characterized by proliferation and loss of differentiation of keratinocytes, angiogenesis with vasodilatation and increased permeability, and in-flammation.2 The cutaneous microcirculation in pso-

Aim. This work has the aim to test the sensibility of VSCAPSI method in the evaluation of effectiveness of a medicated sham-poo for the treatment of scalp psoriasis. Psoriasis is a chronic inflammatory skin disease histologically characterized by proliferation and loss of differentiation of keratinocytes, ang-iogenesis with vasodilatation and increased permeability, and inflammation. Scalp involvement is a common clinical feature of psoriasis, that is present in the 25% of patients who suffer of it. Videodermoscopy (VD) permits a magnified view of the surface components of the epidermis and papillary dermis, which are not visible to the naked eye, together with the abil-ity to capture digitally the viewed images and to store them for later use. Moreover videodermoscopy is a non invasive technique, used to analyze cutaneous peripheral microcircu-lation. Therefore VD could be an useful tool in evaluating the efficacy of treatments for scalp psoriasis. The clinical benefit of currently available medicated shampoos for the treatment of scalp psoriasis is restricted, due to their limited efficacy, low cosmetic appeal and safety and tolerability problems. Therefore effective and safe products are needed especially for the long term management of scalp psoriasis. A specific shampoo designed for the scalp hygiene in psoriatic patients has been recently developed. This shampoo contains urea, glycolic acid, salicylic acid, icthyol pale and laureth 9 (poli-docanol). Aim of the study was to evaluate in a 12‐week pro-spective monocenter, open-study the efficacy tolerability of an emollient, keratolytic shampoo (Iralfaris shampoo ISDIN, Barcelona; Ir-S) applied three times a week in patients with scalp psoriasis. The efficacy of the shampoo has been valu-ated with VSCAPSI. Methods. Seventy subjects with mild to moderate/severe scalp psoriasis were enrolled in the trial, after their informed consent. Efficacy was assessed using a specific and validated videodermoscopy scalp psoriasis severity index (VSCAPSI)

1Department of Internal MedicineLa Sapienza University, Rome, Italy

2Medical Direction Isdin Italia, Rome, Italy

ORIGINAL ARTICLESG ITAL DERMATOL VENEREOL 2012;147:625-9

A. ROSSI 1, G. PRANTEDA 1, A. IORIO 1, E. MARI 1, M. MILANI 2

Efficacy of Iralfaris shampoo in the treatment of scalp psoriasis: a videodermoscopy evaluation prospective study in 70 patients

Corresponding author: A. Rossi, Department of Internal Medicine, La Sapienza University, viale del Policlinico 155, 00161 Rome, Italy. E-mail: [email protected]


Lavoro: 4434-MDtitolo breve: Iralfaris shampoo for the treatment of scalp psoriasisprimo autore:ROSSIpagine: 625-9

IRALfARIS ShAMPOO fOR ThE TREATMENT Of SCALP PSORIASIS


ability problems. A specific shampoo designed for the scalp hygiene in psoriatic patients has been de-veloped (Iralfaris shampoo ISDIN, Barcelona; Ir-S). This shampoo contains urea, glycolic acid, salicylic acid, ichthyol Pale and laureth 9 (polidocanol).8 This formulation could offer a multi-faceted efficacy and benefit in scalp psoriasis.

We evaluated the efficacy of Ir-S in patients with moderate scalp psoriasis by mean of videodermos-copy score (VSCAPSI) in a prospective open-study 12-week trial.


This was a mono-center trial conducted between November 2009 and June 2010. The study assessed a total of 70 subjects with mild to moderate/severe scalp psoriasis (32 male and 38 female; aged be-tween 18-60). Diagnosis of moderate/severe scalp psoriasis was made through the VSCAPSI results: when VSCAPSI was >4 the diagnosis of moderate scalp psoriasis was done. When VSCAPSI was >6 the diagnosis of severe scalp psoriasis was made. The subjects were enrolled in this prospective 12-week open-study. Inclusion criteria for patients to be enrolled in the trial were older than 18 years, a his-tory of stable scalp psoriasis involving at least 10% of the scalp. Patients were not eligible in the study if they were pregnant, had used topical steroid, PUVA or UVB therapies or had used systemic therapies for scalp psoriasis within the two weeks prior the study initiation. Digital dermoscopic images of the scalp were acquired using a dermoscope Trichoscan® (magnification 20-30-40-50-60-70 X). VD was per-formed by an investigator at baseline, after 45 and 90 days of treatment. The investigator performing VD was always the same. The physician performing VD evaluations was blinded to the treatment and to the time of the visit. In this study we used a videoder-moscopy scalp psoriasis severity index (VSCAPSI). This score takes in account the vascular pattern, the severity of erythema and the desquamation. Erythe-ma and desquamation were assessed using a 5-point score (from 0: absence of the sign in the area evalu-ated to 4: very severe presence of the sign in the area evaluated).

The VSCAPSI can range from a minimum score of 0.0 to a maximum of 11.0. The VSCAPSI is 0.0 when the patient is not suffering from psoriasis or

riasis shows many anatomical and functional chang-es compared with normal skin.

Psoriatic microvessels are elongated, widened and tortuous, especially in the papillary dermis. Blood flow in plaque skin is also substantially elevated compared with clinically uninvolved skin of the same subjects and normal skin of unaffected individuals.3 Many studies have shown that these microvascular changes occur early in the development of lesions, before epidermal hyperplasia can be detected clini-cally or histologically.4

Scalp psoriasis is characterized by erythema and desquamation, sometimes associated with itching sensation. Clinical diagnosis of hair and scalp disor-ders is not always straightforward.

Videodermoscopy (VD) is a non-invasive tech-nique which could be used to explore microcircu-latory modifications in skin diseases and permits a magnified view of the surface components of the epidermis and papillary dermis. VD is used in the diagnostic evaluation of body and scalp psoriasis. The standard methods used to diagnose scalp psoria-sis range in sensitivity, reproducibility, and invasive-ness.5, 6

We create a videodermoscopy scalp psoriasis se-verity index (VSCAPSI) for evaluation of scalp pso-riasis, especially mild and moderate forms that often are not clinically appreciable.

Psoriasis presents three pathognomonic vascular patterns: red dots, hairpin vessels and red globular rings. A videodermoscopy scalp psoriasis severity index (VSCAPSI) for evaluation of scalp psoriasis, especially mild and moderate forms that often are not clinically appreciable, has been recently developed by our group and validated.6 VSCAPSI takes into account the area of the scalp affected by psoriasis, the presence and morphology of vascular patterns, the erythema and the desquamation. The VSCAPSI will be useful during clinical trials for evaluating re-sponse to treatment of scalp psoriasis.6

Scalp psoriasis is also a medical challenge in rela-tion with therapy. The clinical benefit of currently available medicated shampoos for the treatment of scalp psoriasis is restricted, due to their limited ef-ficacy, low cosmetic appeal and safety and tolerabil-ity problems, especially in the long term.7 Coal tar shampoos have a low cosmetic acceptance and their use seem to be linked to carcinogenicity. Cortico-steroid-based shampoos could be effective but long term use could be associated with safety and toler-



1=mild itching sensation, 2=moderate itching sen-sation, 3=high itching sensation, 4=very high itch-ing sensation). At the start and at the end of therapy, all patients underwent to a self-assessment test that evaluated with a 5-point score the combness, hair effect-volume, desquamation and itching.

Results

All the enrolled 70 patients concluded the 90 days treatment period. At baseline, 70% of the patients (N.=49) have a mild form of scalp psoriasis and 30% (N.=21) a moderate/severe one. Medicated shampoo lead to an improvement in 31 patients affected by mild scalp psoriasis and in 12 patients affected by moderate/severe scalp psoriasis. A total of 61 out of 70 patients reported itching sensation of the scalp. VSCAPSI score at baseline was 8.5. Ir-S induced a significant reduction of VSCAPSI score in compari-son with baseline value both after 45 and 90 days of treatment. The use of shampoo lead to a progressive reduction of VSCAPSI score having (getting) a score of 4.2 at T45 and a score of 4.0 at T90 (P=0.001 vs. baseline) (figure 1). The use of Ir-S has significantly reduced also itching sensation. Itching sensation was evaluated using a 5-point score (0=absence of itch-ing sensation, 1=mild itching sensation, 2=moderate itching sensation, 3=high itching sensation, 4=very high itching sensation). At baseline itching was re-ported by 85% of the patients (N.=60). This percent-age was reduced to 40% and 45% (N.=31) after 45 and 90 days of treatment (P=0.0001; fisher’s exact test). The treatment was safe and well‐tolerated with a high cosmetic acceptance.

when the patient has psoriasis without the involve-ment of the scalp. The VSCAPSI is 11 when the pso-riasis involves the whole scalp and in each area there are all three vascular pattern and very severe pres-ence of both signs (erythema and desquamation).

The study was approved by the local ethics committee and an informed consent was obtained from the patients who were included in the study. Patients were outpatients from the Department of Dermatology at the University of Rome “La Sapi-enza”. Patients were seen at baseline, after 45 and 90 days. The subjects self-administered the treat-ment (shampoo) to the entire scalp under the in-struction of study personnel. Shampoo should be used three times a week. Patients were instructed not to use other medicated shampoo or other topi-cal drugs for the scalp. The primary outcome of the study with respect to efficacy was the VSCAPSI score evolution from baseline to 90 days. Percent-age of patients reporting itching at baseline and after treatment was a secondary efficacy outcome. Not a formal sample size calculation was per-formed for this study. however, the enrollment goal of at least 70 evaluable patients allowed detecting, with a two-sided 5% significance leveland a power of 90%, an effect size of 0.4 regarding VSCAPSI mean values at different times. Data were analyzed with statistical program Statistical Package for Social Science (SPSS). Wilcoxon rank sum test was used to compare VSCAPSI score at different times. The fisher exact test was used to compare the percent-age of patients reporting itching at different times. Statistical tests were reported using two-tailed test P values. Itching sensation was evaluated using a 5-point score (0=absence of itching sensation,

figure 1.—T0: moderate scalp psoriasis; T45: mild clinical improvement; T90: resolution of scaling.



scales are removed, because reduce the drug penetra-tion.12, 13 This study evaluates for the first time the efficacy of shampoo containing keratolitic, emol-lient and anti-itching compounds in mild to moder-ate/severe scalp psoriasis. The peculiar composition of Iralfaris allows to use an adjuvant can modulate the same time the scaling, itching and inflammation, all characteristic features of psoriasis. Thanks to the presence of urea in this formulation this shampoo provides also a significant emollient and moisturizer additional effect. In conclusion, this study has shown that Iralfaris shampoo is a well-tolerated and effec-tive in controlling scaling and itching that often ac-companies psoriasis of the scalp. In the severe scalp psoriasis, the use of cleansing products, that can im-prove desquamation and itching sensation, can be associated to more complex medical therapies, both topical and systemic. VSCAPSY is resulted useful and sensible during our clinical trial, to evaluate a specific shampoo, as specific treatment for scalp psoriasis.

Riassunto

Efficacia dello shampoo Iralfaris nel trattamento della psoriasi del cuoio capelluto: uno studio prospettico con valutazione videodermatoscopica in 70 pazienti

Obiettivo. Obiettivo del presente studio è stato quello di verificare la sensibilità del metodo VSCAPSI (Videoder-moscopy Scalp Psoriasis Severity Index) nella valutazione dell’efficacia di uno shampoo medicato per il trattamento della psoriasi del cuoio capelluto. La psoriasi è una malat-tia infiammatoria cronica della cute caratterizzata istologi-camente da proliferazione e perdita di differenziazione dei cheratinociti, angiogenesi con vasodilatazione e aumentata permeabilità e infiammazione. Il coinvolgimento del cuoio capelluto è una caratteristica clinica comune della psoria-si, presente nel 25% dei pazienti che soffrono di questa condizione. La videodermatoscopia (VD) consente una visualizzazione amplificata dei componenti superficiali dell’epidermide e del derma papillare, elementi normal-mente invisibili a occhio nudo, oltre alla capacità di cattu-rare digitalmente le immagini visualizzate e memorizzarle per un utilizzo successivo. Inoltre, la videodermatoscopia è una tecnica non-invasiva, utilizzata per analizzare la microcircolazione periferica cutanea. Pertanto, la VD po-trebbe essere un utile strumento per valutare l’efficacia dei trattamenti della psoriasi del cuoio capelluto. Il beneficio clinico degli shampi medicati attualmente disponibili per il trattamento della psoriasi del cuoio capelluto è limitato a causa della loro scarsa efficacia, dello scarso appeal este-tico e dei problemi di sicurezza e tollerabilità. Pertanto,

Discussion

Psoriasis of the scalp is a common condition. It affects approximately 2% of the Western popula-tion. The presence of erythemato-squamous lesions with silver-white scaling is typical of scalp psoriasis. Quality of life can be strongly reduced by this condi-tion and therefore long term treatment is needed in most patients. Not ideal topical products are avail-able for the treatment of scalp psoriasis. Despite a wide range of therapy options, scalp psoriasis re-mains difficult to treat, highlighting a long-standing unmet need for the safe and effective treatment of scalp psoriasis. Many topical therapies for scalp pso-riasis are also difficult or unpleasant to apply, result-ing in decreased adherence and efficacy. In brief, the high level of patient dissatisfaction with currently available treatments for psoriasis supports the need for new, effective and well-tolerated treatment op-tions for scalp psoriasis.7, 8 Corticosteroid-based lo-tions are the most widely used therapy in this clini-cal setting. however, long-term treatment could be limited by safety issues and by rebound problems when discontinued.9 Kragballe et al. reported that few of the therapies currently used for the treatment of scalp psoriasis have been evaluated for efficacy in the setting of well-designed, well-controlled clinical studies. The lack of comparative data impedes the in-terpretation of the results from studies of scalp pso-riasis. Long-term studies of the efficacy and safety of scalp treatments are lacking.10 however, we have to remember that psoriasis is considered a chronic disease, that needs always of medicated shampoos and not only of topical and systemic therapies. Coal tar-based solution or shampoos are difficult to use in view of their low cosmeticity. Therefore their use especially in the long-term could be characterized by a low adherence to the treatment.11 In our study we evaluated by means of videodermoscopy the efficacy of a new shampoo formulation containing urea 5%, salicylic 3% and glycolic 3% acids, icthyol pale and laureth 9 (polidocanol) 1%. Glycolic acid, salicylic acid and urea have a well-known keratolytic and keratoplastic effects. Icthyol pale has an antiprolif-erative and anti-inflammatory activity. Urea has been also used as scalp moisturizers. Polidocanol is a local anaesthetic and antipruritic component of topical prod-ucts and bath additives.8 It relieves itching caused for example by dry skin conditions such as eczema. Many topical treatments do not work well until the thick



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7. 8. Grills CE, Cooper SM. Polidocanol: a potential contact allergen in shampoo. Contact Dermatitis 2007;56:178.

8. 9. Crowley J. Scalp psoriasis: an overview of the disease and avail-able therapies. J Drugs Dermatol 2010;9:912-8.

9. 10. Kragballe K, Menter A, Lebwohl M, Tebbey PW, van de Kerkhof PC; International Psoriasis Council. Long-term manage-ment of scalp psoriasis: perspectives from the international psoriasis council. J Dermatolog Treat 2012 [Epub ahead of print].

10. 11. Kostarelos K, Teknetzis A, Lefaki I, Ioannides D, Minas A. Double-blind clinical study reveals synergistic action between al-pha-hydroxy acid and betamethasone lotions towards topical treat-ment of scalp psoriasis. J Eur Acad Dermatol Venereol 2000;14:5-9.

11. 12. Castela E, Archier E, Devaux S, Gallini A, Aractingi S, Cribier B et al. Topical corticosteroids in plaque psoriasis: a systematic re-view of risk of adrenal axis suppression and skin atrophy. J Eur Acad Dermatol Venereol 2012;26(Suppl 3):47-51.

12. 13. hernánz JM, Sánchez-Regaña M, Izu R, Mendiola V, García-Calvo C. Clinical and therapeutic evaluation of patients with mod-erate to severe psoriasis in Spain: The Secuence Study. Actas Der-mosifiliogr 2012 [Epub ahead of print].

Received on October 19, 2012.Accepted for publication on October 31, 2012.

prodotti sicuri ed efficaci sono necessari soprattutto per la gestione a lungo termine della psoriasi del cuoio capelluto. Di recente è stato sviluppato uno shampoo specifico con-cepito per l’igiene del cuoio capelluto in pazienti affetti da psoriasi. Tale shampoo contiene urea, acido glicolico, aci-do salicilico, ittiolo purificato e laurato 9 (polidocanolo). Obiettivo del presente studio prospettico, in aperto, mo-nocentrico, della durata di 12 settimane, è stato quello di valutare la tollerabilità e l’efficacia di uno shampoo chera-tolitico emolliente (Iralfaris shampoo ISDIN, Barcellona; Ir-S) applicato tre volte alla settimana in pazienti affetti da psoriasi del cuoio capelluto. L’efficacia dello shampoo è stata valutata mediante il metodo VSCAPSI.

Metodi. Settanta soggetti con psoriasi del cuoio capel-luto di grado da lieve a moderato/grave sono stati reclutati nello studio dopo aver fornito il loro consenso informato. L’efficacia è stata valutata utilizzando uno specifico pun-teggio VSCAPSI convalidato, registrato al baseline e dopo 45 e 90 giorni. I pazienti sono stati valutati per la presenza del prurito.

Risultati. Il punteggio VSCAPSI al baseline era pari a 8,5. Lo shampoo Ir-S ha indotto una riduzione significativa del punteggio VSCAPSI rispetto al valore basale sia dopo 45 sia dopo 90 giorni di trattamento. L’utilizzo dello sham-poo ha favorito una progressiva riduzione del punteggio VSCAPSI, ottenendo un punteggio pari a 4,2 a 45 giorni di trattamento e un punteggio pari a 4,0 a 90 giorni di trat-tamento (P=0,001 vs. baseline). L’utilizzo dello shampoo Ir-S ha ridotto in maniera significativa la percentuale di pa-zienti che hanno riportato una sensazione di prurito.

Conclusioni. Il trattamento era sicuro e ben tollerato e ha mostrato un elevato grado di accettazione estetica. Lo shampoo Ir-S è una buona alternativa ad altri shampi me-dicati per il trattamento della psoriasi da lieve a moderata del cuoio capelluto. Inoltre, nel trattamento della psoriasi grave del cuoio capelluto, tale shampoo può favorire un miglioramento se associato a trattamenti topici.Parole chiave: Cuoio capelluto - Psoriasi - Urea.


in geriatric care facilities, the incidence of geriatric skin diseases is more widely acknowledged. Like in other countries, the percentage of elderly people in Italy has grown significantly as a result of economic development, industrialization and improving medi-cal care. The Italian National Institute for Statistics (ISTAT) estimates that 1/5 Italians are over 65 and those over 80 years constitute 5% of the population. In the Siena area, the over 65/under 15 ratio was 222.55 in 2001 and has risen sharply in the last few years.1 In order to provide rapid access to special-ist help, in 2003 we set up a dermatology clinic for geriatric patients age 65 and over. The aim of our study was to determine the characteristic pattern and prevalence of various skin disorders among the geri-atric patients seen at the clinic during the study pe-riod 2003-2009. Previous studies have attempted to identify the prevalence of skin diseases in geriatric patients and have established that both inflammatory skin disorders and malignant skin cancer are com-mon in the elderly.2-9 To our knowledge, no similar studies have been conducted in Italy.


The dermatology clinic for geriatric patients was established in January 2003. The medical staff in-

1Section of Dermatology, Department of Clinical Medicine and Immunological Sciences

University of Siena, Siena, Italy 2Department of Geriatric Medicine, University of Siena,

Siena, Italy


P. RUBEGNI 1, S. POGGIALI 1, N. NAMI 1, M. RUBEGNI 2, M. FIMIANI 1

Skin diseases in geriatric patients: our experience from a public skin outpatient clinic in Siena

Aim. With the progressive aging of the Italian population, geriatric health care has become a major issue for health au-thorities. However, little data is available regarding geriatric skin diseases. In order to provide rapid access to specialist help, in 2003 we created a dermatology clinic dedicated only to geriatric patients age 65 and older.Methods. To determine the characteristic pattern and the prevalence of various skin disorders among the geriatric patients seen at the clinic, we performed a retrospective and descriptive study of all skin diseases in patients seen in our of-fice from January 2003 to December 2009. We evaluated: age, proportion and gender for all skin disease categories.Results. A total of 2100 geriatric patients were examined. The male to female ratio was 1.4 to 1. The most common disor-der was pruritus “sine materia” (18.9%) followed by benign tumors (13.5%); 9.1% of our patients presented with actinic keratoses and 13.2% with malignant tumors. As reported by others, the quality of life in patients with skin cancer was bet-ter than patients with rashes as skin cancer patients tended to wait longer before seeking specialist care. To improve the assessment of skin diseases, we often worked closely with col-leagues from the Department of Geriatric Medicine.Conclusion. The prevalence of skin diseases in our patients emphasized the importance of educating the elderly about sun protection, the early detection of skin cancer, the use of emollients and proper skin care in general.Key words: Skin diseases - Aged - Outpatient clinics, hospital.

The management of dermatoses in older popula-tions emerges as an important area of health care

where improvement is possible. As the population over age 65 rises together with the number of patients

Corresponding author: S. Poggiali, Section of Dermatology, Depart-ment of Clinical Medicine and Immunological Sciences, University of Siena, Policlinico Le Scotte, 53100 Siena, Italy. E-mail: [email protected], [email protected]


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RUBEGNI SKIN DISEASES IN GERIATRIC PATIENTS


cluded three dermatologists, a geriatrician and a nurse. A dermatologist and the geriatrician assessed all patients at their first visit. Follow-up visits were done by one of the dermatologists and the geriatri-cian was only consulted for selected patients with problems regarding internal medicine.

“Geriatric” patients were defined as all patients age 65 and over, according to the WHO definition.

All geriatric patients seen in the dermatology de-partment were evaluated in the geriatric clinic: some were referred by primary care physicians, others were sent by colleagues of our department after a first evaluation and some (urgent situations) came di-rectly to the clinic, without appointment, referred by the medical staff of the emergency room.

Dermatological diagnosis of each skin disease was coded according to the International Classification of Diseases (WHO, ICD9 system). All medical data on our geriatric patients including the diagnostic code have been collected in a database. Our research was conducted on computer records from January 2003 to December 2009. Age, proportion and gender of the specific skin disease categories were evaluated.

Results

A total of 2100 geriatric patients were visited. With respect to the general population of dermatol-ogy patients in our clinic, 43% are geriatric. The number of patients increased from 272 in 2003 to 798 in 2009 (Figure 1).

The most common dermatological diagnoses in

these patients and their subgroups are shown in Table I including their percentages. The most common dis-order was pruritus: 397/2100 (18.9%). The second most frequent disease was “dermatitis” diagnosed in 302/2100 (14.4%). All the patients with dermatitis underwent patch tests according to the Italian Soci-ety of Allergic Dermatology (SIDAPA).

Two-hundred eighty-four out of 2100 (13.5%) suffered from benign tumorsMalignant tumors were found in 277/2100 (13.2 %). Actinic keratoses (AK) found in 191/2100 (9.1%) were considered as “in-traepithelial squamous cell carcinomas in evolution”, according to their recent redefinition, but included in a separate group. Sites varied, but more than 90% of SCC and BCC lesions, as well as AK, were located on sun exposed areas.

Bullous diseases, including senile pemphigoid and pemphigus vulgaris, were found in 139/2100 (6.6%). Other autoimmune disorders (including pso-riasis, lichen planus and connectivitis) were found in 132/2100 (6.3%) and drug eruptions in 111 (5.28%).

Discussion

The burden of dermatological diseases in the eld-erly is expected to increase and health care providers need to be aware of this and reorganize care so that the geriatric population is adequately covered.

Table I reports the distribution by gender and the prevalence of skin diseases in our study population.

Our observation confirmed the well known concept that pruritus, for which an underlying systemic cause was found in 20% of patients, is the most frequent complaint in dermatology surveys in the elderly.

The dermatitis group was the second most fre-quent disorder. Contact dermatitis (irritant and aller-gic contact dermatitis) accounted for 20.5% of these patients and was higher in women. In women with dermatitis of the hands, 70% of cases were due to contact with irritants (ICD) related to housekeeping. Allergic contact dermatitis (ACD) was diagnosed in 3.3% of the patients. The allergen most frequently involved was nickel. Our data confirmed the well known concept that individual susceptibility to ACD in the elderly population is relatively low due to the decreased capacity to mount delayed-type hyper-sensitivity reactions because of depressed immune response (reduced Langerhans cells, decrease in T cells and low vascular reactivity).10

Figure 1.—Geriatric patients seen at our dedicated clinic during the study period.

400

1002003 2005 2007 2009

200

300

Male Female

SKIN DISEASES IN GERIATRIC PATIENTS RUBEGNI


mm, SD=1.68; median =0.74) than those diagnosed in subjects in the 20 to 64 age range (mean=0.87 mm, SD=1.23; median=0.4) (Figure 3). Other au-thors have also reported that incidence and mortality, as well as rates of increase, have been significantly higher in the elderly than in younger age groups. Lower survival rates for cutaneous melanoma among the elderly are mainly the result of the late diagno-sis of tumors having dismal prognostic features. The expansion of current preventive strategies to include older age groups is therefore warranted.11, 12

Bullous diseases and other autoimmune diseases (including psoriasis, lichen and connective tissue diseases) were diagnosed in 12.9 % of our patients. Almost 50% of the cases of bullous pemphigoid were presumed to be drug induced and the geriatrician suggested replacing the anti-hypertensive medica-tion being used. Thiol drugs containing a thiol group

The third major disorder was benign tumors (87%) which were prevalently seborrhoeic keratoses, easily diagnosed even from photographs. This prompted us to establish a telemedicine service (store and for-ward), the results of which were encouraging from the economic and health-care points of view, both for patients and the health system. Four hundred and sixty eight patients (277+191) presented with malig-nant tumors and actinic keratoses. The reason men were more prone to cutaneous malignant and “pre-malignant” lesions is easily explained by their out-door jobs. Until the 1960’s, agriculture was the main occupation of men in the Siena area, whereas women were mostly housewives. We observed that in many cases, malignant tumors were diagnosed at a late stage and patients generally refused treatment. The same was found for melanoma. In patients over 65 years of age, melanomas were thicker (mean=1.30

Table I.—The most common dermatological diagnoses in our geriatric patients.

Disease Number of patients: 2100 (100%) 95% CI Males Females

Pruritus 397 (18.9%) 0.172-0.205 183 214Dermatitis 302 (14.4%) 0.129-0.158 102 200

AD 91/302 (30%) 0.25-0.352AE 63/302 (20.8%) 0.163-0.253ICD 50/302 (17.2%) 0.123-0.207LS 39/302 (12.9%) 0.091-0.166StD 24/302 (7.9%) 0.048-0.109SeD 13/302 (4.3%) 0.020-0.065ACD 10/302 (3.3%) 0.013-0.053

Benign tumors 284 (13.5%) 0.012-0.149 177 107SK 172/284 (60,5%) 0.548-0.066SF 32/284 (11.2%) 0.075-0.149

Malignant tumors 277 (13.2%) 0.117-0.146 199 78BCC 156/277 (56.4%) 0.504-0.621SCC 84/277 (30.3%) 0.249-0.357MM 14/277 (5.0%) 0.024-0.076CTCL 10/277 (3,6%) 0.014-0.058BCL 6/277 (2,1%) 0.004-0.038CM 4/277 (1,4%) 0.013-0.028

Actinic keratoses 191 (9.1%) 0.078-0.103 153 38Bullous diseases 139 (6.6%) 0.055-0.076 67 72Other autoimmune diseases 132 (6.3%) 0.052-0.073 48 84Drug eruptions 111 (5.28%) 0.043-0.062 54 57Tylomas 69 (3.3%) 0.025-0.040 7 62Infections 54 (2.6%) 0.018-0.032 31 23Rosacea 50 (2.4%) 0.017-0.030 22 28Wounds 38 (1.8%) 0.012-0.023 12 26Urticaria 8 (0.4%) 0.001-0.006 2 6Other 48 (2,2%) 0.016-0.029 21 27

AD: atopic dermatitis; AE: asteatotic eczema; ICD: irritant contact dermatitis; LS: lichen simplex chronicus; StD: stasis dermatitis; SeD: seborrheic der-matitis; ACD: allergic contact dermatitis; S: seborrheic keratoses; SF: soft fibromas; BCC: basal cell carcinoma; SCC: squamous cell carcinoma; MM: malignant melanoma; CTCL: cutaneous T cell lymphomas; BCL: B cell lymphomas; CM: cutaneous metastases.



with drug-induced eruptions, diagnosed in 111/ 2100 (5.28%) cases. As previously reported 13 the most common reactions were exanthematic maculopapu-lar eruptions. We diagnosed 3 cases of maculopa-pular exanthema caused by amoxicillin, one case of Steven Johnson’s syndrome carbamazepine-induced, one case of fixed drug eruption related to fluconazole and one case of erythema multiforme of the hands related to 5% imiquimod cream.

However, in most of the cases it was impossible to identify a single drug because of “polypharmacy” (the use of five or more medications). Compared to the incidence of drug eruption in the general popula-tion,14 and considering the fact that elderly patients

(-SH) in their chemical structure and in particular captopril (20% of patients) and enalapril (15%) were suspected in most of these cases. Sulfur-containing drugs (masked thiols) including penicillins, cepha-losporins, and piroxicam, were suspected in 10% of the cases. In all our patients with bullous diseases, recent psoriasis or connective tissue diseases, we looked for a paraneoplastic cause but only one case of paraneoplastic pemphigus associated with lung cancer and one case of paraneoplastic dermatomy-ositis associated with breast cancer were diagnosed. All these patients were also followed up by the geri-atrician.

We also consulted the geriatrician for patients

Figure 2.—Cutaneous metastases from visceral carcinomas observed in our study population: (A) carcinoma of the rete testis; (B) gastric adenocarcinoma; (C) carcinoma of the breast and (D) carcinoma of the uterus.

SKIN DISEASES IN GERIATRIC PATIENTS RUBEGNI


nosis in the elderly, but also by the perceived need for a differentiated area for these patients with extra time devoted to clinical evaluation and health educa-tion. Another advantage of a dedicated service is the extremely reduced waiting list for the first examina-tion compared to a general dermatology clinic.

Riassunto

Malattie cutanee nei pazienti geriatrici: la nostra espe-rienza maturata in un ambulatorio di Dermatologia a loro dedicato a Siena

Obiettivo. Con il progressivo invecchiamento della po-polazione, l’assistenza sanitaria dedicata ai pazienti ge-riatrici è diventata una questione di primaria importanza. Al fine di fornire ai pazienti con età superiore a 65 anni un’assistenza specialistica di rapido accesso, presso la no-stra Clinica abbiamo creato nel 2003 un ambulatorio di Dermatologia esclusivamente a loro dedicato.

Metodi. Per determinare le tipologie e la prevalenza del-le patologie dermatologiche insorte in questa categoria di pazienti, abbiamo eseguito uno studio retrospettivo e de-scrittivo.

Risultati. Dal gennaio 2003 al dicembre 2009 sono stati visitati 2100 pazienti geriatrici con un rapporto maschi-femmine di 1,4 a 1. Il disturbo più comune è risultato il prurito “sine materia” (18,9%) seguito dai tumori benigni (13,5%); il 9,1% dei nostri pazienti presentavano cheratosi attiniche e il 13,2% tumori maligni. Come riportato da altri autori, la qualità della vita nei pazienti con tumori della pelle è risultata migliore rispetto a quella dei pazienti con eruzioni cutanee e gli anziani che presentavano neoplasie della pelle tendenzialmente avevavo atteso più a lungo pri-ma di richiedere cure specialistiche. Per una valutazione migliore dei pazienti geriatrici affetti da malattie derma-tologiche, spesso abbiamo lavorato a stretto contatto con i colleghi del Dipartimento di Medicina Geriatrica.

may be on several medications that accumulate in their bodies due to poor respiratory, excretory and metabolic functions, the percentage of drug erup-tions in our patients was quite low.

Finally, we found that we had low percentages of infections (mostly mycoses, 42.2%), parasites, wounds and urticaria, probably because most of these conditions (herpes zoster, erysipelas, septic pressure ulcers, urticaria with angioedema, ecc.) are gener-ally first seen in the emergency room, after which patients are often hospitalized. Skin disorders of the elderly may also vary from country to country. Table II reported the percentages in our study and those of other studies conducted around the world.

In general, it should be noted that incidences and prevalence in different areas and groups cannot be compared properly when a diagnostic group is not present in one of the study groups. The rest of the percentages increase, but the prevalence remains the same. We also agree with Liao YH et al.7 that there are too many variables, including race, age group, patient source and geographic location which make comparisons difficult.

Conclusions

In conclusion, our results provide insights into the medical impact of geriatric skin diseases and indi-cate the need to plan health care for Italian geriat-ric patients. Special medical services for the elderly can improve the relationship between dermatologists and geriatric patients.

The need for a geriatric consultation, in our opin-ion, is not only justified by the peculiarities of diag-

Table II.—Percentages of each diagnostic group in our study and in previously published studies. *Note: when a diagnostic group is not present in one of the study groups, the rest of the percentages increase but the prevalence remains the same. For example, the inci-dence of tumors is lower in Asia: the number of consultations for tumors in this area is likely to be lower, leading to an increase in the percentage of consultations for other disorders due to the lack of tumors, not to the increase of other disorders, even if the prevalence is the same.

Disease/County Taiwan USA Canada Japan Singapore Tunisia Italy

Eczema 58.8% 37.9% 16.3% 33.7% 35.35% 11.9% 14.4%Benign tumors 12.8% 11.5% 13.8% 4.6% 4.1% 8.1% 13.5%Malignant tumors 2.1% * 9% 12.6% 1%* 0.66%* 3.8% 13.2%Actinic keratoses 0%* 12.1% 24.9% 0.21%* 0%* 0.5% 9.1%Infections 50.3% 7.8% 7,4% 25% 6% 23.7% 2.6%Pruritus 14.2% 1.8% 1.2% 7.5% 1.7% 6.4% 18.9%

[Modified from: Souissi A et al.8].



seen at the NationalSkin Center (Singapore) 1990. Singapore Med J 1994;35:147-50.

7. Liao YH, Chen KH, Tseng MP, Sun CC. Pattern of skin diseases in a geriatric patient group in Taiwan:a 7 year survey from the outpatient clinic of a university medical center. Dermatol 2001;203:308-13.

8. Souissi A, Zeglaoui F, El Fekih N, Fazaa B, Zouari B, Kamoun MR. Pathologie cutanée chez le sujet agé. Etude multicentrique tunisi-enne. Ann Dermatol Venereol 2006;133:231-4.

9. Mseddi M, Borgi N, Sellami L, Meziou TJ, Turki H, Zahaf A. Pathologie cutanée du sujet agé en dermatologie. Ann Dermatol Ve-nereol 2006;133:272-80.

10. Piaserico S, Larese F, Recchia GP, Corradin MT, Scardigli F, Gen-naro F et al. Allergic contact sensitivity in elderly patients. Aging Clin Exp Res 2004; 16:21.

11. van der Meijden WA, van Bruchem-Visser RL, Thio HB, van der Cammen TJ. Melanomas more serious in the elderly Ned Tijdschr Geneeskd. 2010;154:A1535.

12. Lasithiotakis KG, Petrakis IE, Garbe C. Cutaneous melanoma in the elderly: epidemiology, prognosis and treatment. Melanoma Res 2010;20:163-70.

13. Sullivan JR, Shear NH. Drug eruptions and other adverse drug ef-fects in aged skin. Clin Geriatr Med 2002;18:21-42.

14. Naldi L, Conforti A, Venegoni M, Troncon MG, Caputi A, Ghiotto E et al. Cutaneous reaction to drugs: an analysis of spontaneous reports in four Italian regions. Br J Clin Pharmacol 1999;48:839- 46.

Received on September 21, 2011.Accepted for publication on July 4, 2012.

Conclusioni. La prevalenza delle malattie dermatologi-che da noi osservate nei pazienti geriatrici, oltre a rimar-care l’importanza di una diagnosi precoce delle neoplasie cutanee, ci sottolinea la priorità di educare gli anziani a far uso di protezioni solari, creme emollienti e ad avere in generale una corretta cura della propria pelle.Parole chiave: Malattie cutanee - Pazienti anziani - Pa-zienti ambulatoriali, clinica.

References

1. Istat [Homepage]. [Internet]. Available at http://www.istat.it [cited 2012, Jul 4].

2. Kilic A, Gul U, Aslan E, Soylu S. Dermatologic findings in the sen-ior population of nursing homes in Turkey. Aech Gerontol Geriatr 2008;47:93-8

3. Yalçin B, Tamer E, Toy GG, Oztaş P, Hayran M, Alli N. The preva-lence of skin diseases in the elderly: analysis of 4099 geriatric pa-tients. Inter J of Dermatol 2006;45:672-6.

4. Yamamoto T, Ohkawa T. The statistics of skin disorders in the elder-ly seen at geriatric medical centre in Tokyo (in Japanese). Hifubyoh-Shinryon 1991;13:257-62.

5. Adam JE, Reilly S. The prevalence of skin disease in geriatric age group. Australas J Dermatol 1987;28:72-6.

6. Yap KB, Siew MG, Goh CL. Pattern of skin disease in the elderly


Clinical description

Vitiligo is a depigmentation disorder affecting be-tween 1% and 2% of the general population without any racial, sexual or regional differences in preva-lence. Vitiliginous patches contain either reduced melanin or no pigment at all. Initially small, they may enlarge and coalesce into larger patches. Le-sions on the face, back of hands or wrists, axillae, and umbilicus are especially prominent. Vitiligo is most striking around the body orifices: eyes, nostrils, mouth, nipples, umbilicus and genitalia. Obviously, the disease is more noticeable where there is in-creased contrast with the surrounding skin. This can be observed with dark-complexioned patients and patients who become tanned, as vitiliginous patches do not tan in response to ultraviolet light. Additional-ly some lesions have a tendency to be surrounded by hyperpigmented skin. Clinical course and treatment of vitiligo differ depending on the type of vitiligo.

Vitiligo can be separated into segmental and non-segmental types (Table I).5 In non-segmental vitili-go, there is usually symmetric distribution of lesions, and new patches may appear throughout the patient’s life. It may be either generalized or localized. In gen-

1Dermatology and VenereologyUniversity “G. Marconi”, Rome, Italy

2Pediatric DermatologyA. Mayer Hospital, Florence, Italy

3Department of Dermatology, 2nd Medical FacultyCharles University, Prague, Czech Republic

4Dermatology and PediatricsNew Jersey Medical School, Newark, NJ, USA

REVIEWSG ITAL DERMATOL VENEREOL 2012;147:637-47

T. M. LOTTI 1, S. F. BERTI 2, J. HERCOGOVA 3, R. H. HUGGINS 4

B. W. LEE 4, C. K. JANNIGER 4, R. A. SCHWARTZ 4

Vitiligo: recent insights and new therapeutic approaches

Vitiligo represents a selective destruction of the melanocytes. It is a relatively common, probably autoimmune disorder that affects people of all backgrounds and both genders. No particular group seems to be preferentially affected. Half of vitiligo patients have an onset before the age of 18 years. In regions where leprosy is endemic, individuals with vitiligo are often stigmatized due to similarities in appearance between the two diseases. We will review this important subject, em-phasizing the latest therapeutic advances.Key words: Skin diseases - Vitiligo - Autoimmunity.

Vitiligo is the selective destruction of the skin’s melanocytes resulting in the development of

unsightly depigmented patches.1-3 The disease can have devastating consequences on an individual’s relationships with others and internal feelings of self-worth. Fifty percent of vitiligo patients ex-perience disease onset before the age of 18 when they are most concerned about their appearance, and self-image is the most fragile.4, 5 In a Chinese study performed on 541 children with vitiligo, the most frequent age of onset was between 4 and 8 years.6 Additionally, in regions where leprosy is endemic, individuals with vitiligo are stigmatized due to similarities in appearance between the two diseases. Fortunately, advances in our understand-ing and management of vitiligo are reducing its effect on the millions of individuals afflicted with this disease.

Corresponding author: R. A. Schwartz, MD, MPH, Professor and Head of Department, New Jersey Medical School, 185 South Orange Avenue, 07103-2714, Newark, NJ, USA. E-mail: [email protected]


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LOTTI VITILIGO


eralized non-segmental vitiligo there is usually wide-spread distribution of depigmented patches. When vitiligo is so extensive that few normally pigmented patches remain, it is known as vitiligo universalis. In acrofacial vitiligo, skin involvement is limited to the distal digits and periorificial facial areas. Focal vitiligo lesions are limited in quantity and location and have a non-dermatomal distribution (Figure 1). Focal vitiligo may develop into generalized vitiligo or may follow an early-stabilizing clinical course.7 Segmental vitiligo has important differences in etiol-ogy, prevalence of associated illnesses and therapy compared to other forms of vitiligo. It usually has unilateral involvement and a dermatomal distribu-tion. Segmental vitiligo is known for its early on-set and rapid spread. Without treatment, lesions are typically persistent throughout life, but stop develop-ing within two years of onset. Childhood vitiligo, in one survey, consisted primarily of typical general-

ized nonsegmental vitiligo (78%), with focal vitiligo (14.4%) and segmental vitiligo (4.6%) being far less prevalent.8 Similar data on childhood vitiligo were subsequently confirmed by a Chinese study in which the most common type was vitiligo vulgaris (38.1%), followed by focal vitiligo (34.6%), segmental vitili-go (19.4%), acrofacial vitiligo (7.6%) and universal vitiligo (0.4%).6

There are a number of variations of the presen-tation of vitiligo.4, 5 If, in addition to normally pig-mented and amelanotic skin, there is also an inter-mediate, hypopigmented interface, the patient is said to have trichrome vitiligo. Quadrachrome vitiligo describes the presence of a fourth, hyperpigmented band, which may develop during repigmentation. When vitiligo macules develop at sites of postinflam-matory hypermelanosis, “blue vitiligo” is observed. In inflammatory vitiligo, the depigmented macule is surrounded by a raised, erythematous border; sun exposure may cause the whole macule to become erythematous. Confetti vitiligo describes a condition where a patient develops as many as several hundred small macules (less than or equal to 2 mm) with vari-able distribution patterns.

Genetics

The earliest evidence suggesting a genetic basis for vitiligo was its association with a number of other autoimmune disorders known to have heritable pre-dispositions, such as diabetes mellitus. Genetic dis-eases are substantially more prevalent in children of parents who are close relatives. A study conducted in Bangalore, India, a community where consanguine-ous marriages are common, reported that as many as 20% of the population developed depigmented le-sions.9 The risk of vitiligo in the sibling of patients in the Caucasian and Indo-Pakistani population is

Table I.—�Segmental versus non-segmental.

Non-segmental Segmental

Prevalence 72-95% 5-28%Distribution Symmetrical, non-dermatomal Unilateral, dermatomalOnset Any age EarlyCourse Variable rate of growth with new lesions throughout life Rapid initial growth with non-progression

within 2 yearsEtiology (most plausible) Autoimmune NeurochemicalKoebnerization Frequent RareAutoimmune association Strong Rare

Figure 1.—�A focal vitiligo lesion of non-dermatomal distribution in a patient of Northern European lineage.

VITILIGO LOTTI


to a highly significant degree with generalized vitili-go in North American and United Kingdom whites.23 Reduced activity of the VIT1 gene, located on chro-mosome 2p16, has been associated with increased susceptibility to vitiligo, possibly as a result of de-creased melanocyte nucleotide mismatch repair.24

Systemic associations

Non-segmental vitiligo is associated with a number of immune system aberrations. The pres-ence of organ-specific autoantibodies in the serum of vitiligo patients has been well-established in adults as well as children.25, 26 In childhood, non-segmental vitiligo is frequently associated with autoimmune thyroiditis.27 Aside from this, children with vitiligo are usually healthy.28, 29 On the other hand, a sig-nificant incidence of thyroid dysfunction in children with non-segmental vitiligo type has been demon-strated. Therefore, in these patients, it should be use-ful to screen thyroid autoantibodies when symptoms related to thyroid disease are present;30 11.1% of pa-tients had a family history and 0.6% more than one member affected.6 Furthermore, it was demonstrated that an earlier onset of pediatric vitiligo is linked to a positive family history.31

On the contrary, vitiligo in adults is quite strongly associated with a number of autoimmune disorders, including alopecia areata, diabetes mellitus, perni-cious anemia, Addison’s disease, and Hashimoto’s thyroiditis.32, 33 As in children, the strongest associa-tion in adults is found with autoimmune thyroiditis, with a prevalence of 30% among vitiligo patients 24 compared to a 10% prevalence in the general popu-lation.29 Segmental vitiligo has no such association with autoimmune thyroiditis, and is, in fact, rarely associated with any autoimmune diseases.

A number of additional pathologies have also been associated with vitiligo, for instance hair pigmenta-tion loss 33 and subclinical ocular pathologies, espe-cially uveitis and/or major fundal pigmentary abnor-malities, that are frequently encountered in children with non-segmental vitiligo.34 Vogt-Koyanagi-Harada syndrome is a disorder consisting of vitiligo as well as ocular and neurological abnormalities.34,

35 It results from an autoimmune reaction against the ocular melanocytes of the uveal tract with vari-able extension to meningeal, cochlear and epidermal melanocytes.

estimated to be about 6%, a 16-fold higher than the general population.2 Additionally, in patients with non-segmental vitiligo, a significantly earlier onset has been observed when there is a family history of vitiligo (on average, 24.8 versus 42.2 years).10 Ge-netic models suggested by analysis of family studies include a multifactorial model,11 a dominant model with incomplete penetration,12 and a multilocular re-cessive model.13 A more recent study suggests that there may be two coexisting modes of inheritance for vitiligo depending on age of onset.14 In patients with early onset vitiligo (before the age of 30), vitiligo in-heritance most closely followed a dominant mode of inheritance with incomplete penetration. However, a predisposition to vitiligo resulting from a recessive genotype and exposure to certain environmental trig-gers appeared to explain the inheritance pattern of late onset vitiligo (after 30 years of age). Specific HLA haplotypes are strongly associated with vitiligo family history, severity of disease, age of onset and population geography.15-17 HLAs-A2, DR4, -DR7, and -DQB1 are most frequently expressed in patient with vitiligo.2

Gene polymorphisms in the MHC Class II region of the HLA locus have been previously found to be associated with other autoimmune diseases, such as type 1 diabetes mellitus and juvenile-onset rheu-matoid arthritis.18, 19 The HLA genes encoding both the transporter associated with antigen-processing (TAP1) and subunits of the immunoproteasome (LMP2/LMP7) have recently been found to be as-sociated with vitiligo of early onset in Caucasian patients.20 The cytotoxic lymphocyte antigen 4 (CTLA-4) gene encodes a protein involved in the inhibition of improperly-activated T-cells. CTLA-4 variants have been linked to numerous autoimmune diseases. Recently, a study comparing 100 United Kingdom patients with vitiligo to controls found an association between the CTLA-4 polymorphism and vitiligo when it occurred with other autoimmune dis-eases, though not isolated vitiligo.21 Catechol-O-me-thyl transferase (COMT) is an enzyme that plays a major role in the metabolism of toxic or biologically active drugs, neurotransmitters and metabolites. One such metabolite, O-quinones, can be formed during melanin synthesis in the absence of adequate COMT activity. A COMT polymorphism has been found to be significantly associated with acrofacial vitiligo.22 Chromosome 1p31, termed the autoimmune suscep-tibility locus (AIS1), has been found to be associated

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to contain T-cells specific to melanocyte antigens.43 In perilesional skin, T cells are primarily found jux-taposed to the remaining melanocytes.2 The credibil-ity of this mechanism is further supported by stud-ies demonstrating an autoimmune response against antigens present in normal melanosomes in patients with melanomas.44

Other hypotheses revolve around melanocyte self-destruction. Some studies suggest that melanocyte defects that result in increased oxidant stress may ex-plain melanocyte dysfunction.45, 46 Increases in pro-oxidants as well as decreases in antioxidant agents have been reported in patients with vitiligo. Fur-thermore, several studies detected evidence of oxi-dative stress-induced damage within the epidermis of vitiliginous lesions.45 An alternative hypothesis, the melanocytorrhagy theory, suggests autologous melanocyte chronic detachment and transepidermal loss as a possible explanation.46 Disruption of the linkage between keratinocyte cytokines and their re-ceptors (expressed on melanocytes) is another pro-posed etiology.47

There are several other more limited hypotheses regarding vitiligo etiology. Segmental vitiligo is best explained by the neural theory, which proposes that some chemical mediators released from peripheral nerve endings cause decreased production of mela-nin.48 Recent studies have reported ultrastructural evidence of axonal damage 49 and changes in neu-ropeptide balance 50 in the nerves of segmental vi-tiliginous lesions, supporting this hypothesis. Some medications have been associated with vitiligo de-velopment. For example, infliximab has been de-scribed as inducing vitiligo, presumably by the same mechanism as it produces a lupus-like syndrome.51 A chemical-induced vitiligo can result from expo-sure to some industrial chemicals, catechols, alkylat-ed phenols and cinnamic aldehyde.52, 53 Trauma to the skin can cause focal depigmentation in patients with vitiligo.5 This occurrence, known as Koebner’s phenomenon, is rarely seen in segmental vitiligo, but is seen in a third of patients with nonsegmental vi-tiligo. Psychological trauma may even increase an individual’s susceptibility to vitiligo.54

Histopathology

Histopathological examination of vitiligo lesions using melanocyte-specific stains has shown few

Differential diagnosis

In children especially, there are many similari-ties in the clinical appearances of vitiligo, pityriasis alba, tinea versicolor, postinflammatory hypopig-mentation, piebaldism, morphea, leprosy, tuberous sclerosis, nevus depigmentosus, and lichen sclerosis and atrophicus. To properly diagnose vitiligo, one must be able to differentiate between a complete absence of pigment, hypopigmentation and normal skin. This is more difficult in light-complexioned patients. Wood’s lamp examination can help make this differentiation easier. One particularly difficult differentiation is between the macules of confetti vi-tiligo and those of tuberous sclerosis.36 Character-istic signs and symptoms may be helpful in making the proper diagnosis in this and other cases. For ex-ample, depigmented patches shaped like ash leaves would help make the diagnosis of tuberous sclerosis. In another situation, the presence of a white forelock may be helpful in diagnosing piebaldism as opposed to vitiligo.

Etiology

Non-segmental vitiligo is most commonly de-scribed as having an autoimmune etiology. The immune system is undeniably involved in the pathogenesis, as evidenced by the effectiveness of immunomodulatory agents, such as corticoster-oids and calcineurin-inhibitors in treatment.37, 38 Its strong association with autoimmune diseases further supports this hypothesis.32, 33 There are two immune system abnormalities observed in vitiligo patients that provide possible mechanisms for the melanocyte destruction that occurs. Several studies have detect-ed the presence of autoantibodies in serum target-ing melanocyte surface and cytoplasmic antigens.39 In vivo demonstration of melanocyte destruction by vitiligo patient IgG serum adds plausibility to this mechanism.40 Lately, a cell-mediated mechanism has been receiving more attention. Cytotoxic T-lym-phocytes (CTL) have been spatially and temporally associated with depigmentation.41 A recent study re-ported especially dramatic inflammatory changes, in-cluding CTL influx, where one would expect to find the most active pathology: in lesional margins and in the center of newly formed lesions.42 Inflammatory infiltrates from vitiliginous lesions have been found

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vided in medical, physical and surgical, alone or in association (Table II).57 Comparative efficacy of various treatments is reported in Table III.

UVA rays (320-400 nm) are combined to oral (PUVA) or topical (TUVA) administration of furo-coumarin psoralen photosensitizers. Oral psoralens (8-methoxy-psorale, 5-methoxy-psoralen and tri-

melanocytes in early lesions and a lack of melano-cytes in well-established lesions.33 In patches with hyperpigmented borders, the margins were found to contain enlarged melanocytes with elongated den-dritic processes containing melanin. A lymphohis-tiocytic infiltrate along with focal basal layer vacu-olar changes has been observed in marginal tissue. Significantly more infiltrate and other inflammatory changes were appreciated in marginal areas and ear-ly lesions in one study.42

Repigmentation of vitiliginous lesions occurs pre-dominantly in a perifollicular pattern 55 (Figures 2, 3). The outer root shaft of hair follicles contains an inactive melanocyte reservoir. Upon stimulation by certain treatment modalities, these melanocytes di-vide, proliferate and migrate into the adjacent tissue where they become activated. Repigmentation also may occur in diffuse, marginal or combined patterns depending on the particular methods of treatment used. These patterns probably effect repigmentation through mechanisms other than the one described for the perifollicular pattern

Treatment

Nowadays, vitiligo can be treated using tradition-al, new and experimental therapies, each of which has different indications, especially in children, ef-ficacy and side effects.56

Newly available treatment for vitiligo can be di-

Figure 3.—�A close-up of perifollicular repigmentation.Figure 2.—�A diffuse repigmentation of perifollicular pattern over a large abdominal region.

Table II.—�Available treatments for vitiligo.

Medical CorticosteroidsOther topical treatments

Physical Ultraviolet B narrow bandUltraviolet B narrow band microphototherapyUltraviolet B narrow band excimer laser and

monochromatic excimer lightBath PUVA

Surgical

Table III.-Vitiligo treatments and their efficacy.

Efficacy Notes

PUVA 51% 56 High relapse rate 56

NB-UVB 63% 56 Treatment of choice for vitiligo vulgaris 56

Targeted Phototherapy 53% 59 Useful in treating focal vitiligo 48

Skin Grafting 87-95% 56 Treatment of choice for stable lesions 56

Corticosteroids 56% 56 Primarily used in combination therapy 66-68

Calcineurin- Inhibitors 25% 63 Primarily used in combination therapy 66-68

Calcipitriol 56% 64 Primarily used in combination therapy 66-68

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between normal and depigmented skin.64, 65 Fur-thermore NB-UVB are related to less erythema, no phototoxic effects and no epidermal thickening and/or epidermal atrophy after long-term irradiation. In fact it is associated with far fewer side-effects, pos-sibly due to a simpler treatment procedure resulting in shorter sessions and decreased ultraviolet expo-sure time.48

Many different therapeutic protocols are available with an initial dose of irradiation raging from 0.075 J/cm2 to 0.025 J/cm2 and increasing by 20% after each treatment until a slight erythema is reached. Sessions are repeated 2-3 times a week for a maxi-mum period of 6 month- 1 year. Efficacy of NB-UVB is comparable to the one of PUVA (psoralen plus UVA), with advantages, such as avoidance of psoralen side effects and reduction in cumulative dose of radiation.

NB-UVB can be safely used in children and in pregnant women. The efficacy and the safety of NB-UVB radiation therapy in childhood vitiligo has been demonstrated by Njoo et al. in 2000. The treatment resulted in more than 75% overall repig-mentation in 53% of patients and in stabilization of the disease in 80%. Responsiveness to therapy was positively correlated to the location of the le-sions and the compliance of the patients. The bet-ter pigmentation grade was related to the better improvement of life quality.66 On the other hand, we have to remember that NB-UVB are still ra-diations with potential skin cancer-producing, less than PUVA but more than the Broad-Band UVB (290-320 nm).67

In conclusion NB-UVB is an effective, safe and well tolerated treatment option for childhood vitil-igo. Even though it has a carcinogenetic potential, the benefit outweighs the risks.

UV-B microphototherapy is also highly effective in restoring pigmentation using a device called BI-OSKIN that can focus a beam of UV-B (microphoto-therapy) limited to patches of vitiligo.5

The microphototherapy was developed in order to avoid the long-term side effects of UV absorption. Microphototherapy is based on a photo exposition limited to well-defined areas, and it avoids the collat-eral effects associated to diffuse phototherapy (pho-toaging, erythema, burns, teleangectasias, excessive tanning of the non-affected skin, risk of neoplasms). It uses a NB-UVB light (Philips TL-10) with a wave-length peak at 311 nm that is selectively delivered to

methylpsoralen) are used in widespread vitiligo in-volving more than 20% of total body surface. PUVA cannot be administered to patients with cataracts or when taking warfarin, or during pregnancy. PUVA therapy has not been recommended in pediatric pa-tients because of concerns regarding potential long-term side effects, especially cancinogenetic ones. However, PUVA has been used with caution for sev-eral inflammatory and hyperproliferative childhood dermatoses, including vitiligo, without reports of significant adverse events to date. Cooperative chil-dren unresponsive to other treatments are candidate for PUVA.58, 59

On the other hand bath PUVA, characterized by dilution of psoralen in bathwater (bath PUVA), or local application of psoralen (as creams or oint-ments) plus UVA irradiation (TUVA), may provide a wider margin of safety, especially in children, in that less exposure to UVA radiation is required and systemic absorption of psoralen is minimal.60 Topi-cal psoralen lotions can be administered to patients suffering of vitiligo affecting less than 10% of body surface. This form of therapy decreases the total sur-face area treated and avoids possible ocular toxicity of systemic PUVA.

Topical psoralen plus UV-A phototherapy (PUVA therapy) is a well-established treatment for nonseg-mental vitiligo. However, it is only moderately ef-fective (51%) and has a high relapse rate.61 It has been associated with a number of side-effects, in-cluding darkening of normal skin, erythema, scal-ing , hyperthricosis and pruritus. Less common side-effects include nausea, phototoxic effects, photoallergic reactions, hyperkeratosis of lesional skin, cataracts, the potential cumulative risk of ac-tinic damage and rarely, skin malignancies. Khellin is an extract of an Eastern Mediterranean plant that has a chemical structure similar to psoralen. A re-cent study has shown that treatment with UV-A and khellin in place of psoralen results in comparable efficacy (44% for KUVA vs. 53% for PUVA) with a large reduction in adverse effects.62

Narrow-band UV-B (NB-UVB) phototherapy is a treatment of choice for patients with active, general-ized vitiligo with an effectiveness of 63% against this form of the disease.50 It has also been shown to be highly effective in treating stable vitiligo when at least 5% of the total body is involved.63 NB-UVB are more effective, compared with topical UVA treat-ment with faster repigmentation and less contrast

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After the consistent results of BIOSKIN™, other innovations, still experimental, have been intro-duced to treat vitiligo: ultraviolet B narrow band excimer laser (XeCl) and monochromatic excimer light (MEL) at 308 nm. They are similar to the clas-sical narrowband treatment, but are more selective in treating the vitiligo patches with the advantage of lower side effects.56 Targeted phototherapy using these 308 nm light sources is especially useful in treating localized vitiligo

The XeCl has a laser coherent emission of mono-chromatic rays very similar to “classical” narrow-band radiation, while MEL device can generate and selectively deliver 308 nm peak UVB light.69

It has been documented a total pigmentation oc-curs in the affected areas in 12% of subjects and a partial (25-75%) repigmentation in 25%, when treating 24 patients affected by vitiligo using XeCl for 15-57 months.70 The efficacy of XeCl seems to be related to treatment duration and lower mean duration of disease. It is recommended to use the XeCl with fluencies resulted in medium doses (about 3 minimal erythemal dose) for the side ef-fects and the potential long-term carcinogenic risk associated with higher fluencies.70 The XeCl rep-resents the last advance in selective phototherapy, but, because of the data lack and in the absence of long-term follow-up, it must not be proposed as first treatment, even though it has documented as an effective treatment for vitiligo.

The use of monochromatic excimer light has sim-ilar characteristics and results.71 The MEL at 308 nm is a safe and fast-acting therapeutic option in patients with stable vitiligo and skin types 3-6 even though a long-term follow up is necessary.72

These two methods showed good results in term of repigmentation, alone or in association with other agents (i.e., topical steroids or tacrolimus ointment).

The hyperpigmentation of normal skin reported with PUVA treatment is also not observed with this treatment. However, this modality has been found to be slightly less effective than NB-UVB, with a success rate of 53%.73 Still, a number of character-istics of the treatment make it a valuable therapeu-tic option. The targeted exposure of this strategy spares the normal skin from potentially harmful ra-diation. Also rapid therapeutic responses have been observed in several studies,48 with one study ob-serving a 52% success rate within three months.73 These two factors together result in a large decrease

the white patches through an optical fiber handpiece. It enables drastic reduction of total dose of radiation and the most common side effects related to the ex-position to UV rays: excessive tanning of unaffected skin, photoaging, teleangectases, risk of neoplasms. It also avoid an increase in the chromatic contrast between normal and lesional skin.

Furthermore, we can administer different doses of UVB radiation in different areas of the body trough microphototherapy (i.e., hands need more UVB than eyelids to repigment).64 Microphototherapy is indi-cated in patients affected by segmental vitiligo (fre-quent type in childhood) and bilateral symmetrical vitiligo in whom the total amount of body surface involved is less than 20%.

BIOSKIN™ is currently carried out only in Italy. It is an advanced devise and its efficacy has been documented by Menchini et al. in 2003.68

The initial dose of radiation is 20% less than the minimum erythema dose, which is evaluated through the exposition of affected and unaffected skin to in-creasing dose of UVB (80, 160, 240, 320, 400 mW/cm2) at least three days before the beginning of the treatment. During the following sessions, each patch is uniformly irradiated. In sensitive areas (eyelids) 80% of minimum erythema doses are used. The ra-diation dose is increased by 20% at each session. When erythema occurs, the dose is lowered by 20% in the erythematous area only. Sessions are repeated every 21 to 30 days until repigmentation is reached which may take from two months to two years.68

Partial repigmentation is often seen after at least three to six sessions (63% of the cases), beginning just after two months of treatment as a pigment pit-ting around each follicular ostium (follicular repig-mentation).

After one year of therapy Menchini et al. docu-mented, in a survey of 734 patients, 69.8% of pa-tients achieved normal pigmentation on more than 75% of the treated areas, 21.1% obtained 50% to 75% of repigmentation, only 9.4% showed less than 50% repigmentation with no statistical difference between segmental and non-segmental vitiligo.68

The only side effect reported is mild and transient erythema of the treated areas. Microphototherapy is not administered to patients who have actinic sen-sitivity (systemic lupus erythematosus, xeroderma pigmentosum, porphyriasis, cutaneous viral infec-tions) or patients treated with topical or systemic photosensitizing drugs.

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and neck, as been documented by Silverberg et al. in 2004.83 The association of tacrolimus with ul-traviolet B narrow band excimer laser (XeCl) has been proposed to improve repigmentation rate, but it should be used with caution and limited to short therapies for the high frequency of burns and for the unknown effects on skin cancer-producing, espe-cially in childhood.84

Calcipotriol is another topical agent being utilized. It is thought to stimulate melanogenesis through an unknown mechanism involving melanocyte 1-al-pha-25 dihydroxy vitamin D3 receptors. In one tri-al, 10/18 children (56%) treated showed marked to complete re-pigmentation.85 Calcipotriol should be used as an effective alternative therapy especially in childhood vitiligo in which potent topical steroids and PUVA therapy are not advisable for their risk. In 2004 Gargoom et al. documented a complete resolution in 21.4% and a very good improvement (50-80%) in 28.6%, studying a survey of 18 children affected by vitiligo. Only one patient developed ir-ritation. Better results were obtained with ointment than with cream.86

Another innovative topical treatment of vitiligo is represented by the application of prostaglandin E (PGE2). In a recent study, 24 patients affected by vitiligo with less than 5% of skin involvement were treated with a gel containing 166.6 mg/g PGE2, ap-plied once a day for six months on the affected ar-eas. Fifteen patients reported a marked (50-75%) to complete repigmentation, six showed 25% to 50% improvement, and six minimal or none improve-ment.87

Because of their limited effectiveness in mono-therapy, the above topical therapies are used prima-rily in combination therapy to increase the efficacy and, in some cases, decrease the response time of other modalities.81, 88, 89

Extensive vitiligo involving more than 80% of skin may be treated with the permanent removal of pigment from the remaining normally pigmented skin. Bleaching creams used include monobenzyl ether of hydroquinone and 4-methoxy-phenol.4, 5, 33,

34 We prefer 20% monobenzylether of ether for this purpose, cautioning patients to strongly consider the desirability and potential side effects. The latter in-clude contact dermatitis and an acquired ochronosis that may be perceived as even more cosmetically undesirable than the vitiligo itself.4 Depigmentation therapy is not indicated in children.

in the cumulative dosing, which may reduce ad-verse effects and increase patient compliance. On our opinion these two methods are particularly in-dicated in localized and segmental vitiligo, espe-cially in young patients.

Surgical modalities are quite effective in treat-ing certain types of vitiligo.61, 74, 75 Autologous skin grafting is a method of choice for treating stable vitiligo, focal or generalized. Segmental vitiligo, which is particularly unresponsive to medical treat-ment, can be managed well with this treatment.7 The success rate is estimated to be between 87% and 95%.61 The procedure can be very complicated, hav-ing to be performed under general anesthesia. Ad-ditionally, it is only indicated for patients in whom the vitiligo has stopped progressing.74 Mini-grafting techniques have been utilized with some success to determine lesion stability.75 Another surgical treat-ment, manual tattooing of depigmented lesions, is a cheap and effective alternative for patients with any type of localized vitiligo.76 Surgical therapies should be reserved for adolescent or adult patients who are firmly motivated and are not recommend-ed for patients with the tendency to form keloids.77 Better surgical results can be obtained in segmental vitiligo and in patients younger than 20 years.78

Topical therapeutics are frequently used in the treatment of vitiligo. Melagenine, a topical agent de-rived from placenta, has been used successfully in treating some childhood cases of vitiligo.79 Corticos-teroids have been shown to be moderately effective in monotherapy with a success rate of 56%.73 The most efficient topical corticosteroids seem to be class with high potency, such as II class (bethametasone valerate 0.1-0.2%) and I class (clobetasol propionate 0.05%) (highest), applied once or twice daily for 2-4 months.69 Topical steroid should be used for limited times and only in localized vitiligo (less than 10% to-tal body surface), not in segmental vitiligo. Possible side-effects, including atrophy and telangiectasias limit its use in some populations. More recently, the calcineurin-inhibitors pimecrolimus and tacrolimus have been used successfully in vitiligo treatment.50,

80-82 However, patients have been reported to receive only mild benefit from exclusive calcineurin-inhib-itor treatment, with a success rate of 25% after two months of therapy reported by one study.38, 80

The use of tacrolimus ointment is particularly indicated and is an effective alternative treatment in childhood vitiligo, particularly involving head

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biosi G. Age of onset in vitiligo: relationship with HLA supratypes. Clin Genet 1991;39:48-54.

18. Deng GY, Muir A, Maclaren NK, She JX. Association of LMP2 and LMP7 genes within the major histocompatibility complex with insulin-dependent diabetes mellitus: population and family studies. Am J Hum Gen 1995;56:528-34.

19. Prahalad S, Kingsbury DJ, Griffin TA, Cooper BL, Glass DN, Mak-symowych WP, Colbert RA. Polymorphism in the MHC-encoded LMP7 gene: association with JRA without functional significance for immunoproteasome assembly. J Rheumatol 2001;28:2320-5.

20. Casp CB, She JX, McCormack WT. Genes of the LMP/TAP cluster are associated with the human autoimmune disease vitiligo. Genes Immun 2003;4:492-9.

21. Blomhoff A, Kemp EH, Gawkrodger DJ, Weetman AP, Husebye ES, Akselsen HE, Lie BA et al. CTLA4 polymorphisms are asso-ciated with vitiligo, in patients with concomitant autoimmune dis-eases. Pigment Cell Res 2005;18:55-8.

22. Tursen U, Kaya TI, Erdal ME, Derici E, Gunduz O, Ikizoglu G. As-sociation between catechol-O-methyltransferase polymorphism and vitiligo. Arch Dermatol Res 2002;294:143-6.

23. Fain PR, Gowan K, LaBerge GS, Alkhateeb A, Stetler GL, Talbert J et al. A genomewide screen for generalized vitiligo: confirmation of AIS1 on chromosome 1p31 and evidence for additional susceptibil-ity loci. Am J Hum Gen 2003;72:1560-4.

24. Le Poole IC, Sarangarajan R, Zhao Y, Stennett LS, Brown TL, Sheth P et al. ‘VIT1’, a novel gene associated with vitiligo. Pigment Cell Res 2001;14:475-84.

25. Gottumukkala RV, Waterman EA, Herd LM, Gawkrodger DJ, Watson PF, Weetman AP et al. Autoantibodies in vitiligo patients recognize multiple domains of the melanin-concentrating hormone receptor. J Invest Dermatol 2003;121:765-70.

26. Broniarczyk-Dyla G, Arkuszewska C, Omulecki A. Coexistence of vitiligo, morphea and lichen planus in the same patient. Przegl Der-matol 1994;81:569-72.

27. Iacovelli P, Sinagra JL, Vidolin AP, Marenda S, Capitanio B, Leone G et al. Relevance of thyroiditis and of other autoimmune diseases in children with vitiligo. Dermatology 2005;210:26-30.

28. Kemp EH, Waterman EA, Weetman AP. Autoimmune aspects of vi-tiligo. Autoimmunity 2001;34:65-77.

29. Hegedus L, Heidenheim M, Gervil M, Hjalgrim H, Hoier-Madson M. High frequency of thyroid dysfunction in patients with vitiligo. Acta Derm Venereol 1994;74:120-3.

30. Iacovelli P, Sinagra JL, Vidolin AP. Relevance of thryroiditis and other autoimmune diseases in children with vitiligo. Dermatology 2005;210:26-30.

31. Pajvani U, Ahmad N, Wiley A, Levy RM, Kundu R, Mancini AJ et al. The relationship between family medical history and childhood vitiligo. J Am Acad Dermatol 2006;55:238-44.

32. Huggins RH, Janusz CA, Schwartz RA. Vitiligo as a sign of sys-temic disease. Indian J Dermatol Venereol Leprol 2006;72:68-71.

33. Schwartz RA, Janniger CK. Vitligo. Cutis 1997;60:239-44.34. MacKie RM. Vitiligo. In: Clinical dermatology. 5th ed. New York:

Oxford University Press; 2003. p. 227-9.35. Choczaj-Kukula A, Janniger CK. Vogt-Koyanagi-Harada syndrome.

eMedicine Dermatology [journal serial online] 2006. [cited 2012 July 5]. Available at: http://author.emedicine.com/derm/topic739.htm

36. Jozwiak S, Schwartz RA, Janniger CK, Michalowicz R, Chmielik J. Skin lesions in children with tuberous sclerosis complex: their prevalence, natural course, and diagnostic significance. Int J Der-matol 1998;37:911-7.

37. Njoo MD, Spuls PI, Bos JD, Westerhof W, Bossuyt PM. Nonsurgi-cal repigmentation therapies in vitiligo: meta-analysis of the litera-ture. Arch Dermatol 1998;134:1532-40.

38. Lepe V, Moncada B, Castanedo-Cazares JP, Torres-Alvarez MB, Ortiz CA, Torres-Rubalcava AB. A double-blind randomized trial

Riassunto

Vitiligine: recenti conoscenze e nuovi approcci terapeuticiLa vitiligine è causata dalla selettiva distruzione dei me-

lanociti. Si tratta di un disturbo relativamente diffuso di origine probabilmente autoimmune che colpisce persone di ogni background e di entrambi i sessi. Non sembra es-sere interessato maggiormente nessun gruppo specifico. In metà dei pazienti affetti da vitiligine, questa si manifesta prima dei 18 anni di età. Nelle regioni dove la lebbra è endemica, gli individui con vitiligine sono spesso stigma-tizzati a causa delle somiglianze nell’aspetto tra le due ma-lattie. Passeremo in rassegna tale importante argomento, sottolineando i più recenti progressi terapeutici.Parole chiave: Cute, malattie - Vitiligine - Sistema au-toimmunitario.

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comparison study on narrow band (TL-01) UVB phototherapy ver-sus photochemotherapy (PUVA) in the treatment of chronic plaque type psoriasis. Arch Dermatol 1999;135:519-24.

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40. Gilhar A, Zelickson B, Ulman Y, Etzioni A: In vivo destruction of melanocytes by the IgG fraction of serum from patients with vi-tiligo. J Invest Dermatol 1995; 105: 683-6.

41. van den Wijngaard RMJGJ, Wankowicz-Kalinska A, Le Poole IC, Tigges B, Westerhof W, Das PK. Local immune response in skin of generalized vitiligo patients: Destruction of melanocytes is associ-ated with the prominent presence of CLA+ T cells at the perilesional site. Lab Invest 2000;80:1299-309.

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43. Wankowicz-Kalinska A, van den Wijngaard RM, Tigges BJ, We-sterhof W, Ogg GS, Cerundolo V, Storkus WJ et al. Immunopolari-zation of CD4+ and CD8+ T cells to Type-1-like is associated with melanocyte loss in human vitiligo. Lab Invest 2003;83:683-95.

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48. Grimes PE. White patches and bruised souls: advances in the patho-genesis and treatment of vitiligo. J Am Acad Dermatol 2004;51:S5-7.

49. Al’Abadie MS, Warren MA, Bleehen SS, Gawkrodger DJ. Morpho-logic observations on the dermal nerves in vitiligo: an ultrastruc-tural study. Int J Dermatol 1995;34:837-40.

50. Liu PY, Bondesson L, Löntz W, Johansson O. The occurrence of cutaneous nerve endings and neuropeptides in vitiligo vulgaris: a case-control study. Arch Dermatol Res 1996;288:670-5.

51. Ramirez-Hernandez M, Marras C, Martinez-Escribano JA. Inflixi-mab-Induced Vitiligo. Dermatology 2005;210:79-80.

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54. Picardi A, Pasquini P, Cattaruzza MS, Gaetano P, Melchi CF, Baliva G et al. Stressful life events, social support, attachment security and alexithymia in vitiligo. A case-control study. Psychother Psycho-som 2003;72:150-8.

55. Parsad D, Pandhi R, Dogra S, Kumar B. Clinical study of repigmen-tation patterns with different treatment modalities and their correla-tion with speed and stability of repigmentation in 352 vitiliginous patches. J Am Acad Dermatol 2004;50:63-7.

56. Lotti T, Gori A, Zanieri F et al. Vitiligo: new and emerging treat-ments. Dermatol Ther 2008;21:110-7.

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58. Siegfried E, Nopper AJ, Draelos Z, Bree A, Swords S, Laurer SJ. Principles of treatment in pediatric dermatology. Phototherapy. In: Schachner LA, Hansen RC, editors. Pediatric dermatology. 3rd edi-

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86. Gargoom AM, Duweb GA, Elzorghany AH, Benghazil M, Bugrein OO. Calcipotriol in the treatment of childhood vitiligo. Int J Clin Pharmacol Res 2004;24:11-4.

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Received on May 16, 2011.Accepted for publication on July 5, 2012.

81. Passeron T, Ostovari N, Zakaria W, Fontas E, Larrouy JC, Lacour JP et al. Topical tacrolimus and the 308-nm excimer laser: a syn-ergistic combination for the treatment of vitiligo. Arch Dermatol 2004;140:1065-9.

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85. Parsad D, Saini R, Nagpal R. Calcipotriol in vitiligo: a preliminary study. Pediatr Dermatol 1999;6:317-20.


ber 2010 with a rash on the plantar surface of the left foot. The rash appeared during a trip to Brittany, where the pa-tient visited Brest, Concarneau and Lorient. In addition, he visited numerous beaches along the southern coast. Dermatological examination revealed several serpiginous, erythematous, slightly raised tracks. Some pustular lesions were also visible (Figure 2). The patient complained of pruritus. Bacteriological examinations were positive for Staphylococcus aureus. A diagnosis of HrCLM with bacte-rial superinfection was made. The patient was successfully treated with topical gentamycin (2 applications/day for 10 days) and oral amoxicillin (2 g/day for 10 days), followed by oral albendazole (400 mg/day for 7 days). Follow-up (13 months) was negative.

Discussion

HrCLM is an infestation caused by the penetration and migration in the epidermis of nematode larvae. Ancylostoma braziliense and Ancylostoma caninum are the species more frequently involved. HrCLM is characterized clinically by serpiginous, erythema-tous and slightly raised tracks, located especially on the feet. These tracks may be single or multiple, linear or serpiginous, more or less ramified and in-tertwined. The length is variable (up to many cm); the width ranges from 1 to 2 mm. Tracks are often accompanied by severe pruritus.2

Department of Pathophysiology and TransplantationUniversità degli Studi di Milano

Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy

CASE REPORTSG ITAL DERMATOL VENEREOL 2012;147:649-51

S. VERALDI, M. C. PERSICO, C. FRANCIA, V. LA VELA

Appearance of a reservoir of hookworm-related cutaneous larva migrans in Brittany?

We describe two cases of hookworm-related cutaneous larva migrans acquired in Brittany (North-Western France). The patients were a 23-year-old woman and a 28-year-old man. In both patients the feet were involved. In the second patient, a superinfection due to Staphylococcus aureus was recorded. The appearance in Brittany of a reservoir of nematodes ca-pable of causing hookworm-related cutaneous larva migrans is hypothesized.

Key words: Larva migrans - Nematode - Skin diseases.

In 2009, Tamminga et al.1 published a case of hookworm-related cutaneous larva migrans (Hr-

CLM) acquired in Brittany (North-Western France). We describe two patients with HrCLM who acquired the infestation in the same region. The appearance in Brittany of a reservoir of nematodes capable of caus-ing HrCLM is hypothesized.

Clinical series

Case 1.—A 23-year-old woman was admitted to our Department in September 2010 because of a rash on both feet and ankles. The patient had just returned from a trip to Brittany, where she visited Morlaix, Brest and Locronan as well as several beaches in the southern coast. The rash was characterized clinically by several serpiginous, ery-thematous, slightly raised, pruritic tracks (Figure 1). A di-agnosis of HrCLM was made. The patient was successfully treated with oral albendazole (400 mg/day for 7 days). A 13-month follow-up was negative.

Case 2.—A 28-year-old man was admitted in Septem-

Corresponding author: S. Veraldi, via Pace 9, 20122 Milan, Italy. E-mail: [email protected]


Lavoro: 4324-MDtitolo breve: Hookworm-related cutaneous larva migransprimo autore: VERALDIpagine: 649-51

VERALDI HOOkWORM-RELATED CuTANEOuS LARVA MIGRANS


HrCLM is endemic in Eastern Africa, Asia (in par-ticular Thailand) and America (South-Eastern unit-ed States, Caribbeans and Brazil). Rare cases of Hr-CLM were acquired in countries with temperate or cold climate: Great Britain,3-6 Germany,7-10 France,1,

11, 12, Italy,13-16 Spain,17, 18 and New Zealand.19 As far as French cases are concerned, all of them were ob-served in Southern France,11, 12 except for the patient described by Tamminga et al.1 These authors ad-vanced the hypothesis that Uncinaria stenocephala was the aetiological agent. An outbreak of HrCLM involving 22 patients, especially around the city of Fréjus, but also in Avignon and Dijon, was recorded in 2005-2006.12

The cases we have described suggest the appear-ance in Brittany of a previously unreported reservoir of nematodes capable of causing HrCLM. No hypoth-eses can be currently advanced in order to explain this occurrence. However, weather conditions can be important: prevalence of HrCLM is significantly higher in hot-humid climates and rainy season.2 This higher prevalence might be due to longer survival of the larvae in the soil.2 The weather in Brittany, in the summer 2010, was incidentally hot and humid, because of frequent, although short, rains.

Riassunto

Comparsa di un serbatoio di larva migrans cutanea in Bretagna?

Gli autori descrivono due casi di larva migrans cutanea acquisita in Bretagna (Francia nord-occidentale). I pazienti erano una donna di 23 anni e un uomo di 28 anni. In en-trambi i pazienti erano colpiti i piedi. Nel secondo paziente fu osservata una sovrinfezione da Staphylococcus aureus. Viene ipotizzata la comparsa in Bretagna di un serbatoio di nematodi in grado di causare la larva migrans cutanea.Parole chiave: Larva migrans - Nematodi - Cute, ma-lattie.

References

1. Tamminga N, Bierman WFW, De Vries PJ. Cutaneous larva migrans acquired in Brittany, France. Emerg Infect Dis 2009;15:1856-8.

2. Veraldi S, Bottini S, Persico MC, La Vela V. Larva migrans cutanea. Mediprint 2010;1-78.

3. Roest MAB, Ratnavel R. Cutaneous larva migrans contracted in England: a reminder. Clin Exp Dermatol 2001;26:389-90.

4. Beattie PE, Fleming CJ. Cutaneous larva migrans in the west coast of Scotland. Clin Exp Dermatol 2002;27:248-9.

5. Patterson CRS, kersey PJW. Cutaneous larva migrans acquired in England. Clin Exp Dermatol 2003;28:671-2.

Figure 2.−Case 2. Several serpiginous, erythematous, slightly raised tracks and pustular lesions on the plantar surface of the left foot.

Figure 1.−Case 1. Several serpiginous, erythematous, slightly raised tracks on a foot and ankle.

HOOkWORM-RELATED CuTANEOuS LARVA MIGRANS VERALDI


13. Albanese G, Venturi C, Galbiati G. Treatment of larva migrans cu-tanea (creeping eruption): a comparison between albendazole and traditional therapy. Int J Dermatol 2001;40:67-71.

14. Galanti B, Fusco FM, Nardiello S. Outbreak of cutaneous larva migrans in Naples, southern Italy. Trans R Soc Trop Med Hyg 2002;96:491-2.

15. Albanese G, Venturi C. Albendazole: a new drug for human parasi-toses. Dermatol Clin 2003;21:283-90.

16. Morrone A, Paradisi M, Paradisi A, Valenzano M, Fazio R, Fornari u, Franco G. Autochthonous creeping eruption in an italian child. Am J Clin Dermatol 2008;9:205-6.

17. Nicol M. Cutaneous larva migrans. Arch Emerg Med 1990;7:118-20.

18. Sàbat Santandreu M, Ribera Pibernat M, Bielsa Narsol I, Rex Cav-alle J, Ferrándiz Foraster C. Larva migrans cutánea. Presentación de 8 casos. Actas Dermosifiliogr 2002;93:443-7.

19. Manning L, Chambers S, Paltridge G, Maurice P. Cutaneous larva migrans (hookworm) acquired in Christchurch, New Zealand. N Z Med J 2006;119:u1910.

6. Diba VC, Whitty CJM, Green T. Cutaneous larva migrans acquired in Britain. Clin Exp Dermatol 2004;29:555-6.

7. klose C, Mravak S, Geb M, Bienzle u, Meyer CG. Autoch-thonous cutaneous larva migrans in Germany. Trop Med Int Health 1996;1:503-4.

8. Herrmann A, Christoph T, Sebastian G. Larva migrans “saxoniae”: Auftreten einer Infektion mit Larva migrans in Sachsen. J Dtsch Dermatol 2004;2:46-8.

9. kienast A, Bialek R, Hoeger PH. Cutaneous larva migrans in north-ern Germany. Eur J Pediatr 2007;166:1183-5.

10. Müller-Stöver I, Richter J, Häussinger D. In Deutschland erworbene Larva migrans cutanea. Dtsch Med Wochenschr 2010;135:859- 61.

11. Zimmermann R, Combemale P, Piens MA, Dupin M, Le Coz C. Larva migrans cutanée autochtone en France. A propos d’un cas. Ann Dermatol Venereol 1995;122:711-4.

12. Del Giudice P, Caumes E, Boissy C, Leduff F, Delaunay P, Blanc-Amrane V et al. An outbreak of creeping eruption in southern France. Br J Dermatol 2007;157:824-5.



Lavoro: 4265-MDtitolo breve: Cutaneous neonatal lupus: two casesprimo autore: BASSIpagine: 653-4

CORRESPONDENCE

Cutaneous neonatal lupus: two cases

TO THE EDITOR: Neonatal lupus is an uncommon au-toimmune disease, characterized by cutaneous lupus le-sions with or without congenital heart block, autoimmune hepatitis and hEmatological disease.1

We report 2 new cases of cutaneous neonatal lupus and discuss possible pathogenic mechanisms.

A 41-year-old woman, with systemic lupus, presented in 2005, six-week-pregnant (first pregnancy), while on hy-droxychloroquine (6.5 mg/kg/day) and prednisone (6 mg/day). Positive antinuclear antibodies with speckled pattern and titer of 1/1280, positive anti-Sm antibodies (63 AU) and positive high titer anti-Sm/U1RNP antibodies (>100 AU) were noted, while anti-Ro/SSA antibodies were con-sidered threshold limit. Anti-dsDNA antibodies, anticardi-olipin antibodies and lupus anticoagulant were negative. Prednisone was increased up to 30 mg a day between the 14th and the 24th week of pregnancy. After the 24th week, prednisone was slowly tapered up to 10 mg/day until deliv-ery. Hydroxychloroquine was continued throughout preg-nancy. Fetal cardiac ultrasonography was performed every two-four weeks and failed to show any heart damage. Anti-Ro/SSA antibodies were titrated every two months and re-mained unchanged throughout pregnancy (threshold limit), whereas anti-Sm/U1RNP antibodies remained elevated (>100 AU). She gave birth to a healthy baby girl, with no signs of cardiac block. Transaminases were normal. At the age of 2.5-months, the baby presented with erythemato-squamous plaques of both cheeks and erythemato-crusted lesions of the nose root, front, scalp and ears, especially on the left helix (Fig. 1,2). Child laboratory tests showed mild anemia (10.6 g/100ml), mild increased aspartate transami-nase (45 UI/L, normal< 37 UI/L) and positive antinuclear antibodies with speckled pattern and titer of 1/320 together with positive low titer anti-Sm antibodies (45 AU) and high titer anti-Sm/U1RNP antibodies (>100 AU). Complement fractions were normal; anti-Ro/SSA, anti-dsDNA were negative. The cutaneous eruption faded within 15 days, with class 2 topical corticosteroids. Clinical aspect, site, chronology and evolution of skin lesions were typical of cutaneous neonatal lupus.

A 22-year-old-woman, with systemic lupus, presented in February 2003, one-month-pregnant (first pregnancy),

while on hydroxychloroquine (6.5 mg/kg/day). Laboratory showed: positive antinuclear antibodies with speckled pat-tern and titer of 1/1280, positive anti-Sm (62 AU) and posi-tive high titers of anti-Sm/U1RNP (>100 AU), anti-Ro/SSA (99 AU) and anti-La/SSB (95 AU) antibodies. Anti-dsDNA antibodies were positive (titer 1/20). Anti-cardiolipin an-tibodies and lupus anti-coagulant were negative. At the beginning of her pregnancy hydroxychloroquine was re-placed by chloroquine (3 mg/kg/day), as, some years ago, safety of hydroxychloroquine during pregnancy was not assessed. Prednisone was started at 11 weeks of pregnancy at a dose of 0.5 mg/kg. This dose was maintained until the 28th week of pregnancy, then slowly tapered until delivery. Chloroquine was continued throughout pregnancy. Chlo-roquine more common side-effects are: appetite loss; di-arrhea; dizziness; headache; nausea. Rare side-effcts are: severe allergic reactions; change in the color of the skin or mouth; vision problems. Steroid side-effects, for mothers and fetuses, are: growth disturbances, acne, edema, hyper-colesterolemia, diabetes, cataract, osteoporosis, glaucoma. Foetal cardiac ultrasonography was performed every two-four weeks and failed to show any heart damage. Anti-Ro/SSA, anti-La/SSB and anti-Sm/U1RNP antibodies were titrated every three months and resulted constantly el-evated (≥ 100 AU). She gave birth to a healthy baby girl, with no signs of cardiac block. An electrocardiogram was performed at birth and was normal. Six weeks after, she attended the clinic with her baby who presented annular, erythematous finely squamous lesions of the neck and retro-auricular regions, present since 15 days. Cutaneous lesions faded within two weeks, with class 2 topical corti-costeroids. Clinical aspect, site, chronology and evolution of skin lesions were typical of cutaneous neonatal lupus.

We described two cases of isolated cutaneous neonatal lupus erythematosus. The two women were in stable dis-ease while they became pregnant.

Many cases of neonatal heart block and/or cutaneous lupus are reported in the literature. Few studies detail pre-ventive treatment.2 Shinoara et al.3 assessed the efficacy of prednisolone (15-20 mg/day) or betametasone in pre-venting cardiac neonatal lupus. No heart block, but four cutaneous lupus occurred in 26 offspring whose mothers

BASSI CUTANEOUS NEONATAL LUPUS: TWO CASES


had been treated before the 16th week. Even if retrospective and not blind this series suggests that corticosteroids intro-duced before the 16th week could prevent cardiac neonatal lupus.

Women with high titers anti-Ro/SSA and anti-La/SSB antibodies have an increased risk of giving birth to a baby with cardiac block. Only 10% of Ro/SSA positive moth-ers’ offspring will have cutaneous lupus, and 2% only will have cardiac block.1 Anti-U1RNP antibodies have been exceptionally reported to cause cutaneous neonatal lupus, in the absence of anti-Ro/SSA or La/SSB antibodies.4 Pa-tients with positive anti-U1RNP antibodies have usually cutaneous and hEmatological manifestations without car-diac involvement, which is usually related to a better prog-nosis of lupus.

In vivo, the anti-La/SSB response to major B cell epitopes of La/SSB can be blocked by an idiotypic/anti-idioptypic network. Infact, anti-idiotypic antibodies di-rected to autoantibodies against La/SSB (Id antibodies) can protect the fetus by blocking the pathogenic maternal antibodies.5

Intravenous immunoglobulin (IVIG) have been admin-istered to anti-Ro/SSA positive-pregnant women in order to reduce their antibodies’titer and icrease anti-idiotypic protective antibodies.

Concerning specifically cardiac pathogenesis, in vivo and in vitro evidences support a proinflammatory cascade unchained by cardiac apoptosis, which leads to transloca-tion of intracellular Ro and La antigens to foetal cardio-cytes cell surface and thus binding to maternal antibodies (opsonization). Gestational period of higher cardiac foetal vulnerability is the mid-second (16th week of pregnancy) to early-third trimester (24th week of pregnancy), because by that time cardiac conduction system reaches maturity.

For skin damage, a similar process is probable: the translocation of Ro/SSA antigen to the keratinocytes’ cell surface, particularly induced by UV rays, and binding to maternal antibodies has been noted.

In systemic lupus-mothers with positive anti-Ro/SSA and/or La/SSB antibodies, the exposure to hydroxychlo-roquine during pregnancy may decrease the risk of fetal development of cardiac-lupus. Prospective studies and controlled trials are needed to confirm these data.

In conclusion, our two cases suggest that prophylac-tic corticosteroid treatment associated with antimalarials

may not prevent cutaneous neonatal lupus. Physicians and patients must be advised and photoprotection of babies is mandatory.


Acknowledgments.—We would like to thank doctors Chantal An-dré and Aude Gleizes for laboratory investigations.Received on September 9, 2011.Accepted for publication on October 23, 2012.

E. BASSIDepartment of Dermatology, Paris XII University, Henri Mondor HospitalAssistance Publique-Hôpitaux de Paris, Créteil cedex, [email protected]

M. BAGOTDepartment of Dermatology, Paris XII University, Henri Mondor HospitalAssistance Publique-Hôpitaux de Paris, Créteil cedex, France

A. COSNESDepartment of Dermatology, Paris XII University, Henri Mondor HospitalAssistance Publique-Hôpitaux de Paris, Créteil cedex, France

References

1. Lee LA. Neonatal lupus. Clinical features and management. Pediatr Drugs 2004;6:71-8.

2. Yang CH, Chen JI, Lee SC, Luo SF. Successful preventive treat-ment of congenital heart block during pregnancy in a woman with systemic lupus erythematosus and anti-Sjogren’s syndrome A/Ro antibody. J Microbiol Immunol Infect 2005;38:365-9.

3. Shinoara K, Miyagawa S, Fujita T, Aono T, Kidoguchi KI. Neona-tal lupus erythematosus: results of maternal corticosteroids therapy. Obstet Gynecol 1999;93:952-7.

4. Sheth AP, Esterly NB, Ratoosh SL, Smith JP, Hebert AA, Silverman E. U1RNP positive lupus erythematosus: association with anti-La antibodies? Br J Dermatol 1995;132:520-6.

5. Routsias JG, Kyiriakidis NC, Friedman DM, Llanos C, Clancy R, Moutsopoulos HM et al. Association of idiotypic/anti-idiotypic ra-tio with therapeutic response of IVIG in the prevention of recurrent autoimmune associated congenital heart block. Arthritis Rheum 2011;63:2783-9.

Bullous pemphigoid of Lever and celiac disease: a coincidental occurrence or an unusual association?

TO THE EDITOR: A 70 years old man was referred to our clinic for the appearance of tense, serous blisters of varia-ble size scattered all over the tegument, except the cephalic

extremity. Numerous erosions and crusts were intermin-gled with blistering lesions, which occasionally showed a clustered appearance (Figure 1).

CUTANEOUS NEONATAL LUPUS: TWO CASES BASSI


tivity for C3 at the dermal-epidermal junction (not shown).The indirect immunofluorescence on patient’s serum

highlighted the presence of IgE and IgG directed against the dermal-epidermal junction.¹

All the clinical and laboratory results gave evidence in favour of bullous pemphigoid.²

The haematological examinations showed high levels of IgA anti-gliadin antibodies (108 U/mL; n.v. <55), scarce presence of IgG anti-gliadin antibodies (7 U/mL; n.v. <55) and absence of antiendomysium antibodies.³ No other lab-oratory abnormalities were detected.

The gastroenterologist carried out a esophagogastroduo-denoscopy, which showed a severe atrophy of the distal duodenum mucosa. A bioptic specimen of the duodenal mu-cosa, obtained during this examination, showed villous sub-atrophy, hyperplastic crypts and a intense lymphohistiocytic infiltrate of the lamina propria associated to an increased number of intraepithelial T CD3+ lymphocytes (Figure 2).

The patient reported an intense itch about two months before bullae development, firstly on his lower limbs, then all over the body.

The clinical history emphasized the presence of celiac disease for eight years for which a gluten-free diet had been prescribed; moreover, the patient had also developed osteoporosis due to intestinal malabsorbption.

During hospitalization the patient underwent the fol-lowing diagnostic procedures: 1) cutaneous biopsy for histological and direct immunofluorescence examination; 2) hematological research of antiendomysium, antigliadin and anticutaneous basement membrane zone autoantibod-ies; 3) gastroenterological examination.

The histological examination showed a dermal-epi-dermal blister and upper dermal edema associated with a perivascular lymphohistiocytic infiltrate accompanied by conspicuous eosinophils (not shown).

The direct immunofluorescence displayed a linear posi-

Figure 1.—Tense serous blisters all over the tegument (with exception of the cephalic extremity), together with erosions and crusts.

BASSI CUTANEOUS NEONATAL LUPUS: TWO CASES


can be associated to other autoimmune diseases, as diabe-tes mellitus, rheumatoid arthritis and Duhring’s dermatitis herpetiformis; the association between celiac disease and bullous pemphigoid of Lever has been reported only in one pediatric case in the literature.4, 5

We presented this case for the rarity of the association between celiac disease and bullous pemphigoid of Lever in adults. Despite the coexistence of these two clinical enti-ties seems to be merely casual, a debate could be opened on the possibility of a new association of these two autoim-mune diseases. Only the future will tell....

G ITAL DERMATOL VENEREOL 2012;147:654-7Received on March 14, 2011.Accepted for publication on October 23, 2012.

B. MARCONIDepartment of Dermatology, Polytechnic University of Marche, Ospedali Uniti, Torrette, [email protected]

A. CAMPANATIDepartment of DermatologyPolytechnic University of Marche, Ospedali Uniti, Torrette, Ancona

M. MARZIONIDepartment of Gastroenterology, University of MarcheOspedali Uniti, Torrette, Ancona, Italy

I. CATALDIDepartment of DermatologyPolytechnic University of Marche, Ospedali UnitiTorrette, Ancona

G. BRANDOZZIDepartment of DermatologyPolytechnic University of Marche, Ospedali UnitiTorrette, Ancona

K. GIULIODORIDepartment of DermatologyPolytechnic University of Marche, Ospedali UnitiTorrette, Ancona

A. SANTINELLISection of Pathological AnatomyPolytechnic University of Marche, Ospedali UnitiTorrette, Ancona, Italy

E. PISASection of Pathological AnatomyPolytechnic University of Marche, Ospedali UnitiTorrette, Ancona, Italy

G. GANZETTIDepartment of DermatologyPolytechnic University of Marche, Ospedali UnitiTorrette, Ancona

A. OFFIDANIDepartment of DermatologyPolytechnic University of Marche, Ospedali Uniti, Torrette, Ancona

This allowed to reconfirm the previous diagnosis of celiac disease. The presence of a severe duodenal mucosal atrophy in spite of a gluten free diet induced us to interrogate again the patient, who admitted lack of adherence to the diet.

Celiac disease is an inflammatory chronic disease of small intestinal mucosa with a more or less extensive at-rophy of intestinal villi. In genetically prone subjects, it is due to permanent intolerance to gliadin, a proteic fraction of gluten contained in wheat, barley, rye and oats. Accord-ing to the most confirmed hypothesis, the intestinal dam-age could be related to an immunitary reaction induced by gliadin itself; in fact high levels of IgA and IgG antigliadin antibodies (AGA) are detectable in celiac patient’s serum.

The onset of celiac disease may be in any period of life, with a greater incidence beetwen the sixth and twelfth month of life, period of weaning; in more than 50% of cases it affects adults beetwen the third and sixth decade, without any anamnestic precedent.

The beginning of the disease is more severe and acute when it takes place during infancy, with diarrhea, vomit, precocious appearance of a severe dehydratation and aci-dosis, rapid loss of weight and growth arrest; in adults the symptomatology is similar, but less severe, with a more gradual and insidious beginning.

A duodenal-jejunum biopsy proving intestinal villus at-rophy, is mandatory for the diagnosis.

The course of celiac disease is chronic and the prog-nosis is good. The clinical picture improves rapidly with permanent suppression of gluten from diet; the gastroin-testinal symptomatology regresses within the first month from gluten abolition, the histopathological alterations disappear within six to twelve months. The celiac disease

Figure 2.—The duodenal mucosa shows villous sub-atrophy and hyperplastic cripts; in the lamina propria there is an intense inflammatory infiltrate. The number of intraepithelial T lym-phocytes is increased and higher than 30 lymphocytes each 100 enterocytes (immunohistochemical staining for CD3, 160x origi-nal magnification).

CUTANEOUS NEONATAL LUPUS: TWO CASES BASSI


3. Liu E, Li M, Emery L, Taki I, Barriga K, Tiberti C et al. Natural his-tory of antibodies to deamidated gliadin peptides and transglutami-nase in early childood celiac disease. J Pediatr Gastroenterol Nutr 2007;45:293-300.

4. Fasano A. Systemic autoimmune disorders in celiac disease. Curr Opin Gastroenterol 2006;22:674-9.

5. Meenan FO, Cahalane SF. Bullous pemphigoid of childood and ce-liac disease. Report a case. Br J Dermatol 1969;81:777-9.

References

1. Fairley JA, Ling Fu C, Giudice GJ. Mapping the binding sites of anti-BP180 immunoglobulin E autoantibodies in bullous pemphig-oid. J Invest Dermatol 2005;125:467-72.

2. Liu Z. Immunopathology of bullous pemphigoid, an autoimmune and inflammatory skin blistering disease. Keio J Med 2003;52:128-33.

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GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA … · Mario PIPPIONE Andrea PESERICO Dennis LINDER - Nicola PIMPINELLI Pietro QuAgLINO Honorary Members and Editorial Committee M