EORTC Classification for Primary Cutaneous Lymphomas: A Proposal From the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer

Primary cutaneous lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

An unusual case of cytotoxic peripheral T-cell lymphoma

The classification of non-Hodgkin's lymphoma has undergone extensive revision in recent years, particularly with the development of immunophenotypic and genotypic criteria. While most general pathologists now rely upon the Revised European and American Classification of Lymphoma neoplasms (REAL), the cutaneous lymphoma project group of the European Organization for Research and Treatment of Cancer (EORTC) has put forward its own proposal for the classification of primary cutaneous lymphomas. While this is understandable in the context of cutaneous T-cell lymphoma, the EORTC classification of primary cutaneous B-cell lymphoma has proved more controversial: first, because chromosomal changes are largely excluded; secondly, because follicle centre cell lymphoma in the skin is imprecisely defined; and thirdly, because large B-cell lymphoma of the leg is included as a separate entity. This review identifies the main differences between the two systems of classifying B-cell lymphomas in the skin, and the areas of research required to clarify some of the outstanding issues. Pathologists are unlikely to adopt the EORTC proposals for B-cell neoplasms until these issues have been resolved.

EORTC Classification for primary cutaneous lymphomas: A comparison with the R.E.A.L. Classification and the proposed WHO Classification

Cutaneous lymphomas other than mycosis fungoides (MF) are a heterogeneous group with wide variations in clinical presentation, biological behaviour and prognosis. New classification systems have been designed or proposed in recent years, with well-defined disease entities and emphasis on the importance of site. This study aims to analyse a series of non-MF lymphomas in an institution-based dermatological setting in Singapore, based on the European Organization for Research and Treatment of Cancer (EORTC) classification and the World Health Organization (WHO) classification. A secondary objective is to highlight the clinical utility of both classification systems. Forty cases diagnosed over a 12-year period were examined by immunohistochemistry with antibodies targeting CD3, CD4, CD5, CD8, CD20, CD30, CD43, CD45RO, CD56 and CD68 in paraffin-embedded specimens. The immunohistological diagnosis was correlated with the clinical presentation and staging investigations for the final diagnosis and the course of disease recorded. Non-MF T-cell lymphomas presenting in the skin comprised 31 cases (78%) and were 3(1/2) times more common than B-cell lymphomas, which comprised nine cases (22%). The common subtypes were lymphomatoid papulosis, CD30+ large cell cutaneous T-cell lymphoma and subcutaneous panniculitis-like T-cell lymphoma. The commonly ascribed B-cell pattern with infiltrates in the mid and deep dermis and perivascular spaces was seen in 60% of T-cell lymphomas. Overall, there were equal numbers of primary cutaneous T-cell lymphomas and those due to concurrent or secondary cutaneous lymphoma. Five of six cases of subcutaneous panniculitis-like T-cell lymphoma had concurrent cutaneous and systemic involvement and their median survival was 7 months. The predominance of cutaneous T-cell lymphomas in this case series closely matched that reported from east Asia; cutaneous B-cell lymphomas are much less common than in Europe. The EORTC classification, which is designed only for primary cutaneous lymphomas, should be used in conjunction with the WHO classification because of the high prevalence of cutaneous lymphomas as the secondary site of disease from systemic lymphoma. In addition, subcutaneous panniculitis-like T-cell lymphoma is a primary cutaneous lymphoma where systemic involvement is common at initial presentation. We propose full immunophenotyping and complete clinical evaluation with staging investigations for all patients presenting with cutaneous lymphomas other than MF.

Following consensus meetings of the two parent organizations, a new World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification for primary cutaneous lymphomas has recently been published. This important development will now end the ongoing debate as to which of these was the preferred classification. The new classification will facilitate more uniformity in diagnosis, management and treatment of cutaneous lymphomas. In particular, it provides a useful distinction between indolent and more aggressive types of primary cutaneous lymphoma and provides practical advice on preferred management and treatment regimens. This will thereby prevent patients receiving high-grade treatment for low-grade biological disease. This review focuses on those diseases which have found new consensus agreement compared with the original WHO and EORTC classifications. In cutaneous T-cell lymphomas, these include folliculotropic mycosis fungoides, defining features of Sézary syndrome, primary cutaneous CD30+ lymphoproliferative disorders (primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis and borderline lesions) and subcutaneous panniculitis-like T-cell lymphoma. Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma, primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma and cutaneous gamma/delta T-cell lymphoma are allocated provisional entry status and thereby afford better definitions for some cases of currently unspecified primary cutaneous peripheral T-cell lymphoma. In cutaneous B-cell lymphomas, diseases which have found new consensus agreement include primary cutaneous marginal zone B-cell lymphoma, primary cutaneous follicular centre lymphoma, primary cutaneous diffuse large B-cell lymphoma, leg type and primary cutaneous diffuse large B-cell lymphoma, other. CD4+/CD56+ haematodermic neoplasm (early plasmacytoid dendritic cell leukaemia/lymphoma) now appears as a precursor haematological neoplasm and replaces the previous terminology of blastic NK-cell lymphoma. Other haematopoietic and lymphoid tumours involving the skin, as part of systemic disease, will appear in the forthcoming WHO publication Tumours of the Skin. The new classification raises interesting new problems and questions about primary cutaneous lymphoma and some of these are discussed in this article. It is, however, a splendid signpost indicating the direction in which research in cutaneous lymphoma needs to go. In the interim, we have an international consensus classification which is clinically meaningful.

Primary cutaneous lymphomas (PCLs) are a group of extranodal non-Hodgkin lymphomas characterized by early accumulation of mononuclear cells, most of them lymphocytes, on skin, with no evidence of extracutaneous disease at diagnosis. T-cell and natural killer (NK) cell lymphomas (CTCL/NK) with an absolute predominance of mycosis fungoides (MF) represent approximately 44% of all PCLs. The etiology and the exact steps in the pathogenesis of CTCL are not understood. It is more reasonable to assume that these diseases represent the endpoint of several different processes. Genetic, environmental, and infectious factors should all be considered in the etiology of CTCL. The current classification for PCLs was proposed in 2005 by the World Health Organization (WHO) and the European Organization for Research and Treatment of Cancer (EORTC). WHO-EORTC Classification for primary cutaneous T- and NK-cell lymphomas is MF and subtypes of MF (folliculotropic MF, pagetoid reticulosis, granulomatous cutis laxa); Sezary syndrome; adult T-cell leukemia/lymphoma; primary cutaneous CD30+ lymphoproliferative diseases (primary cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis); subcutaneous panniculitis-like T-cell lymphoma; extranodal NK/T-cell lymphoma, nasal type; and primary cutaneous peripheral T-cell lymphoma, unspecified (primary aggressive epidermotropic CD8+ cutaneous T-cell lymphoma, provisional entity; cutaneous γδ T-cell lymphoma, provisional entity; and cutaneous lymphoma of small and medium pleomorphic CD4+ T-cell, provisional entity).

In 1997 the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer (EORTC) published a proposal for a classification for the group of primary cutaneous lymphomas (1). The EORTC classification is the first and only classification that is designed exclusively for the group of primary cutaneous lymphomas. It is also the only classification that has been clinically validated for this group of diseases. As illustrated by this special issue, this classification has resulted not only in the discussion of the definition and terminology of some types of cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma (CBCL), but also in a discussion of whether organ-based classification schemes (separate from existing hematopathologic classification schemes for non-Hodgkin lymphomas) should be used. This article explains why it was necessary to create a separate classification for the group of primary cutaneous lymphomas. A short introduction on the history of the classification of cutaneous lymphomas is provided. Next, the basic principles of the EORTC classification are presented. Finally, controversies between the EORTC classification versus the REAL classification (2) and the proposed WHO classification (3), which still impede the usage of one common classification system, are discussed.

Rationale of a new classification for the group of primary cutaneous lymphomas.

Primary cutaneous large B-cell lymphoma of the leg (LBCLL) is a recently defined type of non-Hodgkin's lymphoma. It forms a separate category in the new classification of primary cutaneous lymphomas elaborated by the European Organization for Research and Treatment of Cancer. It is associated with a less favorable prognosis than the most frequently occurring types of primary cutaneous B-cell lymphoma. The authors present four patients with the typical clinicopathologic constellation of LBCLL. Three of them died during the years 1993-1996. The authors reviewed their courses. The fourth patient was staged by sentinel lymph nodectomy (SLNE), i.e., the selective surgical removal and histologic examination of the first draining lymph node associated with the cutaneous tumor. The courses of the three previous patients were characterized by secondary involvement of regional lymph nodes followed by systemic dissemination of the lymphoma in a third step. Although the conventional staging of the fourth patient had been negative for any extracutaneous lymphoma manifestation, the SLNE revealed initial regional lymph node involvement, which had decisive implications for the choice of therapy. SLNE may gain a prominent role in the staging of circumscribed cutaneous lymphomas, in addition to its already established position in melanoma management. Further positive effects of SLNE are 1) better distinction of primary cutaneous lymphomas with secondary lymph node involvement from primary lymph node lymphomas with skin manifestation, and 2) better insight into the biology of different primary cutaneous lymphoma types.

WHO-EORTC classification for cutaneous lymphomas

Cutaneous B-cell lymphomas encompass a group of B-cell lymphomas that presents in the skin without evidence of extra-cutaneous disease at the time of initial diagnosis; thus, complete laboratory workup and imaging studies are necessary. In 2005 a new consensus classification for cutaneous lymphoma was introduced by the World Health Organization (WHO) and the European Organization for Research and Treatment of Cancer (EORTC). This classification has resulted in a significant improvement on categorization of cutaneous B-cell lymphoma and unified criteria for therapeutic trials. This chapter focuses on primary cutaneous follicle center lymphoma; primary cutaneous marginal zone B-cell lymphoma; cutaneous plasmacytoma; primary cutaneous large B-cell lymphoma, leg type; and other primary cutaneous large B-cell lymphomas including plasmablastic lymphoma and primary cutaneous T-cell/histiocyte-rich B-cell lymphoma.

Primary cutaneous lymphoma is an uncommon, extranodal lymphoma, and it is usually more indolent with a better prognosis than its histologically similar systemic counterpart is. To illustrate the clinicopathologic features of cutaneous lymphomas in Taiwan and to compare the relative frequencies of subtypes of cutaneous lymphoma among different geographic areas. A total of 56 patients with cutaneous lymphomas were retrospectively collected and were reclassified according to the 2005 World Health Organization and the European Organization for Research and Treatment of Cancer and the 2008 World Health Organization classifications. The data were compared with those from other studies for different geographic areas. Thirty-one (55%) tumors were primary cutaneous lymphomas, and twenty-five (45%) tumors were secondary or concurrent cutaneous lymphomas. Among primary cutaneous lymphomas, 23 cases (74%) were T-cell or natural killer-cell lymphomas, and 8 cases (26%) were B-cell lymphomas. The most common types were extranodal natural killer/T-cell lymphoma, nasal type, and primary cutaneous peripheral T-cell lymphoma, unspecified (5 cases each; 16%). In contrast with other primary cutaneous B-cell and T-cell lymphomas, either primary or secondary extranodal cutaneous natural killer/T-cell lymphomas, nasal type, had extremely poor prognoses (1-year overall survival, 0%). This study showed that the frequency of subtypes of primary cutaneous lymphoma varied in different geographic areas. Compared with the Western countries, there was a higher frequency of extranodal natural killer/T-cell lymphoma, nasal type, and a lower frequency of mycosis fungoides in Taiwan. Extranodal natural killer/T-cell lymphoma, nasal type, also had an extremely poor prognosis compared with other lymphomas.

Primary cutaneous large B-cell lymphoma of the leg: Histogenetic analysis of a controversial clinicopathologic entity

Primary cutaneous lymphomas: applicability of current classification schemes (European Organization for Research and Treatment of Cancer, World Health Organization) based on clinicopathologic features observed in a large group of patients