Classification of cutaneous lymphomas The previous classification of ML had the Kiel classification, but this classification was designed according to the study of ML in lymph nodes, based on cytomorphology. Due to modern advances in the knowledge of the cutaneous immune system, the clinical features and biological behavior of LNML, MALT-ML, and PCML have been better understood, and the Kiel classification is considered increasingly inapplicable to PCML. first, lymphocytes have organ-specific homing properties, so that lymphomas associated with different organs have their own unique biological behavior, clinical manifestations, and therapeutic effects. The biological behavior of lymphomas with similar cell morphology varies greatly depending on the site of their initial development. For example, some cutaneous primary large cell lymphomas should be classified as highly aggressive according to the Kiel classification or Working Formulation (WF), yet their clinical presentation is inert lymphoma. Secondly, the classification of cutaneous lymphomas should not be based on histomorphology alone, but rather on a combination of clinical manifestations, histopathology and immunophenotype. For example, primary CD30+ large T-cell lymphoma of the skin has a significantly better prognosis than primary CD30- large T-cell lymphoma of the skin, independent of its morphologic subtype (mesenchymal or non-mesenchymal). For example, it is sometimes difficult or impossible to distinguish between cutaneous primary CD30+ interstitial large T-cell lymphoma and lymphomatoid papulosis based on morphologic classification alone. Therefore, the Dutch Working Group on Cutaneous Lymphoma agreed with the European Organization for Research and Treatment of Cancer (EORTC) on a new classification of PCML based on a study of 626 cases of PCML between 1986 and 1994 (see Table 1). In 1997, R. Willemze et al. wrote a detailed report on the basic principles of the new EORTC classification of PCML, the characteristics of different disease types, and further confirmed the clinical significance of the new EORT C classification by analyzing the clinical data of 626 patients registered by the Dutch Working Group on Cutaneous Lymphoma. In 2001, the WHO Classification of Neoplastic Diseases of Blood and Lymphoid Tissues was published, which includes 14 separate diseases of T and NK cell-derived leukemia, intra- and extranodal lymphoma, and 13 separate diseases of B cell-derived leukemia, intra- and extranodal lymphoma. Although there was much agreement between the EORTC and WHO classifications for CTCL, differences in definitions and terminology for CBCL and some CTCL, particularly CBCL, caused considerable controversy and confusion. The new classification, called the WHO-EORTC cutaneous lymphoma classification, was published in the May 2005 issue of BLOOD.1 The WHO-EORTC cutaneous lymphoma classification is an important development that unifies the understanding of cutaneous lymphoma classification and facilitates the diagnosis and treatment of lymphoma. The new definitions of PCFCL, PCLBCL-legged and PCLBCL-other types allow for a more reliable distinction between inert and aggressive CBCL and facilitate treatment decisions. A major topic of debate in recent years has been the EORTC classification of cutaneous primary follicular center cell lymphoma (PCFCCL) versus cutaneous primary large B-cell lymphoma of the leg type (PCLBCL-leg). the concept of PCFCCL was first used in 1987 and, unlike intra-nodal follicular lymphoma, PCFCCL generally does not express bcl-2 and is associated with t(14,18) unlike intra-nodal follicular lymphoma, PCFCCL generally does not express bcl-2 and is not specifically associated with t(14,18) chromosomal ectopics. Clinically, most patients present with limited lesions of the skin of the head and trunk, which are sensitive to radiotherapy and have a very good prognosis, regardless of the histologic growth pattern or the number of mother cells.4-6 In the 2001 WHO classification, PCFCCL with partial follicular architecture is classified as a variant of follicular lymphoma, designated as cutaneous follicular center lymphoma, whereas PCFCCL with diffuse growth and large central cells or central blasts is classified as a variant of cutaneous follicular center lymphoma. Cases with diffuse growth and a predominance of large centroblasts or centroblasts are generally classified as diffuse large B-cell lymphoma. The portion of cases classified as diffuse large B-cell lymphoma is controversial because it leads to excessive combination chemotherapy rather than just radiation therapy. During the coordination meeting in Zurich, the extensive PCFCCL histology, immunophenotype and clinical data were reviewed. It was recognized that PCFCCL as identified in the EORTC classification actually constitutes a group of disease spectrums including cases with follicular, mixed follicular and diffuse, and diffuse growth patterns with cellular composition ranging from predominantly small centroblasts to predominantly large centroblasts mixed with variable numbers of centroblasts and immunoblasts. This disease is referred to as primary cutaneous follicular center lymphoma (PCFCL) in the WHO-EORTC classification. PCLBCL-leg is also an independent disease. According to several recent studies, cases with similar histologic presentation (predominant or patchy centroblasts and immunoblasts), immunophenotype (strong expression of bcl-2 and Mum-1/IRF4) and prognosis can also be found in sites other than the legs. In the WHO-EORTC classification, the term PCLBCL-leg is proposed to include both lesions occurring on the legs and similar lesions occurring elsewhere in the skin.7 In addition, the term PCLBCL, other is used for those rare cases that are neither PCLBCL-leg nor PCFCL with a large diffuse infiltration of central cells. CTCL other than mycosis fungoides, Sécelli syndrome and a group of primary cutaneous CD30+ lymphoproliferative disorders account for a small percentage (less than 10%) of CTCL, most of which are clinically aggressive and require systemic chemotherapy. Classification of these rare CTCLs is difficult and confusing due to the lack of clinical case data and their apparent heterogeneity. For example, in primary pleomorphic small/medium cell lymphoma of the skin, recent studies have found a better prognosis for CD4+ pleomorphic small/medium T-cell lymphoma limited to lesions, in contrast to CD8+ T-cell lymphoma.8 In addition, CD30- large cell CTCL are also markedly heterologous, such as subcutaneous lipofuscinosis-like T-cell lymphoma (SPTL),9 nasal extra-nodal NK/T-cell lymphoma,10 CD4+/CD56+ hematologic skin tumors (maternal cell NK cell lymphoma),11 aggressive epidermophilic CD8+ CTCL12 and cutaneous γ/δ T cell lymphoma.13 However, SPTL, nasal extranodal NK/T cell lymphoma and maternal cell NK cell lymphoma are classified as separate diseases in the WHO classification, whereas the others are classified as nonspecific The others are classified as non-specific types of peripheral T-cell lymphoma. Recent studies have shown clinical, histologic, and immunophenotypic differences between α/β SPTL and γ/δ SPTL, suggesting that they may be distinct and independent diseases. Although α/β SPTL is homologous and many patients exhibit a degree of inertia, γ/δ SPTL overlaps with other γ/δ+ T and NK cell lymphomas and is always clinically aggressive. Therefore, it is recommended that the term SPTL be used only for α/β type SPTL.14 Recent studies have shown that there are lymphomas that can be classified from the WHO classification of non-specific types of peripheral T-cell lymphomas as provisional lymphoma types. They include aggressive epidermophilic CD8+ CTCL, cutaneous γ/δ+ T-cell lymphomas (including γ/δ-type SPTL), and cutaneous primary small- to medium-sized CD4+ T-cell lymphomas. The term non-specific type of peripheral T-cell lymphoma is still retained in the WHO-EORTC classification, referring mainly to those cases that are not classified as a provisional type. As with the new 1997 EORTC classification, the WHO-EORTC classification was further confirmed by analyzing the clinical data of 1905 patients registered by the Dutch and Austrian working groups on cutaneous lymphoma (see Table 3). Nevertheless, this classification scheme still needs to be extensively validated. The classification of partial CTCL remains difficult and requires further clarification based on accurate clinicopathologically relevant information and some complementary diagnostic techniques. The new classification has clarified α/β type SPTL, extranodal NK/T-cell lymphoma nasal type and CD4+/CD56+ blood-derived skin tumors. However, there is a significant overlap between cutaneous/mucosal γ/δ TCL and aggressive epidermophilic CD8+ CTCL. It may be that γ/δ-positive normal T cells and activated CD8+ cytotoxic T cells have similar biological functions, resulting in similar clinical presentation and aggressiveness of both. With the exception of SPTL and CD4+ polymorphic small/medium CTCL, some rare CTCL have a very poor prognosis and conventional chemotherapy is generally ineffective. More aggressive approaches, including allogeneic bone marrow transplantation, are being taken to treat these aggressive CTCL, progressive mycosis fungoides, and Sézé’s syndrome.15,16 Studies have now begun to investigate the gene and protein expression profiles of different types of cutaneous lymphomas. It is expected that these studies will not only contribute to the understanding of the molecular mechanisms of lymphoma development and facilitate a more precise classification, but also provide molecular targets for diagnosis and treatment.