The World Health Organization (WHO) Classification of Tumours of the Haematopoietic and Lymphoid Tissues has been revised and updated for a new edition (4th Edition) under the auspices of the Society of Hematopathology (SH) and the European Association for Haematopathology (EAHP). This initiative is a continuation of 2001 WHO classification that represented a major advance in terms of broad acceptance and general use during the last years by pathologists and clinicians from all over the world. The successes of this classification was due to the major consensus built among all the players based on a proposal that was biologically sound, clinically relevant and practically ease to use worldwide in different clinical settings. The major principles of the current WHO classification, stratification of the neoplasms primarily according to their lineage and the definition of distinct clinically relevant diseases based on a combination of morphology, immunophenotype, genetic and molecular features and clinical manifestations, are considered a solid framework in which the new knowledge and perspectives should be incorporated. The new knowledge generated over the last years has highlighted several aspects of the current WHO classification that need revision and update, including the need for the clarification of some poorly defined categories, the inclusion of new defined entities, and the consideration of new concepts and information Refinement in definitions, advances in old controversies, and new categories The new classification has refined the definition of well established diseases such as chronic lymphocytic leukemia (CLL) lymphoplasmacytic lymphoma and Waldestrom macroglobulinemia and T-cell lymphomas such as anaplastic large cell lymphoma (ALCL) and subcutaneous panniculitis-like T-cell lymphoma. Consensus on old controversies includes the recognition that it is not clinically relevant to distinguish between grades 1 and 2 of follicular lymphoma (FL) but it is important to segregate grade 3b from 3a since it may correspond to a category that may be closer to diffuse large B-cell lymphoma (DLBCL) than conventional FL. The category of diffuse large B-cell lymphoma has recognized the important contribution of gene expression profiling accepting the two molecular subtypes of germinal center and activated B-cell derived DLBCL. However, the difficulties to diagnose these subtypes with reliable tools other than microarray expression profiling prevents from recommending the use of these categories in the clinical practice. Different subtypes and new entities have been accepted, particularly among DLBCL with a terminal B-cell differentiation such as ALK positive DLBCL, DLBCL associated with chronic inflammation, plasmablastic lymphoma, large cell lymphoma arising in HHV-8 associated multicentric Castleman disease, and EBV+ DLBCL of the elderly. Among peripheral T-cell lymphomas, Anaplastic large cell lymphoma (ALCL) ALK positive is a specific entity that should be distinguished from tumors with similar morphology and phenotype but ALK negative, that are considered a different provisional category. The diagnosis of subcutaneous panniculitis-like T-cell lymphoma is now restricted to the cases with an alpha/beta phenotype since similar tumours with gamma/delta phenotype are reclassified as primary cutaneous gamma/delta T-cell lymphoma, a category that appears to be more aggressive with frequent systemic dissemination. New concepts The classification has recognized early lesions and indolent forms of lymphomas that may correspond to early stages of lymphomagenesis such as Monoclonal B-cell lymphocytosis, or follicular lymphoma and mantle cell lymphoma in situ. The identification of these situations are of conceptual interest to investigate the early mechanisms in lymphomagenesis but also of clinical importance since these patients may need a more conservative management approach. Several new categories have been included in which the age of the patients is a major identifier. Thus, pediatric follicular lymphomas and nodal marginal zone lymphomas or the EBV-positive lymphomas of the childhood and the EBV-positive large cell lymphoma of the elderly are clinico-pathologic situations that suggest the potential influence of age-related biological factors in the pathogenesis and manifestations of certain lymphoid neoplasms. The importance of specific topographic sites as an important feature of certain lymphomas had been recognized previously in certain extranodal lymphomas such as MALT, primary mediastinal, splenic, and certain primary cutaneous lymphomas. This idea has been now expanded incorporating additional B and T-cell primary cutaneous, CNS DLBCL, and also recognizing that follicular lymphomas originated in the duodenum or skin are categories with specific clinicopathologic features and management requirements. This relationship between topography and specific disease entities may be related to specific etiopathogenic mechanisms (infectious diseases), particular lymphoid cells of origin (asteroid cells), site related immunological functions (immunological santuaries) or tumor-host interactions (homing of lymphoid cells). The new classification has also recognized two categories that correspond to lymphomas with overlapping features between different entities, the B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma and the B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma. These categories may not correspond probably to specific entities but are important to be recognized clinically because these patients may need to be distinguished form the more conventional categories for the different clinical evolution and treatment strategies. These patients need further investigations and interestingly, these tumours may represent clinical examples of the plasticity of the lymphoid cells that may be broader than initially thought. Unresolved issues and provisional entities Some issues are not resolved in the new classification. Several categories are still considered provisional or emerging because it is not clear if they may correspond to peculiar variants of other entities. These categories include the diffuse B-cell lymphomas of the splenic red pulp and their possible relationship to hairy cell leukemia variant, primary cutaneous aggressive epidermotropic CD8 positive cytotoxic T-cell lymphoma, primary cutaneous small/medium CD4 positive T-cell lymphoma, and the ALCL ALK-negative among others. Finally, new challenging perspectives have been discussed during the process of updating the classification but it was felt that they require further investigations before being adopted for routine diagnostic use. These topics include the role of biomarkers in the prognosis lymphoma, and the information generated by microarray expression profiling studies in the identification new lymphoma subtypes or the potential clinical value of specific molecular pathogenetic pathways.
Showing the most recent 10 out of 12 publications
