IA02: Principles of lymphoma classification

Lymphomas comprise a diverse group of neoplasms derived from B cells, T cells or NK cells, associated with variable clinical presentation. The classification currently in use is the 2008 edition of the WHO classification of tumours of haematopoietic and lymphoid tissues. This classification which represents an international consensus for diagnosing lymphoid neoplasms, has been validated as being reproducible and clinically relevant. It is founded on the principles defined earlier in 1994 in the « Revised European-American Classification of Lymphoid Neoplasms » (REAL) classification. The major principle of the classification is a multiparametric definition of distinct non-overlapping disease entities according to a combination of morphology (cytology and growth pattern), immunophenotypic, genetic, molecular and clinical features (including importantly age and disease localization). The relative contribution of each of these features varies according to the diseases, but morphology as the starting point is always important and sometimes the primary defining feature. For other disease entities, a peculiar imunophenotypic profile or a given genetic abnormality represents the principal defining criterion. In many instances, the phenotype of the neoplastic lymphoid cells resembles that of a particular stage of normal lymphoid maturation, and the normal cell counterpart is an important determinant of the biological features of the corresponding lymphomas. More than 50 lymphoma entities are recognized, a variety reflecting the several cell lineages and multiple stages of differentiation of normal immune cells. These entities are in most cases unrelated to one another. Several lymphomas have within themselves a range of histologic grade (number of large cells or proliferation fraction) and clinical aggressiveness. Also listed are provisional categories including entities with distinct features that are not yet fully validated, and for borderline categories for lymphoproliferations exhibiting transitional features (overlapping histology, immunophenotype and/or genetic features) that defy traditional diagnostic categories. As a consequence of new and more sensitive techniques in routine diagnosis, early and precursor lesions of lymphoid neoplasms are increasingly recognized, a notion incorporated in the 2008 WHO classification. Dysimmune conditions (either immunodeficiency or autoimmune diseases), and some forms of chronic inflammation (for example Helicobacter Pylori gastritis or gluten-sensitive enteropathy), predispose to the development of lymphomas. Lymphoptropic viruses (HTLV1, EBV and HHV8/KSHV) are implicated as causative agents in particular lymphomas. The historical distinction between Hodgkin lymphomas (HL) and non-Hodgkin lymphomas (NHL) is maintained in the current scheme, because HL (accounting for less than 10% of alll lymphomas), albeit proven to derive from germinal center-experienced B cells, have distinctive pathological and clinical features, and are treated differently. NHL entities are stratified according to their cell lineage (B versus T or NK cells) and their derivation from precursors (lymphoblasts) or mature lymphoid cells. Mature B-cell lymphomas comprise over 80% of non-Hodgkin's lymphomas. Apart from mantle cell lymphoma (MCL) and a subset of small lymphocytic lymphomas/chronic lymphocytic leukemias (SLL), most B-cell lymphomas originate from antigen-exposed B cells that have migrated to or passed through the germinal center (GC) (GC or post-GC cells). Chromosomal translocations juxtaposing one protooncogene (BCL1, BCL2, BCL6, MYC) to an immunoglobulin gene loci represent the hallmark of many B-NHL entites. B-cell NHL composed mainly of small lymphocytes (CLL, follicular lymphoma (FL), marginal zone lymphomas (MZL), lymphoplasmacytic lymphoma (LPL)) have been called « low-grade lymphomas » because of a relatively indolent bejavior. An exception to the rule correlating cell size and prognosis, is MCL, composed mainly by small lymphocytes but with a rather aggressive behaviour. Diffuse large B-cell lymphoma (DLBCL), the most common NHL (about 25%) and the prototype of high-grade lymphoma, is clinically, pathologically and molecularly heterogeneous. In addition to the usual form (DLBCL-NOS) it comprises clinic-pathologic variants characterized by specific features (e.g., age, primary site, immunodeficiency, association with infectious agents). Gene expression profiling studies have identified two molecular subtypes of DLBCL-NOS, related to germinal center (GC-like) and activated blood B-lymphocytes (ABC-like), associated with distinct genetic and molecular aberrations, and distinct prognoses (more favorable for GC-like tumors). Peripheral T-cell lymphomas (PTCLs) comprise a variety of uncommon and overall rare malignancies derived from mature (post-thymic) T cells and NK cells, altogether accounting for less than 15% of all NHL worlwide, with important geographic variations in their relative frequency and epidemiology. Most entities are clinically aggressive with a dismal prognosis. The clinical features and disease localization are critical in defining PTCL entities, which may present as disseminated (leukemic), predominantly extranodal or cutaneous, or predominantly nodal diseases. The diagnosis of PTCLs is often difficult as distinct T/NK-cell tumors have a broad range of cellular composition, distinct PTCLs diseases lack distinct immunophenotypic profiles, and there is significant morphologic and immunophenotypic overlap across different entities. Moreover with the exception of T-prolymphocytic leukemia and ALK-positive anaplastic large cell lymphoma (ALCL), genetic features currently only marginally contribute to the definition of PTCL entities. Recently, with the use high-throughput methods, new recurrent genetic and molecular alterations are being discovered that are expected to refine the classification. Peripheral T-cell lymphomas, not otherwise specified (PTCL-NOS) represents the largest PTCL entity and comprises cases derived from CD4 or CD8 T cells that by default do not fulfill criteria for another category. Angioimmunoblastic T-cell lymphoma, the second most common PTCL, is derived from follicular helper T cells, a feature that appears as a major determinant of its biology