Aggressive B-cell lymphomas—from morphology to molecular pathogenesis

The2016 revised World Health Organization (WHO) classification of lymphoidmalignancies recognizes several distinct entities within the group of diffuselarge B-cell lymphoma (DLBCL) characterized by unique clinical and pathologicalfeatures. Nevertheless, diffuse large B-cell lymphoma, not otherwise specified(DLBCL, NOS) is the most common aggressive B-cell lymphoma. In the last 20 yearsour understanding of the genetic changes and biology of DLBCL has increasedtremendously. According to the 2016 WHO classification, the diagnosis of DLBCL,NOS, should include cell of origin (COO); germinal centre B-cell (GCB) oractivated B-cell (ABC)/non-GCB subtypes, because of their different molecularfeatures, biologic behavior, prognosis and treatment. High-grade B-celllymphoma (HGBL) with MYC and BCL2 and/or BCL6rearrangements (i.e., double-hit or triple-hit lymphoma, DHL or THL) as well asHGBL, NOS, are two new categories in the 2016 revised WHO classification thatsubstituted the provisional category of B-cell lymphoma, unclassifiable (BCLU)with features intermediate between DLBCL and Burkitt lymphoma (BL), which wasintroduced in the 2008 WHO classification. The pathogenesis and molecularchanges of BL are better understood and led to the recognition of a newprovisional entity called Burkitt-like lymphoma with 11q aberration. In thisarticle, we will review the progress made in the last years within the mostcommonly encountered aggressive B-cell lymphomas, highlighting the betterunderstanding of the underlying disease mechanisms that eventually might be translatedinto more rational and effective therapeutic strategies. Controversial issuesabout fluorescent in situ hybridization (FISH) for the detection of MYC,BCL2 and BCL6 translocations will be addressed, as well as newmolecular techniques used to improve diagnosis and prognostication inaggressive B-cell lymphomas.