In the past two decades, major advances have been made in the science of aggressive B-cell lymphoma, and diffuse large B-cell lymphoma (DLBCL) in particular. Once thought to be a single entity, it was initially found through genetic laboratory studies (mostly gene expression profiling), and the discovery of subtype-specific genetic aberrations that DLBCL could be divided into activated B-cell (ABC), germinal center B-cell (GCB), and primary mediastinal large B cell lymphoma (PMBCL) phenotypes. Accompanying these basic science findings were emerging implications for prognosis as well as treatment of these distinct subtypes. In addition, further investigations were undertaken in the laboratory as well as the clinic into less common aggressive lymphoma subtypes, to define their pathologic and genetic characteristics. This session will review these genetic-based classifications, and their potential impact on clinical care.
Dr. David Scott will review gene expression-based classifiers in aggressive B-cell lymphomas, focusing on DLBCL cell-of-origin, the distinction between PMBCL and DLBCL, and the "double hit signature" that is characteristic of cases with coexisting chromosomal rearrangements of the MYC, BCL2 and/or BCL6 oncogenes. He will further discuss the concept that gene expression summates upstream genetic aberrations and that gene expression-based assays can complement the genetics-based classifiers, with implications for clinical trials and treatment decisions.
Dr. Margaret Shipp will discuss the genetic substructure of DLBCL, with implications for diagnosis, prognosis, and therapy. She will present her data on the recurrent mutations, somatic copy number alterations, and structural variants from a large cohort of newly diagnosed DLBCL patients. Five robust DLBCL subsets were subsequently defined, including a previously unrecognized group of low-risk ABC-DLBCLs of extrafollicular/marginal zone origin, two distinct subsets of GCB-DLBCLs with different outcomes and targetable alterations, and an ABC/GCB-independent group with biallelic inactivation of TP53, CDKN2A loss, and associated genomic instability. The genetic features of these distinct DLBCL subsets will be summarized, with implications for disease pathogenesis, outcomes independent of the international prognostic index, and treatment strategies.
Dr. Megan Lim will review "gray zone lymphomas", which typically refers to a group of lymphoid neoplasms exhibiting a spectrum of morphologic, immunophenotypic and pathogenetic features, which poses challenges for reproducible diagnosis and for appropriate selection for novel pathogenetically-relevant clinical trials. Recent updates in the pathologic, genetic, and proteomic features of gray-zone lymphomas of B-lineage (with features intermediate between classic Hodgkin lymphoma, and primary mediastinal/large B-cell lymphoma; Burkitt lymphoma and high-grade B-cell lymphomas) will be discussed.