Abstract

High-grade B-cell lymphomas (HGBLs) represent a diverse and aggressive group of neoplasms that lie at the intersection of diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL), characterized by unique molecular and clinical features. The recently published International Consensus Classification of Myeloid and Lymphoid Neoplasms (ICC) and the fifth edition WHO Classification of Hematolymphoid Tumors have refined the classification of HGBLs dividing them into subtypes based on clinical, morphologic, and molecular features, with subtle differences in terminology and entity characterization. These lymphomas present significant diagnostic challenges due to overlapping features with DLBCL and BL, and their aggressive clinical course necessitates tailored treatment strategies. Conventional therapies, such as R-CHOP, have demonstrated limited efficacy in these patients, prompting exploration of more intensive regimens and targeted therapies. The identification of molecular biomarkers, such as MYC, BCL2, and/or BCL6 rearrangements, as well as the emerging molecular high-grade (MHG) signature, holds promise for better understanding the pathogenesis of these lymphomas and improving prognostic stratification. Despite advances in classification, no clear consensus exists on optimal treatment approaches, and outcomes remain suboptimal, particularly in cases with isolated MYC translocations. This review aims to summarize the current pathologic and molecular classification of HGBLs, highlight the diagnostic challenges, and explore therapeutic implications, including potential future directions for treatment strategies and molecular-targeted therapies.