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Abstract

Aggressive B-cell lymphomas encompass a heterogeneous group of neoplasms unified by their rapid clinical course and potential for cure with appropriate therapy. Traditional classification systems, grounded in morphology, often fail to capture the molecular diversity that shapes prognosis and therapeutic response. While molecular profiling has refined classification in diffuse large B-cell lymphoma (DLBCL), other entities remain poorly defined. Among these, high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBCL-DH/TH) and high-grade B-cell lymphoma, not otherwise specified (HGBCL-NOS), represent challenging diagnostic groups with uncertain biological underpinnings. This thesis aimed to define the molecular landscape of HGBCL-DH/TH and HGBCL-NOS to refine their classification and support a biologically informed taxonomy of aggressive B-cell lymphomas. To achieve this, we assembled large study cohorts with detailed clinicopathological data and performed extensive molecular profiling. In HGBCL-DH/TH, tumors with MYC and BCL6 rearrangements exhibited marked heterogeneity, indicating that they do not constitute a single diagnostic group. In contrast, tumors with MYC and BCL2 rearrangements (HGBCL-DH-BCL2) were biologically uniform and exhibited a characteristic gene expression signature. Molecular profiling demonstrated that in HGBCL-DH-BCL2, cooperative genetic alterations converge to dysregulate pathways active in dark zone germinal center B-cells, and that its characteristic gene expression signature closely aligns with transcriptomic profiles of dark zone B-cells. Expression of this signature, termed the dark zone signature (DZsig), extends beyond HGBCL-DH-BCL2 to identify a broader group of lymphomas unified by a dark zone phenotype, providing a biologically informed framework for classification and highlighting potential therapeutic vulnerabilities. Analysis of HGBCL-NOS confirmed that this category is not biologically cohesive but instead comprises tumors with features aligning with established molecular subgroups. The DZsig resolves a substantial fraction of HGBCL-NOS as dark zone lymphomas, while additional cases can be reclassified through genetics-based subtyping of DLBCL, underscoring the limited utility of HGBCL-NOS as a standalone category. Collectively, these findings demonstrate that morphology-based systems alone obscure meaningful biological distinctions. The addition of molecular profiling clarifies the taxonomy of aggressive B-cell lymphomas, enabling refinement of HGBCL-DH/TH and resolution of HGBCL-NOS into molecularly defined subgroups. This framework provides greater diagnostic precision and lays the foundation for developing targeted therapeutic strategies.