Sinonasal DLBCL: molecular profiling identifies subtypes with distinctive prognoses and targetable genetic features.

Primary sinonasal diffuse large B-cell lymphoma (PSDLBCL) is a rare lymphoma with a variable prognosis and a unique relapse/dissemination pattern involving the CNS and skin. The underlying molecular mechanisms leading to this heterogeneity and progression pattern remain uncharted, hampering patient-tailored treatment. To investigate associated mechanisms, we analyzed clinical data and employed immunohistochemistry, gene-expression profiling, cytogenetics, and next-generation sequencing in a cohort of 117 PSDLBCL patients from the Danish National Pathology Registry. The distribution in cell-of-origin (COO) was 68 (58%) activated B-cell (ABC), 44 (38%) germinal center B-cell (GCB), and 5 (4%) unclassifiable. Cell-of-origin was significantly associated with progression-free-survival (PFS) and lymphoma-specific mortality (LSM) in both the overall cohort (five-year PFS, ABC 43% vs. GCB 73%; LSM, ABC 45% vs. GCB 14%) and in the subgroup of patients receiving immunochemotherapy (five-year PFS: ABC 55% vs. GCB 85%; LSM: ABC 28% vs. GCB 0%). ABC-lymphomas were mainly MCD class, showing a high prevalence of MYD88 (74%) and CD79B (35%) mutations compared to GCB-lymphomas (MYD88 23%, CD79B 10%) (P< 0.01). The ABC subtype frequently displayed cMYC/BCL2 double expression (76% vs. 18% GCB, P<0.001) and loss of HLA-II (48% vs. 10% GCB, P<0.001). PD-L1 expression and copy-number alterations were rare. Epstein-Barr virus was absent in all lymphomas. Our data suggest molecular profiling as a potent tool for detecting prognostic subgroups in PSDLBCL, exposing links to known sites of relapse/progression. The ABC group's MCD genetic-features, shared with lymphomas at other non-professional lymphoid sites, make them potential candidates for targeted B-cell receptor- and toll-like receptor-signaling therapy.