Primary bone diffuse large B-cell lymphoma is characterized by frequent germinal center B-cell associated mutations in B2M, TNFRS14, EZH2 and IRF8, reflecting a favorable prognosis.
Primary bone diffuse large B-cell lymphoma (PB-DLBCL) is a rare extranodal lymphoma subtype. This retrospective study elucidates the currently unknown genetic background of a large clinically well-annotated cohort of osseous DLBCL (O-DLBCL).
99 O-DLBCL patients were included and compared with 61 non-osseous DLBCLs with germinal center B-cell phenotype (NO-DLBCL-GCB). Based on the WHO classification of soft tissue and bone tumors, O-DLBCLs were categorized in respectively 40 PB-DLBCL, 14 polyostotic-DLBCL, and 45 disseminated-DLBCL. Cell-of-origin (COO) was determined by immunohistochemistry and gene-expression profiling (GEP) using (extended) NanoString/Lymph2Cx. Mutational profiles were identified with targeted next-generation sequencing, including 52 B-cell lymphoma-relevant genes.
O-DLBCLs presented predominantly a GCB-phenotype based on immunohistochemistry (71%) and NanoString (88%). Unsupervised hierarchical clustering of extended GEP demonstrated significantly different clusters for PB-DLBCL as opposed to NO-DLBCL-GCB (P<0.001). In PB-DLBCL, the GCB-phenotype was significantly correlated with frequent pathogenic mutations in B2M, EZH2, IRF8, and TNFRSF14 compared to NO-DLBCL-GCB (P=0.022, P=0.041, P=0.032 and P=0.030). PB-DLBCL and the corresponding specific mutational profile was associated with a significantly superior overall survival compared to equivalent Stage I/II NO-DLBCL-GCB (P=0.018 and P=0.049, respectively).
This study is the first to demonstrate that PB-DLBCL is characterized by a GCB-phenotype, with a specific GCB-associated mutational profile, reflecting favorable prognosis. These biological findings provide evidence that PB-DLBCL can be recognized as an exclusive extranodal DLBCL entity and holds potential for targeted therapies (e.g. EZH2-inhibitors).