High-grade B-cell lymphoma (HGBL)-NOS is clinicopathologically and genetically more similar to DLBCL/HGBL-DH than DLBCL.

High-grade B-cell lymphoma, not otherwise specified (HGBL-NOS) is rare and data focused on these neoplasms is lacking. We studied the clinicopathologic and genetic features of 136 HGBL-NOS patients and compared them to patients with DLBCL/HGBL-DH (n = 224, defined by 5th Edition WHO) and DLBCL (n = 217). HGBL-NOS patients had clinical features similar to DLBCL/HGBL-DH patients. MYC rearrangement (MYC-R) was present in 43% of HGBL-NOS. With induction regimen similar to DLBCL/HGBL-DH patients, HGBL-NOS patients had a median overall survival (OS) of 28.9 months, similar to DLBCL/HGBL-DH (p = 0.48) but inferior to DLBCL patients (p = 0.03). R-EPOCH induction was associated with improved OS compared with R-CHOP. MYC-R, history of lymphoma, and high IPI were independent adverse prognostic factors in HGBL-NOS patients. Whole transcriptome profiling performed on a subset of HGBL-NOS cases showed a profile more similar to DLBCL/HGBL-DH than to DLBCL; 53% of HGBL-NOS had a DH-like signature (DH-like-Sig) and were enriched for MYC-R. DH-like-Sig+ HGBL-NOS patients had a poorer OS than DH-like-Sig-negative patients (p = 0.04). In conclusion, HGBL-NOS has clinicopathologic features and a gene expression profile more similar to DLBCL/HGBL-DH than to DLBCL. Cases of HGBL-NOS frequently carry MYC-R and have a DH-like-Sig+. R-EPOCH induction in HGBL-NOS appears associated with improved OS compared with standard R-CHOP.