Distinguishing EBV-positive classic Hodgkin lymphoma from EBV-positive DLBCL, NOS: diagnostic value and limits of immunohistochemical markers.

Epstein-Barr virus-positive (EBV+) classic Hodgkin lymphoma (cHL) may mimic EBV+ diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), creating a clinically relevant diagnostic pitfall. We retrospectively reviewed 62 immunocompetent patients with EBV+ large B-cell neoplasms and classified cases into five reproducible pattern-based groups: monomorphic EBV+ DLBCL, polymorphic/immune-environment rich EBV+ DLBCL (polyDLBCL), EBV+ cHL with retained B-cell marker expression, canonical EBV+ cHL, and rare EBV+ mediastinal gray-zone lymphoma. The principal diagnostic challenge was the distinction between polyDLBCL and EBV+ cHL, both of which may contain Hodgkin/Reed-Sternberg-like cells in inflammatory backgrounds. OCT2 was the most informative B-cell marker, but partial OCT2 retention in EBV+ cHL should not alone prompt reclassification as DLBCL. CD20 and CD79a showed substantial overlap, whereas CD15 and IMP3 lacked sufficient specificity. GATA3 expression supported canonical EBV+ cHL, but negativity did not exclude cHL, particularly when the B-cell program was retained. EBER-positive cell-size distribution and EBV latency type (98% were type II) were of limited discriminatory value. Tumor-cell PD-L1 expression was highest in canonical cHL and lower in cHL with B-cell marker retention and monomorphic DLBCL. Clinically, younger patients more often had nodal cHL and favorable outcomes, whereas older patients showed more monomorphic histology, more advanced disease and poorer prognosis. Adverse outcome correlated most strongly with age and EBV lytic reactivation. These findings support an immune-environment-rich EBV-positive large B-cell lymphoma continuum in which strict separation of EBV+ cHL from polymorphic EBV+ DLBCL may not fully reflect the underlying biology.