Redefining the Spectrum of Epstein-Barr Virus–Positive (EBV+) Diffuse Large B-cell Lymphoma and EBV+ Classic Hodgkin Lymphoma

Epstein-Barr virus-positive (EBV+) diffuse large B-cell lymphoma (DLBCL) and EBV+ classic Hodgkin lymphoma (CHL) are major B-cell lymphomas with EBV infection in elderly patients. Although they are regarded as distinct clinicopathological entities, distinguishing EBV+ CHL from EBV+ DLBCL is often challenging because of their overlapping histologic and immunophenotypic features. We characterized the spectrum of EBV+ large B-cell lymphoma (LBCL) in 57 patients aged 50 years or older, including 35 EBV+ DLBCL (12 polymorphic EBV+ DLBCL [pDLBCL] and 23 monomorphic EBV+ DLBCL [mDLBCL]) and 22 EBV+ CHL. Gene expression profiling revealed interferon gamma (IFN-γ) enrichment with overexpression of indoleamine 2,3-dioxygenase 1 (IDO1), an immunosuppressive enzyme, in more than half of pDLBCL (5/8) but less in mDLBCL (3/19) and CHL (1/19). Fluorescence in situ hybridization showed a higher frequency of 9p24.1-altered cells in CHL (54%; IQR, 42%-89%) but lower frequencies in pDLBCL (18%; IQR, 12%-23%) and mDLBCL (5%; IQR, 0%-30%). Notably, immunohistochemical expression of PDL1 was higher in pDLBCL than in mDLBCL, suggesting IFN-γ-mediated upregulation. DLBCL with EBV latency type III (n = 13) exhibited lower tumor PDL1 expression and reduced IDO1-enriched microenvironment. Multivariate analysis of the total cohort revealed that both EBV latency type III and Eastern Cooperative Oncology Group performance status ≥2 were independently associated with shorter overall survival. The EBV+ LBCL spectrum was reclassified into 4 molecular groups: (1) EBV latency type III suggestive of immune senescence (n = 10, 22%), (2) high proportion of 9p24.1 alteration (n = 9, 20%), (3) high IFN-γ signature score (n = 9, 20%), and (4) low IFN-γ signature score (n = 18, 39%). Moreover, these groups were identified using the following surrogate immunohistochemical markers: EBNA2, PDL1, and IDO1. In conclusion, the molecular studies assessing the tumor-host interaction enhance the understanding of the EBV+ LBCL spectrum and benefit pathological diagnosis and clinical management.