Reappraisal of Epstein–Barr virus (EBV) in diffuse large B‐cell lymphoma (DLBCL): comparative analysis between EBV‐positive and EBV‐negative DLBCL with EBV‐positive bystander cells

Aims Epstein–Barr virus (EBV)‐positive diffuse large B‐cell lymphoma (DLBCL) not otherwise specified is defined as monoclonal EBV+ B‐cell proliferation affecting patients without any known immunosuppression. Non‐neoplastic EBV+ cells proliferating in or adjacent to EBV− DLBCL were reported recently, but their clinical significance is unclear. Thus, the aim of this study was to investigate the prognostic impact of EBV+ cells in DLBCL. Methods and results We compared the clinicopathological characteristics of 30 EBV+ DLBCL patients and 29 and 604 EBV− DLBCL patients with and without EBV+ bystander cells (median age of onset 71, 67 and 62 years, respectively). Both EBV+ DLBCL patients and EBV− DLBCL patients with EBV+ bystander cells tended to have high and high–intermediate International Prognostic Index scores (60% and 59%, respectively), as compared with only 46% of EBV− DLBCL patients without EBV+ bystander cells. EBV− DLBCL patients with EBV+ bystander cells showed a significantly higher incidence of lung involvement than those without EBV+ bystander cells (10% versus 2%, P < 0.05). Furthermore, EBV+ DLBCL patients and EBV− DLBCL patients with EBV+ bystander cells had a poorer prognosis than patients without any detectable EBV+ cells [median overall survival (OS) of 100 months and 40 months versus not reached, P < 0.01]. Notably, EBV+ DLBCL patients and EBV− DLBCL patients with EBV+ bystander cells treated with rituximab showed overlapping survival curves (OS, P = 0.77; progression‐free survival, P = 1.0). Conclusions EBV− DLBCL with bystander EBV+ cells has similar clinical characteristics to EBV+ DLBCL. DLBCL with EBV+ bystander cells may be related to both age‐related and microenvironment‐related immunological deterioration.