Utility of Epstein-Barr Viral Load in Blood for Diagnosing and Predicting Prognosis of Lymphoma A Comparison with Epstein-Barr Virus-Encoded RNA in Situ Hybridization

Epstein-Barr virus (EBV) is a ubiquitous pathogen that persists in a small portion of B cells after primary infection and is etiologically associated with multiple lymphoma subtypes. We evaluated the clinical utility of EBV real-time quantitative PCR in comparison with the widely used Epstein-Barr virus-encoded RNA (EBER) in situ hybridization (ISH) method in 912 patients with four lymphoma sub-types: diffuse large B-cell lymphoma (DLBCL), extranodal natural killer/T-cell lymphoma (ENKTCL), peripheral T-cell lymphoma (PTCL), and Hodgkin lymphoma. We also assessed the impact of EBV positivity determined from each method or a combination of both methods on mortality using Kaplan-Meier survival analysis and Cox proportional hazard regression. EBV real-time quantitative PCR identified more positive cases than EBER-ISH for all subtypes, except ENKTCL. EBV DNA-positive patients with ENKTCL and PTCL displayed poorer overall survival (OS) than EBV DNA-negative patients (P = 0.0016 and P = 0.0013, respectively). In addition, among those with EBER-positive DLBCL and ENKTL and those with EBER-negative PTCL, OS was significantly worse for EBV DNA-positive patients (P = 0.027, P = 0.0016, and P = 0.0018, respectively). EBER positivity was associated with worse OS for DLBCL (P = 0.037), in reanalyses including only the 862 patients with unambiguous EBER-ISH results. Overall, EBV DNA positivity is a more effective prognostic marker than EBER-ISH status for patients with certain lymphoma subtypes.