In situ hybridisation for Epstein-Barr virus as a differential diagnostic tool for T- and natural killer/T-cell lymphomas in non-immunocompromised patients

Abstract

Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus infecting over 90% of humans and the infection persists for life. Although most people are asymptomatic, EBV infection may cause a continuous range of symptoms from transient to severe and protracted diseases depending on the immunological response of the individuals. EBV infects primarily B lymphocytes and rarely T and natural killer (NK) cells. It is implicated in around 1% of human tumours with the majority being haematological malignancies including Hodgkin lymphoma, B- and T-cell non-Hodgkin lymphomas, and immunodeficiency-associated lymphoproliferative disorders (LPDs). As it is a ubiquitous virus the confirmation of EBV-related LPDs depends on the demonstration of the viral DNA by in situ hybridisation for EBV-encoded mRNA (EBER). In current practice, CD3 and EBER positive cytotoxic extranodal lymphomas in non-immunocompromised patients are generally considered as extranodal NK/T-cell lymphoma and accordingly EBER should be performed for such tumours except for the few clinically typical entities such as mycosis fungoides. This review focuses on the application of EBER in the diagnosis of various types of T- and NK/T-cell lymphomas in non-immunocompromised patients and the diagnostic pitfalls, especially their distinction from infectious mononucleosis-related LPD of T- and NK-cell origins and the diagnostic dilemma between various T-cell lymphoma entities with or without EBV association, including nodal cytotoxic EBV positive peripheral T-cell lymphoma.