Epstein-Barr virus-negative diffuse large B-cell lymphoma hosts intra- and peritumoral B-cells with activated Epstein-Barr virus

Although the vast majority of diffuse large B-cell lymphomas (DLBCL) are negative for the Epstein-Barr virus (EBV), a subset of DLBCL in immunocompetent patients carries EBV in the lymphoma cells and expresses EBV-encoded RNA and/or proteins. EBV-positive DLBCL are rare and represent either pyothorax associated DLBCL or EBV-positive DLBCL of the elderly. In all cases of EBV-positive DLBCL, EBV is detectable in virtually all lymphoma cells, indicating that EBV was present at an initial phase of lymphomagenesis. We identified four lymphomas with an unusual EBV expression pattern. The majority of B-cell blasts were EBV-negative, but accompanied by a small number (less than 10 % of all B-cells) of EBV-positive B-cells with blastic morphology. The median age of the patients was 56.5 years, and no clinically evident immunosuppression was reported. In one patient EBV-positive blasts occurred in the gastric mucosa which resembled an EBV-positive mucocutaneous ulcer. In all cases EBV-positive B-cells occurred in small loose clusters within or adjacent to an EBV-negative DLBCL. In one case we were able to study immunoglobulin gene rearrangement in microdissected EBV-positive B-cells and the EBV-negative lymphoma compartment. This revealed different rearrangement patterns in EBV-negative DLBCL than in EBV-positive peritumoral B-cells, without clonal relationship between these B-cell populations. Despite the molecular data being limited to one patient, we suggest that in close proximity to EBV-negative DLBCL intra- and peritumoral EBV-positive B-cells may occur, possibly due to local immune escape mechanisms. This represents a diagnostic pitfall.