The molecular pathogenesis of Epstein-Barr virus-associated B-cell lymphoproliferative disorders: a scoping review

Epstein Barr virus (EBV) latent proteins play a pivotal role in the pathogenesis of EBV-associated lymphoproliferative disorders (EBV LPDs) effectively substituting for oncogenic driver mutations. EBV-related lymphomas are mutationally distinct from their EBV-negative counterpart disease but undergo similar treatment. Advancing therapies for EBV LPDs require a better understanding of the molecular pathogenesis of EBV LPDs. This scoping review summarizes current evidence on the molecular profile in EBV-positive diffuse large B-cell lymphoma (EBV-positive DLBCL, NOS), EBV-positive mucocutaneous ulcer (EBVMCU), DLBCL associated with chronic inflammation (DLBCL-CI), fibrin associated DLBCL (FA-DLBCL), Lymphomatoid granulomatosis (LyG), and classic Hodgkin Lymphoma (cHL). Generally, EBV-positive lymphomas exhibit fewer genomic alterations and less rearrangements in oncogenic driver genes such as BCL2, BCL6, and MYC, compared to their negative counterpart disorders. Also, the mutational landscape of EBV LPDs is delineated by aberrations in NF-kB, JAK-STAT, and NOTCH pathways. Amplification of 9p24.1, causing PD-L1 overexpression, plays a significant role in EBV-positive DLBCL and EBV-positive cHL, whereas EBVMCU, DLBCL-CI, FA-DLBCL, and LyG primarily depend on a (local) immunosuppressive condition. In conclusion, the molecular pathogenesis of EBV LPD is less reliant on driver mutations and instead relies on EBV latent genes and immune evasion; both factors provide promising targets for future therapy.