The Spectrum of Human Herpesvirus 8/Epstein-Barr Virus-Co-Positive Lymphoproliferations and Lymphomas

Human herpesvirus 8 (HHV-8), also known as Kaposi sarcoma–associated herpesvirus (KSHV), is a gamma-2 herpesvirus implicated in a distinctive group of lymphoproliferative disorders (LPD) and lymphomas, in several of which the neoplastic cells are concurrently infected with Epstein–Barr virus (EBV), a gamma-1 herpesvirus. This review summarizes the spectrum of HHV-8/EBV co-positive lymphoproliferations. We first outline the biology of both viruses—their latent and lytic life cycles and the viral gene products (including LANA, vFLIP and v-cyclin for HHV-8 and EBNA-1 and LMP-1 for EBV) through which they deregulate the cell cycle, inhibit apoptosis, and evade immune recognition and may create conditions permissive for B-cell transformation. We then place the principal KSHV/HHV8-associated entities—primary effusion lymphoma and its extracavitary presentation, KSHV/HHV8-positive germinotropic lymphoproliferative disorder, KSHV/HHV8-associated multicentric Castleman disease, and KSHV/HHV8-positive diffuse large B-cell lymphoma—within the current WHO-HAEM5 and ICC frameworks. PEL is frequently EBV-positive, and GLPD is characteristically dual-positive, whereas the KSHV/HHV8-positive lesional cells of MCD and KSHV/HHV8-positive DLBCL are usually EBV-negative. For the purposes of this review, dual positivity denotes demonstration of LANA and EBER within the same morphologically defined lesional cell population and is distinguished from concurrent viral positivity in separate or insufficiently characterized cell populations. Particular attention is given to rare atypical lesions with overlapping features. These cases suggest possible biological relationships among KSHV/HHV8-associated proliferations but do not yet establish a single continuous disease spectrum or a uniform mechanism of viral cooperation.