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 (LPDs) and lymphomas. In some of these entities, lesional cells are concurrently infected with Epstein-Barr virus (EBV), a gamma-1 herpesvirus, raising important questions regarding viral cooperation in lymphomagenesis. This narrative review summarizes the clinicopathological spectrum and biological significance of HHV-8/EBV co-positive lymphoproliferations.

We provide a narrative synthesis of the biology of HHV-8 and EBV, including latent, abortive lytic, and productive lytic infection programmes and viral mechanisms involved in cell-cycle deregulation, apoptosis inhibition, immune evasion, and B-cell transformation. Major HHV-8-associated lymphoproliferative entities are reviewed within the current WHO-HAEM5 and International Consensus Classification frameworks, with particular attention to patterns of EBV co-infection and diagnostically atypical or overlapping lesions.

Primary effusion lymphoma, including its extracavitary presentation, is frequently EBV-positive, whereas HHV-8-positive germinotropic lymphoproliferative disorder is characteristically HHV-8/EBV dual-positive. In contrast, HHV-8-positive lesional cells in multicentric Castleman disease and HHV-8-positive diffuse large B-cell lymphoma are typically EBV-negative. True dual positivity requires demonstration of HHV-8 latency-associated nuclear antigen and EBV-encoded RNA within the same morphologically defined lesional cell population. Rare atypical cases show overlapping clinicopathological features among established entities.

HHV-8/EBV co-positive lymphoproliferations comprise a biologically and diagnostically heterogeneous group. Although unusual overlapping cases suggest potential relationships among HHV-8-associated disorders, current evidence does not support a single continuous disease spectrum or a uniform mechanism of HHV-8/EBV cooperation.