Lymphoproliferations in People Living with HIV: Oncogenic Pathways, Diagnostic Challenges, and New Therapeutic Opportunities

Although efficiently managed by cART, chronic HIV infection remains associated with a high incidence of malignant lymphomas. This diverse group of tumors presents considerable challenges in research, diagnosis, and treatment due to their complex pathogenesis, heterogeneous tumor microenvironment, and frequently aggressive clinical behavior. In this review, we examine the multifactorial pathogenesis of lymphomas arising in people living with HIV (PLWH), encompassing both direct and indirect oncogenic mechanisms. We summarize the key histopathological features and microenvironmental characteristics that may influence therapeutic responses. Current treatment strategies approved for the treatment of lymphomas in PLWH are showing outcomes comparable with those observed in patients without HIV. Notably, the immune reconstitution achieved through cART has renewed interest in immunotherapeutic approaches for HIV-associated lymphomas, with several strategies under clinical investigation. However, progress in the diagnosis and management of these malignancies is hindered by fragmented research efforts and the frequent exclusion of PLWH from pivotal clinical trials. Coordinated efforts are essential to overcome these barriers, reduce lymphoma incidence, and improve survival outcomes in this vulnerable population.