Altered Spectrum of Lymphoid Neoplasms in a Single-Center Cohort of Common Variable Immunodeficiency with Immune Dysregulation

PURPOSE: Common variable immune deficiency (CVID) confers an increased risk of lymphoid neoplasms, but reports describing the precise WHO specification of the lymphoma subtypes and their immunological environment are lacking. We therefore classified lymphomas—occurring in a cohort of 21 adult CVID patients during a 17-year period at our center—according to the 2016 WHO classification and characterized the local and systemic immunological context RESULTS: The median time between the onset of CVID and lymphoma was 14 years. Patients showed a high prevalence of preceding immune dysregulation: lymphadenopathy (n = 13, 62%), splenomegaly (n = 18, 86%), autoimmune cytopenia (n = 14, 67%), and gastrointestinal involvement (n = 15, 71%). The entities comprised extranodal marginal zone lymphoma (n = 6), diffuse large B cell lymphoma (n = 7), plasmablastic lymphoma (n = 1), classic Hodgkin lymphoma (n = 4, including three cases with germline CTLA4 mutations), T cell large granular lymphocytic leukemia (n = 2), and peripheral T cell lymphoma, not otherwise specified (n = 1), but no follicular lymphoma. An Epstein-Barr virus association was documented in eight of 16 investigated lymphomas. High expression of PDL1 by tumor cells in five and of PDL1 and PD1 by tumor-infiltrating macrophages and T cells in 12 of 12 investigated lymphomas suggested a tolerogenic immunological tumor environment. CONCLUSION: In summary, a diverse combination of specific factors like genetic background, chronic immune activation, viral trigger, and impaired immune surveillance contributes to the observed spectrum of lymphomas in CVID. In the future, targeted therapies, e.g., PD1/PDL1 inhibitors in CVID associated lymphomas with a tolerogenic environment may improve therapy outcome. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10875-021-01016-4.