Abstract
PurposeCommon 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 contextResultsThe 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.ConclusionIn 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.
Highlights
Morbidity and mortality of Common variable immune deficiency (CVID) patients under immunoglobulin replacement are mainly determined by malignancies— lymphoid neoplasms and gastric adenocarcinoma—and clinical manifestations of immune dysregulation rather than infections [1–3]
We identified 21 CVID patients with lymphoma (Table 1)
The median time between the onset of first symptoms attributed to CVID and diagnosis of lymphoid malignancy was 14 years (IQR 8–17 years); this was comparable in the subgroup of patients with CTLA4 mutations (15, 17, 18 years)
Summary
Morbidity and mortality of CVID patients under immunoglobulin replacement are mainly determined by malignancies— lymphoid neoplasms and gastric adenocarcinoma—and clinical manifestations of immune dysregulation rather than infections [1–3]. The predisposition of CVID patients to develop lymphoid neoplasms has long been recognized [1, 2, 4–11]. The timely detection and accurate diagnosis of a lymphoid neoplasm in CVID patients are both clinically and pathologically challenging. This can be due to pre-existing and concomitant lymphoid hyperplasia (longstanding lymphadenopathy, splenomegaly) and lack of biomarkers hamper to set the optimal time point for a biopsy. Boundaries between nonmalignant lymphoproliferative disorders (LPD) and overt lymphomas are often difficult to recognize [18, 19]. Non-neoplastic LPDs may present with a profound modulation of the innate lymph node structure and contain morphologically abnormal lymphoid populations, including blast cells, especially in Epstein-Barr virus (EBV)-positive cases. A multiparameter approach integrating routine and ancillary techniques as well as clinical information are mandatory for an appropriate diagnosis
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