When immunity turns rogue: lymphoma and lymphoproliferative disorders in common variable immune deficiency

The purpose of this review is to describe the most recent findings regarding lymphoma and lymphoproliferative disorders (LPDs) in common variable immune deficiency (CVID) patients, presenting epidemiological data regarding the burden of disease, exploring the underlying immunological mechanisms, and offering insights into the role of genetics and possible treatment options.

There have been reports of predisposition to lymphoproliferation in both monogenic forms of CVID and CVID with no identifiable genetic cause. Germline but also somatic mutations have been claimed as possible contributors to lymphomagenesis in CVID. Lower B cell counts, hyper-IgM phenotype, reduction in CD4+T cells and an exaggerated CD8+T cell response, as well preexisting immune dysregulation manifestations, have also been identified as possible predisposing factors for the development of lymphoma and LPDs in CVID patients.

Lymphoma and LPDs represent a significant portion of CVID noninfectious clinical manifestations, both as presenting symptoms and long-term complications. There is a complex interplay between genetic background, humoral and cellular immunity defects, as well as infections, chronic inflammation and immune dysregulation. Diagnosis may be challenging from both a clinical and a histopathological perspective. The toll of mortality is significant, making a high degree of surveillance for hematological malignancy necessary. No consensus on specific treatment guidelines is available; viable options include standard chemo-immunotherapy and hematopoietic stem cell transplantation (HSCT), when comorbidities are permissive. From a pathophysiological standpoint, a possible application of target therapies such as immune checkpoint inhibitors has been hypothesized, though no clinical trials are available yet for the treatment of lymphoma in CVID patients.