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

Abstract

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.

Secondary Immune Deficiency and Primary Immune Deficiency Crossovers: Hematological Malignancies and Autoimmune Diseases

“…There are no consensus guidelines for cancer screening and follow-up in these patients. In addition, some authors have proposed a specific histologic subclassification of PID-associated lymphoma ( 19 ). The approach used should be mindful about whether or not biopsies and scans are needed to establish the diagnosis.…”

Lymphoproliferation in Inborn Errors of Immunity: The Eye Does Not See What the Mind Does Not Know

“…Lymphoma is the second major cause of mortality in CVID after chronic lung disease ( 23 ). B-cell lymphomas arise chiefly from germinal center-experienced mature B-cells that have undergone somatic hypermutation of Ig genes, correlating with a higher frequency of DLBCL, extranodal marginal zone lymphoma (ENMZL), and HL in CVID ( 24 ). Granulomatous CVID has been reported to involve every organ system occurring in 8-20% of CVID cases ( 25 ).…”

“…Immunohistochemistry (IHC), although used routinely for the detection of B-, T- cell, histiocytes, and plasma cell lineage antigens, should be interpreted with caution and in an appropriate clinical context. The tumor cells express high levels of programmed death-ligand 1 (PDL1) in CVID associated EBV+ DLBCL and HL ( 24 ). Immune checkpoint inhibitors are used to block this immune checkpoint protein, PDL1 expressed by tumor cells in HL to augment the T-cell mediated immune response.…”

Genomic characterization of lymphomas in patients with inborn errors of immunity

“…Samples from patients were either described previously 16,24,[28][29][30] or newly collected. IEI syndromes and lymphomas were diagnosed by local clinicians, as summarized in Tables S1 and S2.…”

“…Infection susceptibility may contribute to this increase. However, the mechanism of lymphomagenesis in IEI is more complex and may involve genome instability, mucosal defects permitting chronic antigen stimulation, dysregulated cellular functions, and defective tumor immunosurveillance [16][17][18][19][20] .…”