The Dysfunctional Immune System in Common Variable Immunodeficiency Increases the Susceptibility to Gastric Cancer

Abstract

Gastric carcinoma (GC) represents the most common cause of death in patients with common variable immunodeficiency (CVID). However, a limited number of cases have been characterised so far. In this study, we analysed the clinical features, bacterial/viral infections, detailed morphology and immune microenvironment of nine CVID patients with GC. The study of the immune microenvironment included automated digital counts of CD20+, CD4+, CD8+, FOXP3+, GATA3+ and CD138+ immune cells, as well as the evaluation of PD-L1 expression. Twenty-one GCs from non-CVID patients were used as a control group. GC in CVID patients was diagnosed mostly at early-stage (n = 6/9; 66.7%) and at younger age (median-age: 43y), when compared to non-CVID patients (p < 0.001). GC pathogenesis was closely related to Helicobacter pylori infection (n = 8/9; 88.9%), but not to Epstein-Barr virus (0.0%) or cytomegalovirus infection (0.0%). Non-neoplastic mucosa (non-NM) in CVID-patients displayed prominent lymphocytic gastritis (100%) and a dysfunctional immune microenvironment, characterised by higher rates of CD4+/CD8+/Foxp3+/GATA3+/PD-L1+ immune cells and the expected paucity of CD20+ B-lymphocytes and CD138+ plasma cells, when compared to non-CVID patients (p < 0.05). Changes in the immune microenvironment between non-NM and GC were not equivalent in CVID and non-CVID patients, reflecting the relevance of immune dysfunction for gastric carcinogenesis and GC progression in the CVID population.

Contribution of Helicobacter pylori to the Inflammatory Complications of Common Variable Immunodeficiency

“…In CVID, the expansion of CD21 low B cells has been significantly associated with splenomegaly and autoimmune diseases ( 41 ), although the role of CD21 low B cells in the pathogenesis remains unclear. Interestingly, our previous data on CVID patients with gastric cancer ( 51 ) did not show B-cell infiltration in the biopsies despite these individuals, which are included in our HP+ group, featured the highest frequencies of circulating CD21 low B cells.…”

“…HP impacts particularly the gastric mucosa, where it is a known risk factor for the development of gastric cancer ( 21 ). Gastric cancer is the fifth most frequently diagnosed malignancy in the world and the third leading cause of malignancy-related death in the general population ( 51 ). In CVID, gastric cancer is a leading cause of morbidity and mortality, being 10-fold more frequent and usually diagnosed at least 15 years earlier than in the general population ( 51 ).…”

Collagenous Gastritis in Primary Selective IgM Deficiency: Transition to EBV+ Gastric Adenocarcinoma

“…Gastric malignancy has not been described in SIgMD. Gastric adenocarcinoma has been reported in patients with other primary immunodeficiencies; however, none were reported to be EBV+ [48,[55][56][57][58][59][60][61][62]. Our patient was diagnosed with collagenous gastritis eight years prior to the development of EBV + adenocarcinoma.…”

Gastric Cancer in Common Variable Immunodeficiency

“…The mechanisms behind the GC excess in CVID patients include immune dysregulation, genetic factors, pernicious anemia and chronic Our Helicobacter pylori infection . (4,5) case report adds up to the current evidence that malignancy in CVID patients can rapidly occur even in non-dysplastic mucosa on recent previous endoscopic examination . A (3) more intensive surveillance than that recommended in MAPS II guideline is warranted in CVID patients .…”