Gastric Cancer Is the Leading Cause of Death in Italian Adult Patients With Common Variable Immunodeficiency

Abstract

An increased prevalence of malignant lymphoma and of gastric cancer has been observed in large cohorts of patients with common variable immunodeficiency (CVID), the most frequently symptomatic primary immunodeficiency. Surveillance strategies for cancers in CVID should be defined based on epidemiological data. Risks and mortality for cancers among 455 Italian patients with CVID were compared to cancer incidence data from the Italian Cancer Registry database. CVID patients showed an increased cancer incidence for all sites combined (Obs = 133, SIR = 2.4; 95%CI = 1.7–3.5), due to an excess of non-Hodgkin lymphoma (Obs = 33, SIR = 14.3; 95%CI = 8.4–22.6) and of gastric cancer (Obs = 25; SIR = 6.4; 95%CI = 3.2–12.5). CVID patients with gastric cancer and lymphoma had a worse survival in comparison to cancer-free CVID (HR: 4.8, 95%CI: 4.2–44.4 and HR: 4.2, 95%CI: 2.8–44.4). Similar to what observed in other series, CVID-associated lymphomas were more likely to be of B cell origin and often occurred at extra-nodal sites. We collected the largest case-series of gastric cancers in CVID subjects. In contrast to other reports, gastric cancer was the leading cause of death in CVID. Standardized mortality ratio indicated a 10.1-fold excess mortality among CVID patients with gastric cancer. CVID developed gastric cancer 15 years earlier than the normative population, but they had a similar overall survival. Only CVID diagnosed at early stage gastric cancer survived >24 months. Stomach histology from upper endoscopy performed before cancer onset showed areas of atrophic gastritis, intestinal metaplasia or dysplasia. CVID patients might progress rapidly to an advanced cancer stage as shown by patients developing a III-IV stage gastric cancer within 1 year from an endoscopy without signs of dysplasia. Based on high rate of mortality due to gastric cancer in Italian CVID patients, we hereby suggest a strategy aimed at early diagnosis, based on regular upper endoscopy and on Helicobacter pylori infection treatment, recommending an implementation of national guidelines.

Serum Free Light Chains in Common Variable Immunodeficiency Disorders: Role in Differential Diagnosis and Association With Clinical Phenotype

“…One of these two patients, in particular, initially presented a reduction of both light chains and subsequently developed a significant increase of circulating lambda chain, with no detectable paraprotein and was eventually diagnosed a NHL. This suggests that sFLC assay might also be an effective tool in the follow-up strategy in a population with a well-known risk of hematological malignancies (4,24,25).…”

Lack of Gut Secretory Immunoglobulin A in Memory B-Cell Dysfunction-Associated Disorders: A Possible Gut-Spleen Axis

“…It has been widely recognized that gastrointestinal infections and chronic intestinal inflammation are common in CVID (34)(35)(36) and are associated with high morbidity (37). Moreover, CVID patients have an increased risk of gastric cancer (38), and therefore surveillance gastroscopy with collection of biopsies is regularly performed in our center according to the Italian guidelines (www.ipinet.org). We excluded from the study CVID patients with a histological report of an abnormal tissue architecture (i.e., villous atrophy).…”

Heterogeneity of Liver Disease in Common Variable Immunodeficiency Disorders

“…In contrast with hematological and gastrointestinal mucosal malignancies, very few data are available about prevalence, distribution and outcome of liver cancers in CVID. Four cases of liver cancer were found in an Italian cohort of 455 adult patients (prevalence 0.95%), corresponding to a Standardized Incidence Ratio (SIR) of 1.9 (95% CI 0.3-5.6) in comparison to the Italian National Cancer Registry (Associazione Italiana Registro Tumori -AIRTUM) data (22). Noteworthy, all four patients died and liver cancer accounted for the 5.1% all death in the cohort.…”

“…Compelling evidence suggests a higher cumulative incidence of malignancy in CVID population (widely ranging from 1.5% to 25.5%), with a peak of incidence between the 4th and 6th decade of life (76). Non-Hodgkin lymphomas are the most common type of malignancy in several cohort studies (23), even though epithelial cancers are associated with a higher mortality ratio and gastric cancer has recently emerged as the leading cause of death in a large multicenter Italian study (22,77). The pathogenetic mechanisms underlying cancer development in CVID are not completely understood.…”

“…The cornerstone of CVID treatment is polyvalent human IgG replacement that succeeded, over the past 4 decades, in reducing the burden of infections and improving the prognostic outcome of CVID (18)(19)(20). However, immunoglobulin replacement therapy has no proven effectiveness on immune dysregulation-related complications that consequently have become the major cause of death in CVID patients, thus demanding a more in-depth understanding of the underlying pathogenetic mechanisms (21)(22)(23)(24).…”