Common variable immunodeficiency: an important but little-known risk factor for gastric cancer

ABSTRACT Introduction: although it is a rare disease, common variable immunodeficiency (CVID) stands out as the most frequent primary symptomatic immunodeficiency. Carriers are prone to a variety of recurrent bacterial infections, in addition to the risk of developing autoimmune diseases and neoplasms including gastric cancer (GC). Despite the recognized risk, there are no specific standardized protocols for the management of GC in these patients, so the reported oncological results are varied. Thus, this study aims to describe the clinicopathological characteristics and prognosis of patients with CVID undergoing surgical treatment of GC. Methods: all patients with GC undergoing surgical treatment between 2009 and 2020 were retrospectively evaluated. Later, patients diagnosed with CVID were identified and this group was compared with the remaining patients without any immunodeficiency. Results: among the 1101 patients with GC evaluated in the period, 10 had some type of immunodeficiency, and 5 were diagnosed with CVID. Patients with CVID had younger age, lower BMI, and smaller lesions compared to those without CVID. Four patients underwent curative gastrectomy and one patient underwent jejunostomy. Two patients died (1 palliative and 1 curative) and one patient had disease recurrence. There was no statistically significant difference regarding the incidence of postoperative complications and survival between the evaluated groups. Conclusion: the CVID incidence in patients with GC undergoing surgical treatment was 0.5%, occurring at a less advanced age, but with no difference regarding surgical and oncological results.

the majority of which of unknown cause.People with PID are at increased risk of recurrent and chronic infections, autoimmune diseases, and cancer throughout life.Followed by infections, the occurrence of neoplasms is the second most common cause of death in this population.
Between 4% and 25% of patients with PID will develop some neoplasm 9 .Specifically, the risk of developing GC is around three to four times higher in this population 10 .

Among
PIDs, Common Variable Immunodeficiency (CVID) is one of the most associated with antibody deficiency.Patients with CVID have an even greater risk of developing GC, which can be up to 10 times higher than the general population 11 .Patients with CVID have a higher incidence of premalignant lesions (atrophic gastritis, intestinal metaplasia, and dysplasia) when compared with the general population, with a faster evolution to malignant lesions 12 .However, despite the higher risk of neoplastic development attributed to these patients, there are no specific standardized protocols for the treatment of GC in patients with CVID, so the reported oncological results vary according to the different populations analyzed.
Thus, this study aims to describe the clinicopathological characteristics of patients with GC and CVID undergoing surgical treatment, along with the surgical and oncological results.

METHODS
We retrospectively evaluated all patients with GC undergoing surgical treatment between 2009 and 2020.We gathered the data from the Service's Database, which is maintained prospectively.

Statistical analysis
Descriptive statistics included frequency analysis, with percentage for nominal variables, and means with standard deviation for continuous variables.
We used the t test and the Fisher's exact test to assess continuous and categorical variables, respectively.We estimated disease-free survival (DFS) and overall survival (OS) with the Kaplan-Meier method and examined differences between the curves using the Log-Rank test.
We calculated survival time from the date of operation until the date of death or disease recurrence.Living patients were censored on the date of the last visit.We considered values of p<0.05 as statistically significant.
We performed the analyzes using the SPSS software, version 20.0 (SPSS Inc, Chicago, IL).

RESULTS
Among the 1,101 patients undergoing surgical treatment by GC in the referenced period, 10 (0.9%) had some immunodeficiency.Of these, five patients had CVID and were included in the study.Among   3).

DISCUSSION
We evaluated a series of cases of patients with GC who presented CVID and underwent surgical treatment in a single reference center.We found that tumors in patients with CVID occurred at an earlier age.However, there were no differences in pathological and survival outcomes between the groups.Surgical complications, which are a major concern in immunocompromised patients, were also not different between the evaluated groups.
In patients with PIDs, the presence of gastrointestinal disorders is quite frequent, occurring between 5% and 50% of cases.This is in part because the intestine is the largest lymphoid organ in the human body, containing most lymphocytes and producing large amounts of immunoglobulins.Gastrointestinal manifestations can be related to infection, inflammation, autoimmune diseases, and neoplasms 17 .When compared with the same age group, patients with CVID are at increased risk of developing cancer, particularly non-Hodgkin's lymphomas, leukemia, and gastric cancer 18 .

Common variable immunodeficiency (CVID)
is the most common form of PID, and the prevalence is estimated at 1 in 25,000 to 50,000 people.Its pathogenesis has not been fully elucidated, however mutations of several genes related to the development of B cells in immunoglobulin-producing plasma cells and memory B cells have been described 19  The increased risk of GC in patients with CVID varies according to the incidence rate of GC in patients without CVID in the evaluated country.A Scandinavian study estimated an increased risk of 10 times 11 , while an Australian one showed an increased risk of 7.23 times 18 .
Although there is no conclusive evidence, the most In addition, atrophic pangastritis with little presence of plasma cells, nodular lymphoid aggregates, and apoptotic activity are usually present due to the associated autoimmune gastritis 19 .Given the evidence of increased risk of developing GC, it is important that patients with CVID are included in early screening programs 12,19,21 .Dutch data have shown a high incidence of premalignant histological and/or endoscopic lesions in patients with CVID, such as atrophic gastritis, intestinal metaplasia, and dysplasia, even in asymptomatic individuals.Up to 88% of patients with CVID with no prior gastrointestinal history may have premalignant lesions on endoscopy.The progression rates of these lesions to GC vary between 0% and 1.8% per year in atrophic gastritis, from 0% to 10% per year for intestinal metaplasia, and between 0% and 73% per year when dysplasia is already present 12 .It is recommended that patients with chronic atrophic gastritis undergo endoscopy every three years, while for those with intestinal metaplasia the exam can be indicated every one to three years, reducing to a frequency of six to 12 months in cases of dysplasia 21 .
However, these intervals may not be appropriate for patients with CVID, as GC development may occur more quickly..In the present study, all included patients underwent endoscopies regularly and did not display H. pylori infection.Thus, the effectiveness of screening can be evidenced in part by the smaller size of tumors in the CVID group, although we observed no differences in terms of staging and survival between groups, which may also be due to the small number of patients evaluated with CVID.
There are no specific protocols for the treatment of cancer in patients with CVID.Once the GC diagnosis is made, these patients must undergo standard treatment, the same offered to the immunocompetent population 19,22 .Preoperative nutritional therapy and administration of immunoglobulin are recommended measures.CVID patients can receive the same chemotherapy protocols used in immunocompetent patients 23 .However, short-term protocols are preferable to long-term regimens, with special attention to infection control and prophylaxis for Pneumocystis jirovencii pneumonia 22,23 .When possible, the chemotherapy regimen should be tailored according to individual risk factors and tolerance 23 .
The present study has some limitations, especially the small number of patients with CVID, a fact that limits some analyzes and makes the results more descriptive.However, even with small samples, highlighting characteristics and aspects related to patients with GC who have CVID is important to increase knowledge about this type of immunodeficiency as a risk factor for GC, in addition to reinforcing the importance of adopting rigorous screening protocols in such patients.

CONCLUSION
The

R E S U M O R E S U M O
. Affected individuals commonly present with recurrent upper and lower respiratory tract bacterial infections, autoimmune diseases, granulomatous infiltrative disease, and neoplasms.The most common tumors are lymphoma, gastric cancer, and breast cancer 20 .Diagnosis is based on the significant reduction in serum levels of IgG, IgA, and/ or IgM, in addition to reduced production of antibodies after the application of vaccines.Most patients are diagnosed between the ages of 20 and 40, and treatment consists of monthly administration of immunoglobulin 19 .
accepted mechanism for the increased risk of GC in the presence of CVID is due to the reduction in gastric IgA and hydrochloric acid production -factors that promote chronic gastritis and facilitate colonization by H. pylori, triggering carcinogenesis.This mechanism is supported by the finding that patients with pernicious anemia, who also have achlorhydria and chronic gastritis, have a three times greater risk of developing GC19.The decrease in local immune response also may play a role in neoplastic development, due to the lower number of B cells in the gastric mucosa of the patients with CVID.Cancer diagnosis in patients with CVID usually occurs at an earlier age, on average 15 years earlier than in the general population, a characteristic that was also verified in our study.Regarding the histological diagnosis of the tumor, Lauren's Intestinal type is usually the most frequent, being moderately or poorly differentiated and containing a high number of intra-tumoral lymphocytes.

Table 1 .
Clinical characteristics of patients with gastric adenocarcinoma with and without CVID.
pylori was negative in all cases.Regarding symptoms, four patients reported chronic diarrhea.The clinical characteristics of the five patients with CVID in relation to all patients with GC without immunodeficiencies treated in the period are shown in

Table 1 .
Patients with CVID were younger (50.8 years vs. 62.9 years, p=0.030) and had lower BMI (18.5 vs. Among the five patients with CVID, four underwent gastrectomy with curative intent, and one, palliative jejunostomy due to the presence of liver metastases.Table2shows the pathological characteristics of patients with and without CVID undergoing curative treatment.Patients with CVID had smaller diameter tumors compared with the group without this condition (1.4cm vs. 4.7cm; p=0.025).

Table 2 .
Pathological characteristics of patients with CVID undergoing gastric resection.
The mean length of hospital stay of patients was 8.3 days and 12.1 days in the CVID and non-CVID groups, respectively (p=0.417).No patient with CVID had major postoperative complications.Likewise, there was no postoperative mortality at 30 and 90 days (Table

Table 3 .
Surgical and oncological results of patients with CVID undergoing gastric resection.
DFS: disease-free survival; SG: overall survival.*LogRankTestDuringthefollow-up period, of the four patients treated with curative intent, one died without evidence of disease and one relapsed.The patient submitted to jejunostomy died 12.3 months after the operation.Table4summarizes the characteristics of each of the five patients with CVID analyzed in the study.

Table 4 .
Summary of characteristics of patients with CVID included in the study.