ABSTRACT
Introduction
Risk factors for gastric cancer in the United States are not well understood, especially in populations with a low proportion of immigrants. We conducted a matched case–control study in a Veteran Affairs Medical Center to identify risk factors for gastric cancer.
Materials and Methods
Gastric cancer patients and age- and sex-matched controls were identified in a 1:4 ratio from January 1, 1997 to October 31, 2018. Demographic, medical, endoscopic, and histologic data were extracted. We performed conditional logistic regression to estimate odds ratios and 95% CIs for associations between potential risk factors and gastric cancer.
Results
Most gastric cancer cases were diagnosed on initial endoscopy (71.4%). Of these, the most common presenting stage was stage IV (40.8%). Risk factors for gastric cancer included Black and Asian race and never or current (compared to former) drinkers, although Helicobacter pylori eradication and pernicious anemia were associated with decreased risk.
Conclusions
The high proportion of late-stage gastric cancer diagnoses highlights the need for improved risk stratification as well as screening and surveillance protocols in the U.S. population. Racial disparities among veterans in an equal-access system necessitate further investigation into the etiology of these disparities.
INTRODUCTION
Gastric cancer is the fifth most common and fourth deadliest malignancy worldwide.1,2 In the United States, the incidence of gastric cancer in those under 50 years of age has increased from 2001 to 2015, suggesting that the disease burden of gastric cancer may be rising.3 Despite this concerning trend, there are currently no U.S. screening guidelines for gastric cancer, and the American Gastroenterological Association acknowledges that its guideline recommendations for surveillance of gastric intestinal metaplasia are based on very low quality of evidence.4
Premalignant lesions develop into noncardia gastric cancer through a pathway known as Correa’s cascade.5 Several studies from European and Asian populations have identified premalignant gastric lesions (atrophic gastritis, intestinal metaplasia, low-grade dysplasia, and high-grade dysplasia) as risk factors in the development of noncardia gastric cancers.6–9 The U.S.-based studies have also explored risk factors for the development of gastric cancer and found that East Asian race, age, extensive intestinal metaplasia, and family history of gastric cancer were also positive predictors.10–12 Notably, these U.S.-based studies were all performed at relatively large, urban tertiary centers with a large immigrant population. Few studies have been performed among nonimmigrant U.S. populations.
It is critical to study the risk factors for gastric cancer in largely nonimmigrant populations because 86.3% of the U.S. population was born in the United States,13 and risk factors may differ in nonimmigrant and immigrant populations. Although approximately 13.7% of the overall U.S. population are immigrants, only 3% of veterans are immigrants, a figure that has slightly increased from 2.1% in 1995.13,14 Since existing literature on risk factors in the development of gastric cancer has focused on tertiary academic centers with larger immigrant populations or higher-risk East Asian populations, we identified the veteran population as a group that may provide insights into risk factors in nonimmigrant populations that comprise the majority of the United States. To address the lack of data in U.S. populations with low numbers of recent immigrants, we conducted a matched case–control study in a Veteran Affairs (VA) Medical Center to identify risk factors for gastric cancer. Although a recent study examined risk factors for the development of intestinal metaplasia among veterans, to our knowledge no study has focused on gastric cancer in this population.15
METHODS
We conducted a case–control study at the VA New York Harbor Health Care System (NYHHCS) using data from January 1, 1997 through October 31, 2018. The NYHHCS Institutional Review Board approved this study. Adults over the age of 18 years with gastric adenocarcinoma were identified from the NYHHCS tumor registry or through ICD codes (ICD-9 151.0-151.9, ICD-10 C16.0-C16.9) in the electronic medical record. Controls were identified in the same period from all adults who underwent esophagogastroduodenoscopy with or without a biopsy using current procedural terminology codes (43235-43259). A manual review was performed to ensure that individuals identified with gastric cancer had biopsy-proven gastric adenocarcinoma. Controls were matched to cases in a 4:1 ratio by age (±3 years) and sex, and we preferentially chose controls with earlier dates of endoscopy to minimize the possibility of missing a cancer diagnosis because of insufficient follow-up.
We performed a combination of automated and manual data extraction for a number of variables, including demographics (age, sex, race, and ethnicity), endoscopy date, family history of gastric cancer, smoking status (never, former, or current), alcohol use, history of partial gastrectomy, Helicobacter pylori status (negative, eradicated, or positive), history of pernicious anemia, histology findings on endoscopy (atrophic gastritis, intestinal metaplasia, low-grade dysplasia, high-grade dysplasia, or cancer), cancer stage, location of cancer (cardia vs. noncardia), and cancer subtype by the Lauren classification.16 Alcohol use was categorized as never user, former user, current user, current heavy user, and former heavy user, where heavy use was defined as at least 14 drinks per week. For race and ethnicity, individuals of Hispanic ethnicity were categorized as such, regardless of race. For the Lauren classification, individuals with predominantly signet cell morphology on histology were categorized into the diffuse group. Those with a family history of gastric cancer were subdivided into those with first-degree and non-first-degree relatives.
We compared cases and controls using Student’s t and chi-squared tests for continuous and categorical variables, respectively. Univariate conditional logistic regression was performed to estimate odds ratios (ORs) and 95% CIs for associations between potential risk factors and gastric cancer, and those with P < .05 were entered into the multivariable model. All analyses were conducted using R software (version 3.6.2). To address missing values, we used the multiple imputation by chained equations package (version 3.13.0) and included all variables in the imputation process.17 The level of significance was set at.05.
RESULTS
A total of 910 individuals (182 cases and 728 controls) were included in the analysis. The vast majority were men (97.8%), with a mean age of 76.3 years. Table I shows the demographic and medical characteristics of the study population. Compared to controls, individuals in the case group were less likely to be White, have a history of H. pylori eradication, be current or former alcohol users, be never or current smokers, or have a history of pernicious anemia. Compared to controls, cases were more likely to be never alcohol users and former smokers. Of note, there was a substantial amount of missing data for race and ethnicity and H. pylori status.
TABLE I.
Demographic and Medical Characteristics
| Total (N = 910) | Cases (n = 182) | Controls (n = 728) | P | |
|---|---|---|---|---|
| Demographics | ||||
| Age, mean (SD) | 76.3 (11.2) | 75.3 (11.3) | 76.5 (11.1) | .191 |
| Sex, n (%) | 1 | |||
| Male | 890 (97.8) | 178 (97.8) | 712 (97.8) | |
| Female | 20 (2.2) | 4 (2.2) | 16 (2.2) | |
| Race/ethnicity, n (%) | <.001 | |||
| White | 336 (36.9) | 41 (22.5) | 295 (40.5) | |
| Black | 283 (31.1) | 55 (30.2) | 228 (31.3) | |
| Asian | 8 (0.9) | 3 (1.6) | 5 (0.7) | |
| Hispanic | 144 (15.8) | 21 (11.5) | 123 (16.9) | |
| Other/missing | 139 (15.3) | 62 (34.1) | 77 (10.6) | |
| Medical | ||||
| Helicobacter pylori status | <.001 | |||
| Negative | 278 (30.5) | 64 (35.2) | 214 (29.4) | |
| Eradicated | 390 (42.9) | 19 (10.4) | 371 (51.0) | |
| Positive | 116 (12.7) | 23 (12.6) | 93 (12.8) | |
| Missing | 126 (13.8) | 76 (41.8) | 50 (6.9) | |
| Smoking, n (%) | <.001 | |||
| Never | 235 (25.8) | 40 (22.0) | 195 (26.8) | |
| Former | 454 (49.9) | 95 (52.2) | 359 (49.3) | |
| Current | 189 (20.8) | 31 (17.0) | 158 (21.7) | |
| Missing | 32 (3.5) | 16 (8.8) | 16 (2.2) | |
| Alcohol, n (%) | <.001 | |||
| Never | 233 (25.6) | 71 (39.0) | 162 (22.3) | |
| Former | 148 (16.3) | 18 (9.9) | 130 (17.9) | |
| Current | 261 (28.7) | 46 (25.3) | 215 (29.5) | |
| Former heavya | 148 (16.3) | 25 (13.7) | 123 (16.9) | |
| Current heavya | 79 (8.6) | 7 (3.9) | 72 (9.9) | |
| Missing | 41 (4.5) | 15 (8.2) | 26 (3.5) | |
| Prior partial gastrectomy, n (%) | .925 | |||
| Yes | 41 (4.5) | 8 (4.4) | 33 (4.5) | |
| No | 860 (94.5) | 173 (95.1) | 687 (94.4) | |
| Missing | 9 (1.0) | 1 (0.5) | 8 (1.1) | |
| Pernicious anemia, n (%) | .018 | |||
| Yes | 31 (3.4) | 1 (0.5) | 30 (4.1) | |
| No | 879 (96.6) | 181 (99.5) | 698 (96.9) | |
| Family history of gastric cancer, n (%) | .055 | |||
| First-degree relative | 33 (3.6) | 8 (4.4) | 25 (3.4) | |
| Non-first-degree relative | 3 (0.3) | 1 (0.6) | 2 (0.3) | |
| No | 785 (86.3) | 146 (80.2) | 639 (87.8) | |
| Missing | 89 (9.8) | 27 (14.8) | 62 (8.5) |
Heavy alcohol consumption is defined by >14 drinks per week.
Histologic findings on endoscopy, including the proportion of normal and premalignant findings as well as the characteristics of adenocarcinoma among cases, are shown in Table II. Cases underwent an average of 1.46 endoscopies per patient (265 total), whereas controls underwent 1.34 (975 total). Intestinal metaplasia was the most common premalignant lesion seen in both groups (53.8% for cases in which endoscopies had nonmalignant findings, 22.9% for controls). As expected, the most common finding in the control group was normal, which includes procedures performed without biopsies (75.7%). Most individuals with cancer (71.4%) were diagnosed on the initial endoscopy. Of those diagnosed with cancer on initial endoscopy, the most common presenting stage was stage IV (40.8%). Overall, the majority of cases were diagnosed at the advanced stage (stage III or IV, 54.4%) and the most common anatomic site was noncardia (73.1%). By the Lauren classification, the intestinal subtype (30.2%) was the most common, although there were substantial missing data (44.5%).
TABLE II.
Endoscopic and Histologic Findings
| Cases (n = 182) | Controls (n = 728) | |
|---|---|---|
| Total number of endoscopies | 265 | 975 |
| Number of endoscopies with nonmalignant findings | 93 | 975 |
| Non- and premalignant findings, n (percentage of total nonmalignant endoscopies) | ||
| Normal (including no biopsies) | 30 (32.3) | 738 (75.7) |
| Atrophic gastritis | 0 (0) | 7 (0.7) |
| Intestinal metaplasia | 50 (53.8) | 223 (22.9) |
| Low-grade dysplasia | 2 (2.1) | 3 (0.3) |
| High-grade dysplasia | 11 (11.8) | 4 (0.4) |
| Diagnosis of cancer on initial endoscopy, n (%) | 130 (71.4) | |
| Stage of cancer on first endoscopy, n (percentage of those with cancer diagnosis on initial endoscopy) | ||
| I | 26 (20.0) | |
| II | 12 (9.2) | |
| III | 18 (13.8) | |
| IV | 53 (40.8) | |
| Missing | 21 (16.2) | |
| Stage of cancer, n (%) | ||
| I | 39 (21.4) | |
| II | 16 (8.8) | |
| III | 28 (15.4) | |
| IV | 71 (39.0) | |
| Missing | 28 (15.4) | |
| Anatomic subsite | ||
| Cardia | 34 (18.7) | |
| Noncardia | 133 (73.1) | |
| Missing | 15 (8.2) | |
| Lauren classification | ||
| Intestinal | 55 (30.2) | |
| Diffuse | 42 (23.1) | |
| Mixed | 4 (2.2) | |
| Missing | 81 (44.5) |
We assessed the association between various risk factors and gastric cancer by univariable and multivariable conditional logistic regression (Table III). Compared to White individuals, Black and Asian individuals had a higher risk of gastric cancer (Black: OR 2.21, 95% CI 1.39-3.24; Asian: OR 6.29, 95% CI 1.27-31.21). Hispanic individuals had a similar risk as Whites. Helicobacter pylori eradication was associated with decreased risk (OR 0.13, 95% CI 0.08-0.21) compared to H. pylori negative individuals, although H. pylori positivity was not associated with elevated risk. Compared to former alcohol drinkers, both never drinkers (OR 3.95, 95% CI 2.10-7.43) and current drinkers (OR 2.35, 95% CI 1.24-4.48) had higher risk. Individuals with prior or current heavy alcohol use, defined as >14 drinks in 1 week, had a similar risk as former drinkers. A history of pernicious anemia was associated with decreased risk of gastric cancer (OR 0.10, 95% CI 0.01-0.73). We did not observe significant associations between gastric cancer and smoking status, history of prior partial gastrectomy, or family history of gastric cancer.
TABLE III.
Predictors of Gastric Cancer by Conditional Logistic Regression
| Univariable OR (95% CI) | P | Multivariable OR (95% CI) | P | |
|---|---|---|---|---|
| Race/ethnicity, n (%) | ||||
| White | Reference | Reference | ||
| Black | 1.88 (1.30-2.73) | .001 | 2.12 (1.39-3.24) | <.001 |
| Asian | 4.54 (1.18-17.38) | .027 | 6.29 (1.27-31.21) | .024 |
| Hispanic | 1.26 (0.78-2.05) | .341 | 1.45 (0.83-2.53) | .188 |
| Helicobacter pylori status | ||||
| Negative | Reference | Reference | ||
| Eradicated | 0.15 (0.10-0.24) | <.001 | 0.13 (0.08-0.21) | <.001 |
| Positive | 0.76 (0.49-1.18) | .242 | 0.68 (0.43-1.09) | .111 |
| Smoking, n (%) | ||||
| Never | Reference | |||
| Former | 1.48 (0.97-2.24) | .066 | ||
| Current | 1.01 (0.60-1.69) | .975 | ||
| Alcohol, n (%) | ||||
| Former | Reference | Reference | ||
| Current | 1.57 (0.88-2.80) | .130 | 2.35 (1.24-4.48) | .009 |
| Never | 3.31 (1.90-5.75) | <.001 | 3.95 (2.10-7.43) | <.001 |
| Former heavya | 1.61 (0.86-3.04) | .139 | 1.85 (0.93-3.71) | .081 |
| Current heavya | 0.73 (0.29-1.82) | .495 | 1.06 (0.40-2.84) | .901 |
| Prior partial gastrectomy, n (%) | ||||
| No | Reference | |||
| Yes | 1.06 (0.49-2.29) | .874 | ||
| Pernicious anemia, n (%) | ||||
| No | Reference | Reference | ||
| Yes | 0.13 (0.02-0.95) | .044 | 0.10 (0.01-0.73) | .023 |
| Family history of gastric cancer, n (%) | ||||
| No | Reference | |||
| First-degree relative | 1.15 (0.52-2.53) | .737 | ||
| Non-first-degree relative | 1.33 (0.14-12.82) | .803 |
Heavy alcohol consumption is defined by >14 drinks per week.
DISCUSSION
In this single institution case–control study in a veteran population, we found individuals who were Black, Asian, and never or current drinkers (compared to former drinkers) to be at increased risk for gastric cancer. In addition, H. pylori eradication and pernicious anemia were associated with decreased risk. Although histologic data were limited, intestinal metaplasia was the most common premalignant lesion, and a majority of gastric cancer cases were diagnosed on initial endoscopy and as late-stage disease. This study provides novel insights into gastric cancer risk factors in an understudied, low-immigrant veteran population.
Since the majority of cases (71.4%) were diagnosed on initial endoscopy, we had insufficient power to assess the association between premalignant lesions and gastric cancer. We found that 54.4% of all gastric cancer cases and 54.6% of those diagnosed on initial endoscopy presented with late-stage (stage III or IV) disease. Given the often-insidious onset of gastric cancer, it is not surprising that most cases were diagnosed after patients developed advanced disease. This is consistent with data showing 32% 5-year survival in the United States, where few cases are diagnosed at an early stage, in contrast to 52% survival in Japan, which has a well-established screening program.18,19 The predominance of late-stage gastric cancer on initial endoscopy suggests earlier identification and monitoring of premalignant lesions could be beneficial in a low-immigrant U.S. population, although further research is needed for risk stratification.
Our data on race and ethnicity support the limited but growing evidence on gastric cancer risk among various U.S. subgroups. East Asian countries have historically had significantly higher rates of gastric cancer compared to Western populations, but it is only recently that the question of risk in Asian populations in the United States has been addressed.20 Choi et al. demonstrated that among East Asian immigrant populations in the United States, there was a significantly increased risk of gastric cancer compared to White populations.12 Asian ethnicity was associated with an increased risk of gastric cancer (OR 6.29, 95% CI 1.27-31.21) in our study, although the risk estimate may be imprecise because of the small number of Asian individuals in the cohort.
Some reports have found that Black individuals have an increased risk for gastric cancer, although the association is not as consistently robust as for Asian individuals.21,22 Our study may have been able to identify this association because the relatively large proportion of Black patients (31.1%) allowed for sufficient statistical power. Among veterans in particular, Nguyen et al. studied risk factors for gastric intestinal metaplasia in a similar urban, VA population and found that the prevalence of gastric intestinal metaplasia was higher among Black populations compared to non-Hispanic, White populations.23 Given the well-established association between gastric intestinal metaplasia and gastric cancer, our findings support these data. The potential causes for increased risk of gastric cancer among Black populations in our study may be multifactorial. Barriers to health care access are an important consideration, although disparities in Black vs. White populations have been shown to be greatly reduced or absent in the equal-access VA system for other conditions. Data from a study on gastric cancer at an urban safety–net hospital identified ZIP code–level poverty as being significantly associated with late-stage disease, suggesting that socioeconomic status may contribute to ongoing health disparities among gastric cancer patients.24 Prior research has demonstrated that Black veteran populations have higher rates of H. pylori compared to White veterans.25 Data from a large veteran cohort also showed that among those with H. pylori, Black veterans were at an increased risk of developing gastric adenocarcinoma compared to White veterans, suggesting that Black individuals may have a higher prevalence of other genetic or environmental factors that increase the risk of carcinogenesis.26
The literature describing the association between Hispanic ethnicity and gastric cancer is mixed,10–12,23 which may not be surprising since individuals who identify as Hispanic are a heterogeneous group, and the incidence of gastric cancer in Latin America varies substantially by country.27 We did not find an association between gastric cancer and Hispanic ethnicity in our New York population, where the majority of Hispanic individuals are of Puerto Rican and Dominican heritage. Our findings highlight the importance of determining which minority populations are at increased risk for gastric cancer, as well as challenges created by the lack of disaggregated racial and ethnic data, and reinforce the value of health disparities research.
Our finding that H. pylori eradication was associated with a decreased risk of gastric cancer (OR 0.13, 95% CI 0.08-0.21) is consistent with data from a meta-analysis of randomized control trials.28 Prior research from the United Kingdom demonstrated that only 10% of primary care patients with peptic ulcer disease had received eradication for H. pylori, which may suggest that those individuals who underwent H. pylori eradication in our study may be better connected to the health care system.29 Helicobacter pylori is one of the strongest risk factors for gastric cancer, and the unexpected lack of association between positive H. pylori status and cancer in our study may be attributable to a large proportion of misclassified missing data among cases despite our efforts to address this with multiple imputation.
Gastric cancer risk was increased among current (OR 2.35, 95% CI 1.24-4.48) and never drinkers (OR 3.95, 95% CI 2.10-7.43) compared to former drinkers. The finding for never drinkers is surprising since recent meta-analyses have found that alcohol use is associated with gastric cancer.30,31 This result may be attributed to former alcohol users adopting overall healthier lifestyles that are protective against gastric cancer, although data on lifestyle habits in this population are limited.
Pernicious anemia has been shown to be a risk factor in the development of gastric cancer, but in our study individuals with pernicious anemia were less likely to develop gastric cancer (OR 0.10, 95% CI 0.01-0.73). The prevalence of pernicious anemia among our controls was 4.1%, compared to 0.5% among cases and 0.1% in the general population.32 The over-representation of pernicious anemia in our control group may have been driven by two factors. First, both an American Society for Gastrointestinal Endoscopy guideline and an American Gastroenterological Association clinical practice update recommend a one-time upper endoscopy for all patients with newly diagnosed pernicious anemia, and some of the control patients may have undergone endoscopy for this reason.33,34 Second, individuals with all types of anemia are often referred for and receive diagnostic upper endoscopy, despite minimal evidence that these procedures provide diagnostic clarity.35 Therefore, because all controls underwent esophagogastroduodenoscopy, this likely introduced a selection bias and inflated the true prevalence of pernicious anemia in individuals without gastric cancer.
An additional factor that may have played a role in the development of gastric cancer in our population is epigenetic alterations. Most of the study participants, or their parents, would have experienced the Great Depression and World War II. These highly stressful events could have caused epigenetic changes that predisposed these patients to gastric cancer later in life.36 However, this would not lead to increased risk in the case group since the control group was matched on age.
Our study provides novel insights into gastric cancer risk in the veteran population, but there are several limitations. First, as expected for the veteran population, the vast majority of our cohort was male. Whether the magnitude of association between risk factors and gastric cancer is similar among women warrants confirmation in a different population. Second, a substantial amount of racial/ethnic and H. pylori data were missing, which we attempted to address analytically using multiple imputation. Third, we did not have granular data to categorize intestinal metaplasia into subtypes (e.g., complete vs. incomplete and limited vs. extensive), which could have provided a greater ability to risk stratify this population. The lack of granular data on diet and socioeconomic status also precludes us from assessing the influence of these important factors on gastric cancer development.
This study adds to the limited body of evidence for gastric cancer risk factors in the United States. In the veteran population, gastric cancer diagnosis was commonly diagnosed at the late stage, which highlights the need for early detection. These results may help in the development of future recommendations for gastric cancer screening and surveillance based on histologic findings. Additionally, our study adds to the growing literature that suggests racial disparities exist in gastric cancer, even in an equal-access veteran system. Further research is needed to elucidate the reasons for these disparities. Finally, those who underwent H. pylori eradication and former alcohol users were less likely to develop gastric cancer, an association that may be a result of improved connectedness to the health care system or healthier lifestyles.
ACKNOWLEDGMENTS
None declared.
Contributor Information
Kush Fansiwala, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Yingzhi Qian, Department of Population Health, NYU Langone Health, New York, NY 10016, USA.
Peter S Liang, Department of Population Health, NYU Langone Health, New York, NY 10016, USA; Department of Medicine, VA New York Harbor Health Care System, New York, NY 10010, USA; Department of Medicine, NYU Langone Health, New York, NY 10016, USA.
FUNDING
P.S.L. is supported by grant K08 CA230162 from the National Cancer Institute. The funding source had no role in the analysis of data, preparation of the manuscript, or decision to submit the manuscript for publication.
CONFLICT OF INTEREST STATEMENT
PSL has received research support from Epigenomics and Freenome and is on the advisory board for Guardant Health. The remaining authors have no disclosures.
DATA AVAILABILITY
For VA privacy purposes, the data in this study will not be made available.
INSTITUTIONAL REVIEW BOARD
This study was approved by the NYHHCS Institutional Review Board.
INDIVIDUAL AUTHOR CONTRIBUTION STATEMENT
K.F., Y.Q., and P.S.L. assisted with the data acquisition/preparation; K.F. and P.S.L. assisted with the study design; Y.Q. assisted with the data analysis; K.F., Y.Q., and P.S.L. assisted with the data interpretation; K.F. assisted with the writing; K.F., Y.Q., and P.S.L. assisted with the critical review and editing.
INSTITUTIONAL CLEARANCE
Institutional clearance has been provided.
INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE
Not applicable.
CLINICAL TRIAL REGISTRATION
None declared.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
For VA privacy purposes, the data in this study will not be made available.