Abstract
Background:
Helicobacter pylori infection is an established causal factor for non-cardia gastric cancer. H. pylori negative gastric cancer prevalence among U.S. patients is unclear.
Methods:
This retrospective cohort study examined H. pylori prevalence among consecutive patients with incident non-cardia gastric adenocarcinoma at the Houston VA Hospital (11/2007–10/2018). H. pylori positivity was defined by H. pylori on histopathology, positive antibody serology, stool antigen, or urea breath testing. We examined for trends in H. pylori negative gastric cancer based on year of diagnosis. Associations between histopathologic and cancer-related outcomes with H. pylori positivity were determined using regression models.
Results:
Of 91 patients with gastric adenocarcinoma, most were men (N=87, 95.6%), black (N=47, 51.6%), with mean age at diagnosis of 68.0 years (SD 10.8). In addition to gastric cancer biopsy histopathology, 74 patients (81.3%) had ≥1 testing for H. pylori, including antibody serology (n=34), non-cancer gastric biopsy histopathology (n=63), or stool antigen (n=1). The overall prevalence of H. pylori infection was 38.5% and 45.9% among patients with ≥2 H. pylori tests. The proportions of H. pylori positive gastric cancer decreased from 50.0% (2007–2010) to 43.4% (2011–2014) and 29.3% (2015–2018) (p=0.096). Active/acute gastritis (adjOR 3.74), atrophic gastritis (adjOR 15.30), and gastric intestinal metaplasia (adjOR 3.65) were associated with H. pylori positive gastric cancer.
Discussion:
The prevalence of H. pylori infection among patients with non-cardia gastric adenocarcinoma is relatively low (38.5–45.9%) and decreasing over time. This finding suggests there may be other important causal factors apart from H. pylori for gastric adenocarcinoma.
Keywords: epidemiology, gastric cancer, gastric adenocarcinoma, Helicobacter pylori, Veterans Affairs, prevalence
INTRODUCTION
Gastric cancer is the fifth leading cause of cancer-related mortality globally.1–3 Gastritis related to Helicobacter pylori (H. pylori) infection is the main etiology underlying non-cardia gastric cancer, which accounts for approximately 90% of gastric cancer cases worldwide.4 H. pylori related gastritis has been thought to play a large role in the geographical burden of gastric cancer with the highest incidence and mortality rates in Asia and Latin America.2,5 Although rates of H. pylori infection as well as gastric cancer is declining worldwide, especially in developed countries,6,7 prevalence of H. pylori is dropping at a faster rate than the decrease in gastric cancer incidence8–10, suggesting a rise in H. pylori negative gastric cancer.
H. pylori infection has been thought to be etiologically responsible for the majority of gastric cancers. A previous Japanese study followed 1526 patients for a median of 7.8 years and found 2.9% of those infected with H. pylori (36 of 1246) developed gastric cancer compared to none of the 280 H. pylori negative patients (p<0.001).11 However, more recent studies described higher prevalence of H. pylori negative gastric cancer (i.e., 14.2% in Japan,12,13 4% in South Korea,14 14% in Italy,15 and 24.7% in Germany16); but there have been no such studies from the United States (U.S.).
In the U.S., the prevalence of H. pylori has been decreasing since the 1970s and in 2000–2016, 35.6% of the U.S. population was estimated to be infected with H. pylori.17 This decline is attributed to improved sanitation, refrigeration leading to less smoking and salt preservation of food, and varied diets of fresh fruits and vegetables.18 While the incidence of non-cardia gastric cancer has declined overall in the U.S., there has been a rise in younger age groups10, and the incidence remains relatively high in Asian-Americans and Hispanics, both among recent immigrants as well as those born in the U.S.19 Extracted from the United States Cancer Statistics, among individuals <50 years, the incidence of gastric cancer increased from 1999 to 2013 (annual percentage increase, APC 0.89, 95% CI 0.61–1.16).20 While there seems to be a disconnect in the U.S. with a rise in the incidence of non-cardia gastric cancer and a decrease in H. pylori infection, the proportion of gastric cancer cases in the U.S. attributable to H. pylori is unclear.
The aim of this study was to examine the prevalence of H. pylori negative gastritis among newly diagnosed non-cardia gastric adenocarcinoma in a U.S. population. We also identified sociodemographic and clinical factors associated with H. pylori negative gastric cancer compared to H. pylori positive gastric cancer patients and examined for temporal trends in the incidence of H. pylori negative/positive gastric cancer.
METHODS
Study Design and Population
This was a retrospective cohort study of consecutive patients with newly diagnosed non-cardia gastric adenocarcinoma at the Michael E. DeBakey Veteran Affairs (VA) Medical Center in Houston, Texas identified in the cancer histopathology database from November 2007 to October 2018. We performed a structured review of the VA electronic medical records for laboratory, endoscopy, and histopathology data to verify the diagnosis, location, and date of diagnosis of the non-cardia gastric adenocarcinoma. We performed structured data abstraction of endoscopic and histopathologic findings in all available endoscopic examinations before, during, and after the cancer diagnosis (active gastritis, atrophic gastritis, gastric intestinal metaplasia, dysplasia), cancer staging, receipt of cancer treatment, and sociodemographic and clinical factors. Cancer staging was classified using both the tumor, node, metastasis (TNM) classification and the American Joint Committee on Cancer (AJCC) staging system. Receipt of cancer treatment included endoscopic resection, surgery, chemotherapy, and/or radiation therapy. We searched for all available H. pylori testing including laboratory studies (urea breath test, H. pylori IgG serology, H. pylori stool antigen test) and histopathology of all gastric specimens (endoscopic biopsy or surgical resections), as well as H. pylori treatment.
Sociodemographic and clinical factors included sex, race (white, black, Hispanic, Asian/Pacific Islander, and other), highest body mass index (BMI) in 20 years prior to gastric cancer diagnosis, smoking and alcohol history, gastroesophageal reflux disease (GERD), dyspepsia, use of proton pump inhibitors (PPI) within 10 years prior to gastric cancer diagnosis, family history of gastric cancer, prior gastric surgery, and major comorbidities including cardiopulmonary disease, obstructive sleep apnea, diabetes mellitus, hypertension, and hyperlipidemia.
H. pylori Status
We determined H. pylori positivity prior to, at the time of, or after the diagnosis of gastric cancer by: 1) presence of H. pylori bacteria on histopathology of gastric mucosa with hematoxylin and eosin (H&E) staining, 2) presence of H. pylori bacteria on histopathology of gastric mucosa with special staining (including Genta, immunohistochemical, or Giemsa staining), 3) positive stool H. pylori antigen, 4) positive urea breath test, 5) positive H. pylori IgG serology, or 6) H. pylori treatment in the absence of testing or with negative testing (omeprazole plus 2 of the following: metronidazole, clarithromycin, amoxicillin, bismuth, or tetracycline). If patients did not meet any of the above criteria, they were deemed to have H. pylori negative gastric cancer.
We performed a secondary analysis in which patients who had atrophic gastritis or gastric intestinal metaplasia on histopathology were included as suspected H. pylori positive gastric cancer cases. This was to include potentially misclassified cases of H. pylori gastric cancer because previous literature indicate the possibility of H. pylori infection elimination in the setting of gastric atrophy or gastric intestinal metaplasia.21
Statistical Analysis
We compared the sociodemographic and clinical characteristics of patients with H. pylori positive and H. pylori negative gastric cancer using chi-square tests for categorical variables and t-tests for continuous variables. We used the Cochran-Armitage trend test to examine trends in proportions of H. pylori negative gastric cancer based on year of diagnosis (2007–2010, 2011–2014, 2015–2018). Associations with sociodemographic and clinical characteristics with H. pylori positivity were determined using univariate logistic regression models and multivariate models adjusted for age and race and reported as odds ratios (OR) with 95% confidence intervals (CI). Multivariate Cox hazards regression models, adjusted for age, race, cancer stage, and receipt of treatment, were additionally used to compare differences in survival between H. pylori positive cases and H. pylori negative cases and reported as hazards ratios (HR) with 95% CI.
Statistical analyses were performed using SAS 9.2 (SAS Institute, Cary, NC). Statistical significance was determined at α = 0.05, and all tests for statistical significance were two-sided. The study was approved by the Institutional Review Board at the Michael E. DeBakey Veterans Affairs Medical Center in Houston, Texas.
RESULTS
There were 91 consecutive patients with confirmed incident non-cardia gastric adenocarcinoma diagnosed between November 2007 and October 2018. Most were men (N=87, 95.6%) and black (N=47, 51.6%), and the mean age at diagnosis was 68.0 years (SD 10.8). The median follow-up duration from gastric cancer diagnosis to death or last encounter through January 2019 was 15.0 months.
In addition to gastric cancer biopsy histopathology which was available for all patients, 74 patients (81.3%) had at least one additional H. pylori test including H. pylori antibody serology (n=34, 37.4%), non-cancer gastric biopsy histopathology with (n=38, 41.8%) or without special staining (n=25, 27.5%) and stool H. pylori antigen (n=1, 1.1%). None had testing by urea breath test. In addition to gastric cancer biopsy, 23 patients (25.3%) had 2 or more additional types of test for H. pylori infection. The differences in H. pylori testing between H. pylori positive and negative gastric cancer patients is shown in Table 1.
Table 1.
Characteristics of Helicobacter pylori testing among 35 patients with H. pylori positive gastric cancer and 56 patients with H. pylori negative gastric cancer. Additional comparison included 26 patients with suspected H. pylori gastric cancer (i.e., atrophic gastritis or gastric intestinal metaplasia on gastric biopsy in the setting of negative H. pylori testing).
| H. pylori Positive Gastric Cancer (n=35) | H. pylori Negative Gastric Cancer (n=56) | p-value | H. pylori Positive Gastric Cancer (including suspected) (n=61) | H. pylori Negative Gastric Cancer (excluding suspected) (n=30) | p-value | |
|---|---|---|---|---|---|---|
| Histopathology of non-cancer gastric biopsy without special stain | 14 (40.0) | 11 (19.6) | 0.034 | 20 (32.8) | 5 (16.7) | 0.136 |
| Histopathology of non-cancer gastric biopsy with special stain | 14 (40.0) | 24 (42.9) | 0.788 | 31 (50.8) | 7 (23.3) | 0.014 |
| H. pylori IgG serology | 20 (57.1) | 14 (25.0) | 0.002 | 26 (42.6) | 8 (26.7) | 0.139 |
| H. pylori stool antigen | 0 (0.0) | 1 (1.8) | --- | 0 (0.0) | 1 (3.3) | 0.330 |
| 1 test for H. pylori (meaning gastric cancer biopsy only) | 1 (2.9) | 16 (28.6) | 0.002 | 3 (4.9) | 14 (46.7) | <0.001 |
| ≥2 tests for H. pylori | 34 (97.1) | 40 (71.4) | 0.181 | 58 (95.1) | 16 (53.3) | 0.425 |
| ≥3 tests for H. pylori | 14 (40.0) | 9 (16.1) | 0.624 | 19 (31.1) | 4 (13.3) | 0.765 |
The overall prevalence of H. pylori infection in the study cohort by any test was 38.5% (n=35). Among the 74 patients with at least one test for H. pylori infection in addition to targeted gastric mass biopsy, the prevalence of H. pylori infection was 45.9% (n=34). Of those with at least 2 additional tests (n=23), the prevalence of H. pylori infection was 60.9% (n=14). The proportion of H. pylori negative gastric cancer increased slightly from 50.0% in 2007–2010 (n=10 of 20) to 56.7% in 2011–2014 (n=17 of 30) to 70.7% in 2015–2018 (n=29 of 41) (p-value for trend=0.096; Figure 1). When gastric cancer patients with atrophic gastritis or gastric intestinal metaplasia were classified as suspected H. pylori positive gastric cancer, the overall prevalence of H. pylori infection increased to 67.0% (n=61).
Figure 1.
Prevalence rates of Helicobacter pylori positive and negative gastric cancer over time. H. pylori positive gastric cancer was defined by H. pylori positivity on histopathology of gastric biopsy, IgG serology, or stool antigen testing.
We also included H. pylori treatment (omeprazole plus 2 of the following: metronidazole, clarithromycin, amoxicillin, bismuth, or tetracycline) as a surrogate of H. pylori positivity. All patients in this study cohort who received H. pylori treatment had previously documented positive H. pylori testing. Of the 35 patients who were H. pylori positive, 21 (60%) were prescribed H. pylori treatment. Of the 21 patients given H. pylori treatment, 13 patients (61.9%) were tested for H. pylori eradication (by H. pylori stool antigen, gastric biopsy, or urea breath test) with eradication confirmed in 12 patients.
There were no significant differences between H. pylori positive (n=35) and H. pylori negative gastric cancer (n=56) in terms of age, sex, race, BMI, gastrointestinal symptoms, PPI use, smoking history, alcohol history, or family history of gastric cancer (Table 2). Patients with H. pylori positive gastric cancer were more likely than H. pylori negative cases to have acute or active gastritis (68.6% vs. 32.1%, p=0.004), atrophic gastritis (25.7% vs. 3.6%, p=0.002), gastric intestinal metaplasia (74.3% vs. 46.4%, p=0.009) and less likely to have chronic gastritis (20.0% vs. 30.4%, p=0.004)) on histopathology. There was no significant difference in cancer stage at diagnosis, median survival, or receipt of treatment between H. pylori negative or positive cases (Table 3).
Table 2.
Sociodemographic and clinical characteristics of 35 patients with Helicobacter pylori positive gastric cancer and 56 patients with H. pylori negative gastric cancer. Additional comparison included 26 patients with suspected H. pylori gastric cancer (i.e., atrophic gastritis or gastric intestinal metaplasia on gastric biopsy in the setting of negative H. pylori testing).
| H. pylori Positive Gastric Cancer (n=35) | H. pylori Negative Gastric Cancer (n=56) | p-value | H. pylori Positive Gastric Cancer (including suspected) (n=61) | H. pylori Negative Gastric Cancer (excluding suspected) (n=30) | p-value | |
|---|---|---|---|---|---|---|
| Age, mean (SD) | 66.4 (10.5) | 69.0 (10.9) | 0.270 | 68.2 (9.5) | 67.6 (13.2) | 0.784 |
| Sex | ||||||
| Male | 35 (100.0) | 52 (92.9) | 0.294 | 59 (96.7) | 28 (93.3) | 0.596 |
| Female | 0 (0.0) | 4 (7.1) | 2 (3.3) | 2 (6.7) | ||
| Race | ||||||
| Non-Hispanic White | 8 (22.8) | 21 (37.5) | 0.441 | 17 (27.9) | 12 (40) | 0.065 |
| Black | 21 (60.0) | 26 (46.4) | 33 (54.1) | 14 (46.7) | ||
| Hispanic | 5 (14.3) | 6 (10.7) | 10 (16.4) | 1 (3.3) | ||
| Other | 1 (2.9) | 3 (5.4) | 1 (16) | 3 (10.0) | ||
| BMI | ||||||
| <25 | 6 (17.1) | 9 (16.1) | 0.680 | 10 (16.4) | 5 (16.7) | 0.794 |
| 25–29 | 9 (25.7) | 20 (35.7) | 18 (29.5) | 11 (36.7) | ||
| ≥30 | 20 (57.2) | 27 (48.2) | 33 (54.1) | 14 (46.6) | ||
| GERD | ||||||
| Yes | 12 (34.3) | 24 (42.9) | 0.416 | 22 (36.1) | 14 (46.7) | 0.331 |
| No | 23 (65.7) | 32 (57.1) | 39 (63.9) | 16 (53.3) | ||
| Dyspepsia | ||||||
| Yes | 13 (37.1) | 23 (41.1) | 0.709 | 22 (36.1) | 14 (46.7) | 0.331 |
| No | 22 (62.9) | 33 (58.9) | 39 (63.9) | 16 (53.3) | ||
| PPI in last 10 years | ||||||
| Yes | 21 (60.0) | 30 (53.6) | 0.548 | 34 (55.7) | 17 (56.7) | 0.933 |
| No | 14 (40.0) | 26 (46.4) | 27 (44.3) | 13 (43.3) | ||
| Smoking History | ||||||
| Never | 6 (17.1) | 15 (26.8) | 0.468 | 11 (18.0) | 10 (33.3) | 0.259 |
| Previous | 17 (48.6) | 27 (48.2) | 31 (50.8) | 13 (43.3) | ||
| Current | 12 (34.3) | 14 (25.0) | 19 (31.2) | 7 (23.3) | ||
| Alcohol Drinking History | ||||||
| Never | 14 (40.0) | 23 (41.1) | 0.146 | 28 (45.9) | 9 (30.0) | 0.045 |
| Previous | 7 (20.0) | 20 (35.7) | 13 (21.3) | 14 (46.7) | ||
| Current | 14 (40.0) | 13 (23.2) | 20 (32.8) | 7 (23.3) | ||
| Family History of Gastric Cancer | ||||||
| Yes | 4 (11.4) | 5 (8.9) | 0.411 | 4 (6.6) | 5 (16.7) | 0.110 |
| No | 30 (85.7) | 45 (80.4) | 54 (88.5) | 21 (70.0) | ||
| Missing | 1 (2.9) | 6 (10.7) | 3 (4.9) | 4 (13.3) | ||
| Gastritis | ||||||
| No | 0 (0.0) | 2 (3.6) | 0.004 | 1 (16) | 1 (3.3) | <0.0001 |
| Active/Acute | 24 (68.6) | 18 (32.1) | 36 (59.0) | 6 (20.0) | ||
| Chronic | 7 (20.0) | 17 (30.4) | 18 (29.5) | 6 (20.0) | ||
| Missing | 4 (11.4) | 19 (33.9) | 6 (9.9) | 17 (56.7) | ||
| Atrophic Gastritis | ||||||
| Yes | 9 (25.7) | 2 (3.6) | 0.002 | 11 (18.0) | 30 (100.0) | -- |
| No | 26 (74.3) | 54 (96.4) | 50 (82.0) | 0 (0.0) | ||
| Gastric Intestinal Metaplasia | ||||||
| Yes | 26 (74.3) | 26 (46.4) | 0.009 | 52 (85.2) | 30 (100.0) | -- |
| No | 9 (25.7) | 30 (53.6) | 9 (14.8) | 0 (0.0) | ||
SD: standard deviation; BMI: body mass index; GERD: gastroesophageal reflux disease; PPI: proton pump inhibitor
Table 3.
Comparison of histopathologic and cancer-related outcomes between 35 patients with Helicobacter pylori positive gastric cancer and 56 patients with H. pylori negative gastric cancer. Additional comparison included 26 patients with suspected H. pylori gastric cancer (i.e., atrophic gastritis or gastric intestinal metaplasia on gastric biopsy in the setting of negative H. pylori testing).
| H. pylori Positive Gastric Cancer (n=35) | H. pylori Negative Gastric Cancer (n=56) | p-value | H. pylori Positive Gastric Cancer (including suspected) (n=61) | H. pylori Negative Gastric Cancer (excluding suspected) (n=30) | p-value | |
|---|---|---|---|---|---|---|
| Cancer Stage | ||||||
| Early (stage 0–1) | 12 (34.3) | 16 (28.6) | 0.308 | 23 (37.7) | 5 (16.7) | 0.037 |
| Late (stage 2–4) | 23 (65.7) | 36 (64.3) | 37 (60.7) | 22 (73.3) | ||
| Missing | 0 (0.0) | 4 (7.1) | 1 (16) | 3 (10.0) | ||
| Median survival, months | 17.3 (5.9–51.8) | 14.9 (5.0–28.0) | 0.767 | 15.1 (7.0–33.6) | 12.3 (2.9–26.7) | 0.711 |
| Cancer-related Death | ||||||
| Yes | 18 (51.4) | 31 (55.4)) | 0.49 | 29 (47.5) | 20 (66.7) | 0.166 |
| No | 16 (45.7) | 25 (44.6) | 31 (50.8) | 10 (33.3) | ||
| Missing | 1 (2.9) | 0 (0.0) | 1 (16) | 0 (0.0) | ||
| Chemotherapy | ||||||
| Yes | 17 (48.6) | 26 (46.5) | 0.860 | 27 (44.3) | 16 (53.3) | 0.441 |
| No | 14 (40.0) | 25 (44.6) | 29 (47.5) | 10 (33.3) | ||
| Missing | 4 (11.4) | 5 (8.9) | 5 (8.2) | 4 (13.4) | ||
| Radiation | ||||||
| Yes | 2 (5.7) | 13 (23.2) | 0.086 | 9 (14.8) | 6 (20.0) | 0.531 |
| No | 29 (82.9) | 38 (67.9) | 47 (77.0) | 20 (67.7) | ||
| Missing | 4 (11.4) | 5 (8.9) | 5 (8.2) | 4 (13.3) | ||
| Surgery | ||||||
| Yes | 12 (34.3) | 16 (28.6) | 0.389 | 23 (37.7) | 5 (16.7) | 0.118 |
| No | 19 (54.3) | 37 (66.1) | 34 (55.7) | 22 (73.3) | ||
| Missing | 4 (11.4) | 3 (5.4) | 4 (6.6) | 3 (10.0) | ||
| Endoscopic Resection | ||||||
| Yes | 6 (17.2) | 3 (5.4) | 0.095 | 9 (14.8) | 0 (0.0) | 0.054 |
| No | 25 (71.4) | 50 (89.2) | 48 (78.7) | 27 (90.0) | ||
| Missing | 4 (11.4) | 3 (5.4) | 4 (6.5) | 3 (10.0) | ||
Active/acute gastritis (OR, 3.62; 95% CI, 1.25–10.45), atrophic gastritis (OR, 9.35; 95% CI, 1.88–46.38), and gastric intestinal metaplasia (OR, 3.33; 95% CI 1.33–8.38) was associated with H. pylori positive gastric cancer compared to H. pylori negative gastric cancer. When adjusted for age and race, there was a stronger association for active/acute gastritis (adjOR, 3.74; 95% CI, 1.25–11.20), atrophic gastritis (adjOR, 15.30; 95% CI, 2.67–87.90), and gastric intestinal metaplasia (adjOR, 3.65; 95% CI, 1.31–10.16) with H. pylori positive gastric cancer. H. pylori positive gastric cancer was inversely associated with receiving radiation for treatment (adjOR, 0.13; 95% CI, 0.03–0.69) compared to H. pylori negative gastric cancer (Table 4).
Table 4.
Sociodemographic, clinical, histopathologic, and cancer-related outcome associations with H. pylori positive gastric cancer compared to H. pylori negative gastric cancer. Odds ratios (ORs) and 95% confidence intervals (CIs) reported for univariate and multivariate models, adjusted for age and race.
| H. pylori positive | H. pylori positive (including suspected) | |||
|---|---|---|---|---|
| Unadjusted OR (95% CI) | Adjusted OR (95% CI) | Unadjusted OR (95% CI) | Adjusted OR (95% CI) | |
| Sex (ref female) | ||||
| Male | --- | --- | 2.11 (0.28–15.74) | |
| Race (ref non-Hispanic white) | ||||
| Black | 2.12 (0.78–5.75) | --- | 1.66 (0.63–4.38) | --- |
| Hispanic | 2.19 (0.52–9.23) | --- | 7.06 (0.79–62.72) | --- |
| Other | 0.88 (0.08–9.70) | --- | 0.24 (0.02–2.54) | --- |
| Age (ref <60 years) | ||||
| 60–70 | 0.45 (0.14–1.49) | --- | 1.29 (0.39–4.31) | --- |
| 70+ | 0.53 (0.15–1.82) | --- | 1.70 (0.47–6.18) | --- |
| BMI (ref <25) | ||||
| 25–29 | 0.68 (0.18–2.47) | 0.79 (0.20–3.12) | 1.18 (0.34–4.08) | 1.14 (0.28–4.60) |
| 30+ | 1.11 (0.34–3.63) | 1.13 (0.33–3.90) | 0.82 (0.22–3.03) | 1.34 (0.37–4.88) |
| GERD | 0.70 (0.29–1.67) | 0.85 (0.33–2.17) | 0.65 (0.27–1.57) | 0.70 (0.27–1.86) |
| Dyspepsia | 0.85 (0.36–2.02) | 0.77 (0.30–1.97) | 0.65 (0.27–1.57) | 0.70 (0.27–1.84) |
| PPI in the last 10 years | 1.30 (0.55–3.06) | 1.39 (0.56–3.44) | 0.96 (0.40–2.33) | 0.93 (0.36–2.40) |
| Smoking (ref Never) | ||||
| Current | 2.14 (0.63–7.26) | 1.48 (0.38–5.71) | 2.47 (0.73–8.34) | 2.82 (0.70–11.26) |
| Former | 1.57 (0.51–4.85) | 1.17 (0.35–3.87) | 2.17 (0.74–6.34) | 1.75 (0.55–5.57) |
| Alcohol (ref Never) | ||||
| Current | 1.77 (0.65–4.84) | 1.47 (0.49–4.40) | 0.92 (0.29–2.88) | 0.93 (0.27–3.21) |
| Former | 0.58 (0.19–1.71) | 0.48 (0.15–1.51) | 0.30 (0.10–0.87) | 0.29 (0.09–0.91) |
| Family history of gastric cancer | 1.20 (0.30–4.84) | 1.06 (0.25–4.47) | 0.31 (0.08–1.27) | 0.21 (0.04–1.00) |
| Gastritis (ref None or Inactive/chronic) | ||||
| Active/acute | 3.62 (1.25–10.45) | 3.74 (1.25–11.20) | 2.21 (0.65–7.52) | 2.79 (0.75–10.45) |
| Atrophic gastritis | 9.35 (1.88–46.38) | 15.30 (2.67–87.90) | --- | --- |
| Intestinal metaplasia | 3.33 (1.33–8.38) | 3.65 (1.31–10.16) | --- | --- |
| Cancer Stage (ref Early Stage 0–1) | ||||
| Late (stage 2–4) | 0.85 (0.34–2.12) | 0.82 (0.32–2.08) | 0.07 (0.01–0.85) | 0.30 (0.09–1.00) |
| Chemotherapy | 1.17 (0.48–2.86) | 1.09 (0.42–2.82) | 0.58 (0.23–1.50) | 0.54 (0.20–1.50) |
| Radiation | 0.20 (0.04–0.97) | 0.13 (0.03–0.69) | 0.64 (0.20–2.03) | 0.51 (0.15–1.73) |
| Surgery | 1.46 (0.58–3.70) | 1.59 (0.60–4.17) | 2.98 (0.99–8.99) | 3.43 (1.07–11.02) |
| Endoscopic resection | 4.00 (0.92–17.34) | 3.63 (0.81–16.25) | --- | --- |
BMI: body mass index; GERD: gastroesophageal reflux disease; PPI: proton pump inhibitor
There was no difference in overall mortality of patients with H. pylori positive gastric cancer compared to H. pylori negative gastric cancer in the unadjusted model (HR, 0.81; 95% CI, 0.46–1.41) and when adjusted for age, race, cancer stage, and receipt of treatment (adjHR, 0.85; 95% CI, 0.45–1.62). There was also no difference in cancer-related mortality (adjHR, 0.86; 95% CI, 0.43–1.73) (Table 5).
Table 5.
Associations of mortality and cancer-related mortality with H. pylori positive gastric cancer compared to H. pylori negative gastric cancer. Hazards ratios (HR) and 95% confidence intervals (CI) reported for univariate and multivariate models, adjusted for age, race, cancer stage, and receipt of treatment.
| Unadjusted HR (95% CI) | Adjusted HR (95% CI) | |
|---|---|---|
| Overall Mortality | ||
| H. pylori positive | 0.81 (0.46–1.41) | 0.85 (0.45–1.62) |
| H. pylori positive (including suspected) | 0.62 (0.36–1.07) | 0.61 (0.33–1.12) |
| Cancer-related Mortality | ||
| H. pylori positive | 0.79 (0.44–1.42) | 0.86 (0.43–1.73) |
| H. pylori positive (including suspected) | 0.57 (0.32–1.01) | 0.56 (0.29–1.07) |
In a secondary analysis that classified gastric cancer patients with atrophic gastritis or gastric intestinal metaplasia as suspected H. pylori positive gastric cancer, patients with H. pylori positive gastric cancer were less likely to be non-Hispanic White (27.9% vs. 40.0%, p=0.065) and more likely to have no alcohol history compared to H. pylori negative patients (45.9% vs 30.0%, p=0.045) (Table 2). Patients with H. pylori positive gastric cancer were more likely to have active gastritis on histopathology compared to patients with H. pylori negative gastric cancer (59.0% vs. 20.0%, p<0.0001) (Table 3). H. pylori positive gastric cancer was inversely associated with late stage gastric cancer at diagnosis (stage 2–4 vs. stage 0–1; adjOR, 0.30; 95% CI, 0.09–1.00) and family history of gastric cancer (adjOR, 0.21; 95% CI, 0.04–1.00) when adjusted for age and race (Table 4). H. pylori positive gastric cancer was also associated with receipt of surgery compared to H. pylori negative cases (adjOR, 3.43; 1.07–11.02).
DISCUSSION
The prevalence of H. pylori negative non-cardia gastric adenocarcinoma is high in this U.S. study of mostly male veterans, with an overall prevalence of 61.5% during 2007–2018 and rising over recent years from 50.0% in 2007–2010 to 70.7% in 2015–2018. Using stricter criteria for the diagnosis of H. pylori negative gastric cancer by excluding all patients with atrophic gastritis or gastric intestinal metaplasia or limiting to only those with ≥ 2 tests for H. pylori, the prevalence of H. pylori negative gastric cancer was lower but not lower than 33.0%.
We employed an additional conservative criterion of excluding patients with atrophic gastritis and gastric intestinal metaplasia from H. pylori negative gastric cancer under the assumption that H. pylori infection was originally present but may not have survived in hostile mucosal conditions.21 Kang et al. compared 294 patients with positive rapid urease test (CLOtest) or H. pylori histopathology to 62 patients with only H. pylori positive serology and 80 patients with negative H. pylori serology.21 They found that the grade of atrophic gastritis and antral intestinal metaplasia was significantly higher in patients with only H. pylori positive serology compared to those with positive CLOtest or histopathology with negative serology and concluded that positive serology with negative invasive testing represents past infection with H. pylori rather than a false-positive serology. The 6 patients in our study with H. pylori negative serology but with atrophic gastritis or gastric intestinal metaplasia on histopathology may have had previous H. pylori infection. However, even with this criterion, the overall prevalence of H. pylori negative gastric cancer was high (i.e., 33%) in our study population.
H. pylori negative gastric cancer was previously reported in a wide and generally low range, between 0.42% and 24.7%.12–16 Studies from regions with high background H. pylori infection have generally shown low prevalence of H. pylori negative gastric cancer (0.42%−14.2%).12–14 In a study from Hiroshima, Japan, Matsuo et al. defined H. pylori negative gastric cancer by negative serology, absence of H. pylori by microscopic examination, negative urea breath test, negative rapid urease test, absence of endoscopic atrophy, and absence of histologic gastric corpus and antrum gastritis and found an overall prevalence of only 0.66%.12 Similarly, Ono et al. from Sapporo, Japan found the overall prevalence of H. pylori negative gastric cancer defined by negative urease test, urea breath test, H. pylori culture, histology or serology was 14.2%; however this fell to 0.42% when eliminating patients with atrophy (based on histology, endoscopy, or serology assessed by pepsinogen).13 On the other hand, studies from Europe found higher prevalence rates of H. pylori negative gastric cancer (14%−24.7%).15,16,22 Marrelli et al. reported a 14% prevalence in 297 patients from Italy, and Meimarakis et al. reported a 24.7% prevalence in 166 patients from Germany.15,16 These studies defined H. pylori negative gastric cancer as absence of H. pylori bacteria on endoscopic or surgical specimens and negative serology in the German study16 and absence of vacA by polymerase chain reaction (PCR) of surgical specimens, negative H. pylori serology, and negative CagA serology in the Italian study.15
We did not have enough data to report trends on cancer-related mortality in H. pylori negative gastric cancer, however previous studies have found patients with H. pylori negative gastric cancer to be more likely to have more diffuse and aggressive disease12,16 with a lower 5-year survival rate compared to patients with H. pylori related gastric cancer.15 It has been hypothesized that the better prognosis of H. pylori positive gastric cancer is due to its peritumoral inflammation (rather than genomic instability as a possible cause of H. pylori negative gastric cancer); however further studies are needed.23
The findings that those with H. pylori negative gastric cancer share a different phenotype (thin, non-smoking, non-Hispanic White and less active gastritis) and a family history of gastric cancer compared to those with H. pylori positive gastric cancer is consistent with a previous study of 695 patients with gastritis that found that African-Americans were less likely than non-Hispanic whites to have H. pylori negative gastritis (OR, 0.25; 95% CI, 0.14–0.43).24 It also is consistent with a previous study of 491 patients with gastritis that found those with H. pylori positive gastritis were more likely to have acute gastritis compared to those with H. pylori negative gastritis (antral 61.6 vs. 19.5, p<0.0001; body 64.2 vs. 7.3, p<0.0001).25 The overall different phenotype suggests an epigenetic predisposition.14,26 Kim et al. found that MSI-H (16.7% vs. 8.3%, p=0.195) and p53 expression (56.0% vs. 37.0%, p=0.055) were more frequently observed in H. pylori negative gastric cancer compared to H. pylori positive gastric cancer, however they were not statistically significant.14 Future, larger studies are needed in this area.
This study included a cohort of non-cardia gastric adenocarcinoma patients from a non-immigrant U.S. population; thus, associations and outcomes of H. pylori negative gastric cancer were better evaluated compared to previous studies done in populations with high H. pylori prevalence. H. pylori infection was regularly assessed, with 81.3% of the study population having more than 1 test for H. pylori infection in addition to gastric cancer biopsy histopathology. The time period (date of first VA contact to last date of medical record review in November 2018) covered by our search for H. pylori testing (or H. pylori treatment as a surrogate for testing) ranged from 1.0 to 23.0 years with a mean of 12.8 years (SD 6.6 years). Given that some may not have sought healthcare at all or sought healthcare outside the VA prior to their cancer-diagnosing EGD, H. pylori infection may be underdiagnosed as only 74 of the 91 patients (81.3%) had at least one H. pylori test in addition to gastric cancer biopsy histopathology. H. pylori prevalence rose from 38.5% in the entire study cohort of 91 patients to 45.9% in only those with at least one additional H. pylori test, which supports possible under-diagnosis when using cancer biopsy alone. Testing was not standardized and complete with all known methods for evaluating H. pylori infection (i.e., PCR for vacA alleles of biopsy or surgical specimens, CagA-IgG serology) as these were not readily used, and serology, which has the highest sensitivity for screening, was available in only 37.4%. Additionally, a previous study raised the hypothesis that H. pylori organisms may not be present once gastric atrophy or gastric intestinal metaplasia develops due to hostile mucosal conditions.21 However, we performed a secondary analysis excluding all patients with histologic atrophy or gastric intestinal metaplasia to account for potentially misclassified cases of H. pylori gastric cancer. This study was also limited to male veterans, and our findings may not be generalizable to females or immigrant U.S. populations, which may have considerably higher rates of H. pylori related gastric cancer.
In summary, we found a high prevalence of H. pylori negative gastric cancer in a U.S. population. This prevalence seems to be increasing. Future studies are warranted to validate these results.
Grant support:
This work was supported in part by National Institutes of Health grant P30 DK056338 (Study Design and Clinical Research Core), which supports the Texas Medical Center Digestive Diseases Center. This research was supported in part with resources at the VA HSR&D Center for Innovations in Quality, Effectiveness and Safety (#CIN 13-413), at the Michael E. DeBakey VA Medical Center, Houston, TX. The opinions expressed reflect those of the authors and not necessarily those of the Department of Veterans Affairs, the U.S. government or Baylor College of Medicine.
Footnotes
Conflicts of interest: The authors report no competing interests for this publication.
REFERENCES
- 1.Ferlay J, Soerjomataram I, Ervik M. Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11. International Agency for Research on Cancer. Published 2013. Accessed January, 2019. [Google Scholar]
- 2.Cancer IAfRo. Estimated age-standardized incidence rates in 2018, worldwide, both sexes, all ages. In. Globocan: International Agency for Research on Cancer; 2018. [Google Scholar]
- 3.IARC Helicobacter pylori Working Group. Helicobacter pylori Eradication as a Strategy for Gastric Cancer Prevention2014;No. January, Lyon, France. [Google Scholar]
- 4.Plummer M, Franceschi S, Vignat J, Forman D, de Martel C. Global burden of gastric cancer attributable to Helicobacter pylori. Int J Cancer. 2015;136:487–490. [DOI] [PubMed] [Google Scholar]
- 5.Torre LA, Siegel RL, Ward EM, Jemal A. Global cancer incidence and mortality rates and trends - an update. Cancer Epidemiol Biomarkers Prev. 2016;25:16–27. [DOI] [PubMed] [Google Scholar]
- 6.Burucoa C, Axon A. Epidemiology of Helicobacter pylori infection. Helicobacter. 2017;22:e12403–12407. [DOI] [PubMed] [Google Scholar]
- 7.Mitchell H, Katelaris P. Epidemiology, clinical impacts and current clinical management of Helicobacter pylori infection. Med J Aust. 2016;204(10):376–380. [DOI] [PubMed] [Google Scholar]
- 8.Lim SH, Kim N, Kwon JW, et al. Trends in the seroprevalence of Helicobacter pylori infection and its putative eradication rate over 18 years in Korea: A cross-sectional nationwide multicenter study. PLoS One. 2018;13(10):e0204762. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Eom BW, Jung KW, Won YJ, Yang H, Kim YW. Trends in Gastric Cancer Incidence According to the Clinicopathological Characteristics in Korea, 1999–2014. Cancer research and treatment : official journal of Korean Cancer Association. 2018;50(4):1343–1350. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Anderson WF, Rabkin CS, Turner N, Fraumeni JF Jr., Rosenberg PS, Camargo MC. The Changing Face of Noncardia Gastric Cancer Incidence Among US Non-Hispanic Whites. Journal of the National Cancer Institute. 2018;110(6):608–615. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Uemera N, Okamoto S, Yamamoto S, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med. 2001;345(11):784–789. [DOI] [PubMed] [Google Scholar]
- 12.Matsuo T, Ito M, Takata S, Tanaka S, Yoshihara M, Chayama K. Low prevalence of Helicobacter pylori-negative gastric cancer among Japanese. Helicobacter. 2011;16(6):415–419. [DOI] [PubMed] [Google Scholar]
- 13.Ono S, Kato M, Suzuki M, et al. Frequency of Helicobacter pylori-negative gastric cancer and gastric mucosal atrophy in a Japanese endoscopic submucosal dissection series including histological, endoscopic, and serological atrophy. Digestion. 2012;86:59–65. [DOI] [PubMed] [Google Scholar]
- 14.Kim HJ, Kim N, Yoon H, et al. Comparison between resectable Helicobacter pylori-negative and -positive gastric cancers. Gut Liver. 2016;10(2):212–219. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Marrelli D, Pedrazzani C, Berardi A, et al. Negative Helicobacter pylori status is associated with poor pronogosis in patients with gastric cancer. Cancer. 2009;115(10):2071–2080. [DOI] [PubMed] [Google Scholar]
- 16.Meimarakis G, Winter H, Assmann I, et al. Helicobacter pylori as a prognostic indicator after curative resection of gastrix carcinoma: a prospective study. Lancet Oncol. 2006;7(3):211–222. [DOI] [PubMed] [Google Scholar]
- 17.Hooi J, Lai W, Ng W, et al. Global prevalence of Helicobacter pylori infection: systematic review and meta-analysis. Gastroenterology. 2017;153(2):420–429. [DOI] [PubMed] [Google Scholar]
- 18.Graham D. History of Helicobacter pylori, duodenal ulcer, gastric ulcer and gastric cancer. World J Gastroenterol. 2014;20:5191–5204. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Lui F, Tuan B, Swenson S, RJ W. Ethnic disparities in gastric cancer incidence and survival in the USA: an updated analysis of 1992–2009 SEER data. Dig Dis Sci. 2014;59(12):3027–3034. [DOI] [PubMed] [Google Scholar]
- 20.Wang Z, Graham D, Khan A, et al. Incidence of gastric cancer in the USA during 1999 to 2013: a 50-state analysis. Int J Epidemiol. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Kang H, Kim N, Park Y, et al. Progression of atrophic gastritis and intestinal metaplasia drives Helicobacter pylori out of the gastric mucosa. Dig Dis Sci. 2006;51(12):2310–2315. [DOI] [PubMed] [Google Scholar]
- 22.Palestro G, Pellicano R, Fronda GR, et al. Prevalence of Helicobacter pylori infection and intestinal metaplasia in subjects who had undergone surgery for gastric adenocarcinoma in Northwest Italy. World journal of gastroenterology. 2005;11(45):7131–7135. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Kim JH, Cheung DY. Must-have knowledge about the Helicobacter pylori-negative gastric cancer. Gut Liver. 2016;10(2):157–159. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Shiota S, Thrift AP, Green L, et al. Clinical manifestations of Helicobacter pylori-negative gastritis. Clin Gastroenterol Hepatol. 2017;15:1037–1046. [DOI] [PubMed] [Google Scholar]
- 25.Nordenstedt H, Graham DY, Kramer JR, et al. Helicobacter pylori-negative gastritis: prevalence and risk factors. Am J Gastroenterol. 2013;108(1):65–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Yamamoto Y, Fujisaki J, Omae M, Hirasawa T, Igarashi M. Helicobacter pylori-negative gastric cancer: characteristics and endoscopic findings. Dig Endosc. 2015;27(5):551–561. [DOI] [PubMed] [Google Scholar]