Helicobacter pylori (H. pylori) is the most well-described risk factor for gastric cancer (GC), and recognized as one of the pathogens for gastric non-Hodgkin lymphoma (NHL) (1, 2). In 2014, H. pylori approximately infects 50% of the global population (3). The carcinogenic process is mainly due to its virulence factors including urease, flagella, VacA, and CagA (4, 5) H. pylori infection causes chronic inflammation, which leads to precancerous alterations such as gastritis and intestinal metaplasia. These changes eventually develop to gastric epithelial neoplasms, termed GC (5). GC can be classified into two subtypes, cardia and non-cardia, based on their anatomic sites. H. pylori is more relevant to non-cardia GC, accounting for 90% of cases of the non-cardia GC, while a portion of cardia GC can also be associated with H. pylori atrophic gastritis (6). It has been clearly established that the eradication of H. pylori could prevent and even reverse the carcinogenic process of GC (7, 8).

GC is currently the fifth most frequent cancer and the fourth leading cause of cancer-related death (9). Despite the decrease in incidence and mortality rates in past decades (10), it remains to be a vital contributor to the global burden of cancer. Additionally, NHLs, also known as malignant proliferations of lymphoid cells, are the most common hematological malignancies worldwide (9). NHLs have been on the rise globally during the last few decades (11). The colonization of H. pylori in gastric mucosa may result in the interaction of bacteria and B-cell, followed by the formation of lymphoid follicles and, finally NHL in the gastric location (1, 12). The age- and gender-adjusted annual incidence of gastrointestinal NHL was 1.73 per 100,000 among North American population in 2008 (13).

A study using attributable fractions (AF) to describe the correlation between specific anatomical cancer sites and relevant infectious pathogens showed that AF of H. pylori was 89% to non-cardia GC, 29% to cardia GC and 74% to gastric NHL (14). However, systemic trend analysis of H. pylori-related malignancy remains inadequately characterized. Lack of timely monitoring might impede the formulation of public health policies for H. pylori infection prevention and management, as well as the allocation of the clinical and public health resources for H. pylori-related malignancy management. It is crucial to update the surveillance of the trends in malignancies caused by H. pylori. To decrease the global burden of H. pylori-related cancers, we aimed to determine the trend of cardia and non-cardia gastric cancer and gastric NHLs incidence at the national level in order to provide a reference for better prevention and resource allocation.

From 2000 through 2019, a total of 186,769 H. pylori-related cancer cases were identified in the SEER database, of which 109,469 (58.6%) were White, 23,409 (12.5%) were Black, 32,752 (17.5%) were Hispanic, and 19,541 (10.5%) were Asian. Among those cases, 115,666 (61.9%) were male and 115,514 (61.8%) were of age 65 years or older. Overall, the incidence significantly decreased during 2000–2019 for non-cardia GC (AAPC, −1.0% [95% CI, −1.1 to −0.9%]) and gastric NHL (AAPC, −2.6% [95% CI, −2.9 to −2.3%]), whereas cardia GC levels has plateaued (AAPC, −0.2% [95% CI, −0.7 to −0.3%]). Sensitivity analyses showed the robustness of our findings (Supplementary eResult and eTable 1).

In this study, we found that during 2000–2019, the overall incidence trend of H. pylori-related malignancy among adults in the United States fell dramatically significantly, except for cardia GC that remained relatively stable. For non-cardia GC, the incidence declined more slowly for women and increased among younger adults. The decrease in incidence of cardia GC in Hispanic individuals is limited. For gastric NHL, the decrement in incidence was slower in younger adults and Blacks. Moreover, Asians had the highest incidence of non-cardia GC, while Whites had the highest incidence of cardia GC and Hispanics had the highest incidence of gastric NHL. Geographic variation in incidence rates and trends was observed for all three H. pylori-related cancers, with non-cardia GC being the most prominent.

The decreasing trend in incidence for non-cardia GC and gastric NHL may be related to the control of H. pylori, as H. pylori is a well-known determining factor for non-cardia GC (16, 17). First, the secondary prevention of H. pylori spreading contributed to the decreasing incidence, especially the improvements in sanitary conditions, which significantly limited the H. pylori infection among the deprived population in the US (18). Second, mainstream regimens, including clarithromycin-based triple therapy consisting of a proton pump inhibitor along with clarithromycin and amoxicillin or metronidazole or bismuth-quadruple therapy (19), also effectively inhibited the transmission of the infection, when eradicating and treating H. pylori, regardless of gender (7). The indirect effect of successful treatment on the prevention of H. pylori was also evidenced by a cohort study during 1994–2018 (8).

On the other hand, incidence of cardia GC did not decline profoundly as non-cardia ones. The primary etiology of cardia GC is associated with gastroesophageal reflux (GER), while the secondary is relevant to H. pylori atrophic gastritis (6). N-nitroso compounds which are generated from the refluxate that includes a large volume of acids play a vital role in the former one. The intake of N-nitroso compounds is mainly relevant with dietary habits, lifestyle factors and GER. As a profound risk factor, GER is the most prevalent gastrointestinal disorder in the United States (20), and an increase in GER prevalence in North America and East Asia was observe in recent studies (21). These factors might together prevent a significant decline in cardia GC incidence, especially compared with non-cardia GC which are mostly arouse by H. pylori infection.

Interestingly, the incidence of non-cardia GC significantly increased among younger adults, while all other subgroups showed a declining tendency throughout the same period. This finding is consistent with Arnold's report (22). The decline in gastric NHL incidence was also slower among the younger adults compared with the elderly. These findings may indicate that even while infection-related gastric malignancy, non-cardia GC, and gastric NHL, occurred more often in the elderly, the transmission and morbidity of H. pylori in persons under 65 may continue to be cause for concern. A recent study showed that the ages of patients with H. pylori infection had two prevalence peaks with one at 45–49 years and the other at 70–74 years, and the detected number was higher in patients aged 45–49. More active social events, including dining together, and poor hygiene might contribute to the infection in younger people, while the higher detection rate might also be due to better implementation of early screening and diagnosis in people under 65 (23). Also, lifestyle might also play an important influence in GC onset. Younger adults are more prone to engage in excessive alcohol consumption and tobacco use, resulting in an increase or slower decline in incidence.

Despite the incidence of non-cardia GC being lower in women than in males, a significant slower decreasing trend was found. Our study also suggested that sex disparity in the incidence trend is more significant in some areas. For example, in Kentucky, the trend in non-cardia GC significantly increased for women with an AAPC of 1.5% (95% CI, 0.5–2.6%), while an opposite trend with significance was observed for men. Owning to the correlation between H. pylori infection and non-cardia gastric cancer, the results of this study underscored the urgency of eradicating the spread of H. pylori among females in some regions, despite the possibility that the disparate trends are attributable in part to the more rapid decline in smoking (another risk factor) prevalence in men than in women in the United States (24). This should raise alarm. A sex-based disproportional exposure to risk factors may differ between different regions.

The incidence in three H. pylori-related malignancies showed racial and ethnic disparity, with the highest incidence observed among Asians, Whites, and Hispanics for non-cardia GC, cardia GC and gastric NHL in 2019, respectively. In addition, the incidence rate of Asians in non-cardia GC declined at a significantly higher rate than other racial/ethnic groups. The possible reasons could be their communal eating practices, consumption of pickled foods, and high oil and salt intake, which might facilitate H. pylori's transmission and carcinogenic process (25). However, there has been a progressive and rapid decline in the prevalence of H. pylori infection in Asians, which might be associated with the westernization of lifestyles (such as individual serving) and the improvements in economic conditions (26). The trend disparity in gastric NHL may be attributable to the distinctions in exposure to pathogenic factors (including H. pylori) by ethnicity, which was related with different employment, education, and home value (27). Furthermore, evidences showed that ethnic variation in susceptibility might existed. H. pylori infection led to inflammation that induces normal/abnormal immune responses, and genetic variants in the host normal/abnormal immunity was important for individual susceptibility to gastric NHL (28). Interestingly, the incidence rate of cardia GC in Whites remained at the highest and showed no significant decline in the past 20 years. This might be owing to the lack of relevance between cardia GC and H. pylori, and the increasing obesity epidemics, dietary habits and lifestyle factors might be the possible explanations.

Additionally, the incidence rate of non-cardia gastric cancer differed geographically. Metropolitan areas were proved to have a higher incidence rate than nonmetropolitan areas. In metropolitan regions, the incidence of gastric NHL dropped substantially more slowly. In nonmetropolitan areas, the incidence of cardia GC grew dramatically during the research period, but the incidence remained consistent in metropolitan areas. Diversities in lifestyle, diets, and underlying host genetic factors might contribute to the phenomenon. Even while improved sanitation and hygiene have reduced the intrafamilial transmission of H. pylori in the city to some extent, the widespread use of antibiotics on the human microbiome could contribute to the escalating problem of antibiotic resistance (29, 30). Moreover, the variety of H. pylori, i.e., the difference in the Cag pathogenicity island across the US, may partly contribute in part to the geographic variation. The risk of gastric cancer was proved lower among persons harboring H. pylori strains that lack the cag PAI. In regions with the predominance of strains harboring cagA, type s1 vacA, and other markers linked to gastric cancer, higher rate of gastric cancer might be observed (31).

Better prevention and resource allocation to reduce H. pylori prevalence will not only reduce the three main types of H. pylori infection-related cancers, but would also intervene other potential diseases caused by H. pylori, such as gastritis, peptic ulcer, and extra-gastroduodenal illnesses. Large-scale antibiotic use for eradication of H. pylori might be a cost-effective option in high-risk regions, but its adverse effects and resistance should be further clarified. Furthermore, so far there is a lack of vaccine for the prevention of H pylori, leaving a potential aspect to explore. Screening for pre-cancerous lesions of H. pylori infection-related cancers could also be profound, but no organized screening programs were massively implemented outside Asia (Japan and South Korea) (32), making the most cost-effective test-and-treat strategies for local settings still in need of illustration and testing. Future studies and efforts are warranted to accelerate H. pylori eradication and development new non-invasive biomarkers for H. pylori infection with high accuracy.

We cannot disregard the limitations in this study. First, though GC and gastric NHL is closely related to H. pylori infection, we cannot estimate the number of cases where the infection is pathologically confirmed because the information was not available in the SEER database. This may overestimate the incidence rate. Second, the small sample size, particularly in gastric NHL, prevents us from exploring the variations between gender and race/ethnicity in greater depth.

In summary, we have presented several significant findings. The incidence of H. pylori-related cancer declined dramatically in the US during 2000–2019, with the exception of cardia GC. For young adults and women, the incidence of non-cardia GC is growing and progressively declining, respectively. Also, slower decreasing trends of gastric NHL were reported for women and African Americans. The incidence rate and trend of three H. pylori-related cancers differed by race/ethnicity and geography, but the geographic variance for non-cardia GC was more pronounced and correlated with gender. Regarding the vital role H. pylori has played in the three malignancies, current international guidelines, including the American College of Gastroenterology, recommended H. pylori eradication in diagnosed infection, and a surveillance program, H. pylori Antimicrobial Resistance Monitoring Program, was implemented nationwide (33), which might contribute to the control of H. pylori-related cancer. Nonetheless, to further achieve the goal of H. pylori eradication, clarification of more cost-effective techniques of testing and therapy for H. pylori is warranted, especially the significance of screening programs and vaccines should be strengthened.

All data used in this work were publicly available, shown at: https://seer.cancer.gov.

The study was exempted from ethical review because the data were de-identified and publicly available.

AW, YL, and JL designed the study. HS and ZW contributed to research data. YL, AW, YF, YB, and JL contributed to data analysis and manuscript writing. All authors contributed to supervision, manuscript revision, and gave final approval for publication.

This work was supported by Yunnan Fundamental Research Projects (Grant Nos. 202201AU070007 and 202201AY070001-147) and Scientific Research Fund Project of Yunnan Provincial Department of Education (Grant No. 2022J0211).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

The funding agencies had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.