Volume 34, Issue 7 (10-2026)
JSSU 2026, 34(7): 10421-10437 |
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Amirbeigi Tafti M K, Salman Roghani H, Sheikhalishahi S. Anatomical Subsite–Specific Role of Helicobacter pylori in Gastric Adenocarcinoma. JSSU 2026; 34 (7) :10421-10437
URL: http://jssu.ssu.ac.ir/article-1-6631-en.html
URL: http://jssu.ssu.ac.ir/article-1-6631-en.html
Keywords: Helicobacter pylori Stomach Neoplasms, Adenocarcinoma, Gastritis, Atrophic, Intestinal Metaplasia, Gastroesophageal Reflux
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Extended Abstract
Introduction
Gastric adenocarcinoma remains a major cause of cancer morbidity and mortality worldwide, but its epidemiology and carcinogenic pathways differ according to anatomical subsite. Non-cardia tumors continue to predominate globally and are strongly linked to chronic Helicobacter pylori infection, whereas cardia cancers show more heterogeneous associations that vary across populations and coexist with obesity- and gastroesophageal reflux disease–related pathways. Iran represents an important setting in which a high burden of H. pylori infection and distal gastric cancer coexists with a substantial proportion of proximal tumors. This narrative review synthesized subsite-specific evidence on the role of H. pylori in gastric adenocarcinoma, with particular attention to epidemiologic patterns, gastritis phenotypes, acid and gastrin physiology, bacterial virulence, eradication outcomes, and implications for prevention in Iran.
Methods
Between November 10 and December 10, 2025, a focused narrative search was conducted using PubMed, ScienceDirect, and Google Scholar. To capture national and regional evidence, Persian-language databases, including SID and Magiran, were also searched. Search concepts included Helicobacter pylori, gastric cancer, stomach neoplasms, gastric adenocarcinoma, cardia, non-cardia, antrum, corpus, proximal, distal, gastroesophageal junction, Correa cascade, atrophic gastritis, intestinal metaplasia, eradication, obesity, gastroesophageal reflux disease, Iran, the Middle East, and North Africa. Priority was given to studies that reported H. pylori associations according to anatomical subsite or provided epidemiologic, pathophysiologic, or eradication-related evidence relevant to this distinction. Cohort and case-control studies were used to evaluate subsite-specific risk; population-based studies and temporal trend analyses were used to describe geographical and socioeconomic patterns; randomized and other interventional studies were considered for eradication outcomes; and systematic reviews and meta-analyses were used to contextualize quantitative estimates. Iranian and regional studies were specifically reviewed to compare global evidence with the local epidemiologic setting. Studies that did not define tumor location or did not provide interpretable subsite-specific data were deprioritized, as were isolated case reports and small case series that did not address the review objective. Finally, we synthesized the evidence narratively, emphasizing the distinction between cardia and non-cardia adenocarcinoma, while also additional consideration of gastritis distribution, gastric acid physiology, bacterial virulence, and the timing and expected benefit of H. pylori eradication.
Results
Globally, research consistently that H. pylori had the strongest and most reliable link to non-cardia gastric adenocarcinoma. The biological basis is compatible with the Correa cascade: chronic infection can progress from active gastritis to corpus involvement, glandular atrophy, intestinal metaplasia, dysplasia, and adenocarcinoma. Gastritis phenotype appears central to anatomical risk. Antral-predominant infection is generally associated with reduced somatostatin signaling, hypergastrinemia, preserved corpus mucosa, and higher acid output, whereas corpus-predominant gastritis or pangastritis is associated with parietal-cell loss, hypochlorhydria, atrophy, and a stronger carcinogenic milieu for non-cardia cancer. Notably, corpus-predominant gastritis may also reduce the likelihood of reflux esophagitis risk, helping explain differing epidemiologic associations with reflux-related proximal malignancies.
The risk profile is further influenced by bacterial virulence factors. CagA-positive strains and virulent VacA genotypes are associated with more extensive inflammation, corpus involvement, atrophy, and greater gastric cancer risk. Iranian data from high-risk areas such as Ardabil support enrichment of high-risk H. pylori genotypes among patients with non-cardia gastric cancer.
The cardia relationship was markedly more heterogeneous. Large Asian studies, including data from China, support a positive association between H. pylori and cardia cancer in addition to the stronger association with non-cardia cancer. In contrast, studies from lower-risk Western settings often report neutral or inverse associations, where obesity, reflux, and gastroesophageal-junction pathways may be more prominent. Iranian evidence also demonstrates substantial anatomical heterogeneity. Northern and northwestern provinces carry a high gastric cancer burden and high H. pylori prevalence, while studies from Golestan, Tehran, Mashhad, southern Iran, and multicenter datasets show that proximal/cardial tumors account for a considerable proportion of cases. These findings support an intermediate epidemiologic pattern rather than a purely distal, infection-dominant model, although current Iranian data do not justify directly attributing proximal tumors to reflux or obesity.
Eradication evidence was most robust for prevention of non-cardia gastric cancer. Randomized trials, long-term follow-up studies, and meta-analyses indicate that H. pylori eradication reduces future gastric cancer risk, with the greatest preventive potential when treatment occurs before advanced premalignant lesions develop. Benefit is also observed after endoscopic treatment of early gastric cancer, where eradication reduces metachronous gastric cancer. Recent trial-level evidence suggests benefit may persist in patients with intestinal metaplasia or dysplasia, although residual risk remains and surveillance may still be required. The effect of eradication specifically on cardia cancer remains incompletely quantified because many intervention studies do not report outcomes separately by gastric subsite.
Conclusion
H. pylori has a central and well-supported role in non-cardia gastric carcinogenesis, whereas its relationship with cardia cancer is context-dependent and varies with geographical setting, gastritis phenotype, bacterial virulence, and competing reflux- and obesity-related pathways. Eradication reduces future gastric cancer risk, particularly when performed before advanced precancerous change, and remains relevant in selected high-risk patients after premalignant or early neoplastic disease. For Iran, the combination of a high gastric cancer burden, widespread H. pylori infection, and heterogeneous anatomical distribution supports evaluation of population-based or targeted screen-and-treat strategies in high-risk settings while simultaneously addressing proximal cancer pathways. Implementation should consider local disease burden, infection prevalence, feasibility, surveillance capacity, and cost-effectiveness.
Gastric adenocarcinoma remains a major cause of cancer morbidity and mortality worldwide, but its epidemiology and carcinogenic pathways differ according to anatomical subsite. Non-cardia tumors continue to predominate globally and are strongly linked to chronic Helicobacter pylori infection, whereas cardia cancers show more heterogeneous associations that vary across populations and coexist with obesity- and gastroesophageal reflux disease–related pathways. Iran represents an important setting in which a high burden of H. pylori infection and distal gastric cancer coexists with a substantial proportion of proximal tumors. This narrative review synthesized subsite-specific evidence on the role of H. pylori in gastric adenocarcinoma, with particular attention to epidemiologic patterns, gastritis phenotypes, acid and gastrin physiology, bacterial virulence, eradication outcomes, and implications for prevention in Iran.
Methods
Between November 10 and December 10, 2025, a focused narrative search was conducted using PubMed, ScienceDirect, and Google Scholar. To capture national and regional evidence, Persian-language databases, including SID and Magiran, were also searched. Search concepts included Helicobacter pylori, gastric cancer, stomach neoplasms, gastric adenocarcinoma, cardia, non-cardia, antrum, corpus, proximal, distal, gastroesophageal junction, Correa cascade, atrophic gastritis, intestinal metaplasia, eradication, obesity, gastroesophageal reflux disease, Iran, the Middle East, and North Africa. Priority was given to studies that reported H. pylori associations according to anatomical subsite or provided epidemiologic, pathophysiologic, or eradication-related evidence relevant to this distinction. Cohort and case-control studies were used to evaluate subsite-specific risk; population-based studies and temporal trend analyses were used to describe geographical and socioeconomic patterns; randomized and other interventional studies were considered for eradication outcomes; and systematic reviews and meta-analyses were used to contextualize quantitative estimates. Iranian and regional studies were specifically reviewed to compare global evidence with the local epidemiologic setting. Studies that did not define tumor location or did not provide interpretable subsite-specific data were deprioritized, as were isolated case reports and small case series that did not address the review objective. Finally, we synthesized the evidence narratively, emphasizing the distinction between cardia and non-cardia adenocarcinoma, while also additional consideration of gastritis distribution, gastric acid physiology, bacterial virulence, and the timing and expected benefit of H. pylori eradication.
Results
Globally, research consistently that H. pylori had the strongest and most reliable link to non-cardia gastric adenocarcinoma. The biological basis is compatible with the Correa cascade: chronic infection can progress from active gastritis to corpus involvement, glandular atrophy, intestinal metaplasia, dysplasia, and adenocarcinoma. Gastritis phenotype appears central to anatomical risk. Antral-predominant infection is generally associated with reduced somatostatin signaling, hypergastrinemia, preserved corpus mucosa, and higher acid output, whereas corpus-predominant gastritis or pangastritis is associated with parietal-cell loss, hypochlorhydria, atrophy, and a stronger carcinogenic milieu for non-cardia cancer. Notably, corpus-predominant gastritis may also reduce the likelihood of reflux esophagitis risk, helping explain differing epidemiologic associations with reflux-related proximal malignancies.
The risk profile is further influenced by bacterial virulence factors. CagA-positive strains and virulent VacA genotypes are associated with more extensive inflammation, corpus involvement, atrophy, and greater gastric cancer risk. Iranian data from high-risk areas such as Ardabil support enrichment of high-risk H. pylori genotypes among patients with non-cardia gastric cancer.
The cardia relationship was markedly more heterogeneous. Large Asian studies, including data from China, support a positive association between H. pylori and cardia cancer in addition to the stronger association with non-cardia cancer. In contrast, studies from lower-risk Western settings often report neutral or inverse associations, where obesity, reflux, and gastroesophageal-junction pathways may be more prominent. Iranian evidence also demonstrates substantial anatomical heterogeneity. Northern and northwestern provinces carry a high gastric cancer burden and high H. pylori prevalence, while studies from Golestan, Tehran, Mashhad, southern Iran, and multicenter datasets show that proximal/cardial tumors account for a considerable proportion of cases. These findings support an intermediate epidemiologic pattern rather than a purely distal, infection-dominant model, although current Iranian data do not justify directly attributing proximal tumors to reflux or obesity.
Eradication evidence was most robust for prevention of non-cardia gastric cancer. Randomized trials, long-term follow-up studies, and meta-analyses indicate that H. pylori eradication reduces future gastric cancer risk, with the greatest preventive potential when treatment occurs before advanced premalignant lesions develop. Benefit is also observed after endoscopic treatment of early gastric cancer, where eradication reduces metachronous gastric cancer. Recent trial-level evidence suggests benefit may persist in patients with intestinal metaplasia or dysplasia, although residual risk remains and surveillance may still be required. The effect of eradication specifically on cardia cancer remains incompletely quantified because many intervention studies do not report outcomes separately by gastric subsite.
Conclusion
H. pylori has a central and well-supported role in non-cardia gastric carcinogenesis, whereas its relationship with cardia cancer is context-dependent and varies with geographical setting, gastritis phenotype, bacterial virulence, and competing reflux- and obesity-related pathways. Eradication reduces future gastric cancer risk, particularly when performed before advanced precancerous change, and remains relevant in selected high-risk patients after premalignant or early neoplastic disease. For Iran, the combination of a high gastric cancer burden, widespread H. pylori infection, and heterogeneous anatomical distribution supports evaluation of population-based or targeted screen-and-treat strategies in high-risk settings while simultaneously addressing proximal cancer pathways. Implementation should consider local disease burden, infection prevalence, feasibility, surveillance capacity, and cost-effectiveness.
Type of Study: Review article |
Subject:
Internal diseases
Received: 2026/01/31 | Accepted: 2026/09/5 | Published: 2026/10/7
Received: 2026/01/31 | Accepted: 2026/09/5 | Published: 2026/10/7
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