The Clinical Evidence Linking Helicobacter pylori to Gastric Cancer

Gastric cancer has long been recognized to be accompanied and preceded by chronic gastritis, lasting decades. Arguably, the most important development in our understanding of gastric cancer pathogenesis over the past 50 years has been the realization that, for most cases of gastric cancer, Helicobacter pylori is the cause of the underlying gastritis. Gastritis can promote gastric carcinogenesis, typically via the Correa cascade of atrophic gastritis, intestinal metaplasia, and dysplasia. Nested case-control studies have shown that H pylori infection increases the risk of gastric cancer significantly, both of the intestinal and diffuse subtypes, and that H pylori is responsible for approximately 90% of the world’s burden of noncardia gastric cancer. Based largely on randomized studies in high gastric cancer prevalence regions in East Asia, it appears that primary and tertiary intervention to eradicate H pylori can halve the risk of gastric cancer. Some public health authorities now are starting screening and treatment programs to reduce the burden of gastric cancer in these high-risk areas. However, there is currently much less enthusiasm for initiating similar attempts in the United States. This is partially because gastric cancer is a relatively less frequent cause of cancer in the United States, and in addition there are concerns about theoretical downsides of H pylori eradication, principally because of the consistent inverse relationship noted between H pylori and esophageal adenocarcinoma. Nevertheless, establishing a link between chronic H pylori infection and gastric cancer has led to novel insights into cancer biology, the gastrointestinal microbiome, and on individual and population-based gastric cancer prevention strategies. Gastric cancer has long been recognized to be accompanied and preceded by chronic gastritis, lasting decades. Arguably, the most important development in our understanding of gastric cancer pathogenesis over the past 50 years has been the realization that, for most cases of gastric cancer, Helicobacter pylori is the cause of the underlying gastritis. Gastritis can promote gastric carcinogenesis, typically via the Correa cascade of atrophic gastritis, intestinal metaplasia, and dysplasia. Nested case-control studies have shown that H pylori infection increases the risk of gastric cancer significantly, both of the intestinal and diffuse subtypes, and that H pylori is responsible for approximately 90% of the world’s burden of noncardia gastric cancer. Based largely on randomized studies in high gastric cancer prevalence regions in East Asia, it appears that primary and tertiary intervention to eradicate H pylori can halve the risk of gastric cancer. Some public health authorities now are starting screening and treatment programs to reduce the burden of gastric cancer in these high-risk areas. However, there is currently much less enthusiasm for initiating similar attempts in the United States. This is partially because gastric cancer is a relatively less frequent cause of cancer in the United States, and in addition there are concerns about theoretical downsides of H pylori eradication, principally because of the consistent inverse relationship noted between H pylori and esophageal adenocarcinoma. Nevertheless, establishing a link between chronic H pylori infection and gastric cancer has led to novel insights into cancer biology, the gastrointestinal microbiome, and on individual and population-based gastric cancer prevention strategies. SummaryThe vast majority of gastric cancer worldwide is attributable to Helicobacter pylori, a chronic and persistent infection that is usually acquired in childhood. In some regions of the world with especially high gastric cancer prevalence, intervention programs have been established to eradicate H pylori with the expectation that this will significantly decrease mortality from this disease. This review focuses on the link between H pylori and gastric cancer established from clinical studies, and discusses the consequences of novel insights into cancer biology, the gastrointestinal microbiome, and on individual and population-based gastric cancer prevention strategies that this work has stimulated. The vast majority of gastric cancer worldwide is attributable to Helicobacter pylori, a chronic and persistent infection that is usually acquired in childhood. In some regions of the world with especially high gastric cancer prevalence, intervention programs have been established to eradicate H pylori with the expectation that this will significantly decrease mortality from this disease. This review focuses on the link between H pylori and gastric cancer established from clinical studies, and discusses the consequences of novel insights into cancer biology, the gastrointestinal microbiome, and on individual and population-based gastric cancer prevention strategies that this work has stimulated. It is now appreciated that infection with Helicobacter pylori is the most important risk factor for the development of noncardia gastric cancer, responsible for almost 90% of such cases worldwide and approximately 5% of the total burden from all cancers globally.1Plummer M. Franceschi S. Vignat J. et al.Global burden of gastric cancer attributable to Helicobacter pylori.Int J Cancer. 2015; 136: 487-490Crossref PubMed Scopus (567) Google Scholar It is remarkable that the critical contribution of H pylori to gastric carcinogenesis was almost unknown when the Funderburg family started funding gastric cancer research in 1992. As the first recipient of the award to investigate H pylori (my project, funded in 2002, was entitled “Regulation of Gastric Epithelial p27kip1 by H pylori”), this review focuses on the clinicopathologic and epidemiologic data that have emerged over the past 30 years establishing H pylori as the most important etiologic agent in gastric adenocarcinoma, and discusses the implications of this association for gastric cancer prevention. Our understanding of H pylori–induced inflammation leading to cancer is built on the work of 3 pioneering pathologists (Figure 1). Rudolf Virchow, a 19th century Prussian physician-scientist, is widely regarded as the father of modern pathology. Among his many contributions to outlining the scientific basis of disease was the idea, based on many of his own observations, that cancer arose from initially normal cells in response to chronic irritation, or inflammation.2Balkwill F. Mantovani A. Inflammation and cancer: back to Virchow?.Lancet. 2001; 357: 539-545Abstract Full Text Full Text PDF PubMed Scopus (6031) Google Scholar Numerous examples of inflammation-induced cancers are now appreciated, including many of the common gastrointestinal tract and hepatobiliary malignancies, such as acid reflux–induced esophageal adenocarcinoma, inflammatory bowel disease–associated colon cancer, and hepatocellular neoplasms associated with chronic viral hepatitis.2Balkwill F. Mantovani A. Inflammation and cancer: back to Virchow?.Lancet. 2001; 357: 539-545Abstract Full Text Full Text PDF PubMed Scopus (6031) Google Scholar Throughout the 20th century, evidence accrued that gastric cancers tended to arise in stomachs already affected by chronic inflammation, especially atrophic gastritis with its accompanying hypochlorhydria, and that gastric cancer was a consequence and not a mere accompaniment of the gastritis.3Hurst A.F. Schorstein lecture: on the precursors of carcinoma of the stomach.Lancet. 1929; 214: 1023-1028Abstract Scopus (5) Google Scholar These ideas set the stage for Pelayo Correa, a pathologist from Colombia, a country with a particularly high gastric cancer prevalence. After training in pathology in Colombia and in the United States (Emory University), Correa devoted his professional career at home and subsequently in the United States (at the National Cancer Institute, Louisiana State University, and now Vanderbilt University) to understanding the etiology of gastric cancer. In 1975, Correa et al,4Correa P. Haenszel W. Cuello C. et al.A model for gastric cancer epidemiology.Lancet. 1975; 2: 58-60Abstract PubMed Scopus (899) Google Scholar from the National Cancer Institute, Massachusetts Institute of Technology, and from his home country, published a “Model for Gastric Cancer Development.” In this landmark report, it was hypothesized that the development of the more common intestinal subtype of gastric cancer resulted from a stepwise process, beginning with chronic atrophic gastritis and progressing to intestinal metaplasia and cancer over the next 30–50 years. The initial changes were postulated to occur in the first decade of life, which we now know to be when H pylori colonization occurs.5Malaty H.M. El-Kasabany A. Graham D.Y. et al.Age at acquisition of Helicobacter pylori infection: a follow-up study from infancy to adulthood.Lancet. 2002; 359: 931-935Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar A more detailed model, published in 1988,6Correa P. A human model of gastric carcinogenesis.Cancer Res. 1988; 48: 3554-3560PubMed Google Scholar included what was known of the phenotypic markers accompanying these sequential changes. Correa initially thought that the agent(s) responsible for promoting this slow progression from gastritis to cancer were environmental, based on studies of migrants from high gastric cancer risk areas. For example, Japanese immigrants to Hawaii and European immigrants to the United States had been shown to have lower gastric cancer rates than their parents and grandparents, more similar to those of the native population where they settled.7Haenszel W. Kurihara M. Segi M. et al.Stomach cancer among Japanese in Hawaii.J Natl Cancer Inst. 1972; 49: 969-988PubMed Google Scholar, 8Staszewski J. Migrant studies in alimentary tract cancer.Recent Results Cancer Res. 1972; 39: 85-97Crossref PubMed Scopus (19) Google Scholar The prime environmental culprit originally was thought to be a diet high in salt and N-nitroso-compounds and low in micronutrients from fresh fruits and vegetables. It was postulated that this led to the promotion of gastric mutagenesis and, together with hypochlorhydria, bacterial overgrowth, thereby contributing to further nitrosamine formation. Interestingly, in his 1988 publication, Correa briefly discussed a possible role for Campylobacter pylori, a newly discovered gastric bacterium, in the initiation of the disease. Correa’s subsequent work has focused primarily on the role of H pylori in gastric cancer, and this model has stood the test of time (Figure 2). For his outstanding contributions to the field of gastric carcinogenesis, Correa received the American Gastroenterological Association’s Distinguished Achievement Award in 2013. The third pathologist of note is Robin Warren from Australia who, together with Barry Marshall, was awarded the Nobel Prize in Physiology or Medicine in 2005 for the discovery of H pylori and its role in gastritis and peptic ulcer disease.9Parsonnet J. Clinician-discoverers–Marshall, Warren, and H. pylori.N Engl J Med. 2005; 353: 2421-2423Crossref PubMed Scopus (25) Google Scholar In the 1970s, the widespread use of gastrointestinal endoscopy allowed pathologists the opportunity to view gastric tissue that had been removed during a biopsy and fixed rapidly, without the artifacts inherent to the ischemia and autolysis of surgical specimens. Warren recognized that spiral gastric bacteria were common in fresh gastritis specimens. He then recruited Marshall, a medical resident looking for a research project, to correlate the pathologic findings with the endoscopic features.10Moss S.F. The rediscovery of H. pylori bacteria in the gastric mucosa by Robin Warren, and implications of this finding for human biology and disease.Dig Dis Sci. 2013; 58: 3072-3078Crossref PubMed Scopus (7) Google Scholar Together, they discovered that these bacteria (initially termed Campylobacter pyloridis, then C pylori, and, subsequently, H pylori) were very common in peptic ulcer patients. Eventually, they successfully cultured these formerly elusive bacteria and showed that they caused gastritis and ulcer disease.11Marshall B.J. Warren J.R. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration.Lancet. 1984; 1: 1311-1315Abstract PubMed Scopus (4233) Google Scholar, 12Warren J.R. Marshall B.J. Unidentified curved bacilli on gastric epithelium in active chronic gastritis.Lancet. 1983; 1: 1273-1275PubMed Google Scholar, 13Marshall B.J. Goodwin C.S. Warren J.R. et al.Prospective double-blind trial of duodenal ulcer relapse after eradication of Campylobacter pylori.Lancet. 1988; 2: 1437-1442Abstract PubMed Scopus (970) Google Scholar, 14Marshall B.J. Armstrong J.A. McGechie D.B. et al.Attempt to fulfil Koch's postulates for pyloric Campylobacter.Med J Aust. 1985; 142: 436-439Crossref PubMed Scopus (1050) Google Scholar In retrospect, other investigators also had observed such bacteria over the preceding century, but their clinical significance had not been appreciated and they had even been proven to be a post mortem artifact15Palmer E.D. Investigation of the gastric mucosa spirochetes of the human.Gastroenterology. 1954; 27: 218-220Abstract Full Text PDF PubMed Google Scholar before their rediscovery in Australia. Although Warren and Marshall did not investigate the role of H pylori in gastric cancer directly, they were aware of the relationship between gastritis and cancer. Indeed, Marshall speculated with amazing prescience in their very first publications (in unusual side-by-side, single-author letters in 1983) that “if these bacteria are truly associated with antral gastritis, as described by Warren, they may have a part to play in other poorly understood, gastritis associated diseases (ie, peptic ulcer and gastric cancer).”12Warren J.R. Marshall B.J. Unidentified curved bacilli on gastric epithelium in active chronic gastritis.Lancet. 1983; 1: 1273-1275PubMed Google Scholar Initial investigations into a possible association of H pylori with gastric cancer that were conducted in the 1980s and early 1990s provided only weak evidence for a link between H pylori and gastric cancer. A positive correlation between H pylori seroprevalence and gastric cancer in cross-sectional sampling was reported in a study conducted among 13 European nations.16An international association between Helicobacter pylori infection and gastric cancer. The EUROGAST Study Group.Lancet. 1993; 341: 1359-1362Abstract PubMed Scopus (1251) Google Scholar However, although some other publications reported similar trends,17Correa P. Fox J. Fontham E. et al.Helicobacter pylori and gastric carcinoma. Serum antibody prevalence in populations with contrasting cancer risks.Cancer. 1990; 66: 2569-2574Crossref PubMed Scopus (389) Google Scholar, 18Forman D. Sitas F. Newell D.G. et al.Geographic association of Helicobacter pylori antibody prevalence and gastric cancer mortality in rural China.Int J Cancer. 1990; 46: 608-611Crossref PubMed Scopus (251) Google Scholar several others did not find a positive correlation between the presence of H pylori antibodies and either gastric cancer or precancerous gastric lesions.19Sierra R. Munoz N. Pena A.S. et al.Antibodies to Helicobacter pylori and pepsinogen levels in children from Costa Rica: comparison of two areas with different risks for stomach cancer.Cancer Epidemiol Biomarkers Prev. 1992; 1: 449-454PubMed Google Scholar, 20Palli D. Decarli A. Cipriani F. et al.Helicobacter pylori antibodies in areas of Italy at varying gastric cancer risk.Cancer Epidemiol Biomarkers Prev. 1993; 2: 37-40PubMed Google Scholar, 21Fukao A. Komatsu S. Tsubono Y. et al.Helicobacter pylori infection and chronic atrophic gastritis among Japanese blood donors: a cross-sectional study.Cancer Causes Control. 1993; 4: 307-312Crossref PubMed Scopus (64) Google Scholar, 22Tsugane S. Kabuto M. Imai H. et al.Helicobacter pylori, dietary factors, and atrophic gastritis in five Japanese populations with different gastric cancer mortality.Cancer Causes Control. 1993; 4: 297-305Crossref PubMed Scopus (128) Google Scholar Around this time, clinicopathologic studies performed to look for evidence of H pylori infection (by serum antibodies) or in gastric tissue directly in cases of gastric cancer also yielded inconsistent results. Some studies showed H pylori infection rates no higher than those observed in noncancer controls. This is most likely because by the time gastric cancer has developed, extensive intestinal metaplasia and hypochlorhydria had rendered the stomach less hospitable to persistent H pylori colonization,23Siurala M. Sipponen P. Kekki M. Campylobacter pylori in a sample of Finnish population: relations to morphology and functions of the gastric mucosa.Gut. 1988; 29: 909-915Crossref PubMed Scopus (145) Google Scholar thus also explaining some of the negative findings in the cross-sectional studies discussed earlier. Much more convincing evidence for the role of H pylori in gastric cancer came from 3 large cohorts with nested case-controls, in which serum had been banked from cancer-free subjects and the cohort had been followed up for approximately a decade.24Forman D. Newell D.G. Fullerton F. et al.Association between infection with Helicobacter pylori and risk of gastric cancer: evidence from a prospective investigation.BMJ. 1991; 302: 1302-1305Crossref PubMed Scopus (1302) Google Scholar, 25Parsonnet J. Friedman G.D. Vandersteen D.P. et al.Helicobacter pylori infection and the risk of gastric carcinoma.N Engl J Med. 1991; 325: 1127-1131Crossref PubMed Scopus (3611) Google Scholar, 26Nomura A. Stemmermann G.N. Chyou P.H. et al.Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii.N Engl J Med. 1991; 325: 1132-1136Crossref PubMed Scopus (1715) Google Scholar In each cohort, evidence of prior H pylori infection (evaluated by enzyme-linked immunosorbent assay ELISA in the banked serum) was found to be significantly more common in those subjects who subsequently developed gastric cancer compared with a sample of those who had not (Table 1). In a meta-analysis, these 3 studies provided an overall odds ratio for gastric cancer development in H pylori–infected vs -uninfected persons of 3.8 (95% confidence interval CI, 2.3–6.2).27Forman D. Webb P. Parsonnet J. H pylori and gastric cancer.Lancet. 1994; 343: 243-244Abstract PubMed Scopus (235) Google ScholarTable 1The Three Cohort Studies That Led to the Classification of H pylori as a Class 1 Carcinogen in 1994StudyCohort descriptionTime from cohort inception to cancer, meanCases of H pylori seroprevalence, n (%)Controls with H pylori seroprevalence, n (%)Odds ratio (95% CI)Forman et al,24Forman D. Newell D.G. Fullerton F. et al.Association between infection with Helicobacter pylori and risk of gastric cancer: evidence from a prospective investigation.BMJ. 1991; 302: 1302-1305Crossref PubMed Scopus (1302) Google Scholar 1991British men6 y29 (69)116 (47)2.8 (1.0–8.0)Parsonnet et al,25Parsonnet J. Friedman G.D. Vandersteen D.P. et al.Helicobacter pylori infection and the risk of gastric carcinoma.N Engl J Med. 1991; 325: 1127-1131Crossref PubMed Scopus (3611) Google Scholar 1991Californian men and women14 y109 (84)109 (61)3.6 (1.8–7.3)Nomura et al,26Nomura A. Stemmermann G.N. Chyou P.H. et al.Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii.N Engl J Med. 1991; 325: 1132-1136Crossref PubMed Scopus (1715) Google Scholar 1991Japanese–American men in Hawaii13 y109 (94)109 (76)6.0 (2.1–17) Open table in a new tab Based on the compelling results of these cohort studies, the World Health Organization’s International Agency for Research on Cancer declared in 1994 that there was sufficient evidence to classify H pylori as a definite (group 1) carcinogen.28IARC Working Group on the Evaluation of Carcinogenic Risks to HumansSchistosomes, liver flukes and Helicobacter Risks 1994; Google Scholar This was the that at that time there was no evidence from either or research worldwide has and the early epidemiologic studies, with the clinical findings as cancers are not associated with H pylori S. et of the relationship between Helicobacter pylori and gastric Full Text Full Text PDF PubMed Scopus Google Scholar the that cancers arise via with risk more similar to cancers of the and lower S. S.F. and risk in gastric Cancer. 2015; PubMed Scopus Google and Gastric Cancer Gastric cancer and Helicobacter a of studies nested prospective 2001; 49: PubMed Scopus Google Scholar the odds ratio for H pylori in gastric cancer was no different when intestinal vs diffuse cancer in addition to promoting the P. Haenszel W. Cuello C. et al.A model for gastric cancer epidemiology.Lancet. 1975; 2: 58-60Abstract PubMed Scopus (899) Google Scholar cascade of H pylori is as a risk factor for the much less leading to gastric H pylori by prior and, the attributable H pylori risk in noncardia cancer, because of results. For example, in a case-control prior a H pylori A than a the odds ratio from (95% to (95% M. et al.Helicobacter pylori in gastric cancer established by as a of past 2001; Full Text Full Text PDF PubMed Scopus Google noncardia gastric H pylori are the more common the risk of gastric cancer to a than by the more et of the relationship between and gastric Full Text Full Text PDF PubMed Scopus Google Scholar This is consistent with the of the that have been in S. N. W. and of the Helicobacter pylori 2015; PubMed Scopus Google pylori eradication can reduce the risk of gastric cancer In a study patients who had a Japanese endoscopy et N. S. S. et al.Helicobacter pylori infection and the development of gastric Engl J Med. 2001; PubMed Scopus Google Scholar showed that those who were H pylori–infected in the infection was not had a much higher of progression to gastric cancer over the subsequent years than the patients who had no initial evidence of H However, to that H pylori is responsible for the gastric cancer prospective studies were