Gastric Cancer as Preventable Disease

Gastric cancer, 1 of the 5 most common causes of cancer death, is associated with a 5-year overall survival rate less than 30%. A minority of cancers occurs as part of syndromic diseases; more than 90% of adenocarcinomas are considered as the ultimate consequence of a longstanding mucosal inflammation. Helicobacter pylori infection is the leading etiology of non–self-limiting gastritis, which may result in atrophy of the gastric mucosa and impaired acid secretion. Gastric atrophy establishes a field of cancerization prone to further molecular and phenotypic changes, possibly resulting in cancer growth. This well-understood natural history provides the clinicopathologic rationale for primary and secondary cancer prevention strategies. A large body of evidence demonstrates that combined primary (H pylori eradication) and secondary (mainly endoscopy) prevention efforts may prevent or limit the progression of gastric oncogenesis. This approach, which is tailored to different country-specific gastric cancer incidence, socioeconomic, and cultural factors, requires that the complementary competences of gastroenterologists, oncologists, and pathologists be amalgamated into a common strategy of health policy. Gastric cancer, 1 of the 5 most common causes of cancer death, is associated with a 5-year overall survival rate less than 30%. A minority of cancers occurs as part of syndromic diseases; more than 90% of adenocarcinomas are considered as the ultimate consequence of a longstanding mucosal inflammation. Helicobacter pylori infection is the leading etiology of non–self-limiting gastritis, which may result in atrophy of the gastric mucosa and impaired acid secretion. Gastric atrophy establishes a field of cancerization prone to further molecular and phenotypic changes, possibly resulting in cancer growth. This well-understood natural history provides the clinicopathologic rationale for primary and secondary cancer prevention strategies. A large body of evidence demonstrates that combined primary (H pylori eradication) and secondary (mainly endoscopy) prevention efforts may prevent or limit the progression of gastric oncogenesis. This approach, which is tailored to different country-specific gastric cancer incidence, socioeconomic, and cultural factors, requires that the complementary competences of gastroenterologists, oncologists, and pathologists be amalgamated into a common strategy of health policy. Intestinal-type adenocarcinoma is the most frequent gastric malignancy.1DeSantis C.E. Lin C.C. Mariotto A.B. et al.Cancer treatment and survivorship statistics, 2014.CA Cancer J Clin. 2014; 64: 252-271Crossref PubMed Scopus (1166) Google Scholar, 2Cancer Genome Atlas Research NetworkComprehensive molecular characterization of gastric adenocarcinoma.Nature. 2014; 513: 202-209Crossref PubMed Scopus (953) Google Scholar A solid body of epidemiologic studies support the primary etiologic role of the environment (infectious agents, diet, and lifestyle) and directly link Helicobacter pylori infection to the risk for gastric cancer (GC).3Graham D.Y. Helicobacter pylori update: gastric cancer, reliable therapy, and possible benefits.Gastroenterology. 2015; 148: 719-731.e3Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 4Piazuelo M.B. Epplein M. Correa P. Gastric cancer: an infectious disease.Infect Dis Clin North Am. 2010; 24 (vii): 853-869Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar In a small proportion of patients, GC is associated with genetic syndromes; because of their peculiar molecular profile, this review will exclude these syndromic cancers. Most non-syndromic (so-called sporadic) GCs are the ultimate consequence of a cascade of progressive mucosal changes initiated by longstanding inflammation (ie, inflammation associated cancers), which may result in both structural and functional alterations (ie, gastric mucosa atrophy) on which GC arises.5Hunt R.H. Camilleri M. Crowe S.E. et al.The stomach in health and disease.Gut. 2015; 64: 1650-1668Crossref PubMed Scopus (38) Google Scholar Gastric atrophy, defined as “loss of appropriate glands”,6Rugge M. Correa P. Dixon M.F. et al.Gastric mucosal atrophy: interobserver consistency using new criteria for classification and grading.Aliment Pharmacol Ther. 2002; 16: 1249-1259Crossref PubMed Scopus (202) Google Scholar is the result of either an absolute loss of glandular structures or their replacement by metaplastic-transformed glands (pseudopyloric and/or intestinal); in most patients, the 2 types of atrophic changes coexist. Metaplastic epithelia may further dedifferentiate, acquiring most of the biological profile of neoplastic cells but still lacking the ability for invasion (a phenomenon known as dysplasia, now classified as intraepithelial neoplasia [IEN]).7Rugge M. Correa P. Dixon M.F. et al.Gastric dysplasia: the Padova international classification.Am J Surg Pathol. 2000; 24: 167-176Crossref PubMed Scopus (291) Google Scholar Once it acquires the invasive phenotype, IEN further progresses into invasive GC (Figure 1). This review, which lays its foundations on the natural history of sporadic GC (as opposed to syndromic),8Correa P. Haenszel W. Cuello C. et al.A model for gastric cancer epidemiology.Lancet. 1975; 2: 58-60Abstract PubMed Scopus (680) Google Scholar, 9Correa P. Gastric cancer: overview.Gastroenterol Clin North Am. 2013; 42: 211-217Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar aims to provide the clinicobiological rationale behind a multidisciplinary approach for primary and secondary prevention strategies. In 2015 there were 1.3 million GC incident cases worldwide and 819,000 deaths due to GC.10Fitzmaurice C. Allen C. et al.Global Burden of Disease Cancer CollaborationGlobal, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the global burden of disease study.JAMA Oncol. 2017; 3: 524-548Crossref PubMed Scopus (6) Google Scholar GC is twice as frequent in men as in women, and its risk increases with age.11Bosman F.T. Carneiro F. Hruban R.H. et al.World Health Organization classification of tumours of the digestive system. IARC Press, Lyon2010Google Scholar The highest incidence rates are found in Eastern Asia, Eastern Europe, and the mountainous regions of several Latin American countries.9Correa P. Gastric cancer: overview.Gastroenterol Clin North Am. 2013; 42: 211-217Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 12Tsukanov V.V. Butorin N.N. Maady A.S. et al.Helicobacter pylori infection, intestinal metaplasia, and gastric cancer risk in eastern Siberia.Helicobacter. 2011; 16: 107-112Crossref PubMed Scopus (0) Google Scholar In the past 50 years the incidence of distal GC has been declining in many parts of the world13Anderson W.F. Camargo M.C. Fraumeni Jr., J.F. et al.Age-specific trends in incidence of noncardia gastric cancer in US adults.JAMA. 2010; 303: 1723-1728Crossref PubMed Scopus (170) Google Scholar; however, there are significant differences in GC risk among different ethnic groups within the same geographical area. The International Agency for Research on Cancer recently confirmed H pylori infection as a necessary (not sufficient) cause of non-cardia GC.14IARC Working Group on the Evaluation of Carcinogenic Risks to HumansPersonal habits and indoor combustions: volume 100 E—a review of human carcinogens.IARC monographs on the evaluation of carcinogenic risks to humans/World Health Organization, International Agency for Research on Cancer. 2012; 100: 1-538Google Scholar In contrast, meta-analyses show no overall association of cardia GC with H pylori infection.15Cavaleiro-Pinto M. Peleteiro B. Lunet N. et al.Helicobacter pylori infection and gastric cardia cancer: systematic review and meta-analysis.Cancer Causes Control. 2011; 22: 375-387Crossref PubMed Scopus (0) Google Scholar Less common conditions promoting gastric carcinogenesis account for 3%–10% of GCs and include Epstein-Barr virus infection, autoimmune gastritis, Ménétrier’s disease, and alkaline reflux disease for some proximal GCs.16Rugge M. Genta R.M. Graham D.Y. et al.Chronicles of a cancer foretold: 35 years of gastric cancer risk assessment.Gut. 2016; 65: 721-725Crossref PubMed Scopus (5) Google Scholar The role of H pylori–negative chronic gastritis remains unclear.17Nordenstedt H. Graham D.Y. Kramer J.R. et al.Helicobacter pylori-negative gastritis: prevalence and risk factors.Am J Gastroenterol. 2013; 108: 65-71Crossref PubMed Scopus (27) Google Scholar, 18Genta R.M. Sonnenberg A. Helicobacter-negative gastritis: a distinct entity unrelated to Helicobacter pylori infection.Aliment Pharmacol Ther. 2015; 41: 218-226Crossref PubMed Scopus (15) Google Scholar Epstein-Barr virus infection is associated with 90% of lymphoepithelioma-like GCs, is more common in men and in proximal cancers (13% in cardia-corpus versus 5% in antrum), and is highest (35%) in tumors arising in postsurgical gastric stump.19Chen X.Z. Chen H. Castro F.A. et al.Epstein-Barr virus infection and gastric cancer: a systematic review.Medicine. 2015; 94: e792Crossref PubMed Scopus (0) Google Scholar Meta-analyses of observational studies have demonstrated a positive association between consumption of salt-cured foods (fish, meat, vegetables) and GC, which is stronger in subjects with H pylori infection.9Correa P. Gastric cancer: overview.Gastroenterol Clin North Am. 2013; 42: 211-217Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 20Tsugane S. Salt, salted food intake, and risk of gastric cancer: epidemiologic evidence.Cancer Sci. 2005; 96: 1-6Crossref PubMed Scopus (0) Google Scholar There is a positive interaction between tobacco smoking and H pylori infection.21Gonzalez C.A. Pera G. Agudo A. et al.Smoking and the risk of gastric cancer in the European Prospective Investigation Into Cancer and Nutrition (EPIC).Int J Cancer. 2003; 107: 629-634Crossref PubMed Scopus (0) Google Scholar The available information on the role of alcohol consumption is contradictory.22Tramacere I. Negri E. Pelucchi C. et al.A meta-analysis on alcohol drinking and gastric cancer risk.Ann Oncol. 2012; 23: 28-36Crossref PubMed Scopus (0) Google Scholar A healthy lifestyle index (ie, negative smoking status, limited alcohol consumption, and Mediterranean diet) is associated with a significantly lower risk of non-cardia GC.23Buckland G. Travier N. Huerta J.M. et al.Healthy lifestyle index and risk of gastric adenocarcinoma in the EPIC cohort study.Int J Cancer. 2015; 137: 598-606Crossref PubMed Scopus (13) Google Scholar Other dietary factors such as green tea24Tsubono Y. Nishino Y. Komatsu S. et al.Green tea and the risk of gastric cancer in Japan.N Engl J Med. 2001; 344: 632-636Crossref PubMed Scopus (0) Google Scholar and omega-3 fatty acid consumption25MacLean C.H. Newberry S.J. Mojica W.A. et al.Effects of omega-3 fatty acids on cancer risk: a systematic review.JAMA. 2006; 295: 403-415Crossref PubMed Scopus (0) Google Scholar have not been shown to affect the risk for GC. A family history of GC confers a 2- to 10-fold risk to develop GC.26Gonzalez C.A. Agudo A. Carcinogenesis, prevention and early detection of gastric cancer: where we are and where we should go.Int J Cancer. 2012; 130: 745-753Crossref PubMed Scopus (0) Google Scholar Subjects with hereditary diffuse GC syndrome, familial adenomatous polyposis, Peutz-Jeghers syndrome, and Li-Fraumeni syndrome,11Bosman F.T. Carneiro F. Hruban R.H. et al.World Health Organization classification of tumours of the digestive system. IARC Press, Lyon2010Google Scholar as well as Lynch syndrome patients, particularly in those with MLH1 or MSH2 mutation(s), have an increased risk for GC,11Bosman F.T. Carneiro F. Hruban R.H. et al.World Health Organization classification of tumours of the digestive system. IARC Press, Lyon2010Google Scholar as do patients with immune deficiencies (ie, acquired immunodeficiency syndrome and post-transplant immunodeficiency, among others).11Bosman F.T. Carneiro F. Hruban R.H. et al.World Health Organization classification of tumours of the digestive system. IARC Press, Lyon2010Google Scholar Longstanding mucosal inflammation is the main promoter of the oncogenetic cascade leading to sporadic GC. Two etiologic models of non–self-limiting inflammation (H pylori–associated and primary autoimmune) are described, both resulting in the atrophic remodeling of the native gastric mucosa. The epidemiologic impact of H pylori gastritis far exceeds that of autoimmunity. H pylori is both the most common and the best understood gastric carcinogen.3Graham D.Y. Helicobacter pylori update: gastric cancer, reliable therapy, and possible benefits.Gastroenterology. 2015; 148: 719-731.e3Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar The infection causes an unrelenting lifelong inflammation, producing genotoxic molecules (ie, reactive oxygen and reactive nitrogen intermediates) resulting in both oxidative damage and nitrosation of DNA bases.27Hanada K. Graham D.Y. Helicobacter pylori and the molecular pathogenesis of intestinal-type gastric carcinoma.Expert Rev Anticancer Ther. 2014; 14: 947-954Crossref PubMed Scopus (0) Google Scholar H pylori strains differ in virulence; strains that express the cag-pathogenicity island are associated with an enhanced inflammatory response and, therefore, with an increased risk of clinically significant outcomes (ie, peptic ulcer and GC).3Graham D.Y. Helicobacter pylori update: gastric cancer, reliable therapy, and possible benefits.Gastroenterology. 2015; 148: 719-731.e3Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar Although H pylori can survive in an acid environment, it electively replicates at neutral/near-neutral pH. The normal acid-secreting gastric corpus initially restricts H pylori to the oxyntic mucosal surface,5Hunt R.H. Camilleri M. Crowe S.E. et al.The stomach in health and disease.Gut. 2015; 64: 1650-1668Crossref PubMed Scopus (38) Google Scholar whereas the lack of acid secretion makes the antrum the ideal site for colonization. The (progressive) oxyntic spreading of the inflammatory/atrophic lesions (primarily occurring at the antral-corpus border28Kimura K. Takemoto T. An endoscopic recognition of the atrophic border and its significance in chronic gastritis.Endoscopy. 1969; 1: 87-97Crossref Google Scholar) further modifies the gastric microenvironment, also promoting both the corpus colonization and the transdifferentiation of chief cells into metaplastic pyloric-like columnar epithelia (ie, pseudopyloric metaplasia, currently referred to as spasmolytic peptides metaplasia).29Weis V.G. Goldenring J.R. Current understanding of SPEM and its standing in the preneoplastic process.Gastric Cancer. 2009; 12: 189-197Crossref PubMed Scopus (56) Google Scholar Further transdifferentiation or mutations may result in the transformation of the native oxyntic or pseudopyloric epithelia into intestinal metaplasia, which initially tends to be focal. The cancer risk associated with H pylori gastritis can be stratified according to the extent and severity of mucosal atrophy. This is the rationale behind the 2 histologic staging systems, the Operative Link on Gastritis Assessment or Operative Link on Gastric Intestinal Metaplasia, currently used to assess and express the individual risk for GC.30Rugge M. Correa P. Di Mario F. et al.OLGA staging for gastritis: a tutorial.Dig Liver Dis. 2008; 40: 650-658Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 31Capelle L.G. de Vries A.C. Haringsma J. et al.The staging of gastritis with the OLGA system by using intestinal metaplasia as an accurate alternative for atrophic gastritis.Gastrointest Endosc. 2010; 71: 1150-1158Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar, 32Sugano K. Tack J. Kuipers E.J. et al.Kyoto global consensus report on Helicobacter pylori gastritis.Gut. 2015; 64: 1353-1367Crossref PubMed Scopus (152) Google Scholar Autoimmunity selectively damages oxyntic cells; when their loss reaches a certain threshold, hypochlorhydria and eventually achlorhydria develop. The end stage of this disease is characterized by corpus atrophy (ie, oxyntic glands replaced by spasmolytic peptides metaplasia and intestinal metaplasia) and a histologically normal or reactive antrum. Oxyntic atrophy results in increased intragastric pH, antral G-cells overactivity, and hypergastrinemia, which in turn triggers enterochromaffin-like cell hyperplasia. Enterochromaffin-like hyperplasia may progress to neuroendocrine tumors (microcarcinoids and type I carcinoids).33Coati I. Fassan M. Farinati F. et al.Autoimmune gastritis: pathologist's viewpoint.World J Gastroenterol. 2015; 21: 12179-12189Crossref PubMed Scopus (13) Google Scholar The real risk for GC in autoimmune gastritis remains undefined.33Coati I. Fassan M. Farinati F. et al.Autoimmune gastritis: pathologist's viewpoint.World J Gastroenterol. 2015; 21: 12179-12189Crossref PubMed Scopus (13) Google Scholar Corpus atrophy may also occur with H pylori gastritis, but it remains unclear whether H pylori serves as a trigger for a (secondary) autoimmune process. In the past when H pylori infection was more prevalent, autoimmune gastritis was commonly associated with H pylori infection, and GC was the most common malignancy in these patients, with up to 30% of their cancers being gastric.34Kaplan H.S. Riger L.G. Pernicious anemia and carcinoma of the stomach: autopsy study concerning their relationship.Am J Med Sci. 1945; 209: 339-348Crossref Google Scholar Although several studies have reported that patients with pernicious anemia (the end stage of autoimmune gastritis)34Kaplan H.S. Riger L.G. Pernicious anemia and carcinoma of the stomach: autopsy study concerning their relationship.Am J Med Sci. 1945; 209: 339-348Crossref Google Scholar had a 3-fold increase in GC compared with the general population,35Murphy G. Dawsey S.M. Engels E.A. et al.Cancer risk after pernicious anemia in the US elderly population.Clin Gastroenterol Hepatol. 2015; 13: 2282-2289.e4Abstract Full Text Full Text PDF PubMed Google Scholar the relative contribution of H pylori and autoimmune gastritis to the cancer risk cannot be retrospectively dissected. Recent studies have shown that GC in autoimmune gastritis is mostly restricted to patients with concurrent H pylori gastritis.36Rugge M. Fassan M. Pizzi M. et al.Autoimmune gastritis: histology phenotype and OLGA staging.Aliment Pharmacol Ther. 2012; 35: 1460-1466Crossref PubMed Scopus (0) Google Scholar The original definition of precancerous gastric lesions virtually coincided with that of dysplasia. However, 2 significant discoveries resulted in a reassessment of both the nomenclature and the identification of the gastric precancerous spectrum: (1) the molecular similarities between dysplastic and cancer cells led to relabeling dysplastic epithelia as neoplastic (IEN)37Fassan M. Baffa R. Kiss A. Advanced precancerous lesions within the GI tract: the molecular background.Best Pract Res Clin Gastroenterol. 2013; 27: 159-169Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar and (2) the significantly increased cancer risk associated with the extensive atrophic/metaplastic transformation of the gastric mucosa (ie, stages III and IV gastritis)16Rugge M. Genta R.M. Graham D.Y. et al.Chronicles of a cancer foretold: 35 years of gastric cancer risk assessment.Gut. 2016; 65: 721-725Crossref PubMed Scopus (5) Google Scholar emphasized the precancerous potential of these histologic lesions. As a result, gastric precancerous lesions currently include 2 sequential phenotypes: (1) early non-neoplastic precancerous lesions, covering the most advanced stages of the atrophic mucosa (stages III and IV gastritis); and (2) advanced neoplastic noninvasive lesions (APLs), equivalent to IEN.38Rugge M. Cassaro M. Di Mario F. et al.The long term outcome of gastric non-invasive neoplasia.Gut. 2003; 52: 1111-1116Crossref PubMed Scopus (0) Google Scholar, 39Rugge M. Capelle L.G. Cappellesso R. et al.Precancerous lesions in the stomach: from biology to clinical patient management.Best Pract Res Clin Gastroenterol. 2013; 27: 205-223Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar When Pelayo Correa8Correa P. Haenszel W. Cuello C. et al.A model for gastric cancer epidemiology.Lancet. 1975; 2: 58-60Abstract PubMed Scopus (680) Google Scholar initially proposed his cascade model, the main cause of gastritis was still unknown. The obvious consequence of the identification of H pylori as the causal agent of the inflammation-associated GC risk40Marshall 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 (3439) Google Scholar is that the first step toward its prevention is the evaluation for H pylori infection. This starts with a clinical assessment focused on any history of H pylori–associated disease, peptic ulcer, previous H pylori testing, and eradication treatment. The medical history should also explore other risk factors including GC among relatives. Several Asian and Western studies have reported higher prevalence of both H pylori infection and precancerous lesions among first-degree relatives of GC patients than among controls.41Chang Y.W. Han Y.S. Lee D.K. et al.Role of Helicobacter pylori infection among offspring or siblings of gastric cancer patients.Int J Cancer. 2002; 101: 469-474Crossref PubMed Scopus (0) Google Scholar, 42Brenner H. Bode G. Boeing H. Helicobacter pylori infection among offspring of patients with stomach cancer.Gastroenterology. 2000; 118: 31-35Abstract Full Text Full Text PDF PubMed Google Scholar This may be related to several factors including common environment, a genetically determined increase in susceptibility to H pylori,43Mayerle J. den Hoed C.M. Schurmann C. et al.Identification of genetic loci associated with Helicobacter pylori serologic status.JAMA. 2013; 309: 1912-1920Crossref PubMed Scopus (65) Google Scholar the transmission of more pathogenic H pylori strains within a family,44Roma-Giannikou E. Karameris A. Balatsos B. et al.Intrafamilial spread of Helicobacter pylori: a genetic analysis.Helicobacter. 2003; 8: 15-20Crossref PubMed Scopus (0) Google Scholar or enhanced chronic active gastritis related to a proinflammatory genotype. The medical history should also focus on medication use. Long-term use of proton pump inhibitors in patients with H pylori infection is associated with pangastritis and accelerated progression to atrophy.45Kuipers E.J. Lundell L. Klinkenberg-Knol E.C. et al.Atrophic gastritis and Helicobacter pylori infection in patients with reflux esophagitis treated with omeprazole or fundoplication.N Engl J Med. 1996; 334: 1018-1022Crossref PubMed Scopus (641) Google Scholar Although no increased risk for gastric malignancy has been shown, this observation suggested considering a H pylori test-and-treat strategy in patients likely to receive proton pump inhibitors for extended periods.46Malfertheiner P. Megraud F. O'Morain C.A. et al.Management of Helicobacter pylori infection: the Maastricht IV/Florence Consensus Report.Gut. 2012; 61: 646-664Crossref PubMed Scopus (1288) Google Scholar In contrast, chronic use of certain anti-inflammatory drugs (including aspirin, nonsteroidal anti-inflammatory drugs, and statins) may be associated with a decreased risk for precancerous conditions as well as GC.47Wong B.C. Zhang L. Ma J.L. et al.Effects of selective COX-2 inhibitor and Helicobacter pylori eradication on precancerous gastric lesions.Gut. 2012; 61: 812-818Crossref PubMed Scopus (0) Google Scholar, 48Ye X. Fu J. Yang Y. et al.Frequency-risk and duration-risk relationships between aspirin use and gastric cancer: a systematic review and meta-analysis.PloS One. 2013; 8: e71522Crossref PubMed Scopus (0) Google Scholar, 49Singh P.P. Singh S. Statins are associated with reduced risk of gastric cancer: a systematic review and meta-analysis.Ann Oncol. 2013; 24: 1721-1730Crossref PubMed Scopus (58) Google Scholar Noninvasive serologic tests can be used to determine the etiology of gastritis and to provide useful approximations on the presence of atrophy.50Burucoa C. Delchier J.C. Courillon-Mallet A. et al.Comparative evaluation of 29 commercial Helicobacter pylori serological kits.Helicobacter. 2013; 18: 169-179Crossref PubMed Scopus (40) Google Scholar, 51Ricci C. Holton J. Vaira D. Diagnosis of Helicobacter pylori: invasive and non-invasive tests.Best Pract Clin Gastroenterol. 2007; 21: 299-313Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 52Gisbert J.P. de la Morena F. Abraira V. Accuracy of monoclonal stool antigen test for the diagnosis of H. pylori infection: a systematic review and meta-analysis.Am J Gastroenterol. 2006; 101: 1921-1930Crossref PubMed Scopus (0) Google Scholar, 53Ferwana M. Abdulmajeed I. Alhajiahmed A. et al.Accuracy of urea breath test in Helicobacter pylori infection: meta-analysis.World J Gastroenterol. 2015; 21: 1305-1314Crossref PubMed Scopus (21) Google Scholar, 54Kuipers E.J. Perez-Perez G.I. Meuwissen S.G. et al.Helicobacter pylori and atrophic gastritis: importance of the cagA status.J Natl Cancer Inst. 1995; 87: 1777-1780Crossref PubMed Scopus (476) Google Scholar However, these tests do not yield information about the severity of precancerous lesions. Serologic assessment of the functional status of the gastric mucosa can be made by measuring serum pepsinogen I and II and fasting gastrin levels.5Hunt R.H. Camilleri M. Crowe S.E. et al.The stomach in health and disease.Gut. 2015; 64: 1650-1668Crossref PubMed Scopus (38) Google Scholar Gastric atrophy leads to a decrease of serum pepsinogens (pepsinogen I in particular) and thus a decrease of the pepsinogen I/II ratio.55Kuipers E.J. In through the out door: serology for atrophic gastritis.Eur J Gastroenterol Hepatol. 2003; 15: 877-879Crossref PubMed Google Scholar Atrophy, with reduction in acid output, induces increased serum gastrin levels.56Agreus L. Kuipers E.J. Kupcinskas L. et al.Rationale in diagnosis and screening of atrophic gastritis with stomach-specific plasma biomarkers.Scand J Gastroenterol. 2012; 47: 136-147Crossref PubMed Scopus (0) Google Scholar The serologic profile of these atrophy markers in different combinations can be applied to population screening to detect individuals at risk for advanced precancerous lesions to be further evaluated by endoscopy and biopsy. In a Japanese cohort study, the risk for progression to cancer inversely correlated with serology (pepsinogen I and pepsinogen I/II ratio).57Yanaoka K. Oka M. Mukoubayashi C. et al.Cancer high-risk subjects identified by serum pepsinogen tests: outcomes after 10-year follow-up in asymptomatic middle-aged males.Cancer Epidemiol Biomarkers Prev. 2008; 17: 838-845Crossref PubMed Scopus (0) Google Scholar When H pylori status was included, the risk of cancer was very low in H pylori–negative subjects with normal pepsinogens, slightly increased in H pylori–positive subjects with normal pepsinogens, and further increased in H pylori–positive patients with low pepsinogen I and I/II ratio; it was the highest in H pylori–negative subjects with decreased pepsinogens.58Yanaoka K. Oka M. Yoshimura N. et al.Risk of gastric cancer in asymptomatic, middle-aged Japanese subjects based on serum pepsinogen and Helicobacter pylori antibody levels.Int J Cancer. 2008; 123: 917-926Crossref PubMed Scopus (0) Google Scholar, 59Enomoto S. Maekita T. Ohata H. et al.Novel risk markers for gastric cancer screening: present status and future prospects.World J Gastrointest Endosc. 2010; 2: 381-387Crossref PubMed Google Scholar The latter group predominantly included cases with low levels or spontaneous clearance of H pylori, possibly resulting from widespread mucosal atrophy. In an Italian cohort study, pepsinogen I/II ratio at baseline significantly predicted the development of intraepithelial or invasive neoplastic lesions after a follow-up period longer than 10 years.60Rugge M. de Boni M. Pennelli G. et al.Gastritis OLGA-staging and gastric cancer risk: a twelve-year clinico-pathological follow-up study.Aliment Pharmacol Ther. 2010; 31: 1104-1111PubMed Google Scholar Despite our incremental advances in detecting cancer-prone patients, no reliable serologic cancer markers are available for the detection of advanced precancerous lesions. An encouraging aspect of serologic testing is its high negative predictive value with respect to atrophy, which allows us to identify patients who are unlikely to immediately benefit from endoscopy and biopsy.4Piazuelo M.B. Epplein M. Correa P. Gastric cancer: an infectious disease.Infect Dis Clin North Am. 2010; 24 (vii): 853-869Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar Endoscopy has a central role in the diagnosis and surveillance of patients with precancerous gastric lesions. The detection of such lesions requires a detailed inspection of the stomach, including incisura angularis, smaller curvature, and corpus/fundus.61Dixon M.F. Genta R.M. Yardley J.H. et al.Classification and grading of gastritis: the updated Sydney System—International Workshop on the Histopathology of Gastritis, Houston 1994.Am J Surg Pathol. 1996; 20: 1161-1181Crossref PubMed Scopus (0) Google Scholar With conventional white-light endoscopes it is difficult to reliably recognize atrophy and metaplasia; this explains the low accuracy of endoscopy in detecting these lesions when no standardized biopsy protocols are applied.62Dinis-Ribeiro M. Areia M. de Vries A.C. et al.Management of precancerous conditions and lesions in the stomach (MAPS): g