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Screening and surveillance for gastric cancer in the United States: Is it needed?

Published:February 29, 2016DOI:https://doi.org/10.1016/j.gie.2016.02.028

      Background and Aims

      Although the incidence of gastric cancer in the United States is relatively low, the incidence of gastric cancer is higher than for esophageal cancer, for which clear guidelines for screening and surveillance exist. With the increasing availability of endoscopic therapy, such as endoscopic submucosal dissection, for treating advanced dysplasia and early gastric cancer, establishing guidelines for screening and surveillance of patients who are at high risk of developing gastric cancer has the potential to diagnose and treat gastric cancer at an earlier stage and improve mortality from gastric cancer. The aims of this article were to review the data regarding the risk factors for developing gastric cancer, methods for gastric cancer screening, and results of national screening programs.

      Methods

      A review of the existing literature related to the aims was performed.

      Results

      Risk factors for gastric cancer that were identified include race/ethnicity (East Asian, Russian, or South American), first-degree relative diagnosed with gastric cancer, positive Helicobacter pylori status, and presence of atrophic gastritis or intestinal metaplasia. Endoscopy has the highest rate of detecting gastric cancer compared with other gastric cancer screening methods. The national screening program in Japan has demonstrated a mortality reduction from gastric cancer based on cohort data.

      Conclusions

      Gastric cancer screening with endoscopy should be considered in individuals who are immigrants from regions associated with a high risk of gastric cancer (East Asia, Russia, or South America) or who have a family history of gastric cancer. Those with findings of atrophic gastritis or intestinal metaplasia on screening endoscopy should undergo surveillance endoscopy every 1 to 2 years. Large prospective multicenter studies are needed to further identify additional risk factors for developing gastric cancer and to assess whether gastric cancer screening programs for high-risk populations in the United States would result in improved mortality.

      Abbreviations:

      AG (atrophic gastritis), CI (confidence interval), EGC (early gastric cancer), IM (intestinal metaplasia), OR (odds ratio), PG (pepsinogen), UGI (upper GI)
      Gastric cancer is one of the world’s leading causes of morbidity and mortality from malignant disease. An estimated 1 million cases of gastric cancer (952,000 cases; 6.8% of all cancers) occurred globally in 2012, making it the fifth most-common malignancy in the world, after lung, breast, colorectal, and prostate cancers.
      • Ferlay J.
      • Soerjomataram I.
      • Dikshit R.
      • et al.
      Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.
      • Ferlay J.
      • Soerjomataram I.
      • Ervik M.
      • et al.
      GLOBOCAN 2012 v1.0, Cancer incidence and mortality worldwide: IARC CancerBase No. 11.
      More than 70% of gastric cancer cases occur in the developing world, and approximately 50% occur in East Asia.
      • Ferlay J.
      • Shin H.R.
      • Bray F.
      • et al.
      Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008.
      Gastric cancer is less common in the United States, with the incidence of gastric cancer among males and females in the United States at 12.3 and 6.0 per 100,000/year, respectively; however, there is a disproportionally higher incidence in Asians.
      • Lui F.H.
      • Tuan B.
      • Swenson S.L.
      • et al.
      Ethnic disparities in gastric cancer incidence and survival in the USA: an updated analysis of 1992-2009 SEER data.
      The estimated number of new cases of gastric cancer in the United States in 2015 was 24,590 (1.5% of all cancers) and 10,720 deaths (1.8% of all cancer deaths).

      Surveillance, Epidemiology, and End Results Program. Cancer query system: SEER Incidence Statistics (2000-2012). Available at: http://seer.cancer.gov/. Accessed March 3, 2015.

      It should be noted that the estimated number of new cases of esophageal cancer in the United States for 2015 was 16,980 (1.0% of all cancers), which is less than the number of new cases of gastric cancer. Guidelines for esophageal cancer screening and surveillance of Barrett’s esophagus exist; however, guidelines for gastric cancer screening and surveillance of gastric intestinal metaplasia (IM) are lacking.
      Since the 1970s there have been notable improvements in the 5-year relative survival rates for gastric cancer in the United States, from 15% in 1975 to 29% in 2009.
      • Siegel R.L.
      • Miller K.D.
      • Jemal A.
      Cancer statistics, 2015.
      However, these low survival rates suggest that most cases (over 65%) are still diagnosed at an advanced stage.

      Surveillance, Epidemiology, and End Results Program. Cancer query system: SEER Incidence Statistics (2000-2012). Available at: http://seer.cancer.gov/. Accessed March 3, 2015.

      The overall 5-year relative survival rate is about 20% in most parts of the world, but in Japan and Korea 5-year survival rates above 70% for stage I and II gastric cancer have been reported.
      • Isobe Y.
      • Nashimoto A.
      • Akazawa K.
      • et al.
      Gastric cancer treatment in Japan: 2008 annual report of the JGCA nationwide registry.
      • Jang J.S.
      • Shin D.G.
      • Cho H.M.
      • et al.
      Differences in the survival of gastric cancer patients after gastrectomy according to the medical insurance status.
      • Bollschweiler E.
      • Boettcher K.
      • Hoelscher A.H.
      • et al.
      Is the prognosis for Japanese and German patients with gastric cancer really different?.
      A multicenter retrospective study of 2191 patients with gastric cancer undergoing surgical resection showed that early gastric cancer (EGC) comprised approximately 20% of all surgically resected cancers in North America compared with 50% of resected cancers in Japan.
      • Noguchi Y.
      • Yoshikawa T.
      • Tsuburaya A.
      • et al.
      Is gastric carcinoma different between Japan and the United States?.
      Although these differences can be explained by multiple factors, one of most plausible reasons is the implementation of a screening program for detection of EGC in Japan and Korea.
      Identification of risk factors involved in carcinogenesis and interventions to address these risk factors may reduce the incidence of gastric cancer. Reducing gastric cancer mortality also requires early identification of patients who are at high risk for gastric cancer and management strategies to slow or prevent progression of gastric cancer. It is likely to be more cost-effective to detect and treat early-stage gastric cancer with endoscopic resection rather than surgical resection. In this review we discuss risk factors for gastric cancer, define high-risk groups, and summarize current guidelines for screening and surveillance strategies for these high-risk groups. Finally, we propose an algorithm for screening and surveillance of individuals who are at high risk for gastric cancer in the United States.

      Risk factors for gastric cancer

      Gastric cancer is a multifactorial disease involving both genetic and environmental risk factors. Its risk factors differ depending on whether cancers arise in the proximal cardia region or in the distal noncardia region. Advanced age, male sex, smoking, and family history are common risk factors for both cardia and noncardia cancers. In terms of race/ethnicity, whites tend to develop cardia cancer, whereas Hispanics and Asians tend to develop noncardia cancer. Helicobacter pylori infection and dietary factors, such as high intake of salt, increase the risk of noncardia cancer. On the other hand, obesity and GERD are mainly associated with cancers arising from the cardia. The estimates of risk factors for gastric cancer are summarized in Table 1.
      Table 1Main risk factors for gastric cancer according to the tumor location
      Risk estimates (95% CI)Reference
      Noncardia cancerCardia cancer
      H pylori infectionRR 2.97 (2.34-3.77)RR .99 (.72-1.35)Helicobacter and Cancer Collaborative Group
      Helicobacter and Cancer Collaborative Group
      Gastric cancer and Helicobacter pylori: a combined analysis of 12 case control studies nested within prospective cohorts.
      Cigarette smokingRR 1.60 (1.41-1.80)RR 1.87 (1.31-2.67)Ladeiras-Lopes et al
      • Ladeiras-Lopes R.
      • Pereira A.K.
      • Nogueira A.
      • et al.
      Smoking and gastric cancer: systematic review and meta-analysis of cohort studies.
      AlcoholRR 1.07 (.91-1.26)RR .94 (.78-1.13)Tramacere et al
      • Tramacere I.
      • Negri E.
      • Pelucchi C.
      • et al.
      A meta-analysis on alcohol drinking and gastric cancer risk.
      Obesity (BMI > 30)RR 1.26 (.89-1.78)RR 2.06 (1.63-2.61)Yang et al
      • Yang P.
      • Zhou Y.
      • Chen B.
      • et al.
      Overweight, obesity and gastric cancer risk: results from a meta-analysis of cohort studies.
      VegetablesRR .75 (.59-.95)RR .63 (.50-.79)Lunet et al.
      • Lunet N.
      • Valbuena C.
      • Vieira A.L.
      • et al.
      Fruit and vegetable consumption and gastric cancer by location and histological type: case-control and meta-analysis.
      FruitRR .61 (.44-.84)RR .58 (.38-.89)Lunet et al.
      • Lunet N.
      • Valbuena C.
      • Vieira A.L.
      • et al.
      Fruit and vegetable consumption and gastric cancer by location and histological type: case-control and meta-analysis.
      High salt intakeOR 2.05 (1.60-2.62)Ge et al.
      • Ge S.
      • Feng X.
      • Shen L.
      • et al.
      Association between habitual dietary salt intake and risk of gastric cancer: a systematic review of observational studies.
      Family history of gastric cancerOR 2.82 (1.83-4.46)Shin et al.
      • Shin C.M.
      • Kim N.
      • Yang H.J.
      • et al.
      Stomach cancer risk in gastric cancer relatives: interaction between Helicobacter pylori infection and family history of gastric cancer for the risk of stomach cancer.
      Intestinal metaplasiaRR 6.4 (2.6-16.1)
      In H pylori–positive individuals.
      Uemura et al.
      • Uemura N.
      • Okamoto S.
      • Yamamoto S.
      • et al.
      Helicobacter pylori infection and the development of gastric cancer.
      CI, Confidence interval; RR, relative risk; BMI, body mass index; OR, odds ratio.
      In H pylori–positive individuals.

      Age

      The incidence of gastric cancer increases with age. Between 2007 and 2011 only 6% of cases occurred in individuals younger than age 45 in the United States, whereas approximately 70% of cases were diagnosed in individuals aged 55 to 84.

      Sex

      Compared with women, men have a higher risk of both cardia (5-fold) and noncardia (2-fold) gastric cancer.
      • Brown L.M.
      • Devesa S.S.
      Epidemiologic trends in esophageal and gastric cancer in the United States.
      The reason for this difference is unclear, but environmental or occupational exposures may play a role. Men have historically tended to smoke more than women, whereas estrogens may protect against the development of gastric cancer.
      • Karimi P.
      • Islami F.
      • Anandasabapathy S.
      • et al.
      Gastric cancer: descriptive epidemiology, risk factors, screening, and prevention.
      Delayed menopause and increased fertility may lower the risk of gastric cancer, whereas antiestrogen drugs such as tamoxifen may increase the rates of gastric cancer.
      • Derakhshan M.H.
      • Liptrot S.
      • Paul J.
      • et al.
      Oesophageal and gastric intestinal-type adenocarcinomas show the same male predominance due to a 17 year delayed development in females.
      • Sheh A.
      • Ge Z.
      • Parry N.M.
      • et al.
      17Beta-estradiol and tamoxifen prevent gastric cancer by modulating leukocyte recruitment and oncogenic pathways in Helicobacter pylori-infected INS-GAS male mice.
      These hormones may protect against gastric cancer among women of childbearing age, but their effect is diminished after menopause. Consequently, women develop gastric cancer in a manner similar to men, albeit with a 10- to 15-year lag period.
      • Camargo M.C.
      • Goto Y.
      • Zabaleta J.
      • et al.
      Sex hormones, hormonal interventions, and gastric cancer risk: a meta-analysis.

      Race/ethnicity

      There is significant variability in the gastric cancer incidence across different ethnicities in the United States. Data from the 2002 to 2006 Surveillance, Epidemiology, and End Results registries show that the incidence of gastric cancer among whites (men, 10.7 per 100,000/year, and women, 5.0 per 100,000/year) is approximately half that of Asians/Pacific Islanders (men, 20.8 per 100,000/year, and women, 11.7 per 100,000/year), African Americans (men, 18.4 per 100,000/year, and women, 9.2 per 100,000/year), and Hispanics (men, 17.1 per 100,000/year, and women, 10.0 per 100,000/year) for both men and women (Fig. 1).
      • Lui F.H.
      • Tuan B.
      • Swenson S.L.
      • et al.
      Ethnic disparities in gastric cancer incidence and survival in the USA: an updated analysis of 1992-2009 SEER data.

      Surveillance, Epidemiology, and End Results Program. Cancer query system: SEER Incidence Statistics (2000-2012). Available at: http://seer.cancer.gov/. Accessed March 3, 2015.

      Among Asian American subgroups, Korean and Japanese Americans have an especially high incidence rate (Fig. 2).
      • Miller B.A.
      • Chu K.C.
      • Hankey B.F.
      • et al.
      Cancer incidence and mortality patterns among specific Asian and Pacific Islander populations in the U.S.
      In a study evaluating the effect of immigration on the incidence of gastric cancer among Japanese in Hawaii, first-generation participants had high rates of gastric cancer
      • Maskarinec G.
      • Noh J.J.
      The effect of migration on cancer incidence among Japanese in Hawaii.
      ; however, after 2 generations, gastric cancer rates among Japanese Americans had decreased to a level that was similar to those of Americans of European ancestry.
      Figure thumbnail gr1
      Figure 1Incidence of gastric cancers according to age and race in the United States, Japan, and Korea.

      Surveillance, Epidemiology, and End Results Program. Cancer query system: SEER Incidence Statistics (2000-2012). Available at: http://seer.cancer.gov/. Accessed March 3, 2015.

      Korean Statistical Information Service. Cancer registration statistics in 2012. Available at: http://kosis.kr/. Accessed July 15, 2015.

      Cancer Information Service. Cancer statistics in Japan ’13. Available at: http://ganjoho.jp/. Accessed August 6, 2015.

      Figure thumbnail gr2
      Figure 2Age-adjusted incidence rate of gastric cancer by race/ethnicity in the United States.
      • Lui F.H.
      • Tuan B.
      • Swenson S.L.
      • et al.
      Ethnic disparities in gastric cancer incidence and survival in the USA: an updated analysis of 1992-2009 SEER data.
      • Miller B.A.
      • Chu K.C.
      • Hankey B.F.
      • et al.
      Cancer incidence and mortality patterns among specific Asian and Pacific Islander populations in the U.S.
      By anatomic site, noncardia gastric cancer is approximately half as common in whites compared with other ethnic groups,
      • El-Serag H.B.
      • Mason A.C.
      • Petersen N.
      • et al.
      Epidemiological differences between adenocarcinoma of the oesophagus and adenocarcinoma of the gastric cardia in the USA.
      whereas cardia gastric cancer is approximately twice as common.
      • Brown L.M.
      • Devesa S.S.
      Epidemiologic trends in esophageal and gastric cancer in the United States.
      The risk of noncardia gastric cancer in the United States is highest among Asians/Pacific Islanders, African Americans, and Hispanics and is least common in whites.
      • Siegel R.L.
      • Miller K.D.
      • Jemal A.
      Cancer statistics, 2015.

      Helicobacter pylori

      H pylori infection triggers a series of inflammatory reactions, which are considered an important cause of chronic gastritis. Progression from chronic gastritis to gastric atrophy and IM is an early step of mucosal changes in the stomach leading to dysplasia and ultimately cancer.
      • Correa P.
      Human gastric carcinogenesis: a multistep and multifactorial process—First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention.
      H pylori has been classified as a World Health Organization Class I carcinogen since 1994 because several studies have demonstrated an association between H pylori infection and development of gastric cancer, especially intestinal-type noncardia gastric cancer.
      • Pounder R.E.
      • Ng D.
      The prevalence of Helicobacter pylori infection in different countries.
      Gastric cancer develops in approximately 1% of H pylori–infected subjects
      • de Vries A.C.
      • Kuipers E.J.
      Epidemiology of premalignant gastric lesions: implications for the development of screening and surveillance strategies.
      ; conversely, more than 90% of patients with gastric cancer have had current or past H pylori infection.
      • Kato S.
      • Matsukura N.
      • Tsukada K.
      • et al.
      Helicobacter pylori infection-negative gastric cancer in Japanese hospital patients: incidence and pathological characteristics.
      In a pooled analysis of 12 prospective studies, which included 762 patients and 2250 control subjects, the odds ratio (OR) of H pylori infection for noncardia cancer was 2.97 (95% confidence interval [CI], 2.34-3.77).
      Helicobacter and Cancer Collaborative Group
      Gastric cancer and Helicobacter pylori: a combined analysis of 12 case control studies nested within prospective cohorts.
      On the other hand, the OR of H pylori infection for cardia cancer was .99 (95% CI, .40-1.77) in an analysis of 274 patients and 827 control subjects.
      Helicobacter and Cancer Collaborative Group
      Gastric cancer and Helicobacter pylori: a combined analysis of 12 case control studies nested within prospective cohorts.
      When only cases occurring at least 10 years after the blood draw used for H pylori diagnosis were included in the pooled analysis, the OR increased to 5.93 (95% CI, 3.41-10.3) for noncardia cancer but decreased to .46 (95% CI, .23-.90) for cardia cancer.

      Family history of gastric cancer

      Having a first-degree relative with gastric cancer is associated with an OR of 2 to 10 for developing gastric cancer, depending on race.
      • Yaghoobi M.
      • Bijarchi R.
      • Narod S.A.
      Family history and the risk of gastric cancer.
      Two Western studies showed that a first-degree family history of gastric cancer increased the risk by 2.6- to 3.5-fold, with a calculated attributable risk of 8%.
      • Palli D.
      • Galli M.
      • Caporaso N.E.
      • et al.
      Family history and risk of stomach cancer in Italy.
      • La Vecchia C.
      • Negri E.
      • Franceschi S.
      • et al.
      Family history and the risk of stomach and colorectal cancer.
      A Korean study examining subjects with first-degree relatives with gastric cancer found a comparable adjusted OR of 2.85 (95% CI, 1.83-4.46).
      • Shin C.M.
      • Kim N.
      • Yang H.J.
      • et al.
      Stomach cancer risk in gastric cancer relatives: interaction between Helicobacter pylori infection and family history of gastric cancer for the risk of stomach cancer.
      In addition, in a meta-analysis studying H pylori infection and gastric histology in the first-degree relatives of gastric cancer patients, individuals with a family history of gastric cancer were approximately twice as likely to have H pylori infection, atrophic gastritis (AG), and IM.
      • Rokkas T.
      • Sechopoulos P.
      • Pistiolas D.
      • et al.
      Helicobacter pylori infection and gastric histology in first-degree relatives of gastric cancer patients: a meta-analysis.
      Up to 1% to 3% of gastric cancer cases are thought to be related to hereditary syndromes (Table 2).
      • Lynch H.T.
      • Grady W.
      • Suriano G.
      • et al.
      Gastric cancer: new genetic developments.
      Hereditary diffuse gastric cancer is a rare, autosomal dominant, genetic syndrome characterized by the early onset of diffuse gastric adenocarcinoma (ie, before age 40), an increased risk of lobular breast cancer and signet-ring cell colorectal cancer, and a poor prognosis.
      • Corso G.
      • Marrelli D.
      • Roviello F.
      Familial gastric cancer and germline mutations of E-cadherin.
      • Fitzgerald R.C.
      • Hardwick R.
      • Huntsman D.
      • et al.
      Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research.
      This syndrome is caused by a germline mutation in the CDH1 gene on chromosome 16q22, which encodes for E-cadherin. In hereditary diffuse gastric cancer families, carriage of the abnormal E-cadherin gene confers a greater than 80% lifetime risk of developing gastric cancer; therefore, carriers of the CDH1 mutation are recommended to undergo prophylactic total gastrectomy or endoscopic screening.
      • Fitzgerald R.C.
      • Hardwick R.
      • Huntsman D.
      • et al.
      Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research.
      Table 2Hereditary syndromes associated with increased risk for gastric cancer
      Hereditary syndromesGenesGastric cancer risk
      Hereditary diffuse gastric cancerCGH1>80%
      Lynch syndromeMLH1, MSH2, MSH6, PMS2, Epcam6%-13%
      Hereditary breast/ovarian cancer syndromeBRCA1/22.6%-5.5%
      Li-Fraumeni syndromep532.8%
      Familial adenomatous polyposis syndromeAPC.5%-2%
      Juvenile polyposis syndromeSMAD4, BMPR1A21%
      Peutz-Jeghers syndromeSTK1129%
      Gastric cancer risk is also increased in patients with Lynch syndrome, with affected individuals carrying a 10% lifetime risk.
      • Lynch H.T.
      • Grady W.
      • Suriano G.
      • et al.
      Gastric cancer: new genetic developments.
      Most gastric cancers (90%) that develop in patients with Lynch syndrome are intestinal-type cancers and have the same natural history as sporadic intestinal-type gastric cancer.
      • Aarnio M.
      • Salovaara R.
      • Aaltonen L.A.
      • et al.
      Features of gastric cancer in hereditary non-polyposis colorectal cancer syndrome.
      Other hereditary syndromes such as hereditary breast and ovarian cancer, Li-Fraumeni, familial adenomatous polyposis, Peutz-Jeghers, and juvenile polyposis are also associated with an increased risk for gastric cancer.
      • Chun N.
      • Ford J.M.
      Genetic testing by cancer site: stomach.

      Atrophic gastritis and intestinal metaplasia

      AG and IM are considered precursor conditions of gastric cancer, and both are strongly associated with H pylori infection.
      • Correa P.
      Human gastric carcinogenesis: a multistep and multifactorial process—First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention.
      A nationwide cohort study in the Netherlands reported that the risk of gastric cancer increased in a stepwise manner according to the severity of premalignant gastric lesions. Within 5 years of diagnosis, the annual incidence of gastric cancer was .1% for patients with AG, .25% for IM, .6% for mild-to-moderate dysplasia, and 6% for severe dysplasia.
      • de Vries A.C.
      • van Grieken N.C.
      • Looman C.W.
      • et al.
      Gastric cancer risk in patients with premalignant gastric lesions: a nationwide cohort study in the Netherlands.
      Although the risk of gastric cancer in individuals with AG depends on the severity of AG, the adjusted relative risk of gastric cancer in patients with severe AG was 5.76.
      • Tatsuta M.
      • Iishi H.
      • Nakaizumi A.
      • et al.
      Fundal atrophic gastritis as a risk factor for gastric cancer.
      Gastric cancer incidence in IM patients was reported to range from 0% to 10% in a systematic review,
      • Rugge M.
      • Correa P.
      • Dixon M.F.
      • et al.
      Gastric dysplasia: the Padova international classification.
      which may be because of the variation in sample size and follow-up period in the included studies. A nationwide, histology-based Dutch study including 61,707 patients with IM showed that the cumulative 10-year incidence of gastric cancer was 1.8% (.18% yearly),
      • de Vries A.C.
      • van Grieken N.C.
      • Looman C.W.
      • et al.
      Gastric cancer risk in patients with premalignant gastric lesions: a nationwide cohort study in the Netherlands.
      and a large Japanese study of 1246 H pylori–infected individuals with IM with a mean follow-up period of 7.8 years showed that the relative risk of progression to gastric cancer was 6.4 (95% CI, 2.6-16.1).
      • Uemura N.
      • Okamoto S.
      • Yamamoto S.
      • et al.
      Helicobacter pylori infection and the development of gastric cancer.
      The progression from gastric IM to gastric cancer is highly associated with the histologic subtype of IM. IM can be subclassified as complete type or incomplete type. Complete-type IM is characterized by the presence of a small intestinal-type mucosal phenotype with goblet cells containing sialomucin interspersed among absorptive cells and with a well-defined brush border, whereas incomplete-type IM is characterized by a colonic-type mucosal phenotype with tortuous crypts lined by tall columnar cells containing abundant sulfomucin. Incomplete type is considered to be a more advanced stage of IM and has a higher risk of progressing to gastric cancer.
      • Busuttil R.A.
      • Boussioutas A.
      Intestinal metaplasia: a premalignant lesion involved in gastric carcinogenesis.
      In a pooled analysis, 13 of 14 cross-sectional studies and 6 of 10 cohort studies reported significantly higher gastric cancer prevalence in the patients with incomplete-type IM than complete-type IM, with a relative risk of 4 to 11.
      • Uemura N.
      • Okamoto S.
      • Yamamoto S.
      • et al.
      Helicobacter pylori infection and the development of gastric cancer.
      • Gonzalez C.A.
      • Sanz-Anquela J.M.
      • Gisbert J.P.
      • et al.
      Utility of subtyping intestinal metaplasia as marker of gastric cancer risk. A review of the evidence.
      Therefore, patients found to have incomplete-type IM should undergo surveillance for gastric cancer.

      Other risk factors

      Other factors such as cigarette smoking, alcohol, obesity, fruit/vegetable consumption, and salt intake have also been investigated. Their effects appear to be modest compared with the risk factors discussed. Risk estimates are summarized in Table 1.

      Screening for gastric cancer: who and when

      Screening can be performed in the general population (mass screening) or only for individuals identified to have an increased risk for developing gastric cancer. Although the effectiveness of mass screening for gastric cancer still remains controversial,
      • Leung W.K.
      • Wu M.S.
      • Kakugawa Y.
      • et al.
      Screening for gastric cancer in Asia: current evidence and practice.
      it has been undertaken in Korea and Japan, where there is a high incidence of the disease.

      Korean Statistical Information Service. Cancer registration statistics in 2012. Available at: http://kosis.kr/. Accessed July 15, 2015.

      Cancer Information Service. Cancer statistics in Japan ’13. Available at: http://ganjoho.jp/. Accessed August 6, 2015.

      On the other hand, in countries with a low incidence of gastric cancer, such as the United States, mass screening would not be cost-effective, and only individuals identified to be at high risk for gastric cancer should be considered for screening.
      Abundant evidence shows that H pylori infection, family history of gastric cancer, and AG/IM are associated with an increased risk of gastric cancer, and therefore individuals with these risk factors could be considered high risk. However, there is significant confusion regarding management of patients with risk factors among practicing gastroenterologists, particularly in Western countries.
      • Gomez J.M.
      • Wang A.Y.
      Gastric intestinal metaplasia and early gastric cancer in the west: a changing paradigm.
      Because of the low incidence of gastric cancer in the United States, endoscopic screening is not currently recommended. However, screening and surveillance strategies are well established in the United States for Barrett’s esophagus, which likely has a lower rate of progression to adenocarcinoma than do the aforementioned risk factors for progression to gastric cancer.
      • Gomez J.M.
      • Wang A.Y.
      Gastric intestinal metaplasia and early gastric cancer in the west: a changing paradigm.
      Because endoscopic resection techniques such as EMR and endoscopic submucosal dissection are becoming increasingly available in the United States, many EGCs can be endoscopically resected without the need for surgery. Given these developments, a change in our approach to managing individuals at high risk for developing gastric cancer is needed. Because a high-risk patient population exists and endoscopic screening can further risk-stratify patients, the establishment of a screening and surveillance protocol for high-risk individuals is warranted.
      The optimal age to start screening for gastric cancer is not clear. It has been reported that it would take 44 months for early-stage gastric cancer to develop to advanced-staged disease.
      • You W.C.
      • Brown L.M.
      • Zhang L.
      • et al.
      Randomized double-blind factorial trial of three treatments to reduce the prevalence of precancerous gastric lesions.
      Because the incidence of gastric cancer increases sharply after age 40, it has been suggested that individuals older than 40 may undergo screening in high-incidence countries such as Japan and Korea.
      • Lin J.T.
      Screening of gastric cancer: who, when, and how.
      However, based on evolving data demonstrating a decreasing incidence of gastric cancer in individuals between ages 40 and 49 years in Japan, the new national guidelines in Japan now recommend that screening be started at age 50. Other authors outside Korea also recommend screening commencement after age 50.
      • Areia M.
      • Carvalho R.
      • Cadime A.T.
      • et al.
      Screening for gastric cancer and surveillance of premalignant lesions: a systematic review of cost-effectiveness studies.
      Given the incidence of gastric cancer by age and the incidence threshold used to recommend colorectal cancer screening in the United States (∼50 per 100,000), endoscopic screening for gastric cancer in asymptomatic adults from high-risk populations should be considered starting at age 50. A study evaluating the cost-effectiveness of screening the general population for upper GI (UGI) cancers including EGC in the United States by performing an upper endoscopy at the time of screening colonoscopy showed that the incremental cost-effectiveness ratio for this intervention was $95,559 per quality-adjusted life year saved; this is comparable with published incremental cost-effectiveness ratios for other cancer screening interventions that are commonly performed in the United States.
      • Gupta N.
      • Bansal A.
      • Wani S.B.
      • et al.
      Endoscopy for upper GI cancer screening in the general population: a cost-utility analysis.
      Therefore, a screening program targeting a smaller high-risk population should be substantially more cost-effective.

      Methods for gastric cancer screening

      Screening for gastric cancer generally involves 4 methods: UGI series, serum pepsinogen (PG) testing, H pylori serology, and endoscopy. The ideal screening test should be simple, safe, validated, and tolerable to patients; however, there is no single method that meets all these criteria. Pros and cons of each screening method are discussed below and summarized in Table 3.
      Table 3Pros and cons of each screening method for gastric cancer
      ProsCons
      H pylori serologyNoninvasiveVery low sensitivity

      Does not detect premalignant lesions
      Serum pepsinogen testingNoninvasive

      Acceptable sensitivity and specificity

      Predicts premalignant lesions
      Optimal cut-off values can be affected by several factors (age, sex, race)

      Requires endoscopy for confirmation
      Upper gastrointestinal seriesNoninvasive

      Moderate evidence
      Exposure to radiation

      Requires endoscopy for confirmation
      EndoscopyMost accurate

      Biopsy sampling can be performed
      Invasive and expensive

      Low evidence

      H pylori serology

      H pylori serology as a screening test for gastric cancer is limited by low sensitivity and a failure to detect premalignant lesions. It is often negative in the presence of longstanding AG/IM. Even though H pylori virulence factors such as Cag A, Vac A, and Bab A may increase its sensitivity for gastric cancer detection, their sensitivity is still low.
      • Ley C.
      • Mohar A.
      • Guarner J.
      • et al.
      Screening markers for chronic atrophic gastritis in Chiapas, Mexico.
      Therefore, H pylori serology is not useful as a stand-alone screening test.

      Serum PG testing

      PG is a precursor of pepsin that is produced in the gastric mucosa. PG is classified biochemically and immunologically into 2 different isozymes, PG I and PG II. PG I is produced by chief cells in the gastric fundus and body, and PG II is produced by the cells throughout the entire stomach.
      • Samloff I.M.
      Cellular localization of group I pepsinogens in human gastric mucosa by immunofluorescence.
      • Samloff I.M.
      • Liebman W.M.
      Cellular localization of the group II pepsinogens in human stomach and duodenum by immunofluorescence.
      A decrease in serum PG I level and PG I/II ratio is associated with the extent of gastric atrophy and reduction in gastric acid secretion ability. Stepwise decrease in the PG I/II ratio is closely correlated with the progression of gastric atrophy.
      • Borch K.
      • Axelsson C.K.
      • Halgreen H.
      • et al.
      The ratio of pepsinogen A to pepsinogen C: a sensitive test for atrophic gastritis.
      • Asaka M.
      • Kato M.
      • Kudo M.
      • et al.
      Relationship between Helicobacter pylori infection, atrophic gastritis and gastric carcinoma in a Japanese population.
      Therefore, serum PG level has been suggested to be a useful marker of AG, which in turn is a precursor of intestinal-type adenocarcinoma in the stomach.
      To detect gastric cancer, serum PG testing, followed by endoscopic examination, has been introduced in mass screenings of high-risk patients for gastric cancer. PG I ≤ 70 ng/L and PG I/II ratio ≤ 3.0 are associated with an increased risk for gastric cancer.
      • Watabe H.
      • Mitsushima T.
      • Yamaji Y.
      • et al.
      Predicting the development of gastric cancer from combining Helicobacter pylori antibodies and serum pepsinogen status: a prospective endoscopic cohort study.
      • Yanaoka 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.
      • Oishi Y.
      • Kiyohara Y.
      • Kubo M.
      • et al.
      The serum pepsinogen test as a predictor of gastric cancer: the Hisayama study.
      In a pooled meta-analysis assessing approximately 300,000 people, the sensitivity and specificity of serum PG testing for gastric cancer screening were 77% and 73%, respectively.
      • Dinis-Ribeiro M.
      • da Costa-Pereira A.
      • Lopes C.
      • et al.
      Validity of serum pepsinogen I/II ratio for the diagnosis of gastric epithelial dysplasia and intestinal metaplasia during the follow-up of patients at risk for intestinal-type gastric adenocarcinoma.
      In a case-control study using serum PG level for gastric cancer screening, the ORs for death from gastric cancer among control subjects screened within 1 and 2 years were .24 (95% CI, .06-.93) and .38 (95% CI, .16-.91), respectively.
      • Yoshihara M.
      • Hiyama T.
      • Yoshida S.
      • et al.
      Reduction in gastric cancer mortality by screening based on serum pepsinogen concentration: a case-control study.
      These results suggest that gastric cancer screening using serum PG level may decrease gastric cancer mortality; however, the evidence was not considered to be strong enough to incorporate serum PG testing into the national screening program in Japan.
      • Sugano K.
      Screening of gastric cancer in Asia.
      The limitations of using serum PG include variable proposed cut-off values for PG I and the PG I/II ratio, lack of sensitivity and specificity, variability of PG I and the PG I/II ratio (depending on age, sex, and race), and scant and inconclusive data outside of Japan.
      Combining H pylori serology and serum PG testing may provide additional information for predicting the development of gastric cancer. It has been reported that a combination of low PG I or PG I/II ratio with negative H pylori serology antibodies suggests the highest risk for gastric cancer,
      • Watabe H.
      • Mitsushima T.
      • Yamaji Y.
      • et al.
      Predicting the development of gastric cancer from combining Helicobacter pylori antibodies and serum pepsinogen status: a prospective endoscopic cohort study.
      because it may indicate extensive atrophy where the H pylori burden in the stomach is reduced.

      UGI series

      The barium meal indirect radiograph examination was introduced as a mass screening program for gastric cancer in the 1960s in Japan.
      • Hisamichi S.
      • Sugawara N.
      Mass screening for gastric cancer by X-ray examination.
      In a meta-analysis including 5 case-control studies and 2 cohort studies, gastric cancer screening using UGI series was reported to be useful,
      • Hamashima C.
      • Shibuya D.
      • Yamazaki H.
      • et al.
      The Japanese guidelines for gastric cancer screening.
      but the evidence is weak.
      • Asaka M.
      • Kato M.
      • Takahashi S.
      • et al.
      Guidelines for the management of Helicobacter pylori infection in Japan: 2009 revised edition.
      The sensitivity of UGI series ranged from 60% to 80%, whereas the specificity and true positive rate were 90% and .7% to 2.0%, respectively.
      • Kato M.
      • Asaka M.
      Recent development of gastric cancer prevention.
      Case-control studies conducted in Japan showed that screening by UGI series resulted in a 40% to 60% reduction in gastric cancer mortality, which is the primary reason this remains an accepted method for the national gastric cancer screening programs in Japan and Korea.
      • Fukao A.
      • Tsubono Y.
      • Tsuji I.
      • et al.
      The evaluation of screening for gastric cancer in Miyagi Prefecture, Japan: a population-based case-control study.
      • Inaba S.
      • Hirayama H.
      • Nagata C.
      • et al.
      Evaluation of a screening program on reduction of gastric cancer mortality in Japan: preliminary results from a cohort study.

      Endoscopy

      Endoscopy is the only method available for direct visual examination of the gastric mucosa, and it allows for biopsy sampling so that histologic evaluation can be performed. Endoscopy is the criterion standard test for diagnosing gastric cancer because of its high detection rate. Although UGI series was the initial tool for mass screening of gastric cancer, a cohort analysis demonstrated that endoscopy resulted in a 3- to 5-fold higher detection rate for EGC compared with UGI series and was also more cost-effective.
      • Tashiro A.
      • Sano M.
      • Kinameri K.
      • et al.
      Comparing mass screening techniques for gastric cancer in Japan.
      • Cho E.
      • Kang M.H.
      • Choi K.S.
      • et al.
      Cost-effectiveness outcomes of the national gastric cancer screening program in South Korea.
      The sensitivity of endoscopy for identifying gastric cancer is reported to be 78% to 84%.
      • Hosokawa O.
      • Hattori M.
      • Takeda T.
      • et al.
      Accuracy of endoscopy in detecting gastric cancer.
      • Otsuji M.
      • Kouno Y.
      • Otsuji A.
      • et al.
      Assessment of small diameter panendoscopy for diagnosis of gastric cancer: comparative study with follow-up survey date.
      In Japan and Korea, endoscopy has become the primary method for gastric cancer screening given its superior test characteristics, availability, and affordability (EGD costs approximately U.S.$40 in Korea).
      • Cho E.
      • Kang M.H.
      • Choi K.S.
      • et al.
      Cost-effectiveness outcomes of the national gastric cancer screening program in South Korea.
      However, the use of endoscopy for gastric cancer screening in the United States does have several potential limitations, such as the need for additional trained endoscopists to meet the increased demand, potential adverse events of endoscopy, patient acceptance, and cost.
      • Kato M.
      • Asaka M.
      Recent development of gastric cancer prevention.
      Several studies suggest that advanced endoscopic imaging modalities such as chromoendoscopy or narrow-band imaging can increase accuracy for diagnosing gastric neoplasia compared with standard white light endoscopy. Chromoendoscopy using indigo carmine and acetic acid has been demonstrated to clarify subtle mucosal irregularities and to delineate the lateral extent of EGCs.
      • Lee B.E.
      • Kim G.H.
      • Park do Y.
      • et al.
      Acetic acid-indigo carmine chromoendoscopy for delineating early gastric cancers: its usefulness according to histological type.
      • Eleftheriadis N.
      • Inoue H.
      • Ikeda H.
      • et al.
      Acetic acid spray enhances accuracy of narrow-band imaging magnifying endoscopy for endoscopic tissue characterization of early gastric cancer.
      Methylene blue magnification chromoendoscopy was shown to identify IM and intestinal dysplasia with sensitivities of 76% and 97% and specificities of 87% and 81%, respectively, and good interobserver agreement (κ = .74).
      • Areia M.
      • Amaro P.
      • Dinis-Ribeiro M.
      • et al.
      External validation of a classification for methylene blue magnification chromoendoscopy in premalignant gastric lesions.
      Narrow-band imaging and digital-based image enhancement technologies such as computed virtual chromoendoscopy have been reported to increase the diagnostic yield and accuracy for the detection of gastric neoplasia; however, imaging criteria are inconsistent between studies and comparative or validation studies have yet to be performed.
      • Kaise M.
      Advanced endoscopic imaging for early gastric cancer.
      • Li H.Y.
      • Dai J.
      • Xue H.B.
      • et al.
      Application of magnifying endoscopy with narrow-band imaging in diagnosing gastric lesions: a prospective study.
      • Li C.Q.
      • Li Y.
      • Zuo X.L.
      • et al.
      Magnified and enhanced computed virtual chromoendoscopy in gastric neoplasia: a feasibility study.
      • Alaboudy A.A.
      • Elbahrawy A.
      • Matsumoto S.
      • et al.
      Conventional narrow-band imaging has good correlation with histopathological severity of Helicobacter pylori gastritis.
      • Capelle L.G.
      • Haringsma J.
      • de Vries A.C.
      • et al.
      Narrow band imaging for the detection of gastric intestinal metaplasia and dysplasia during surveillance endoscopy.
      • Pohl J.
      • May A.
      • Rabenstein T.
      • et al.
      Computed virtual chromoendoscopy: a new tool for enhancing tissue surface structures.
      Furthermore, because of the rapid development of imaging technologies (including the resolution of white-light endoscopy), it is difficult to make any definitive conclusions regarding any of the advanced imaging technologies. A consensus on criteria for characterizing mucosal patterns is needed to further study the role of mucosal enhancement imaging technologies to obtain an accurate assessment of their validity and performance. Further studies are required to assess the ability of new imaging technologies to identify gastric IM and EGCs. Based on the existing evidence and ease of use, it is reasonable to apply technologies such as narrow-band imaging or digital-based image enhancement technologies in addition to high-definition white-light endoscopy to examine the gastric mucosa and target biopsy sampling.

      Results of national screening programs

      In Japan, annual gastric cancer screening for all residents aged 40 years and older with UGI series was initiated in 1983.
      • Hamashima C.
      • Shibuya D.
      • Yamazaki H.
      • et al.
      The Japanese guidelines for gastric cancer screening.
      In 2015 the Japanese guidelines were updated to allow screening to be performed with either UGI series or endoscopy based on studies from Japan demonstrating a decrease in mortality from gastric cancer when screening is performed with either method.
      • Sugano K.
      Screening of gastric cancer in Asia.
      • Hamashima C.
      • Ogoshi K.
      • Okamoto M.
      • et al.
      A community-based, case-control study evaluating mortality reduction from gastric cancer by endoscopic screening in Japan.
      • Hosokawa O.
      • Miyanaga T.
      • Kaizaki Y.
      • et al.
      Decreased death from gastric cancer by endoscopic screening: association with a population-based cancer registry.
      • Lee K.J.
      • Inoue M.
      • Otani T.
      • et al.
      Gastric cancer screening and subsequent risk of gastric cancer: a large-scale population-based cohort study, with a 13-year follow-up in Japan.
      • Mizoue T.
      • Yoshimura T.
      • Tokui N.
      • et al.
      Prospective study of screening for stomach cancer in Japan.
      In addition, screening starting at age 50 and performed every 2 to 3 years is now recommended. The proportion of EGC in Japan is more than 50% of all gastric cancers diagnosed, whereas in Europe EGC only comprises 15% of all cases.
      • Yoon H.
      • Kim N.
      Diagnosis and management of high risk group for gastric cancer.
      Similarly, in Korea the National Cancer Screening Program for gastric cancer screening that began in 1999 recommends endoscopy or UGI series for individuals aged 40 years and older every 2 years.
      • Choi I.J.
      Gastric cancer screening and diagnosis.
      As a result approximately 46% to 67% of gastric cancers are detected at an early stage by screening,
      • Choi K.S.
      • Kwak M.S.
      • Lee H.Y.
      • et al.
      Screening for gastric cancer in Korea: population-based preferences for endoscopy versus upper gastrointestinal series.
      and the 5-year survival rate has increased from 43% in 1993 to 1995 to 69% in 2006 to 2011; however, reduction in mortality from gastric cancer as a result of screening has yet to be demonstrated.

      Korean Statistical Information Service. Cancer registration statistics in 2012. Available at: http://kosis.kr/. Accessed July 15, 2015.

      These data from Japan and Korea support the effectiveness of screening for gastric cancer in high-risk populations.

      Screening intervals

      Few studies have addressed the optimal interval for endoscopic screening for gastric cancer, and no guidelines exist. In a prospective study in which population-based screening using endoscopy was performed twice over a 5-year interval in China, which also has a high incidence of gastric cancer, no reduction in mortality from gastric cancer was observed.
      • Riecken B.
      • Pfeiffer R.
      • Ma J.L.
      • et al.
      No impact of repeated endoscopic screens on gastric cancer mortality in a prospectively followed Chinese population at high risk.
      On the other hand, in a Japanese study the 5-year survival rate for patients who had undergone endoscopy within 2 years before the detection of gastric cancer was significantly higher than that for patients who had not undergone endoscopy within 2 years.
      • Mori Y.
      • Arita T.
      • Shimoda K.
      • et al.
      Effect of periodic endoscopy for gastric cancer on early detection and improvement of survival.
      However, the survival rates were not different between the patients who had undergone endoscopy within 1 year before the detection of gastric cancer and the patients who had undergone endoscopy between 1 and 2 years. These results suggest that every 2 years may be an optimal interval for endoscopic screening for gastric cancer. Another Korean study also showed that endoscopic screening every 2 years decreased the incidence of gastric cancer and that endoscopic resection could be applied to more patients who underwent EGD screening within 2 years.
      • Nam S.Y.
      • Choi I.J.
      • Park K.W.
      • et al.
      Effect of repeated endoscopic screening on the incidence and treatment of gastric cancer in health screenees.
      Appropriateness of the above-mentioned interval for surveillance endoscopy is not well documented in Western countries. However, 2 cohort studies in England
      • Whiting J.L.
      • Sigurdsson A.
      • Rowlands D.C.
      • et al.
      The long term results of endoscopic surveillance of premalignant gastric lesions.
      and Italy
      • Tava F.
      • Luinetti O.
      • Ghigna M.R.
      • et al.
      Type or extension of intestinal metaplasia and immature/atypical “indefinite-for-dysplasia” lesions as predictors of gastric neoplasia.
      showed that only 36% and 38% of detected gastric cancers were in an early stage when the endoscopic surveillance interval was 1 or 2 years, respectively. Based on these results, it seems that a 3-year interval follow-up is not appropriate in clinical practice. Therefore, a European review article proposed that annual endoscopic surveillance would appear justified in all patients with IM having at least 1 of following additional risk factors: IM extension > 20%, presence of incomplete-type IM, first-degree relative with gastric cancer, and smokers.
      • Zullo A.
      • Hassan C.
      • Romiti A.
      • et al.
      Follow-up of intestinal metaplasia in the stomach: when, how and why.
      In the remaining IM patients, surveillance endoscopy with a 2- to 3-year interval is recommended. According to the consensus guidelines from the European Gastroenterology Societies, it is recommended that patients with extensive AG and/or IM should be offered surveillance endoscopy once every 3 years.
      • Dinis-Ribeiro M.
      • Areia M.
      • de Vries A.C.
      • et al.
      Management of precancerous conditions and lesions in the stomach (MAPS): guideline from the European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter Study Group (EHSG), European Society of Pathology (ESP), and the Sociedade Portuguesa de Endoscopia Digestiva (SPED).
      Correa et al
      • Correa P.
      • Piazuelo M.B.
      • Wilson K.T.
      Pathology of gastric intestinal metaplasia: clinical implications.
      proposed that U.S. patients with extensive gastric IM (defined as IM present in at least 2 gastric locations or moderate or marked IM in at least 2 biopsy specimens) or incomplete-type IM found on index endoscopy undergo surveillance endoscopy with mapping or serum PG testing at 1 year and then repeat surveillance endoscopy every 3 years if extensive AG/IM or incomplete-type IM persists.
      At the present time there are no well-defined guidelines regarding screening for gastric cancer or surveillance of gastric intestinal metaplasia in the United States. The 2015 American Society for Gastrointestinal Endoscopy guidelines suggest that surveillance endoscopy be performed in patients with gastric intestinal metaplasia who are at an increased risk of gastric cancer because of ethnic background or family history and that surveillance intervals should be individualized.
      • Evans J.A.
      • Chandrasekhara V.
      • Chathadi K.V.
      • et al.
      ASGE Standards of Practice Committee
      The role of endoscopy in the management of premalignant and malignant conditions of the stomach.
      Table 4 summarizes previously proposed intervals for endoscopic surveillance in individuals at high risk for gastric cancer.
      Table 4Suggested intervals of surveillance endoscopy in individuals at high risk for gastric cancer
      Country/regionIndication for surveillanceSurveillance interval (y)Reference and year
      AustraliaIM1-3Busuttil et al,
      • Busuttil R.A.
      • Boussioutas A.
      Intestinal metaplasia: a premalignant lesion involved in gastric carcinogenesis.
      2009
      United StatesExtensive AG/IM
      Definition of extensive AG: serum PG I level < 70 μg/L and a PG I/PG II ratio < 3; definition of extensive IM: (1) IM present in at least 2 gastric locations or (2) moderate or marked IM in at least 2 biopsy specimens.
      3Correa et al,
      • Correa P.
      • Piazuelo M.B.
      • Wilson K.T.
      Pathology of gastric intestinal metaplasia: clinical implications.
      2010
      ItalyHigh-risk IM
      (1) IM extension > 20%, (2) the presence of incomplete type IM, (3) first-degree relative of gastric cancer patients, and (4) smokers.
      1Zullo et al,
      • Zullo A.
      • Hassan C.
      • Romiti A.
      • et al.
      Follow-up of intestinal metaplasia in the stomach: when, how and why.
      2012
      Low-risk IM2-3
      EuropeExtensive AG/IM1Dinis-Ribeiro et al,
      • Dinis-Ribeiro M.
      • Areia M.
      • de Vries A.C.
      • et al.
      Management of precancerous conditions and lesions in the stomach (MAPS): guideline from the European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter Study Group (EHSG), European Society of Pathology (ESP), and the Sociedade Portuguesa de Endoscopia Digestiva (SPED).
      2012
      KoreaAG/IM or family history of gastric cancer1Yoon et al,
      • Yoon H.
      • Kim N.
      Diagnosis and management of high risk group for gastric cancer.
      2015
      IM, Intestinal metaplasia; AG, atrophic gastritis.
      Definition of extensive AG: serum PG I level < 70 μg/L and a PG I/PG II ratio < 3; definition of extensive IM: (1) IM present in at least 2 gastric locations or (2) moderate or marked IM in at least 2 biopsy specimens.
      (1) IM extension > 20%, (2) the presence of incomplete type IM, (3) first-degree relative of gastric cancer patients, and (4) smokers.

      Proposed algorithm for screening and surveillance of gastric cancer in the United States

      Based on the aforementioned evidence and guidelines, we propose the following simplified strategy for gastric cancer screening and surveillance of high-risk individuals (excluding those with hereditary diseases) according to race, H pylori infection status, family history of gastric cancer, and AG/IM status (Fig. 3). We recommend endoscopic screening for gastric cancer starting at age 50 for individuals who are first- or second-generation immigrants from high-incidence regions (East Asia, Russia, and South America). Individuals with a family history of gastric cancer are recommended to begin endoscopic screening 10 years before diagnosis in the affected relative, similar to recommendations for colorectal cancer.
      • Samadder N.J.
      • Jasperson K.
      • Burt R.W.
      Hereditary and common familial colorectal cancer: evidence for colorectal screening.
      At the time of screening endoscopy, at least 5 nontargeted biopsy specimens should be obtained according to the updated Sydney System, which includes 2 biopsy samples from the antrum (lesser and greater curvature), 1 biopsy sample from the incisura angularis, and 2 biopsy samples from the body (lesser and greater curvature).
      • Dixon 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.
      Biopsy specimens should be submitted for pathologic evaluation in separate vials labeled by region of the stomach (antrum, incisura angularis, and body). This biopsy protocol has been demonstrated to be both sensitive for the identification of H pylori infection and AG/IM when performed in a population considered to be at high risk for gastric preneoplastic lesions.
      • Guarner J.
      • Herrera-Goepfert R.
      • Mohar A.
      • et al.
      Diagnostic yield of gastric biopsy specimens when screening for preneoplastic lesions.
      Additional targeted biopsy samples of visible lesions should also be obtained and submitted in separate vials.
      • Dinis-Ribeiro M.
      • Areia M.
      • de Vries A.C.
      • et al.
      Management of precancerous conditions and lesions in the stomach (MAPS): guideline from the European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter Study Group (EHSG), European Society of Pathology (ESP), and the Sociedade Portuguesa de Endoscopia Digestiva (SPED).
      Figure thumbnail gr3
      Figure 3Suggested screening algorithm for gastric cancer in the United States. East Asia, Russia, and South America. If there is a first-degree relative with gastric cancer, start screening 10 years before the age at diagnosis in the first-degree relative or age 50 (whichever is earlier).
      HP, H pylori; FHx, family history of gastric cancer; AG, atrophic gastritis; IM, intestinal metaplasia.
      After screening EGD, those with no H pylori infection, no family history of gastric cancer, and no AG/IM identified on screening endoscopy require no further follow-up. Those with H pylori infection alone should be treated for H pylori eradication therapy with confirmation of eradication and then undergo endoscopic examination in 3 to 5 years to evaluate for progression to AG/IM. If there is no evidence of progression to AG/IM, then surveillance can be discontinued because the risk of gastric cancer is low in the absence of AG/IM. Additionally, those at high risk (family history of gastric cancer or presence of AG/IM) should undergo endoscopy every 1 to 2 years with eradication therapy in patients with H pylori infection. Prospective studies are needed to assess whether this screening and surveillance protocol for gastric cancer in the United States will produce a survival benefit similar to that observed in Korea and Japan.

      Conclusions

      Comprehensive U.S. guidelines for gastric cancer screening and surveillance of high-risk individuals are warranted. The optimal gastric cancer prevention program will combine risk stratification for screening and surveillance for high-risk groups. Because race, H pylori infection, family history of gastric cancer, and AG/IM are significant risk factors for gastric cancer, the initial approach should be to identify individuals with these risk factors. Although large, prospective, multicenter studies are needed to evaluate the effectiveness of screening and surveillance strategies to detect gastric cancer, it would be reasonable to begin screening individuals who are at high risk for developing gastric cancer and then to perform surveillance endoscopy at 1- or 2-year intervals if IM is identified on screening endoscopy or if the patient has a family history of gastric cancer. Gastric cancer screening in the appropriate population will likely lead to an increase in the detection of EGCs, which may improve the likelihood of being able to intervene with endoscopic therapy, such as endoscopic submucosal dissection, and reduce mortality from gastric cancer.

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