Atrophic Gastritis and Stomach Cancer Risk: Cross-sectional Analyses

The relationship between atrophic gastritis and stomach cancer risk was investigated in case-control analyses involving 387 cases with stomach cancer and 5,422 control subjects who received gastroscopic examination at Aichi Cancer Center Hospital from April, 1985 to March, 1989. The presence of atrophic gastritis, the degree and extension of the atrophy and the presence of granularity and erosion were diagnosed endoscopically by six gastroenterologists. The prevalence of atrophic gastritis increased with age and was higher in males than in females. The relative risk (RR) of stomach cancer was S.13 (95% confidence interval (CI): 2.79–9.42) if a subject had any type of atrophic gastritis. The risk further increased with advancing degree of atrophy and increasing extension on the greater and lesser curvatures. The RR associated with severe atrophy was 7.73 (95% CI: 3.95–15.12). These associations remained significant when analyzed by sex and age. The presence of granularity and erosion did not much affect the estimated risks. A clear difference in risk appeared in the analyses by histological type of cancer. The RR associated with atrophic gastritis was 24.71 (95% CI: 3.46–176.68) for the intestinal type and 3.49 (95% CI: 1.77–6.87) for the diffuse type. These findings may suggest a need for intensive follow-up of patients with severe atrophic gastritis.     

Atrophic gastritis and stomach cancer risk: cross-sectional analyses.

The relationship between atrophic gastritis and stomach cancer risk was investigated in case-control analyses involving 387 cases with stomach cancer and 5,422 control subjects who received gastroscopic examination at Aichi Cancer Center Hospital from April, 1985 to March, 1989. The presence of atrophic gastritis, the degree and extension of the atrophy and the presence of granularity and erosion were diagnosed endoscopically by six gastroenterologists. The prevalence of atrophic gastritis increased with age and was higher in males than in females. The relative risk (RR) of stomach cancer was 5.13 (95% confidence interval (CI): 2.79-9.42) if a subject had any type of atrophic gastritis. The risk further increased with advancing degree of atrophy and increasing extension on the greater and lesser curvatures. The RR associated with severe atrophy was 7.73 (95% CI: 3.95-15.12). These associations remained significant when analyzed by sex and age. The presence of granularity and erosion did not much affect the estimated risks. A clear difference in risk appeared in the analyses by histological type of cancer. The RR associated with atrophic gastritis was 24.71 (95% CI: 3.46-176.68) for the intestinal type and 3.49 (95% CI: 1.77-6.87) for the diffuse type. These findings may suggest a need for intensive follow-up of patients with severe atrophic gastritis.     

A prospective study of atrophic gastritis and stomach cancer risk.

The relation of atrophic gastritis, other gastric lesions and lifestyle factors to stomach cancer risk was prospectively studied among 3,914 subjects who underwent gastroscopic examination and responded to a questionnaire survey at the Aichi Cancer Center Hospital. During 4.4 years of follow-up on average, 45 incident cases of stomach cancer were identified at least three months after the initial examination. If the baseline endoscopic findings indicated the presence of atrophic gastritis, the risk of developing stomach cancer was increased 5.73-fold, compared with no indication at the baseline. The risk further increased with advancing degree of atrophy and increasing extension of atrophy on the lesser curvature. These trends in the relative risks were statistically significant (P = 0.027 and P = 0.041, respectively). The risk of developing stomach cancer was statistically significantly increased among subjects with gastric polyps, but not among those with gastric ulcer. Stomach cancer cases tended to consume more cigarettes, alcohol, rice, pickles and salted fish gut/cod roe and less fruits and vegetables and to have more family histories of stomach cancer than noncases, although these differences were not statistically significant. The results of the present study provide additional evidence on the relation between atrophic gastritis and stomach cancer and suggest a need for intensive follow-up of patients with atrophic gastritis and gastric polyps.     

A Prospective Study of Atrophic Gastritis and Stomach Cancer Risk

The relation of atrophic gastritis, other gastric lesions and lifestyle factors to stomach cancer risk was prospectively studied among 3,914 subjects who underwent gastroscopic examination and responded to a questionnaire survey at the Aichi Cancer Center Hospital. During 4.4 years of follow-up on average, 45 incident cases of stomach cancer were identified at least three months after the initial examination. If the baseline endoscopic findings indicated the presence of atrophic gastritis, the risk of developing stomach cancer was increased 5.73-fold, compared with no indication at the baseline. The risk further increased with advancing degree of atrophy and increasing extension of atrophy on the lesser curvature. These trends in the relative risks were statistically significant ( P = 0.027 and P = 0.041, respectively). The risk of developing stomach cancer was statistically significantly increased among subjects with gastric polyps, but not among those with gastric ulcer. Stomach cancer cases tended to consume more cigarettes, alcohol, rice, pickles and salted fish gut/cod roe and less fruits and vegetables and to have more family histories of stomach cancer than noncases, although these differences were not statistically significant. The results of the present study provide additional evidence on the relation between atrophic gastritis and stomach cancer and suggest a need for intensive follow-up of patients with atrophic gastritis and gastric polyps.     

A comparative case-control analysis of stomach cancer and atrophic gastritis

We conducted a comparative case-control analysis of stomach cancer and atrophic gastritis involving 427 cases with stomach cancer, 1414 cases with atrophic gastritis, and 3014 control subjects based on a questionnaire survey conducted for the subjects who received gastroscopic examination at Aichi Cancer Center Hospital from April 1985 to March 1989. The risk of atrophic gastritis in both males and females was not associated with any environmental factors. The risk of stomach cancer compared with the control subjects was positively associated with an intake of salted fish guts or cod roe [relative risk (RR) = 1.52, 95% confidence interval (CI) = 1.08-2.15] and smoking (RR for 20 or more cigarettes per day = 2.84; 95% CI = 1.79-4.51) and inversely associated with Western-style breakfast (RR = 0.68; 95% CI = 0.48-0.96) in males. Additionally, the risk of stomach cancer was inversely associated with a daily intake of raw vegetables (RR = 0.56; 95% CI = 0.34-0.94) in males when compared with the patients with atrophic gastritis as controls. Several environmental factors, such as intake of green-yellow vegetables, fruit, and meat, and a family history of stomach cancer, were only associated with intestinal types of cancer in females, whereas a clear difference between diffuse and intestinal types was not observed in males. The results of the present study suggest that risk factors for stomach cancer may be different from those for premalignant lesions.     

An investigation of possible risk factors associated with gastric cancer after benign ulcer operations

The risk of developing gastric cancer has been investigated in a case-control study and in a prospective investigation. In the case-control study, 1495 cases of gastric cancer were identified in five city hospitals and matched with autopsy controls from the same hospitals. The frequency of operations for benign ulcer [partial gastrectomy (PG) and gastroenterostomy] was similar in the two groups. Thus, there was no increased risk for late gastric cancer after an ulcer operation. A total of 140 operated ulcer subjects [80 truncal vagotomy and drainage (TVD), 60 PG and 78 nonoperated cases attending with dyspepsia (C)] were examined by endoscopy, multiple gastric biopsy and analysis of gastric juice for nitrite. Biopsies were graded for gastritis and a gastritis index was derived (normal, 1; superficial gastritis, 2; chronic atrophic gastritis: mild, 3; moderate, 4; severe, 5). More atrophic gastritis was found in operated subjects than in controls: TVD, 2.3 +/- 0.08 (mean +/- SE); PG, 2.6 +/- 0.1 versus C, 1.8 +/- 0.08, p less than 0.01. The severity of atrophic gastritis increased after an operation interval of 20 years in PG subjects (p less than 0.05). Intestinal metaplasia was a common change, but unequivocal epithelial dysplasia was not observed. Two cases of operated stomach cancer were found. High levels of nitrite were positively correlated with pH and a high gastritis index. This evidence does not suggest that ulcer surgery leads to either an increased risk of cancer or a precancerous condition.     

Functional promoter polymorphisms of the macrophage migration inhibitory factor gene in gastric carcinogenesis

The macrophage migration inhibitory factor (MIF) is a key proinflammatory mediator. Two functional polymorphisms have been identified in the promoter region of the MIF gene. We attempted to clarify the associations of these polymorphisms with the development of gastric cancer. The study was performed in 229 patients with gastric cancer and 428 subjects with no evidence of gastric malignancies on the upper gastro-duodenal endoscopy. The severity of histological chronic gastritis was classified according to the updated Sydney system. Overall, the 5-CATT carriers had a reduced risk of developing gastric cancer (OR, 0.67; 96% CI, 0.48-0.93; p=0.015), especially the diffuse type cancer. In subjects >60 years, the adjusted risk for gastric cancer among individuals who were -173C carriers was 1.71 (range, 1.03-2.84; p=0.038) compared to the G/G homozygous genotype. The number of 7-CATT alleles was also positively correlated with the development of intestinal type gastric cancer (adjusted OR, 1.70; 95% CI, 1.02-2.58; p=0.043). In subjects <60 years, the 7/7-CATT homozygous genotype was linked with a risk for the progression of atrophic gastritis (adjusted OR, 8.74; 95% CI, 1.31-58.6; p=0.026). In addition, the number of 7-CATT alleles was significantly correlated with the activity and inflammation scores (p=0.010 and 0.030, respectively). Our results suggested that functional promoter polymorphisms of the MIF gene are associated with the progression of gastric mucosal inflammation and the development of mucosal atrophy at an early stage in life and these genotypes may increase the risk for the subsequent development of gastric cancer, especially the intestinal type, in older subjects.     

Helicobacter pylori gastritis and serum pepsinogen levels in a healthy population: development of a biomarker strategy for gastric atrophy in high risk groups.

This study aimed to estimate the prevalence and type of chronic gastritis in an asymptomatic working population and to determine whether a combination of serum pepsinogen levels and Helicobacter pylori serology could be used to identify a subgroup with atrophic gastritis at elevated risk of gastric carcinoma. A 10% subsample of 544 male volunteer factory workers aged 18-63 years and participating in a larger study underwent endoscopy and biopsy. Of these men, 29 were seropositive for Helicobacter pylori; all but three (89.7%) had chronic gastritis. Serum pepsinogen A levels increased with progression from a corpus predominant pattern of gastritis through pangastritis to an antral predominant pattern. Nine subjects had corpus atrophy, which was in most cases accompanied by fasting hypochlorhydria and hypergastrinaemia. A combination of pepsinogen A below 80 ng ml-1 and Helicobaceter pylori seropositivity detected corpus atrophy with sensitivity 88.9% and specificity 92.3%. A second screening stage, using a pepsinogen A/C ratio of below 2.5 as a cut-off, resulted in a reduction in numbers requiring further investigation but with some loss of sensitivity (77.8%). Application of this two-stage screening programme to the original sample of 544 workers would have resulted in 11 (2.2%) men being selected for follow-up, excluding 25 (5.1%) false negatives. Our results suggest that a combination of serum pepsinogen levels and Helicobacter pylori serology could be useful as a biomarker strategy for detection of individuals at increased risk of gastric carcinoma and for non-invasive investigation of the natural history of Helicobacter pylori gastritis.     

Lifestyle factors associated with atrophic gastritis among <Emphasis Type="Italic">Helicobacter pylori</Emphasis>-seropositive Japanese-Brazilians in SÃo Paulo

Background Studies of lifestyle factors related to gastric atrophy development in Helicobacter pylori-infected individuals are limited. The present cross-sectional study aimed to examine the associations between lifestyle factors and serum pepsinogens (PGs) among anti-H. pylori antibody-seropositive Japanese in Brazil, where gastric cancer mortality was reported to be as high as in Japanese in Japan, and seropositive individuals were still frequently detected.Methods The subjects were 291 seropositive individuals (129 males and 162 females; age, 30 to 69 years) out of 656 Japanese-Brazilian volunteers in SÃo Paulo city. Information on lifestyle factors was obtained using a self-administered questionnaire. Atrophic gastritis was defined as a PG1 serum level less than 70ng/ml and PG1/PG2 ratio less than 3.Results The prevalence of atrophic gastritis was 31.9% (95% confidence intervals, 26.6%–37.6%). The proportion of subjects with atrophic gastritis increased with age, but there were no significantly marked differences in the proportions of subjects with atrophic gastritis among the three generations studied (first generation [Issei], second generation [Nisei], and third generation [Sansei]) for any 10-year age group. The associations with smoking and alcohol drinking were not significant. Length of education was inversely associated with gastric atrophy, while infrequent rice intake was preventive; the odds ratio relative to everyday rice intake was 0.13 (95% confidence intervals, 0.39–0.46) on multivariate analysis.Conclusions The present study demonstrated that frequent rice intake was a risk factor for atrophic gastritis among the H. pylori-infected Japanese-Brazilians, suggesting that diet including rice plays a role in the step from H. pylori infection to gastric atrophy.     

Fundal atrophic gastritis as a risk factor for gastric cancer

The role of atrophic gastritis of the gastric corpus (fundal atrophic gastritis) as a high-risk factor was investigated by studying operative findings and follow-up data on 690 patients with benign gastric diseases recorded at the Osaka Cancer Registry. The extent of fundal atrophic gastritis was determined by the endoscopic Congo red test. The patients were followed-up from the time of endoscopic examination (1968 to 1976) to December 31, 1987. The vital status of 654 patients (94.8%) at the end of the observation period was determined. During the follow-up period, 22 patients were found to have gastric cancer. The extent of fundal atrophic gastritis was shown to be closely related with the risk of developing gastric cancer. Patients who had been diagnosed as having severe fundal atrophic gastritis showed significantly higher risk of gastric cancer than patients who had been diagnosed as having little or no fundal atrophic gastritis (5.76-fold, calculated with adjustments for age, sex and the follow-up period). A positive linear relationship was found between the risk of developing gastric cancer and the extent of fundal atrophic gastritis. The observed number of gastric cancers was compared with the expected number calculated from the incidence in Osaka Prefecture. Analysis of the results showed that the observed and expected numbers of gastric cancers in patients with severe fundal atrophic gastritis were 11 and 4.8, respectively, the ratio of observed to expected numbers being 2.3 (p < 0.05). These findings indicate that severe fundal atrophic gastritis is a major risk factor for gastric cancer.     

贲门组织体内癌变规律的内镜研究

目的研究早期贲门癌在体内的发生规律。方法在食管癌高发现场建立前瞻性研究队列(106人),定期普查,利用内镜检查的方法,前后对照式地观察贲门癌高发位点贲门脊根部粘膜变化情况,在相同区域咬取相同块数的活检组织。活检组织经中性福尔马林液固定,常规脱水,石蜡包埋,切片,HE染色,做病理学检查。结果4年后,本组106人,8例贲门粘膜正常者,3例正常,4例出现慢性胃炎,1例发生粘膜内癌;61例慢性胃炎,11例出现腺上皮萎缩,4例发生腺上皮轻度不典型增生,2例腺上皮高度不典型增生;9例腺上皮萎缩病例,5例无变化,4例变为慢性胃炎;22例腺上皮轻度不典型增生,17例消退,4例无变化,1例进展为腺上皮高度不典型增生;1例腺上皮高度不典型增生变为轻度不典型增生;5例未经任何治疗的粘膜内癌,1例成为浸润癌,1例仍为早期癌,3例变为贲门粘膜轻度不典型增生。结论早期贲门癌发生经历慢性胃炎、腺上皮萎缩、不典型增生几个癌前阶段;早期贲门癌和癌前病变在体内处于动态的可复性的变化过程中。     

贲门组织体内癌变规律的内镜研究

Objective： To study the rule of development of early cancer of gastric cardia in vivo in public screening. Methods： A prospective cohort study on gastric cardiac cancer was performed in the high incidence area of cancer of esophagus and stomach in china. 106 subjects had been examined regularly by endoscopy to observe the change of mucosa in high incident area of gastric cardiac carcinoma developing at the root of gastric cardiac ridge by taking biopsy specimen. All specimens were diagnosed through normal pathological process to study the prognosis of pro-cancer lesions of gastric cardia. Results： The results of 106 subjects who had been observed for 4 years were： （1） Of 8 normal persons, 3 stayed normal, 4 turned to chronic gastritis, 1 developed early gastric cardiac cancer. （2） Of 61 persons with chronic gastritis, 11 were observed to have gland atrophy, 4 mild atypical hyperplasia, and 2 highly atypical hyperplasia. （3） Of 9 subjects showing atrophic chronic gastritis, 5 revealed no change, and 4 became chronic gastritis. （4） Of 22 subjects who revealed mild atypical hyperplasia, 17 resolved, 4 showed no change, and 1 advanced to highly atypical hyperplasia. （5） One person with highly atypical hyperplasia reverted to mild atypical hyperplasia. （6） Of 5 subjects with early gastric cardiac cancer without any treatment, 1 became advanced cancer, 1 still stayed in early cancer stage, and 3 turned to atypical hyperplasia. Conclusion： The development of early cancer of gastric cardia would proceed through the stages of chronic gastritis, gland atrophy, and atypical hyperplasia. （2） The early cancer and pre-cancer lesions of gastric cardia is reversible, though possessing malignant possibility.     

Gastric cancer risk in chronic atrophic gastritis: statistical calculations of cross-sectional data

Relative risk (RR) and cumulative risk of gastric cancer (GCA) were calculated for different grades of atrophic gastritis (AG) of the antrum and body. Cross-sectional data on the occurrence of AG in a representative population sample (371 subjects), and Finnish Cancer Registry data on GCA were used in the calculations. The RR was increased significantly in severe AG of the antrum and the body (18.1 and 4.6 times, respectively), but not significantly in the less severe grades of AG. As a risk factor, severe antral and body gastritis were independent of each other. The cumulative risk, i.e., the probability of contracting GCA within the following 10 years in age groups 50-54 . . . 70-74 years was calculated to vary from 2.3% to 9.3% and from 8.7% to 31.9% in severe antral AG and from 0.9% to 4.5% and from 3.6% to 16.6% in severe body AG in males and females, respectively.     

空腹胃液中挥发性亚硝胺含量与胃癌和萎缩性胃炎关系的研究

目的验证胃癌的亚硝胺病因假说。方法在江苏省扬中县,对经过胃镜和病理确认的胃癌１０２例、萎缩性胃炎９０例、正常及浅表性胃炎１４６例,用气相色谱热能分析仪的方法,测定比较其胃液挥发性亚硝胺的含量,并用试纸法测定了胃液的ｐＨ值。结果胃液的ｐＨ值随胃粘膜的病变严重程度而上升。人群亚硝胺的总检出率在各组都很高,胃癌组、萎缩性胃炎组、正常及浅表性胃炎组的亚硝胺的总检出率分别为９９０２％、９８８９％、９８６３％。组间无显著差异（Ｐ＞００５）。但各种亚硝胺,如二甲基亚硝胺、二乙基亚硝胺、甲基卞基亚硝安、亚硝基吡咯烷、亚硝基哌啶的检出率,胃癌组、萎缩性胃炎组都比正常浅表性胃炎组有增高趋势。这种升高趋势从亚硝胺含量的比较上则更为显著。胃癌组和萎缩性胃炎组二甲基亚硝胺、二乙基亚硝胺含量及亚硝胺总量都比正常和浅表性胃炎组有显著增高（Ｐ＜００１）。结论亚硝胺可能与胃癌和萎缩性胃炎的发生有一定的关系。     

Helicobacter pylori, atrophic fundal gastritis and risk for gastric adenocarcinoma

Fundal atrophic gastritis and Helicobacter pylori have been implicated as possible etiologic factors in gastric cancer. This case-control study was performed to determine which risk factor is more closely related to gastric cancer. The endoscopic Congo red test was performed to evaluate the extent of fundal atrophic gastritis in 43 patients with gastric cancer and 86 cancer-free control subjects, who were individually matched by age, sex, and date of endoscopy (within 3 months). The prevalance of H. pylori infection and severe fundal gastritis were significantly higher in patients with differentiated adenocarcinoma, but not with undifferentiated adenocarcinoma, than in control subjects. The odds ratios for differentiated and undifferentiated adenocarcinomas were 6.85 (95% confidence interval, 1.94-11.82) and 1.50 (95% CI, 0.84-3.11), respectively. However, the odds ratio of H. pylori infection was greater than that of severe fundal gastritis. Moreover, multivariate analysis provided similar results. H. pylori infection is an independent indicator of a higher risk of the differentiated adenocarcinomas of the stomach than is severe fundal gastritis.     

胃癌及癌前病变与幽门螺杆菌感染相关性的临床分析

目的:测定幽门螺杆菌在萎缩肠化生胃炎,异型增生及胃癌中感染情况,探讨Hp与它们的相关性。方法:萎缩肠化生胃炎(A组)患者342例,异型增生(B组)229例,胃癌患者(C组)298例,采用Hp抗体ELISA法检测血清抗Hp-IgG抗体。结果:肠化生患者较非肠化生胃黏膜中的Hp感染多见。异型增生和胃癌的Hp感染率均高于萎缩性胃炎组(P<0.05),异型增生和胃癌两者间的Hp感染率亦存在差异(P<0.05)。幽门螺杆菌感染的萎缩肠化生胃炎及异性增生较非幽门螺杆菌感染者发生癌变的差异性显著,P<0.05;幽门螺杆菌感染的胃癌5年生存期显著短于非感染者,P<0.05。结论:Hp感染与萎缩肠化生胃炎,异型增生及胃癌有密切相关性,并缩短萎缩肠化生胃炎,异型增生癌变时间,缩短胃癌5年生存时间。     

Screening,Monitoring, and Treatment of Precancerous Atrophic Gastritis in the Prospective Study for Seven Years

AIM: Develop a program to identify, treat, and prevent severe atrophic gastritis to reduce gastric cancer incidence and mortality. MAterials and Methods: In total, 2,847 people aged > 40 years old underwent serological noninvasive screening for atrophic gastritis by identifying postprandial gastrin-17 and pepsinogen-1 in the fasting state. Anti-H pylori IgG was found in 2,134 patients. Seven years later, 2,220 patientswho had undergone serological noninvasive screening were asked to fill out a questionnaire survey (were interviewed). We could not find any information on 627 of 2,847 patients. Next, 75 patients with multifocal atrophic gastritis who underwent gastroscopy and biopsies (the Updated Sydney System (USS)) were selected. To study gastrin-17 production, morpho-functional correlation was studies in 75 patients with multifocal atrophic gastritis. Results: During seven years, no reported case of gastric cancer was done among 2,220 persons who underwent serological screening and treatment. In the same population, 4.3 persons who did not receive screening during the same period, developed gastric cancer and died of it. In this study, we can say that 4.3 lives were saved out of 2,220 tested persons. The cost for screening this number of people amounted to €23,750. A comparison of the prevalence rate of the four stages of multifocal atrophic gastritis based on the data of the histopathology tests and noninvasive serologic screening in accordance with OLGA classification showed a strong correlation (the correlation coefficient is 0.812). This finding suggested that using this classification not only for histopathology tests for atrophic gastritis but also for serologic markers of antral mucosa and corpus ventriculi atrophy: gastrin-17 and pepsinogen-1. Conclusion: Complex pathogenetic treatment of atrophic gastritis significantly reduced gastric cancer risk and incidence for such patients.     

Effect of Helicobacter pylori infection combined with CagA and pepsinogen status on gastric cancer development among Japanese men and women: a nested case-control study.

BACKGROUND: Although accumulating evidence suggests that Helicobacter pylori plays a role in gastric carcinogenesis, the magnitude of the risk remains uncertain. Aim: We aimed to estimate the magnitude of the risk of gastric cancer associated with H. pylori infection by a large case-control study nested within a prospective cohort. Possible effect modification by CagA status, and serum pepsinogen status, as a marker of atrophic gastritis, was also considered to see its effect on developing gastric cancer. Subjects and METHODS: Subjects (n = 123,576) were followed up from 1990 to 2004; 511 gastric cancer cases matched to 511 controls were used in the analysis. Plasma immunoglobulin G antibody to H. pylori, CagA, and pepsinogen I and II were measured. RESULTS: The adjusted odds ratio (95% confidence interval) of gastric cancer associated with H. pylori infection was 5.1 (3.2-8.0). Assuming all CagA-positive subjects are true H. pylori positives doubled this risk. Atrophic gastritis was also associated with an elevated risk of gastric cancer and the risk increased further with pepsinogen levels. CONCLUSIONS: Subjects with pepsinogen levels indicative of severe atrophic gastritis may need careful examination regularly regardless of H. pylori infection. Those who have other pepsinogen levels but who are H. pylori seropositive are likely to benefit from H. pylori eradication therapy. Considering both the cost and the potential for misclassification that may occur using multiple serologic tests, caution is needed in interpreting or extrapolating these findings into a screening strategy.     

Cancer development based on chronic active gastritis and resulting gastric atrophy as assessed by serum levels of pepsinogen and Helicobacter pylori antibody titer

Our study investigated the relationship between gastric cancer development and activity of Helicobacter pylori‐associated chronic gastritis or the resulting chronic atrophic gastritis (CAG). A cohort of 4,655 healthy asymptomatic subjects, in whom serum pepsinogen (PG) and H. pylori antibody titer had been measured to assess the activity and stage of H. pylori‐associated chronic gastritis, was followed for up to 16 years, and cancer development was investigated. In subjects with a serologically diagnosed healthy stomach (H. pylori‐negative/CAG‐negative), cancer incidence rate was low, at 16/100,000 person‐years. With the establishment of H. pylori infection and progression of chronic gastritis, significant stepwise cancer risk elevations were seen from CAG‐free subjects (H. pylori‐positive/CAG‐negative) [hazard ratio (HR) = 8.9, 95% confidence interval (CI) = 2.7–54.7] to subjects with CAG (H. pylori‐positive/CAG‐positive) (HR = 17.7, 95% CI = 5.4–108.6) and finally to subjects with metaplastic gastritis (H. pylori‐negative/CAG‐positive) (HR = 69.7, 95% CI = 13.6–502.9). In H. pylori‐infected CAG‐free subjects, significantly elevated cancer risk was observed in the subgroup with active inflammation‐based high PG II level or potent immune response‐based high H. pylori antibody titer; the former was associated with a particularly high risk of diffuse‐type cancer, and both subgroups showed high cancer incidence rates of around 250/100,000 person‐years, comparable to that in subjects with CAG. No such risk elevation was observed in H. pylori‐infected subjects with CAG. These results clearly indicate that gastric cancer develops mainly from the gastritis‐atrophy‐metaplasia‐cancer sequence and partly from active inflammation‐based direct carcinogenesis, and that serum levels of PG and H. pylori antibody titer provide indices of cancer development in H. pylori‐infected subjects.