The long-term risk of gastric cancer after the successful eradication of Helicobacter pylori
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- Take, S., Mizuno, M., Ishiki, K. et al. J Gastroenterol (2011) 46: 318. doi:10.1007/s00535-010-0347-9
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We previously reported that eradication of Helicobacter pylori reduced the risk of developing gastric cancer in patients with peptic ulcer diseases. In the present study, we further followed up our patient group to investigate the occurrence and clinical features of gastric cancers that developed after cure of the infection.
Prospective post-eradication evaluations were conducted on 1674 consecutive patients who had received successful H. pylori eradication therapy. The patients had undergone endoscopic examination before eradication therapy to evaluate peptic ulcers, background gastric mucosal atrophy, and H. pylori infection. After confirmation of cure of the infection, follow-up endoscopy was performed yearly.
The patients were followed for up to 14.1 years (a mean of 5.6 years). During the follow-up, gastric cancer developed in 28 of the 1674 patients as long as 13.7 years after the cure of H. pylori infection. The risk of developing gastric cancer was 0.30% per year. Histologically, 16 of the gastric cancers were the intestinal type and 12 were the diffuse type; the risk of each cancer type was 0.17 and 0.13% per year, respectively. There was no significant inflammatory cell infiltration in the background gastric mucosa at the time the cancers were recognized.
There is a risk of developing gastric cancer of both the intestinal and diffuse types even after the cure of H. pylori infection and extinction of gastric inflammation. It is important to inform patients about the risk of gastric cancer after eradication therapy and offer them surveillance endoscopy.
KeywordsEradication therapyGastric cancerHelicobacter pylori
Helicobacter pylori is a causative bacterium for several important upper gastrointestinal diseases such as peptic ulcer and gastric cancer [1–3]. Worldwide, gastric cancer remains one of the commonest cancers and accumulating evidence indicates that H. pylori infection is a necessary, although not sufficient, cause of gastric cancer [1, 3–7]. Eradication of H. pylori was expected to virtually eliminate gastric cancer and reduce mortality by eliminating the reservoir of H. pylori infection . However, the effect of prophylactic H. pylori eradication on the development of gastric cancer in those who have already been infected with this bacterium for a long time is still under debate [9, 10]. In a Japanese population at high risk for gastric cancer, eradication therapy reduced the risk of developing metachronous gastric cancer after endoscopic mucosal resection of early gastric cancer [11–13], but in a study in a Chinese population, the beneficial effect was restricted to those patients who were free of precancerous lesions .
We have been following a cohort of patients who had received H. pylori eradication therapy. We have reported results on several important medical issues in these patients [15–22]. Most importantly, the eradication of H. pylori in patients with peptic ulcer diseases in whom the cancer was not yet established reduced their risk of developing gastric cancer to approximately one-third. However, gastric cancer developed in some patients even after the cure of H. pylori infection [19, 21]. In the present study, we further followed up our patients and extended our previous work to investigate the occurrence and clinical features of gastric cancers that developed after the cure of the infection.
Patients and methods
We enrolled 1674 consecutive patients who had received successful eradication therapy for H. pylori infection at the outpatient clinic of Nippon Kokan Fukuyama Hospital from June 1995 to June 2007. There were 221 women and 1453 men, with a mean age of 50.8 years (range 14–80 years). The patients were mostly male factory workers at JFE Steel Corporation, West Japan Works. The patients underwent endoscopic examination at enrollment to evaluate peptic ulcers, background gastric mucosal histology, and H. pylori infection, and we documented that none of patients had gastric cancer. Nine hundred and eight patients had gastric ulcer, 590 had duodenal ulcer, 120 had both diseases, and 56 had no ulcer. The patients who were reported in our previous study [19, 21] were included in this study.
Gastric mucosal atrophy was evaluated according to the endoscopic-atrophic-border scale described by Kimura and Takemoto [23, 24], which correlates with the results of histological evaluation [25, 26], and was classified by degree into three grades: mild (C-1 and C-2 patterns), moderate (C-3 and O-1 patterns), or severe (O-2 and O-3 patterns). We excluded patients who had previously undergone gastrectomy or received endoscopic therapy (i.e., endoscopic mucosal resection, endoscopic submucosal dissection) for gastric neoplasms (i.e., early gastric cancer, gastric adenoma); those who were pregnant; those who had an allergy to penicillin, clarithromycin, or metronidazole; those who were taking anticoagulants; and those who had used a proton pump inhibitor, H2 receptor antagonist, adrenocortical steroids, or nonsteroidal anti-inflammatory drugs within the month preceding the eradication therapy.
Eradication therapy and post-eradication schedule
H. pylori infection was defined as a positive bacterial culture from endoscopic biopsy specimens taken before eradication therapy was begun. The specimens were obtained from the greater curvature of the body and the antrum of the stomach, and cultured using Brucella agar with 7% horse blood and antibiotics. Urease activities of the specimens were tested with a modified rapid urease test (MR UREA S; Institute of Immunology Co., Tokyo, Japan).
Patients received H. pylori eradication therapy as described . Treatment regimens included a proton pump inhibitor together with amoxicillin or together with two of the following three drugs: amoxicillin, clarithromycin, or metronidazole. One to 2 months after the completion of therapy, including the cessation of maintenance therapy with acid secretion inhibitors, a 13C-urea breath test and endoscopy were carried out in each patient to determine H. pylori status and to reconfirm that there was no gastric cancer. H. pylori infection was considered cured when the bacterial culture, rapid urease testing, and urea breath test (cutoff value, 3.5 per mil)  were all negative. H. pylori were eradicated in 1508 patients after the first course of treatment and in 166 after additional therapy. After confirmation of eradication and the absence of gastric cancer, endoscopy was carried out yearly.
Gastric cancer was defined as a malignant epithelial tumor of the stomach mucosa with glandular differentiation  and classified according to Lauren as intestinal or diffuse type . The biopsy specimens obtained from the greater curvature of the body and the antrum of the stomach were stained with hematoxylin and eosin, and the degree of inflammatory cell infiltration was classified according to the updated Sydney system . The pathologists were not aware of the clinical data, including patients’ H. pylori status. The study was conducted according to the guidelines of the Declaration of Helsinki. A local ethics committee approved the study protocol. The objective of the study was explained to all patients before their participation, and written informed consent was obtained from each patient.
Survival curves were constructed by the Kaplan–Meier method, and statistically significant differences between curves were tested by the log-rank test. The risk of developing gastric cancers was assessed by using Cox’s proportional-hazards models.
Patients’ demographic characteristics
Patients’ demographic characteristics
n = 1674
50.8 ± 8.4
Background mucosal atrophy (mild/moderate/severe)a
Duration of follow-up (years)
5.6 ± 3.6
Number of Helicobacter pylori treatment courses (one/more)
H. pylori re-infection (absence/presence)
Analysis of factors associated with the development of gastric cancer in patients with peptic ulcers (Cox’s proportional-hazards model)
Gastric mucosal atrophya
Age (per 10-year increment)
Inflammatory scores of the background gastric mucosa at the time of development of gastric cancers
Follow-up period until the development of gastric cancers
Within 5 years
More than 5 years
We previously reported that H. pylori eradication reduced the risk of developing gastric cancer to approximately one-third in patients with peptic ulcer diseases in whom the cancer was not yet established. We observed also that the grade of gastric mucosal atrophy present before the patients received eradication therapy was closely related to the development of gastric cancer after the eradication of H. pylori [19, 21]. However, gastric cancer developed in some patients even after the cure of H. pylori infection. In the present study, we found that the rate of developing gastric cancer after the cure of H. pylori infection was 0.30% per year and that the cancer could develop as long as 10 years after H. pylori were eradicated and even when gastric inflammation had completely disappeared. Also, the risk of developing cancer was nearly the same for both the intestinal and diffuse types of cancer, a finding that does not support the suggestion of others [32, 33] that eradication of H. pylori is more effective for the prevention of the intestinal type than of the diffuse type of cancer.
The findings of the present study (Fig. 3) corroborate our previous finding that the risk of developing gastric cancer increased according to the background gastric mucosal atrophy at the time of eradication therapy  and are compatible with recent findings by others [34, 35]. Evidently, even mild gastric atrophy can lead to the development of gastric cancer if patients are followed for long enough: in our previous study with 3.9 years’ mean follow-up, no gastric cancer developed in patients with mild atrophy , whereas in the present study, in which the mean follow-up period was extended to 5.6 years, one gastric cancer, which was intestinal type, was found in a patient who had mild atrophy. Perhaps the eradication of H. pylori is maximally effective in preventing gastric cancer if it is achieved before significant gastric atrophy has developed. This opinion is compatible with the findings of a recent retrospective cohort study from Taiwan , in which early eradication therapy in peptic ulcer patients was most effective in reducing the risk of gastric cancer later.
We found that the macroscopic type of gastric cancers discovered after eradication was mostly the superficial type. Also, two cancers mimicked submucosal tumors and were not readily diagnosed by the usual biopsy method; one needed burrowing biopsy and the other needed endoscopic mucosal resection in order for a pathological diagnosis to be made. Therefore, in the endoscopic follow-up of patients for the development of gastric cancer after the eradication of H. pylori it is especially important to look for the characteristic endoscopic features.
Infection with H. pylori induces a characteristic inflammation in the gastric mucosa with the infiltration of mononuclear cells or/and neutrophils. Many reports have mentioned improvement of the inflammatory cell infiltration in the gastric mucosa after H. pylori eradication [36, 37]. Chronic inflammation is a risk factor for several gastrointestinal malignancies, and the inflammatory environment favors the formation of cancer at any level of carcinogenesis [38–40]. However, we found no significant inflammatory cell infiltration in the gastric mucosa at the time of the development of gastric cancers after H. pylori eradication, especially when cancer developed more than 5 years after cure of the infection. Thus, inflammation seems no longer necessary for the development of gastric cancer in this situation.
Eradication of H. pylori results in the healing of some gastrointestinal diseases, such as chronic active gastritis, peptic ulcer diseases [41–43], gastric hyperplastic polyp , and gastric mucosa-associated lymphoid tissue lymphoma , as well as some diseases outside the gastrointestinal tract, such as idiopathic thrombocytopenic purpura [46, 47], chronic idiopathic urticaria , and iron-deficiency anemia in adolescents . H. pylori eradication may also reduce the risk of developing gastric cancer in patients who have gastric ulcers [19, 21] and in patients who have already received successful endoscopic mucosal resection of early gastric cancer [11–13]. In Japan, it is likely in the years ahead that the numbers of people who will have received H. pylori eradication therapy will increase and the prevalence of gastric cancer may correspondingly decrease. Nevertheless, our observations suggest that gastric cancer cannot be completely prevented by eradication of the bacteria. Recently, others reported the development of gastric cancer 14 years after H. pylori eradication therapy , as we found in the present study. Thus, periodic follow-up endoscopic examination of patients who have been treated for H. pylori infection should be continued for more than 10 years. It is important to inform patients about the risk of gastric cancer after eradication therapy and offer them surveillance endoscopy. It remains to be determined whether there are high-risk populations who should receive especially rigorous surveillance, for how many years such surveillance is required after eradication therapy, and the appropriate intervals for examination. At least, our results suggest that special attention should be paid to the patients with severe gastric mucosal atrophy.
The authors thank Drs. Tetsuji Okuno, Tsuyoshi Okamoto, Tomomi Hakoda, Masako Kataoka, Yoshimi Itoh, Rumiko Suzuki, and Hideaki Inoue (Nippon Kokan Fukuyama Hospital) for supporting this work and Dr. William R. Brown (Denver Health Medical Center, Denver, CO, USA) for assistance in preparation of the manuscript.
Conflict of interest
None to declare.