Journal of Gastroenterology

, Volume 46, Issue 3, pp 318–324

The long-term risk of gastric cancer after the successful eradication of Helicobacter pylori

Authors

  • Susumu Take
    • Department of Internal MedicineFukuwatari Municipal Hospital
    • Department of Internal MedicineNippon Kokan Fukuyama Hospital
    • Department of Gastrointestinal EndoscopyHiroshima City Hospital
  • Kuniharu Ishiki
    • Department of Internal MedicineNippon Kokan Fukuyama Hospital
  • Tomowo Yoshida
    • Department of Internal MedicineNippon Kokan Fukuyama Hospital
  • Nobuya Ohara
    • Department of PathologyOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
  • Kenji Yokota
    • Department of BacteriologyOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
  • Keiji Oguma
    • Department of BacteriologyOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
  • Hiroyuki Okada
    • Department of Medicine and Medical ScienceOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
  • Kazuhide Yamamoto
    • Department of Medicine and Medical ScienceOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
Original Article—Alimentary Tract

DOI: 10.1007/s00535-010-0347-9

Cite this article as:
Take, S., Mizuno, M., Ishiki, K. et al. J Gastroenterol (2011) 46: 318. doi:10.1007/s00535-010-0347-9
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Abstract

Background

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.

Methods

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.

Results

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.

Conclusion

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.

Keywords

Eradication therapyGastric cancerHelicobacter pylori

Introduction

Helicobacter pylori is a causative bacterium for several important upper gastrointestinal diseases such as peptic ulcer and gastric cancer [13]. 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, 37]. Eradication of H. pylori was expected to virtually eliminate gastric cancer and reduce mortality by eliminating the reservoir of H. pylori infection [8]. 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 [1113], but in a study in a Chinese population, the beneficial effect was restricted to those patients who were free of precancerous lesions [14].

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 [1522]. 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 [19]. 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) [27] 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 [28] and classified according to Lauren as intestinal or diffuse type [29]. 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 [30]. 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.

Statistical analysis

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.

Results

The baseline characteristics of the 1674 patients who received successful eradication therapy are provided in Table 1. Patients were followed for up to 14.1 years (a mean of 5.6 years) until November 2009. Positive urea breath tests, suggesting possible reinfection with H. pylori, were noted in 37 patients 3.7 ± 2.7 years (mean ± standard deviation) after the start of follow-up; analysis of these patients was stopped at the time of the possible reinfection.
Table 1

Patients’ demographic characteristics

Patients’ demographic characteristics

n = 1674

Gender (male/female)

1453/221

Age (years)

50.8 ± 8.4

Smoking (absence/presence)

600/1074

Drinking (absence/presence)

624/1050

Background mucosal atrophy (mild/moderate/severe)a

511/678/485

Duration of follow-up (years)

5.6 ± 3.6

Dual/triple/metronidazole-based therapyb

437/1071/166

Number of Helicobacter pylori treatment courses (one/more)

1508/166

H. pylori re-infection (absence/presence)

1637/37

aGastric mucosal atrophy was evaluated according to the endoscopic-atrophic-border scale and was classified by degree into three grades; mild (the C-1 and C-2 patterns), moderate (the C-3 and O-1 patterns), or severe (the O-2 and O-3 patterns) as described in the text

bH. pylori eradication therapy; dual, a proton pump inhibitor together with amoxicillin; triple, a proton pump inhibitor together amoxicillin and clarithromycin; metronidazole, a proton pump inhibitor together with metronidazole and amoxicillin or clarithromycin

During the follow-up period, gastric cancer developed in 28 of the 1674 patients. The longest interval between H. pylori eradication and the occurrence of cancer was 13.7 years. By Kaplan–Meier analysis (Fig. 1), the risk of developing gastric cancer in the patients cured of infection was 0.30% per year. Histologically, 16 of the gastric cancers were of the intestinal type, and 12 were of the diffuse type. The risk of developing each type of cancer was 0.17 and 0.13% per year, respectively (Fig. 2). Eleven gastric cancers developed within 5 years after cure of the infection, 14 developed after 5 years, and 3 developed after 10 years. Twenty-three cancers were superficial type [superficial depressed type (0–IIc) [31], n = 14; superficial depressed + superficial elevated type (0–IIc + IIa), n = 5; superficial flat type (0–IIb), n = 3; superficial elevated type (0–IIa), n = 1]. Two cancers mimicked a submucosal tumor; two cancers were depressed type (0–III); and one was Borrmann’s classification type 4 (diffuse infiltrative type). Most of the gastric cancers were at early TNM stages (stage IA, n = 25; stage IB, n = 2), but one was at stage IIIA.
https://static-content.springer.com/image/art%3A10.1007%2Fs00535-010-0347-9/MediaObjects/535_2010_347_Fig1_HTML.gif
Fig. 1

Kaplan–Meier analysis of the proportion of patients who remained free of gastric cancer in patients with peptic ulcers after cure of Helicobacter pylori infection. During the follow-up period, gastric cancer developed in 28 of the 1674 patients. The risk of developing gastric cancer was 0.30% per year

https://static-content.springer.com/image/art%3A10.1007%2Fs00535-010-0347-9/MediaObjects/535_2010_347_Fig2_HTML.gif
Fig. 2

Kaplan–Meier analysis of the proportion of patients who remained free of gastric cancer in patients with peptic ulcers after cure of H. pylori infection according to histological types of gastric cancer. Intestinal-type gastric cancers developed in 16 patients, and diffuse-type cancer developed in 12 patients. The risk of each of these two types of cancer was 0.17 and 0.13% per year, respectively

Twenty-four gastric cancers developed in patients with gastric ulcer, 2 developed in patients with duodenal ulcer, and 2 developed in patients without peptic ulcers. In the background gastric mucosa at enrollment, many patients had moderate or severe atrophy of the gastric mucosa (Table 1), and the frequency of developing cancer correlated with the severity of atrophy. Thus, gastric cancer developed in 1 of 511 patients who had mild atrophy (0.04% per year), 11 of 678 who had moderate atrophy (0.28% per year), and in 16 of 485 who had severe atrophy (0.62% per year) (Fig. 3, p = 0.0006, log-rank test). Analysis with the Cox’s proportional-hazards model (Table 2) identified baseline gastric mucosal atrophy [severe: hazard ratio, 14.4; 95% confidence interval (CI), 1.9–110.2, p = 0.01 vs. mild] as a significant factor for the risk of developing gastric cancer. Increasing age was identified as a risk factor by univariate but not by multivariate analysis. Cigarette smoking and alcohol consumption were not found to be risk factors for gastric cancer.
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Fig. 3

Kaplan–Meier analysis of the proportion of patients with mild atrophy, patients with moderate atrophy, and patients with severe atrophy who remained free of gastric cancer in patients with peptic ulcers after the cure of H. pylori infection. Gastric cancer developed in 1 of 511 patients with mild atrophy (0.04% per year), 11 of 678 patients with moderate atrophy (0.28% per year), and in 16 of 485 patients with severe atrophy (0.62% per year); the risk of developing gastric cancer after receiving successful H. pylori eradication therapy was increased according to the background gastric mucosal atrophy (p = 0.0006, log-rank test)

Table 2

Analysis of factors associated with the development of gastric cancer in patients with peptic ulcers (Cox’s proportional-hazards model)

Factors

Univariate analysis

Multivariate analysis

p value

Hazard ratio

p value

Hazard ratio

95% CI

Gastric mucosal atrophya

 Mild

 

1

 

1

 

 Moderate

0.05

7.6

0.06

7.1

0.9–55.3

 Severe

0.006

16.9

0.01

14.4

1.9–110.2

Age (per 10-year increment)

0.02

1.8

0.12

1.5

0.9–2.4

Smoking

 Absence

 

1

   

 Presence

0.37

1.5

   

Drinking

 Absence

 

1

   

 Presence

0.79

1.1

   

95% CI 95% confidence interval

aBackground gastric mucosal atrophy at the time of eradication therapy. Gastric mucosal atrophy was evaluated according to the endoscopic-atrophic-border scale described and was classified by degree into three grades; mild (the C-1 and C-2 patterns), moderate (the C-3 and O-1 patterns), or severe (the O-2 and O-3 patterns) as described in the text

The inflammatory scores of the gastric mucosa at the time of the development of gastric cancers are given in Table 3. In 2 cases, biopsy samples were not suitable for examination; therefore, we evaluated inflammation in 26 cases. No neutrophil infiltration was observed in the background gastric mucosa in any cases. Mononuclear cell infiltration was noticed sometimes when gastric cancers developed within 5 years after the cure of H. pylori infection, whereas it was detected in only 2 of 15 patients when gastric cancers developed after more than 5 years.
Table 3

Inflammatory scores of the background gastric mucosa at the time of development of gastric cancers

Follow-up period until the development of gastric cancers

n

Antrum

Body

Neutrophils

Mononuclear cells

Neutrophils

Mononuclear cells

Within 5 years

11

0% (0/11)

36% (4/11)

0% (0/11)

55% (6/11)

More than 5 years

15

0% (0/15)

13% (2/15)

0% (0/15)

7% (1/15)

Biopsy specimens were obtained from the greater curvature of the body and the antrum of the stomach and were stained with hematoxylin and eosin. The degree of inflammatory cell infiltration was classified according to the updated Sydney system [30]

Discussion

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 [21] 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 [21], 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 [34], 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 [3840]. 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 [4143], gastric hyperplastic polyp [44], and gastric mucosa-associated lymphoid tissue lymphoma [45], as well as some diseases outside the gastrointestinal tract, such as idiopathic thrombocytopenic purpura [46, 47], chronic idiopathic urticaria [48], and iron-deficiency anemia in adolescents [49]. 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 [1113]. 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 [50], 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.

Acknowledgments

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.

Copyright information

© Springer 2010