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O R I G I N A L A R T I C L E — A L I M E N T A R Y T R A C T

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

Susumu Take • Motowo Mizuno • Kuniharu Ishiki •

Tomowo Yoshida • Nobuya Ohara • Kenji Yokota •

Keiji Oguma • Hiroyuki Okada • Kazuhide Yamamoto

Received: 24 July 2010 / Accepted: 26 October 2010 / Published online: 20 November 2010

Ó Springer 2010

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 inves-

tigate 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 eradicationtherapy to evaluate peptic ulcers, background gastric

mucosal atrophy, and H. pylori infection. After confirma-

tion 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 therapy Á Gastric cancer Á

 Helicobacter pylori

Introduction

 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].

S. Take

Department of Internal Medicine, Fukuwatari Municipal

Hospital, 1000 Fukuwatari, Takebe-cho, Kitaku,Okayama 709-3111, Japan

M. Mizuno (&)

Department of Gastrointestinal Endoscopy, Hiroshima City

Hospital, 7-33 Motomachi, Nakaku, Hiroshima 730-8518, Japan

e-mail: mmizuno@isis.ocn.ne.jp

S. Take Á K. Ishiki Á T. Yoshida

Department of Internal Medicine, Nippon Kokan

Fukuyama Hospital, 1840 Tsunoshita, Daimon-cho,

Fukuyama 721-0927, Japan

N. Ohara

Department of Pathology, Okayama University Graduate School

of Medicine, Dentistry and Pharmaceutical Sciences,2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan

K. Yokota Á K. Oguma

Department of Bacteriology, Okayama University Graduate

School of Medicine, Dentistry and Pharmaceutical Sciences,

2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan

H. Okada Á K. Yamamoto

Department of Medicine and Medical Science,

Okayama University Graduate School of Medicine,

Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho,

Kitaku, Okayama 700-8558, Japan

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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 developingmetachronous 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 [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

[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 inves-

tigate 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 pre-

vious 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 submuco-

sal dissection) for gastric neoplasms (i.e., early gastric

cancer, gastric adenoma); those who were pregnant; those

who had an allergy to penicillin, clarithromycin, or met-

ronidazole; 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 eradi-

cation therapy.

Eradication therapy and post-eradication schedule

 H. pylori infection was defined as a positive bacterial cul-

ture from endoscopic biopsy specimens taken before erad-

ication 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 withtwo of the following three drugs: amoxicillin, clarithro-

mycin, or metronidazole. One to 2 months after the com-

pletion 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 nega-

tive. 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 

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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 inTable 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 ± stan-

dard deviation) after the start of follow-up; analysis of these

patients was stopped at the time of the possible reinfection.

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 can-cers 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.

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 corre-

lated with the severity of atrophy. Thus, gastric cancer

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

a Gastric mucosal atrophy was evaluated according to the endo-

scopic-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 textb

 H. 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

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

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

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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 multi-

variate analysis. Cigarette smoking and alcohol consump-

tion were not found to be risk factors for gastric cancer.

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 forexamination; 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.

Discussion

We previously reported that H. pylori eradication reducedthe 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

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 intervala Background 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

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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 eradica-

tion 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] andare 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 endo-

scopic mucosal resection in order for a pathological diag-

nosis 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 infiltra-

tion in the gastric mucosa after H. pylori eradication

[36, 37]. Chronic inflammation is a risk factor for several

gastrointestinal malignancies, and the inflammatory envi-

ronment 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[44], and gastric mucosa-associated lymphoid tissue lym-

phoma [45], as well as some diseases outside the gastro-

intestinal 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 [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 corre-

spondingly decrease. Nevertheless, our observations sug-

gest 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 sur-

veillance, 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

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 andeosin. The degree of inflammatory cell infiltration was classified according to the updated Sydney system [ 30]

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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.

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