The Korean Journal of Helicobacter and Upper Gastrointestinal Research Vol. 11, No. 2, 117-123, September 2011
Helicobacter pylori Eradication Suppresses Metachronous Gastric Cancer and Cyclooxygenase-2 Expression after Endoscopic Resection of Early Gastric Cancer
Background/Aims: The impact of Helicobacter pylori (H. pylori) eradication after endoscopic resection (ER) of early gastric cancer (EGC) has not been fully evaluated. We tried to find out the effect of H. pylori eradication therapy on the development of metachronous gastric cancers and changes in Cyclooxygenase-2 (COX-2) expression following attempts to eradicate H. pylori after ER of EGC. Materials and Methods: We eradicated H. pylori in the patients with EGC after ER. Biopsy samples were taken according to the follow-up schedules for surveillance after ER. Results: Fifty five patients were enrolled and finished the follow up schedules. Of the 55, 28 were successfully treated H. pylori infection, and the other 27 were failed eradication of H. pylori. The mean follow-up period was 60.8 months. Five in the H. pylori ongoing infection group developed metachronous gastric cancer, whereas no new gastric cancers were found in the 28 eradication group (P=0.023). COX-2 expression in the eradication group was significantly decreased (1.4±0.2, n=28), compared to that in H. pylori ongoing infection group (3.0±0.4, n=27, P=0.0001) after the follow-up. Conclusions: The eradication of H. pylori seems to have a preventative effect on the development of metachronous adenocarcinomas and a suppressive effect on COX-2 expression in the patients after ER for EGC. (Korean J Helicobacter Upper Gastrointest Res 2011;11:117-123) Key Words: Helicobacter pylori; Gastric cancer; Cyclooxygenase 2
Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon, Korea Hwa Jong Kim, Su Jin Hong, Bong Min Ko, Won Young Cho, Joo Young Cho, Joon Seong Lee, Moon Sung Lee Received：April 30, 2011 Accepted：May 29, 2011 Corresponding author: Su Jin Hong Department of Internal Medicine, Soonchunhyang University College of Medicine, 1174, Jung-dong, Wonmi-gu, Bucheon 420-767, Korea Tel: 032-621-5087 Fax: 032-621-5080 E-mail:
[email protected]
ally an incurable disease. However, resection of the tumor at an early stage can confer a relatively favorable prognosis.
INTRODUCTION
Complete cures have been obtained in some early gastric canDespite its decreasing incidence over recent decades, gastric
cers (EGC), especially with the use of endoscopic treatment
cancer is still the second leading cause of cancer-related deaths
modalities such as endoscopic mucosal resection (EMR) and
1 worldwide. The development and progression of gastric cancer
endoscopic submucosal dissection (ESD).
seem to result, in part, from the accumulation of multiple genet-
lymph node metastasis is 0.36% in mucosal gastric cancer pa-
ic alterations, which lead to oncogene overexpression and tumor
tients who have no lymphatic invasion, no histological ulcer-
2,3
suppressor loss.
8,9
The most important single factor responsible
The incidence of
ation, and a tumor diameter of less than 30 mm.
10
for the development of gastric cancer is Helicobacter pylori (H.
After endoscopic resection (ER), the disease can recur in the
pylori) infection, which affects more than 50% of the world’s
stomach in two patterns, local recurrence or metachronous gas-
4
population. The risk for developing gastric cancer in patients
tric cancers. Many metachronous gastric cancers are thought to
with H. pylori infection is about two- to six-fold increases in
be de novo cancers and may arise from the same high-risk
5-7
non-infection individuals, according to epidemiological studies.
background mucosa.
When diagnosed at an advanced stage, gastric cancer is usu-
The relationship between metachronous recurrence and H.
117
118
The Korean Journal of Helicobacter and Upper Gastrointestinal Research：제 11 권 제 2 호 2011 11
pylori infection remains controversial. Arima et al.
reported
2. Study design
that H. pylori infection showed no significant relationship with metachronous recurrence. However, others have observed that
Biopsy samples were taken from the cancer, the adjacent
H. pylori eradication inhibited the development of metachro-
non-cancerous area, and two additional areas (two samples from
12,13
nous carcinoma in the remnant stomach.
the antrum, within 2 cm of the pyloric channel, and two from
Cyclooxygenase-2 (COX-2) is a rate-limiting enzyme in
the corpus) before the EMR procedure. All gastric specimens
prostaglandin synthesis from arachidonic acid. COX-2 ex-
were fixed in 10% buffered formalin for H&E staining or
pression is thought to be a relatively early event during gastric
COX-2 immunostaining. The presence of H. pylori was de-
carcinogenesis. Previous studies have demonstrated increased
termined by a CLO test (Delta West Ltd., Perth, Australia) and
COX-2 expression in both H. pylori-related gastritis and gastric
a
14-17
adenocarcinomas.
COX-2 expression is increased in in-
13
C-urea breath test.
Patients with EGC were considered suitable candidates for
testinal-type gastric cancers and in the crypts with intestinal
endoscopic resection at our institution if they met all of the fol-
18 metaplasia. Relatives of gastric cancer patients showed higher
lowing criteria: clinical findings of intramucosal adenocarci-
gastric COX-2 expression and higher incidence of precancerous
noma, differentiated-type adenocarcinoma, protruding-type or
lesions after H. pylori infection than did relatives of H. pylo-
superficial elevated type no more than 3 cm in diameter, or su-
19
Furthermore, pa-
perficial depressed type no more than 2 cm in diameter; no ul-
tients with intestinal-type adenocarcinomas had frequent atro-
ceration in the cancer; and no evidence of lymph node or dis-
phy and intestinal metaplasia in the surrounding gastric mucosa,
tant metastases. Endoscopic resection was performed using con-
compared to patients with diffuse-type adenocarcinoma, gastric
ventional EMR or endoscopic submucosal dissection.
ri-infected patients with duodenal ulcers.
20
lymphoma, or no neoplasia.
After the endoscopic resection procedure, all patients were
H. pylori infection resulted in overexpression of COX-2 that 21,22
was reversed by H. pylori eradication.
Therefore, eradication
therapy may reduce the risk of gastric cancer development.
attempted to treat for H. pylori infection using proton pump inhibitors based triple therapy. Endoscopic follow-up with biopsies was performed on each patient at 3, 12, 24, 36, 48, 60, and 72
Given this information, we sought to assess the effects of H.
months after ER. In addition, in patients with upper gastro-
pylori eradication on the development of new gastric cancers
intestinal system symptoms, we performed esophagogas-
in patients who underwent endoscopic resection to treat early
troduodenoscopy at that time. We looked for any metachronous
gastric cancer and on the expression of COX-2.
gastric cancer and cancer relapse, and collected gastric biopsy specimens for histological examination and COX-2 immunos-
MATERIALS AND METHODS 1. Patients The study was enrolled a total of 55 consecutive patients
13 taining. Each patient underwent a CLO test and a C-urea breath
test to determine H. pylori status, with endoscopic surveillance. 3. Immunohistochemistry for COX-2
with H. pylori infection (36 males, 19 females; mean, age 60.7
A paraffin-embedded mucosal biopsy specimen was mounted
years) who had received successful ER for EGC between
on a silane-coated glass slide. Immunohistochemical staining
March 2001 and November 2003 and follow-up for more than
was performed using antibodies specific for COX-2; the COX2
24 months at Bucheon Hospital, Soonchunhyang University,
antibody was a monoclonal antibody raised in a mouse against
Korea. Patients taking aspirin, non-steroidal anti-inflammatory
a synthetic peptide corresponding to human COX-2, amino
drugs (NSAIDs), antibiotics, bismuth preparations, or proton
acids 580-598 (DAKO, Carpinteria, CA, USA). For immunos-
pump inhibitors during the month before the examination were
taining, the COX-2 antibody (diluted 1：100) was incubated
excluded from the study. All patients provided informed con-
o with the sections for 1 h at 37 C, using a microwave method.
sent about histological analysis and preserve of H. pylori status
The primary antibody was omitted as a negative control.
after primary eradication therapy for H. pylori.
The immunoreactivity was recorded using semi-quantitative and subjective grading, considering both the intensity of staining and the number of immunoreactive cells. The intensity was
Hwa Jong Kim, et al：H. pylori Eradication and Metachronous Gastric Cancer
recorded as 0 (no staining) to 3 (strong staining), using fundic
119
performed using SPSS v.10 (SPSS Inc., Chicago, IL, USA).
glandular cells as controls. Positive reactions similar to those in the control cells were scored as 2 (moderate staining). Tissue
RESULTS
specimens showing significantly more intense staining than the control cells were scored as 3 (strong staining), specimens with
Table 1 shows the characteristics of the 55 patients. The
a readily noticeable reduction in staining intensity were scored
mean follow-up period of the patients was 60.8 months. A total
as 1 (weak staining), and specimens with undetectable or negli-
of 55 patients with H. pylori infection (36 males, 19 females;
gible expression were scored as 0 (no staining). The staining
mean age, 60.7 years) who underwent successful ER for EGC
area, defined as the total amount of positively staining cells,
and were followed up. Of the 55, 28 were successfully treated
was recorded as 0 (none or positive staining in ＜5% of the
with triple therapy for H. pylori infection, and the other 27
cells), 1 (positive staining in 5∼30%), 2 (positive staining in
were failed eradication of H. pylori or couldn’t take those medi-
31∼60%), or 3 (positive staining in ＞60%). The staining in-
cations by poor compliance or side effects. There was no sig-
dex, which ranged from 0 to 9, was obtained by multiplying
nificant difference in any demographic characteristic between
the score for staining intensity times the staining area.
the groups. During the endoscopic follow up period, no newly developed cancers were observed in the eradication group.
4. Statistical analysis
However, metachronous gastric cancers were detected in other
All results are expressed as means±SEM. For statistical analy-
regions in five patients (18.5%) belonging to the ongoing in-
sis, ANOVA single-factor analysis was performed. Differences were deemed significant when P＜0.05. The incidence of cancer in other regions was compared between the two groups using 2 the χ test and Student’s t-test. All statistical computations were
Table 1. Characteristics of the Patients Variable
Eradication group
Ongoing infection P value group
Number 28 27 a 62 (43∼80) 60 (45∼81) Age (years) Gender (male/female) 19/10 17/9 Depth of EGC (m1/m2/m3) 3/20/5 3/17/7 Mean size of EGC (mm) 12.3 11.6 Site (antrum/angle/corpus) 14/4/10 15/5/7
NS NS NS NS NS NS
NS, not significant. a Mean (range).
Fig. 1. A Kaplan-Meier plot shows the proportion of patients free of metachronous cancer after eradication therapy for H. pylori.
Table 2. Demographic Features of Patients with Metachronous Gastric Cancer nd
1 2 3 4 5
Age (yr)
Gender
Time to 2 cancer (months)
Depth of 2nd cancer
46 68 64 75 54
Male Male Male Female Female
13 14 48 36 36
m2 m2 m2 m3 m2
Location
Size of 2nd cancer
1 cancer
2nd cancer
0.7×0.6 0.8×0.4 0.6×0.4 1.0×0.8 1.2×1.0
Antrum Corpus Antrum Antrum Antrum
Antrum Antrum Antrum Angle Antrum
cm cm cm cm cm
st
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The Korean Journal of Helicobacter and Upper Gastrointestinal Research：제 11 권 제 2 호 2011
fection group; this was significantly higher than the occurrence 2
treatment period (antrum: 1.7±0.2, corpus: 2.3±0.1, P＜0.01).
in the eradication group (P=0.023, χ test, Fig. 1). The meta-
The atrophy score declined from 1.9±0.1 to 1.6±0.1 (P=0.030)
chronous gastric cancers were found in the five patients within
in the corpus and from 2.0±0.2 to 1.6±0.1 in the antrum
4 years of ER: two at 13-14 months, two at 36 months, and
(P=0.048) after H. pylori eradication. Furthermore, the grade
one at 48 months after ER. Each metachronous gastric cancer
of intestinal metaplasia (IM) in the corpus significantly de-
was less than 10 mm in size and was located in the mucosal
creased, from 1.9±0.2 to 1.6±0.2 (P=0.043).
layer (Table 2).
Slightly increased COX-2 expression was found in the cancer
In the eradication group, we analyzed the grade of gastritis
tissues (4.5±0.5), compared to their respective paired H. pylo-
in the pre-eradication period and that of last follow-up biopsies
ri-infected normal adjacent mucosa (3.2±0.3), but the difference
after H. pylori eradication. The neutrophil infiltration scores in
was not statistically significant (P=0.07). There was no differ-
the antrum and the corpus were markedly decreased (antrum:
ence in COX-2 immunoreactivity in the mucosa adjacent to
1.1±0.1, corpus: 1.4±0.1), compared to the scores in the pre-
cancer tissues between the groups before EMR therapy (3.3±0.3 versus 3.0±0.4, P=0.914). However, COX-2 expression in adjacent mucosa in the eradication group was significantly decreased (1.4±0.2), compared to that in the ongoing infection group (3.0±0.4, P=0.0001), at the last follow-up (Fig. 2, 3). COX-2 expression of the mucosa adjacent to cancer tissue was high in the patients with metachronous gastric cancer compared to that in the patients without metachronous cancer of ongoing infection group (5.6±0.9 versus 2.5±2.0, P=0.003).
DISCUSSION The intestinal type of gastric adenocarcinoma forms glandular structures that somewhat resemble the glands of the gasFig. 2. COX-2 expression in the mucosa adjacent to the cancer. COX-2 expression in the adjacent mucosa was significantly lower in the eradication group than in the ongoing infection group at the last follow-up.
trointestinal tract. This type has glandular atrophy with IM in 23
the background mucosa. The second histological type, the diffuse carcinoma, invades the organ without forming well-defined
Fig. 3. Immunohistochemical staining for COX-2. (A) COX-2 expression is present in epithelial cells and inflammatory mononuclear cells of patients after endoscopic resection for early gastric cancer and before eradication of H. pylori (original magnification, ×100). (B) COX-2 expression significantly decreased after eradication of H. pylori (original magnification, ×100).
Hwa Jong Kim, et al：H. pylori Eradication and Metachronous Gastric Cancer
121
structures such as glands. No clear precancerous lesions have
ciated with risk for colorectal, lung, bladder, and gastric
been identified for the diffuse type. The diffuse type of gastric
cancers.
adenocarcinoma has different features and characteristics from
creased risk for gastric cancer, and an additionally elevated risk
24,25
the intestinal type.
Furthermore, a diffuse histotype has been
31-34
Subjects with the −1195 AA genotype had in-
for gastric cancer was observed in subjects exhibiting the -1195 34
Subjects
related to earlier presences of lymph node metastases. An abso-
AA genotype and H. pylori infection or smoking.
lute indication for ER of EGC can be considered the intestinal
with the −1195 AA genotype also had high COX-2 expression,
type of intramucosal cancer. Accordingly, patients with ER
compared to subjects with the 1195 GG genotype. This genetic
therapy for EGC retain potentially carcinogenic mucosa, which
variation leads to differences in the metabolism of NSAIDs, in
can develop into overt gastric adenocarcinoma at any time.
prostaglandin synthesis, and in individual cancer risk. Although
COX-2, an inducible isoform of cyclooxygenase enzyme,
we did not evaluate COX-2 genotypes, we believe that the
converts arachidonic acid to prostanoids and is strongly ex-
elimination of H. pylori blocked over-expression of COX-2 and
pressed throughout the H. pylori-associated gastric carcino-
suppressed metachronous gastric cancer in our patients who
genesis pathway, from chronic active gastritis, to gastric atro-
were at high risk for gastric adenocarcinoma.
19,20
All our
The eradication rate of this study was 50.9% by in-
subjects had carcinogenic mucosa and H. pylori infection, and
tention-to-treat analysis. Hwang, et al. showed that the erad-
COX-2 expression was demonstrated in their epithelium. The
ication rate of H. pylori depends on the antibiotic resistance.
expression of COX-2 in the eradication group was significantly
In the study, the overall eradication rate of PPI triple therapy
decreased after H. pylori eradication. However, the ongoing in-
was 63.6% by intention-to-treat analysis. Our study also in-
fection group revealed continuous, strong expression of COX-2
cluded the patients who did not complete the medicines for H.
in our study.
pylori eradication on account of poor compliance or side
phy and IM, and finally to gastric adenocarcinoma.
Mucosal COX-2 expression has been shown to continue in 26
patients with IM, even after eradication of H. pylori infection.
35
effects. We also assumed that a lot of the patients with antibiotic resistance were enrolled in the study.
Other investigators have found that patients with IM exhibited
We found 5 patients with metachronous gastric cancer in the
reduced COX-2 expression at 1 year after successful H. pylori
ongoing infection group. The rate of the metachronous gastric
eradication, compared to expression before eradication therapy.
27
cancer was relatively high compared to previous study in
Our results are consistent with the latter observation. Our can-
13 Japan. Most of previous studies were performed during only
cer patients with high carcinogenic background mucosa, includ-
3 years after ER.
ing IM, showed decreased carcinogenic potential of the mucosa
were observed at 36 months and 48 months after ER. Fukase’s
at more than 3 years after H. pylori eradication. This is based
study showed that 167 patients of control group could be fol-
on decreased COX2 expression and the regression of atrophy
lowed up at 3 years. The cumulative incidence of metachronous
and corporal IM in our patients after H. pylori eradication.
gastric cancer was 14.4% among the 167 patients. The cumu-
Furthermore, newly developed metachronous early gastric can-
lative incidence rate of the study is very similar to the rate of
cers were detected only in the ongoing infection group.
our study at 3 years after ER.
Some studies have suggested that the suppression of COX-2 28-30
13,36
Three metachronous cancers of our study
Limitations of our study include the involvement a relatively
Methods of suppressing COX-2
small number of patients. A randomized multicenter trial as-
in gastric mucosa include the ingestion of probiotics and H. py-
sessing the preventive effect of H. pylori eradication on occur-
lori eradication therapy for H. pylori-infected mucosa, in addi-
rence of new gastric carcinomas after ER was published in
reduced tumor development.
20
tion to COX-2 inhibitors. However, the ability of these meth-
36 Japan. However, the results of this Japanese study showed a
ods to actually suppress the incidence of gastric cancer develop-
relatively short-term outcome during 3 years. In our study, we
ment in high-risk patients remains controversial.
observed long-term suppression of the development of meta-
Helicobacter pylori infection plays an important role in gas-
chronous gastric adenocarcinomas and decreased COX-2 ex-
tric carcinogenesis, but the mechanism of COX-2 expression in
pression after H. pylori eradication therapy in the patients who
H. pylori-related carcinogenesis is still unclear. Several studies
underwent ER of EGC. Further studies on a larger scale may
have suggested that genetic polymorphisms in COX-2 are asso-
confirm the usefulness of H. pylori eradication therapy in these
122
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patients.
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