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Helicobacfer Pylori Infection in Patients with Gastric
Carcinoma in Biopsy and Surgical Resection
Tomoyuki Shibata, M.D.
lchiro Imoto, Y.D.
Yoshio Ohuchi, M.D.
Yukiko Taguchi, M.D.
Satoshi Takaji, M.D.
Norihisa Ikemura, M.D.
Kazuyuki Nakao, M.D.
Teruo Shima, M.D.
Third Department of Internal Medicine, Mie University School of Medicine, Mie Prefecture, Japan.
BACKGROUND. The discrepancy between the high seropositivity for Helicobacfer
pylori ( H . pylori) and the low diagnostic yield of H. pylori organism in gastric
biopsies of patients with gastric carcinoma has yet to be clarified. The present
study attempted to clarify this controversial point by performing a comparative
evaluation between the detection rate of H. pylori in biopsy and in surgical specimens.
METHODS. The presence of H. pylori in biopsy samples from 50 patients with gastric
carcinoma and 50 age-matched controls was evaluated histologically. Six histologic
sections were obtained from gastric noncancerous areas and the presence of H.
pylori was evaluated in those H . p-vlori negative patients who underwent gastrectomy.
RESULTS. H. pylori was positive in 35 of 50 controls (70%).I n biopsy samples, H.
p.v/uri was detected in 29 of 37 patients (78.4%)with early gastric carcinoma, 7 of
13 (53.8%)with advanced carcinoma, 16 of 23 (69.6%)with intestinal type of gastric
carcinoma, and 20 of 27 (74.1%)with diffuse type of carcinoma. Studies carried
out in gastrectomy specimens increased the diagnostic yield of H. pylori to 33
(89.2%), 12 (92.3%),19 (82.6%), and 26 (96.3%)in patients with early, advanced,
intestinal, and diffuse types of gastric carcinoma, respectively. Overall, H. pylori
was positive in 36 biopsy specimens (72%) and 45 gastrectomy specimens (90%).
Namely, the detection of H. pylori infection was significantly higher in patients
with gastric carcinoma using gastrectomy specimens than in patients with gastric
carcinoma using biopsy specimens only ( P < 0.05).
CONCLUSIONS. These results indicate that the actual prevalence of H. pylori in
patients with gastric carcinoma is considerably higher than that previously reported. Cancer 1996; 721044-9. 0 1996 Americari Cancer Sociefy
KEYWORDS: Helicobacter p y M , gastric carcinoma, gastrectomy, histological
Address for reprints: Shibata, M.D., Edobashi
2-chorne, 174 banchi, Tsu-city, Mie Prefecture,
514, Japan.
Received July 24, 1995; revision received November 13.1995; accepted NovemberBO, 1995.
0 1996 American Cancer Society
t is well-known that Helicobacter pylori ( H . pylori) is a causative factor of
chronic antral gastritis.' Chronic active gastritis may progress to chronic
atrophic gastritis with intestinal metaplasia and finally to dysplasia and
gastric carcinoma.' Although the incidence a n d mortality rates of gastric
cancer decreased over the past decades, gastric cancer is still the most
common malignancy in Japan." The role of H. pylori infection in gastric
carcinogenesis has recently become a subject of major concern. Some
epidemiologic studies have shown the existence of a significant correlation between the incidence or mortality of gastric carcinoma and the
prevalence of H. pylori seropositivity in China and C ~ l o r n b i a .Recently,
several serologic studies reported a strong association between H . pylori
and gastric carcinoma."* However, despite the frequent detection of anti-
Helicobacter pylori and Gastric CancerlShibata et at.
Helicobacter pylon’ Positivity In Control Subjects and in Patients with Gastric Carcinoma
No. of
Patients with Rastric carcinoma
50 (37113)
50 (37113)
Mean age
H.pykvi positivity
in biopsy
specimens (%I
H. pylori positivity in
biopsy and resected
specimens (46)
35 (70)
36 (721
45 (901“
m:male: I: female.
’ P < 0.05: comparedwith conlrol subjects.
’ P < 0.05; comparedwith positivity in biopsy specimens.
body against H. pylori in patients with H. pylori infection,
histologic diagnosis of H. pylori from biopsy specimens
is low, particularly in those cases with diffuse types of
cancer.”,” Namely, the actual prevalence of H. pylori infection in patients with gastric carcinoma remains still
In this study, we investigated the prevalence of H.
pylori infection in the same patients with gastric carcinoma using both biopsy and gastrectomy specimens.
The histologic type of gastric carcinoma was classified in diffuse and intestinal types following the classification of Lauren.13 When two histologic types coexisted
in the tissue, the diagnosis was based on the predominant
histologic type.
Three anatomical parts of the stomach were considered (according to the classification scheme of the lapanese Research Society for Gastric Cancer)’: C (upper
third), M (middle third), and A (lower third).
Endoscopic Examination
Patients with Gastric Carcinoma and Control Subjects
Upon endoscopic examination, four biopsy specimens
were collected from each patient: two (one for histologic
study and another for culture) from the lesser curvature
of the antrum, and two (one for histology and another
for culture) from the greater curvature of the corpus.
Olympus endoscopes (Olympus, Tokyo, Japan) and biopsy forceps were washed and sterilized before the endoscopic procedure. Informed consent was obtained from
all of the patients and control subjects before the initiation of the study.
Fifty patients with histologically proven gastric carcinoma
and 50 age-matched control subjects were examined.
There were 37 males and 13 females and the mean age
of the patients was 62 years. The control subjects were
those referred to our hospital because of radiologic abnormalities of the stomach or duodenum found during
health check, or because of gastrointestinal complaints
without radiologic abnormalities. Subjects who were finally found not to have any localized disease in the stomach or the duodenum by endoscopy, and without any
history of gastric surgery or of systemic disease, were
grouped as control subjects.
Classification of gastric carcinoma was done according to the pathologic stage, histologic type, and localization of the tumors. The pathologic staging of gastric
carcinoma was done following the Japanese Gastroenterological Society Classification.’’ This differentiates two
groups of gastric carcinoma; a group in early pathologic
stage in which the tumoral lesion is confined within the
gastric mucosa or submucosa regardless of the presence
or absence of metastatic disease in the perigastric lymph
node lesion, and a group in advanced stage characterized
by tumoral extension within or beyond the muscularis
propia. Early gastric carcinoma was further classified according to the gross appearance of the tumors into a
protruded (I), superficially elevated (Ha), flat (IIb),superficially depressed (IIcj, and excavated types (111). Gastric
carcinoma in advanced stage was also grouped according
to the Borrmann’s classification (class 1, 2, 3, and 4).12
Histologic Examination
The biopsy specimens obtained from two sites of the
stomach were fixed in 10% formalin and embedded in
paraffin. Paraffin sections were cut and stained with
0.01% acridine orange. The presence of H. pylori infection
was assessed by examining the sections on light microscope ( ~ 1 0 0 0and
by the growth of the bacteria in the
Six histologic specimens from noncancerous sites
were taken from the resected portion of the stomach of
patients previously diagnosed as not having H. pylori infection by biopsy study and the histologic presence of H.
pylori was evaluated following the aforementioned
We also investigated the presence of active chronic
gastritis, atrophic gastritis, and intestinal metaplasia (IM)
using hematoxylin & eosin (H & E) and periodic acidSchiff staining methods. Active chronic gastritis was diagnosed according to the description of Warren and Mar-
CANCER March 15, 1996 / Volume 77 / Number 6
Helicobacter pylon Positivity and Cancer Pathologlc Stage
Early Stage
Advanced Stage
Bor. 1
Bor. 2
Bor. 3
Bor. 4
H. pylon positivity in
biopsy specimens (W)
29 (78.4)
No. of
7 (53.8)
H. pylon positivity in
biopsy and resected
specimens (W)
33 (89.2)
Helicobacter pjbn PositMty and Tumor Histology
If. pylon positivity in
No. of
H. pybd positivity in
biopsy specimens (%)
14 (60.9)
16 (69.6)
2 (8.7)
20 (74.1)
15 (55.6)
5 (18.5)
biopsy and resected
specimens (%)
19 (82.6)
15 (65.2)
4 (17.4)
26 (96.3)
18 (66.7)
8 (29.6)
12 (92.3)
H e l i c o h r pjhri Positivity and Cancer Location
Bor.: Borrmann.
H. pylori positivity in
No. of
shalLi4 Atrophic gastritis and IM were diagnosed according to the classification of Whitehead et aLL5
Culture Methods
Biopsy specimens for culture were plated directly onto
trypticase soy agar containing 5% sheep's blood (Becton
Dickinson Co., Tokyo, Japan) and incubated at 37°C under microaerophilic environment for 5 days. The culture
was considered positive for H. pylori if one or more colonies of gram-negative, oxidase, catalase, and urease-positive grew in the medium.
Enzyme-Linked lmmunosorbent Assay
Anti-H. pylori antibody in the serum of 6 patients with
gastric carcinoma was measured by enzyme-linked immunoadsorbent assay (ELISA) using stocked sera preserved at less than -2OOC. The measurements were carried out using the HM-CAP immunoassay (Enteric Products Inc. Westbury, NY).
Statistical Analysis
Statistical analysis was performed using the Student's t
test, and the cell chi-square test with Yates' correction. A
P < 0.05 was considered a significant difference.
Biopsy studies revealed a frequency of H. pylori infection
in patients with gastric carcinoma of 72% (36 of 50) and
in control subjects of 70% (35 of 50). The frequency of
H. pylori infection between these two groups was not
significantly different (Table 1).
The incidence of H. pylori infection in patients with
different clinical stages of gastric carcinoma is summarized in Table 2. The mean age of patients with early
H. pylon positivity in
biopsy specimens (96)
3 (60)
18 (69.2)
15 (78.9)
biopsy and resected
specimens (%)
4 (801
25 (96.2)'
16 (84.2)
C upper third of stomach; M: middle third of sromach; A: lower third of stomach
P < 0.02: comoared with wsitive bioosv soecimen.
and advanced gastric carcinoma was 62.1 and 61.6 years,
respectively. H. pylori was positive in 29 of 37 patients
(78.4%)with early gastric carcinoma, and in 7 of 13 patients (53.8%)with advanced cancer. Eight patients with
early gastric carcinoma were negative for H. pylori in biopsy specimens. Among these patients, in 4 of 5 (80%)
undergoing surgical therapy, the surgical specimen was
positive for H. pylori. Three non-operated cases in this
stage were endoscopically treated. All six patients with
advanced cancer judged as H. pylori negative by biopsy
study underwent surgical treatment. H. pylori was detected in the surgical specimen in 5 of 6 patients (83.3%).
Overall, H. pylori was positive in 89.2% of the patients
with early gastric carcinoma and in 92.3%of the patients
with advanced cancer (Table 2).
Twenty-three patients presented intestinal type of
cancer and 27 presented diffuse type. The mean age of
these two groups of patients was 66.9 and 57.9 years,
respectively. Biopsy studies were positive in 69.6% and
in 74.1% of the patients with intestinal and diffuse types,
respectively. The inclusion of positive cases of H. pylori
in the surgical specimen yielded a total positivity for H.
pylori of 82.6% and 96.3% in the intestinal and diffuse
types of gastric carcinoma, respectively (Table 3).
The relationship between H. pylori positivity and
cancer location is summarized in Table 4. The detection
rate of H. pylori increased significantly from 69.2% to
He/imbactef py/ofi and Gastric CancerlShibata et al.
Features of Gastritis in Biopsy Samples of Helhbacfer pylon
Negative Patients
Features of Gastritis in Resected Specimens of Helicobacter pylon
Negative Patients
Number of ACC (96)
Number of AC (%I
Number of IM (96)
12/14 (85.7)
11/14 (78.6)
6/14 (42.9)
9/14 (64.3)
14/14 (100)
11/14 (78.6)
ACC: active chronic eastritis:AG: atroDhic easlritis: IM: intestinal rnetaDlasia
96.2%( P < 0.02) in the M group after including the posi-
tive cases diagnosed by evaluating the surgical specimens
(Table 41.
The features of gastritis from biopsy samples of H.
pylori negative patients are shown in Table 5. Atrophic
gastritis was found in all specimens of the antrum. In the
group with a high detection rate of H. pylori in resected
specimens, the frequency of IM tended to be lower than
in the group with a low positive rate for H. pylori. (Table
6).The number of cases with positive H. pylori in resected
specimens was 28, and that with negative H. pylori was
38. (Table 7). The frequency rate of atrophic gastritis was
higher in negative specimens than in positive specimens
for H. pylori infection. The frequency of IM was significantly higher in the negative specimens than that in the
positive samples for H. pylori (Table 7).
Among 14 H. pylori negative patients diagnosed only
by biopsy, 11 underwent surgery and of those, 9 had H.
pylori infection (81.8%). The positivity of H. pylori in gastric carcinoma was 44/47 in patients undergoing surgical
treatment (93.6%).Surgical specimen studies increased
the final positivity of H. pylori to 90%. The frequency of
H. pylori in patients with gastric carcinoma using surgical
specimens was significantly higher than that in the
matched control subjects and higher than that obtained
in those patients in whom the detection of H. pylori was
assessed by biopsy study alone. (90%vs. 70% and 72%,
P < 0.05) (Table 1).
In six patients with H. pylori positive in histologic
specimens, the serum anti-H. pylori antibody was also
found to be positive.
The mortality for gastric carcinoma remains still high in
Japan (40:100,000).Recent studies suggested that patients
infected with H. pylori might have an increased risk of
developing gastric c a r c i n ~ m a . ~This
~ ' ~ ~assumption is
based on previous observations that superficial chronic
gastritis caused by H. pylori may lead potentially to the
development of atrophic gastritis and intestinal metaplasia.16-20Many previous reports have shown this potential
association of H. pylori infection with the occurrence of
No. of H. pylori
positive specimens
of ACG
of AG
of IM
ACC: active chronic eastritis:A G anoohic eastritb: IM: intestinal metaolasia.
Features of Gastritis in Resected Specimens of HeliGo6ucter pylon
Negative Patients
No. of
Presence of
Presence of
AG (%I
Presence of
25/28 (89.3)
20128 (71.4)
18128 (64.3)
28/38 (73.7)
38138 (100)
38138 (100)'
H. pylori positive
H. pylon' negative
ACG: active chronic gastritis;AC: atrophic gaslrilis; IM:inteslinal metaplasia.
' P < 0.05; comDared with Dositkt soecimens.
gastric carcinoma based on the detection of anti-H. pylori
antibodies in the serum or by detecting the bacteria in
surgical or biopsy specimens of patients with gastric carcinoma.& 1021.22
Comparative study between biopsy and surgically resected specimens can not always be performed. However,
in this study, we investigated the H. pylori infection in
surgical specimens of patients who were operated on and
judged as H. pylori negative by biopsy study. The present
investigation is the first to demonstrate an association
between H. pylori and gastric carcinoma using biopsy
and surgical specimens from the same patients. The positivity of H. pylori was evaluated in biopsy samples and
then the actual prevalence of H. pylori infection was reassessed histologically in resected specimens. The detection of H. pylori in gastric carcinoma based on biopsy
specimens was found to be lower than H. pylori serologic
positivity. The initial detection rate of H. pylori in advanced cancer may also be common based on histologic
methods. Previous studies have shown a lower detection
CANCER March 15,1696 / Volume 77 I Number 6
rate of H. pylori using histologic methods as compared
with serologic studies in a proportion of 19%to 89%.9.22,23
This discrepancy may be due, in part, to the disappearance of the H. pylori infection during the process of atrophy and subsequent gastric carcinoma, while the seropositivity continues for at least a few months as it was
recently demonstrated by Karnes et aLZ4Also, H. pylori
infection can not persist for a long time in a mucosa with
intestinal metaplasia. Since gastric mucosal atrophy is
severe in advanced cancer or intestinal type of cancer,
various biopsy examples may show false negative results
for H. pylori infection. In this study, the features of gastritis in both biopsy and resected samples may support this
theory. Namely, detection rate of H. pylori decreased
when the prevalence of IM increased. Similar tendency
was observed in the frequency of atrophic gastritis and
in the detection rate of H. pylori. Another explanation for
the diagnostic yield discrepancy between histologic and
serologic studies may be the patchy distribution of H.
pylori in the gastric ~ L I C O S Fixed
~ . ~ ~biopsy studies may
yield more frequently false negative results due to this
type of distribution.
The final detection rate of H. pylori in this study was
relatively high compared with that obtained in previous
studies. The final detection rate in advanced cases increased to 92.3%. This percentage is higher than that reported in previous histologic studies using biopsy specimens alone. The small number of patients in this study
may explain this high rate. However, the addition of results in nonoperated patients did not change the overall
diagnostic yield of H. pylori. Consequently, the actual
prevalence of H. pylori infection in gastric carcinoma obtained by histologic studies was almost similar to that
obtained using serologic methods.
The detection of H. pylori in diffuse type of cancer
was high even in biopsy specimens. This result is different
from that of previous studies carried out in non-Japanese
populations,6 and from that obtained in Japanese populations with early stage gastric carcinoma.'o The different
methods used for the detection of H. pylori may explain
the different results obtained in each study. Furthermore,
ethnic factors may also account for this discrepancy.
Cancerous lesions located in the M lesion showed an
interesting result. Although the initial detection rate of
H. pylori was 69.2%, the final positivity was 96.2%. This
statistically significant increase suggests that the frequency of H. pylori infection in patients with tumor located in M lesion may be associated with body mucosal
atrophy. The reason why there was a high rate of false
negative for H. pylori infection may be due to the fact
that most of the patients had advanced cancer or because
they were older than age 60 years.
Concerning the relationship of H. pylori detection in
biopsy and surgical specimens with the result of serum
anti-H. pylori antibodies, except in one patient, all patients who were found to be positive for H. pylori in histologic specimens, also had anti-H. pylori antibody in their
sera. Further, the patient in whom H. pylori was not detected in the histologic specimen has a very low level of
serum anti-H. pylori antibody. From the foregoing data,
there seems to be a correlation between serum anti-H.
pylori antibodies and the presence of H. pylon in histologic specimens. However, further studies in a larger population are required to confirm these data.
In conclusion, in patients with gastric carcinoma, a
sampling error can easily occur, especially in advanced
and intestinal types of gastric carcinoma and in tumors
originated in the M lesion of the stomach. Therefore, the
actual prevalence of H. pylori infection may be considerably higher than the previously reported frequency based
on biopsy studies alone. The detection rate obtained in
the current study is similar to that obtained using serologic methods. H. pylori infection is possibly associated
with all types of gastric carcinoma, though in previous
studies the association between H. pylori and gastric carcinoma was not described in all types of gastric carcinoma. We concluded that to ascertain the presence of H.
pylori in patients with gastric carcinoma it is necessary
to carry out serologic studies and histologic methods using both biopsy and surgical resected specimens.
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