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Jpn J Clin Oncol 2010;40(9)828 – 837

doi:10.1093/jjco/hyq119

Recent Knowledge of the Relationship Between Helicobacter pylori


and Gastric Cancer and Recent Progress of Gastroendoscopic
Diagnosis and Treatment for Gastric Cancer
Mototsugu Kato 1,* and Masahiro Asaka 2
1
Division of Endoscopy, Hokkaido University Hospital and 2Department of Gastroenterology, Hokkaido University
Graduate School of Medicine, Sapporo, Hokkaido, Japan

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*For reprints and all correspondence: Mototsugu KATO, Division of Endoscopy, Hokkaido University Hospital North
14, West 5, Kita-ku, Sapporo, Hokkaido 060-8468, Japan. E-mail: m-kato@med.hokudai.ac.jp
Received May 4, 2010; accepted June 18, 2010

Gastric cancer is a multi-step process and multi-factorial disease. However, Helicobacter


pylori plays the most important role in gastric carcinogenesis because most gastric cancers
including both intestinal type and diffuse type arise from mucosa infected by H. pylori. The
relationship between H. pylori infection and gastric cancer has been proved in epidemiological
studies, animal experiments with Mongolian gerbils, and clinical prospective studies.
Significant preventive effect of H. pylori eradication was reported in Japanese randomized
study for secondary gastric cancer after endoscopic resection of primary gastric cancer and
meta-analysis of randomized studies. The Japanese Society for Helicobacter Research has
published a guideline recommending that H. pylori infection should be treated by eradication
therapy to suppress the incidence of gastric cancer. The development of endoscopic technol-
ogy has advanced the diagnosis and treatment of gastric cancer. In the diagnosis of gastric
cancer, image enhancement endoscopy including magnifying observation with narrow-band
imaging system and microscopic magnifying observation opens the possibility of optical
biopsy. Endoscopic resection for early stage of gastric cancer has been established as proper
treatment of early gastric cancer. Recently endoscopic submucosal dissection had made
en bloc resection possible for mucosal cancers .2 cm in diameter. Because of endoscopic
submucosal dissection, endoscopic resection is indicated in a greater number of cases.
Although the use of endoscopic treatment for gastric cancer has been increasing steadily,
long-term outcome data is necessary.

Key words: gastric cancer – H. pylori eradication – prevention – image enhancement endoscopy –
endoscopic submucosal dissection

INTRODUCTION
development of gastric cancer is now accepted. There is a
Gastric carcinogenesis in humans is a multi-step and precancerous period, in which the gastric mucosa undergoes
multi-factorial process. Carcinogenesis factors are divided a series of changes resulting in chronic gastritis, atrophic
into environments, host genetics and aging (1). change and intestinal metaplasia, before developing even-
Environmental factors include low acid secretion, high tually into gastric cancer. H. pylori infection in gastric
salt consumption, N-nitroso compounds in foods and mucosa induces chronic active gastritis with infiltration of
tobacco use. However, Helicobacter pylori plays an neutrophils and mononuclear cells. Most gastric cancers,
important role in gastric carcinogenesis. H. pylori infec- including both intestinal type and diffuse type, arise from
tion is necessary but not sufficient for carcinogenesis of mucosa infected by H. pylori, and these tumors very rarely
gastric cancer. arise from gastric mucosa without inflammation. In Japan,
Nearly a quarter century has elapsed since the discovery 80% or more of H. pylori-infected persons develop atrophic
of H. pylori (2). Due to the progress of research during this gastritis (3). Studies have shown that the presence of gastric
period, the relationship between H. pylori infection and the mucosal atrophy and intestinal metaplasia increase the risk
# The Author (2010). Published by Oxford University Press. All rights reserved.
Jpn J Clin Oncol 2010;40(9) 829

of gastric cancer (4). Experimental studies using Mongolian Gastric cancer is one of many diseases associated with
gerbils with H. pylori infection (5, 6) and a prospective H. pylori infection. Researchers around the world have an
study (7) conducted in Japan have clarified the high risk for interest in the role of this bacterium in gastric carcinogen-
the development of gastric cancer with H. pylori infection. It esis. The relationship between H. pylori infection and gastric
has been an issue of interest around the world as to whether cancer has been examined in epidemiological studies, animal
the eradication of H. pylori can prevent gastric cancer. In experiments and clinical studies.
2008, the results of a multi-center randomized study from
Japan revealed that the incidence of gastric cancer fell to
EPIDEMIOLOGICAL STUDY
approximately one-third by the eradication of H. pylori (8).
Meta-analysis of randomized studies reported that H. pylori In 1991, three nested case-controlled studies were reported
eradication reduces the incident risk of gastric cancer (9). (33 – 35). According to these reports, the positive rate of

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Nowadays, gastrointestinal endoscopy is an indispensable H. pylori antibody was shown to be higher in the patients
tool in the gastroenterological field. The development of with gastric cancer than in the control group. In 1993, results
endoscopic technology has advanced the diagnosis and treat- were reported for a large-scale comparison of the positive
ment of gastric cancer. Image enhancement endoscopy rates for H. pylori antibodies between young and old patients
including magnifying observation with a narrow-band in various countries, with the patients matched for the inci-
imaging (NBI) system and microscopic magnifying obser- dence and mortality rate of gastric cancer (36). These results
vation opens the possibility of optical biopsy (10). clearly demonstrated that countries in which asymptomatic
Assessment of changes in the microsurface structure and the patients had a high positivity rate for H. pylori antibodies
microvascular architecture of gastric lesions is useful for were also countries in which gastric cancer had a high
diagnosing histological findings (11). incidence.
In Japan, mucosal gastric cancer is usually resected by In 1994, the International Agency for Research on Cancer,
endoscopic treatment. Endoscopic submucosal dissection a subordinate organization of the WHO, identified H. pylori
(ESD) makes en bloc resection possible for mucosal cancers as a ‘Group 1 (definite carcinogen)’ (37); that is, the IARC
.2 cm in diameter (12). ESD removes tumor lesions using concluded that H. pylori is certainly related to carcinogenesis
round cut and submucosal dissection without requiring a on the basis of the results of epidemiologic studies. In the
snare device. Because of ESD, endoscopic resection has WHO carcinogen classification, substances are divided into
become indicated in a greater number of cases (13). The use four groups that range from Group 1 (definite) to Group 4
of endoscopic treatment for gastric cancer has been increas- (not a carcinogen). Like tobacco smoking and hepatitis B
ing steadily. virus, H. pylori was classified as Group 1, i.e. with a definite
relationship to carcinogenesis. Generally, experimental data
tend to be required in addition to epidemiologic data when a
substance is identified as a Group 1 carcinogen. In the case
of H. pylori, however, the classification was assigned on the
THE RELATIONSHIP BETWEEN H. PYLORI
basis of epidemiologic data alone.
INFECTION AND GASTRIC CANCER
The odds ratios for gastric cancer patients and control
H. pylori infects the gastric mucosa and causes pathological patients were of higher value for patients with early gastric
gastritis (14, 15). H. pylori infection often persists for life cancer than for patients with advanced cancer (38). Since
and chronic inflammation of the gastric mucosa leads to a intestinal metaplasia spreads before early gastric cancer pro-
wide variety of upper gastrointestinal tract diseases, such as gresses to advanced cancer, it is inferred that H. pylori almost
atrophic gastritis, gastroduodenal ulcer, gastric adenocarci- completely disappears from the stomach as a result and the
noma, gastric mucosal associated lymphoid tissue lymphoma antibody titer decreases. A study of gastric cancer patients
and hyperplastic gastric polyps (7, 16 – 25). In addition, aged 40 years or younger reported that the odds ratio was
H. pylori infection influences gastric function, including much higher for younger patients than for elderly patients
gastric acid secretion, and alters the intragastric environment (39). In addition, these epidemiological studies demonstrated
(26, 27). An association between H. pylori infection and that H. pylori infection is closely associated with both types
extra-gastroduodenal diseases, such as idiopathic thrombocy- of gastric cancers, intestinal type and diffuse type.
topenic purpura and iron-deficiency anemia, has also been Six meta-analyses of cohort studies, case-controlled
reported (28, 29). studies and nested case-controlled studies revealed a positive
It is known that approximately half the population of odds ratio between H. pylori seropositivity and gastric
Japan is infected with H. pylori (30, 31). Although not all cancer (38, 40 – 44) (Table 1). All these meta-analyses
infected people develop the above-mentioned diseases, they showed that H. pylori infection is associated with approxi-
form a high-risk population for such complications. mately a 2-fold increased risk of developing gastric cancer.
Successful eradication of H. pylori improves histological Research concerning the association between gastric cancer
gastritis and may prevent various diseases associated with and H. pylori has achieved enormous progress. One of the
H. pylori infection (32). greatest concerns is to ascertain whether H. pylori-induced
830 H. pylori and gastroendoscopy

Table 1. Meta-analysis of the relationship between H. pylori seropositivity Table 2. Gastric carcinogenesis in H. pylori-infected Mongolian gerbils
and gastric cancer
Author Year Strains Chemical Cancer Histology Period
Author Year Selected paper Odds rate 95% CI agents incidence (weeks)

Haung 1998 19 cohort, CC 1.92 1.32–2.78 Watanabe 1998 TN2GF4 None 10/27 well:10 62
(37%)
Danesh 1999 10 nested CC 2.5 1.9–3.4
Honda 1999 ATCC43504 None 2/5 well:2 72
Eslick 1999 42 cohort, CC 2.04 1.69–2.45
(40%)
HCCG 2001 12 nested CC 2.36 1.98–2.81
Hirayama 1999 ATCC43504 None 1/56 well:1 52
Xue 2001 11 CC 2.56 1.85–3.55 (2%)

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Haung 2003 16 CC 2.28 1.71–3.05 Sugiyama 1998 ATCC43504 MNU 13/37 well:5, 40
(35%) por:2,
sig:6
CC, case-control study; HCCG, Helicobacter and Cancer Collaborative
Group. Shimizu 1999 ATCC43504 MNNG 15/25 well:9, 50
(60%) por:1,
sig:4
gastritis ultimately results in gastric cancer. The onset of Tokieda 1999 ATCC43504 MNNG 4/6 well:4 52
gastric cancer can be explained as being caused not only by (67%)
H. pylori infection, but also by a combination of various
factors such as food and the environment. MNU, N-methyl-N-nitrosourea; MNNG, N-methyl-N-nitro-N-nitrosoguanidine;
well, well differentiated tubular adenocarcinoma; por, poorly differentiated
adenocarcinoma; sig, signet-ring cell carcinoma.

EXPERIMENTAL STUDY
An experimental model of persistent H. pylori infection in was studied using H. pylori infected and MNU-treated
its early stage has been difficult to create. However, such Mongolian gerbils (54). The tumor incidences were related
models have been successfully created in pot-bellied pigs to the period of inflammatory status induced by H. pylori
(45), mice (46), monkeys (47), Mongolian gerbils (48) and infection. Eradication at an earlier period effectively reduced
other animals. Mongolian gerbils resemble humans in their gastric carcinogenesis initiated with a chemical carcinogen.
susceptability and response to H. pylori infection (13), Eradication at an early stage of inflammation might be effec-
which can induce chronic active gastritis, gastric ulceration tive in preventing H. pylori-related gastric carcinogenesis.
and duodenal ulceration. The appearance of intestinal meta- This result may suggest that H. pylori eradication treatment
plasia was reported in Mongolian gerbils at 6 months after is promising for gastric cancer prevention in humans.
infection with H. pylori (48). It has become evident from
these results that persistent H. pylori infection can cause
CLINICAL STUDY
atrophy and intestinal metaplasia, even in animals.
Therefore, the Mongolian gerbil model has an advantage A prospective follow-up study using endoscopic surveillance
for investigating the gastric carcinogenesis developed by in Japan examined the association between H. pylori infec-
H. pylori infection in humans. Several strong pieces of evi- tion and the development of gastric cancer (7). In follow-up,
dence that H. pylori infection produces gastric adenocarci- gastric cancer developed in 2.9% of the H. pylori-infected
noma in animals are accumulating (5, 6, 49 – 52) (Table 2). subjects compared with none of the uninfected subjects.
Mongolian gerbils with long-term infection of H. pylori Among the patients with H. pylori infection, corpus-
developed gastric cancer, with or without exposure to predominant gastritis with severe gastric atrophy and intesti-
low-dose chemical carcinogens, N-methyl-N-nitrosourea nal metaplasia were at significantly higher risk for gastric
(MNU) or N-methyl-N-nitro-N-nitrosoguanidine (MNNG). cancer, especially the intestinal type (Fig. 1). While diffuse-
These six reports came from different experimental con- type gastric cancer arose from pangastritis, usually gastric
ditions, namely co-treatment of chemical carcinogens, strain cancer does not occur from antrum predominant gastritis,
differences and different observation period. These studies which is background gastritis of duodenal ulcer.
have provided experimental evidence that H. pylori plays the Randomized and non-randomized studies on the prevention
main role in carcinogenesis of gastric cancer. of gastric cancer by H. pylori eradication in healthy subjects
An experimental study for gastric cancer prevention or in peptic ulcer patients were conducted around the world.
reported that H. pylori eradication was able to decrease the Five non-randomized intervention studies, in which eradicated
incidence of gastric carcinomas in Mongolian gerbils and non-eradicated subjects underwent endoscopic follow-up
induced by H. pylori inoculation plus administration of to assess the development of gastric cancer, were reported
low-dose chemical carcinogens (53). To evaluate the effect from Japan (55 – 59) (Table 3). The results of three studies
of eradication on gastric carcinogenesis, an experimental have suggested an inhibitory effect of H. pylori eradication on
model with eradication in the early, middle or late period gastric cancer incidence.
Jpn J Clin Oncol 2010;40(9) 831

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Figure 1. H. pylori-induced gastritis presents in three patterns. Gastric ulcer and intestinal-type gastric cancer generally occur in corpus gastritis. Pangastritis
is associated with diffuse-type gastric cancer. Antrum gastritis has high risk of duodenal ulcer and low risk of cancer.

Table 3. Japanese non-randomized studies of H. pylori eradication and gastric cancer development

Author Year Number of subjects Group Follow (Y) Incidence rate of gastric cancer P-value Intestinal type Diffuse type

Take 2005 1342 Control 3.4 4/176 (2.3%) 0 5


GU/DU Eradication 3.4 8/944 (0.8%) P , 0.01 4 3
Takenaka 2007 1807 Control 2.9 5/288 (1.7%) 4 1
GU/DU Eradication 3.3 6/1519 (0.4%) P , 0.05 2 4
Ogura 2008 708 Control 3.1 13/304 (4.3%) 11 2
GU/DU Eradication 3.2 6/404 (1.5%) P , 0.01 3 3
Yanaoka 2009 4141 Control 9.3 55/3658 (1.5%) 36 19
Healthy Eradication 9.3 5/473 (1.1%) n.s. 4 1
Mabe 2009 4133 Control 5.2 9/352 (2.6%) 5 4
GU/DU Eradication 5.6 47/3781 (1.2%) n.s. 35 10

n.s., nonsignificant; Y, year.

However, a large-scale double-blind randomized study in assessed gastric cancer or progression of preneoplastic lesions
China showed that gastric cancer still occurred after successful during follow-up were included in a meta-analysis study (8, 9,
eradication of H. pylori and that H. pylori eradication did not 60 – 65) (Table 4). Overall, 37 of 3388 (1.1%) treated patients
lead to significant decrease in the incidence of gastric cancer developed gastric cancer compared with 56 of 3307 (1.7%)
(60). A total of 1630 people with H. pylori infection in Fujian control participants (14). Since the relative risk for gastric
Province, where the mortality rate due to gastric cancer is cancer was 0.65 (95% CI: 0.43 – 0.98), H. pylori eradication
high, were randomly assigned to an H. pylori eradication treatment seems to reduce the risk of gastric cancer.
therapy group or a placebo group, and were followed for 7.5 In Japan, mucosal gastric cancer is usually resected by
years. During follow-up, development of gastric cancer was endoscopic treatment. As only a small part of the gastric
observed in seven subjects from the H. pylori eradication mucosa is resected, secondary gastric cancer after endoscopic
therapy group and 11 subjects from the placebo group, with no resection of primary gastric cancer often develops at another
significant difference between the two groups (P ¼ 0.33). For site of the stomach. The length of follow-up has varied in
the subgroup without precancerous lesions (atrophy, intestinal reports to date, but the secondary cancer rate has ranged from
metaplasia and dysplasia), however, the incidence of gastric 2.5 to 14% (66, 67). We conducted a large-scale, multi-
cancer was significantly lower in the H. pylori eradication center, randomized controlled open-label study to determine
therapy group than in the placebo group (P ¼ 0.02). whether eradication of H. pylori had inhibitory effects on the
Six randomized trials that compared eradication treatment development of metachronous gastric carcinomas after endo-
with no treatment in H. pylori-positive patients and that scopic resection (8). The 542 subjects were randomly
832 H. pylori and gastroendoscopy

Table 4. Randomized studies of H. pylori eradication and gastric cancer development

Author Year Double blind Placebo control Follow (Y) Incident rate of gastric Relative risk 95% CI Outcome measure
cancer (%)

Eradication Control

Correa 2000 No No 6 3/491 2/485 1.48 0.25– 8.83 Secondary


Wong 2004 Yes Yes 7.5 7/817 11/813 0.65 0.25– 1.63 Primary
Leung 2004 Yes Yes 5 4/295 6/292 0.66 0.19– 2.31 Secondary
You 2005 Yes Yes 7.3 19/1130 27/1128 0.7 0.39– 1.26 Secondary

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Saito 2006 No No 4 2/379 3/313 0.55 0.09– 3.27 Secondary
Zhou 2008 Yes Yes 8 2/276 7/276 0.29 0.06– 1.36 Secondary
Fukase 2008 No No 3 9/250 24/255 0.35 0.16– 0.78 Primary

Y, year.

allocated to the eradication arm (n ¼ 271) and the control


arm (n ¼ 271) and examined endoscopically at 6, 12, 24 and
36 months after allocation. During follow-up of 3 years,
metachronous gastric cancer developed in 33 cases, including
9 in the eradication group and 24 in the control group. The
incidence of metachronous gastric cancer in the eradication
group was significantly lower than in control group both in
the analysis ignoring observation period (Odds ratio: 0.353,
95% CI: 0.161 – 0.775, P ¼ 0.009) and in the analysis taking
it into consideration (Hazard ratio: 0.34, 95% CI: 0.16 – 0.70,
P ¼ 0.003). Overall results show that H. pylori eradication
reduces the risk of developing new gastric cancer even in the
highest risk group. This was the first randomized study in
which patients who received intervention by H. pylori eradi- Figure 2. H. pylori infection has the possibility of both initiating and pro-
cation therapy were compared with control patients and a sig- moting the development of gastric cancer. The preventive effect of H. pylori
eradication depends on the stage of gastric cancer.
nificant difference was found at the primary endpoint
(development of gastric cancer). Based on the results of this 1932 after development of many different straight rigid
study, H. pylori eradication may also be effective in patients tubes, Schindler developed a flexible gastroscope with a
who have mucosal atrophy and intestinal metaplasia. bendable tip. In 1950, Uji ushered in a new age for gas-
H. pylori infection has the possibility of both initiating troscopy with the introduction of a gastrocamera. The
and promoting the development of gastric cancer. It seems concept was to take pictures of the gastric surface with a
that H. pylori eradication almost completely suppresses the miniature camera inserted in the stomach. This gastrocamera
incidence of gastric cancer before carcinomatous change quickly became the principal diagnostic tool for gastric dis-
develops, the same as seen in experimental studies. The eases in Japan. In 1957, Hirschowitz developed a prototype
potential effect of H. pylori eradication on preclinical cancer of the fiberscope, in which images of gastric mucosa are
and clinical cancer is to markedly suppress development or transmitted through a fiberglass bundle. Therefore, the fiber-
to slow growth (68) (Fig. 2). The Japanese Society for scope makes possible diagnosis under real-time observation.
Helicobacter Research has published a guideline recom- As the technology of the fiberscope advanced, endoscopic
mending that H. pylori infection be treated by eradication diagnosis and treatment have made rapid progress.
therapy (69). It is problematic that the therapy recommended Videoendoscope was realized in 1968 owing to advancement
in the guideline is not covered by the Japanese National in television technology and the advent of the charged-
Health Insurance System. coupled device. Videoscope featuring instantaneous and
sequential system of image reproduction has become the
standard for endoscopy today. The high-technology video-
scope provides image enhancement endoscopy such as mag-
DEVELOPMENT OF GASTROENDOSCOPY nifying imaging, macroscopic imaging, NBI, infra-red
The history of gastroendoscopy started from an attempt with imaging, auto-fluorescence imaging and flexible spectral
the use of a straight rigid tube by Kussmaul in 1868 (70). In imaging color enhancement (Fig. 3).
Jpn J Clin Oncol 2010;40(9) 833

Laser-scanning confocal microscopic images of the gastroin-


testinal tract have been reported to match the resolution of
microscopic images (77). The observation of gastrointestinal
mucosa in vivo is currently performed using laser-scanning
confocal microscopy. Since images of macroscopic magnify-
ing endoscopy are similar to macroscopic images in histologi-
cal examination, the former offers the possibility of optical
biopsy in clinical practice.

NARROW-BAND IMAGING

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NBI is a novel spectral technique that rotates narrow-band
red/green/blue filters instead of the full range of the white
light spectrum (78). The depth of penetration differs accord-
Figure 3. Image-enhanced endoscopy includes several imaging systems.
ing to wavelength, with a short wavelength penetrating only
superficially and a longer one penetrating into deeper layers.
MAGNIFYING ENDOSCOPY In the NBI system, optical filters allow narrow-band light to
pass at wavelengths of 415 and 540 nm. Small capillary
Magnifying endoscopies of the stomach have not been as
vessels on the mucosal surface can be seen most clearly at
widely used in clinical practice as have magnifying colonos-
415 nm, which is the wavelength that corresponds to the
copies, often used for histological diagnosis and invasive
hemoglobin absorption band, while large collecting vessels
diagnosis of colorectal tumor (71). Although magnifying
located in the deep layer of the mucosa can be observed at
endoscopy has not had an impact on routine endoscopic
540 nm. NBI technology enhances visualization of the fine
examination of the stomach, magnified observation with NBI
capillary vessel structure on the surface layer.
is starting to play an important role in diagnosis and treat-
In general magnifying endoscopy with NBI system is used
ment of gastric cancer.
to detect the microsurface structure and the microvascular
In 1964, gastric mucosal appearance of resected stomach
architecture of the gastrointestinal mucosa (79) (Fig. 4). The
using stereoscopic microscopy was first reported (72).
microsurface structure of the mucosa includes normal struc-
Magnified observation using optical endoscopy started from
ture, changed structure by inflammation and biological
1967. In spite of many trials using magnifying endoscopy
response and tumor-specific structure. Microvascular architec-
with 5 – 30-fold magnification, optical magnifying endoscopy
ture includes normal vascular system and tumor microvessels.
has not become common because of its difficulty. In the
Magnifying endoscopy with NBI shows a regular linear or
period of videoendoscopy, clinical studies of magnifying
reticular pattern with a crypt-opening and regular coil-shaped
endoscopy of the stomach have been tried again.
capillary network in the antrum without H. pylori infection.
Technology of magnification is mainly divided into elec-
A regular oval pattern with crypt-opening and regular capil-
tronic and optical. Electronic magnification simply expands
lary loops surrounding the necks of the gastric crypt and col-
the image, and fails to preserve the image quality. Variable
lecting venules (CV) with a honeycomb-like appearance are
focus technology produces a greatly magnified image by
detected in the body without H. pylori infection using mag-
moving the position of the focus lens. A microsize actuator at
nifying endoscopy with NBI. In the magnified view with
the distal end shifts the position of the focus lens from a stan-
NBI, H. pylori infection changes it to an enlarged, prolonged
dard view to a magnified view. Consequently variable focus
pit with an increased density of the capillary network and
technology is able to achieve 80 to 100 magnification.
unclear CV according to development of atrophy and intesti-
nal metaplasia.
The characteristic findings for gastric cancer are the disap-
MACROSCOPIC MAGNIFYING ENDOSCOPY
pearance of the regular capillary network pattern, the pres-
Macroscopic magnifying endoscopy has been used to observe ence of an irregular microvascular pattern and the presence
the characteristics of cells on the surface layer of gastrointesti- of a demarcation line between the cancerous and non-
nal mucosa. Two different systems of macroscopic magnify- cancerous mucosa (80, 81). For early gastric cancer whose
ing endoscopy have been developed. The concept of an extent is unclear using conventional endoscopy, magnifying
endocytoscopy system led to the application of contact endo- endoscopy with the NBI system is able to determine the
scopy to examine the surface of the genital tract as a form of lateral extent of early gastric cancer from the demarcation
microhysteroscopy (73). Microscopic observation at the cellu- line and tumor vessels before endoscopic resection.
lar level using endocytoscopy has been achieved in the eso- A systematic but simple classification system based on the
phagus, stomach and colorectum (74–76). On the other hand, microvascular pattern and microsurface pattern (the ‘VS
laser-scanning confocal microscopy has been developed as an classification’) has been proposed (83). The technique, based
alternative system of ultra-high magnification endoscopy (77). on the principles described here, can be applied not only in
834 H. pylori and gastroendoscopy

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Figure 4. Magnifying endoscopic image of gastric mucosal surface provides the assessment of microsurface structure and microvascular architecture.

Figure 5. The procedure of EMR consists of three steps: marking, lifting and cutting with snare device.

routine endoscopic examination but also in the detailed preo- EMR is indicated for patients with a small mucosal cancer
perative assessment of the lateral extent of early gastric and no concomitant lymph node metastasis (86). Indicated
cancer. Magnifying endoscopic observation with the NBI lesions for EMR are intestinal-type (well and/or moderately
system is helpful for the identification of early gastric cancer. differentiated adenocarcinoma and/or papillary carcinoma)
mucosal cancers without evidence of an ulcer or ulcer scar
measuring less than 2 cm in diameter.
En bloc resection is preferable because of the risk of
ENDOSCOPIC TREATMENT FOR EARLY residual cancer left behind by EMR. En bloc resection was
STAGE OF GASTRIC CANCER achieved in 76% of EMR cases from the analysis of 12
Endoscopic treatment of early gastrointestinal cancers has major institutions in Japan (87). Although various EMR
been shown to be effective in curing mucosal malignancies techniques have been developed for the purpose of removing
without lymph node metastasis. Endoscopic mucosal resec- gastric lesions more easily, the guideline indicates that 2 cm
tion (EMR) designed to remove mucosal lesions in sections is maximum cancer size for en bloc resection (88 – 90).
through the submucosa is the most important technique for However, gastric mucosal cancers with a diameter of more
endoscopic treatment of early gastric cancers (84, 85). than 2 cm with no lymph node metastasis have been
According to gastric cancer treatment guidelines issued in detected. For example intestinal mucosal cancers without
March 2001 by the Japanese Gastric Cancer Association, ulceration and involvement of the lymphatic or venous
Jpn J Clin Oncol 2010;40(9) 835

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Figure 6. The procedure of ESD consists of three steps: marking, lifting and submucosal cutting with knife device.

vessels have practically no risk of lymph node metastasis endoscopy can provide an accurate diagnosis of early gastric
irrespective of tumor size (91). A new technique has been cancer for smaller size. The establishment of ESD can
required to expand the indications for endoscopic resection expand the endoscopic indication criteria of early gastric
in selected situations that have no risk of lymph node cancer. The combination of H. pylori eradication and endo-
metastasis. scopic screening of gastric cancer is recommended to
The recently developed EMR procedure, ESD, makes decrease mortality due to gastric cancer.
en bloc resection possible for mucosal cancers greater than
2 cm in diameter (12, 92 – 95). In principle EMR consists of
three steps: marking, lifting and cutting (Fig. 5). In the Conflict of interest statement
marking step, the superficial extent of the lesion is precisely
determined using chromoscopy, and the peripheral margin is
None declared.
outlined by electrocoagulation. The next step, lifting, con-
sists of lifting the lesion to render it polypoid by saline injec-
tion. The mucosal and submucosal layers are separated from
the muscularis propria at this stage. In the final step, cutting, References
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