Gastrointest Endoscopy Clin N Am

18 (2008) 513522

Gastric Cancer: Pathogenesis, Screening,

and Treatment
Kentaro Sugano, MD, PhD
Department of Medicine, Jichi Medical University, Yakushiji 3311-1, Shimotsuke-City,
Tochigi 329-0498, Japan

Gastric cancer is the second leading cause of cancer-related death in the

world and in Japan. Although the incidence of gastric cancer has been
declining, almost 50,000 Japanese die of gastric cancer and more than
100,000 new cases are diagnosed every year (Fig. 1). It thus remains one
of the biggest health problems in Japan. In the United States, however,
interest in gastric cancer has declined because the incidence and mortality
have dramatically decreased over the past 70 to 80 years. It still accounts
for more than 30,000 deaths annually, however, exceeding the mortality
for esophageal adenocarcinoma, a cancer recently highlighted because of
its increasing incidence [1]. Most of these trends, both in Japan and the
United States, seem to be attributable to a declining incidence of distal gastric cancer. By contrast, it has been reported that the incidence of cancer of
the gastric cardia is sharply increasing in the United States and other
Western countries [2]. We should still be attentive to this curable cancer
when early detection and treatment are possible.
Gastric cancer: heterogeneity
As indicated by changing time trends in the incidence of gastric cancer
arising in dierent locations, gastric cancers exhibit great diversity reected
in the various causes, cellular origins, histologic architecture, and genetic
alterations seen in these tumors (Box 1). There is a multitude of interactions
between the etiologic factors, further complicating the carcinogenic pathways of gastric cancers and the diverse pathologies (Fig. 2). Because of
the complexity of the meticulous histologic classications, a simplied
This work is supported in part by Grants-in-Aid for Scientific Research (18390224) from
the Japan Society for the Promotion of Science.
E-mail address: sugano@jichi.ac.jp
1052-5157/08/$ - see front matter 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.giec.2008.05.003
giendo.theclinics.com

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60
US Mortality M

50
40

US Mortality F
Japan Mortality M
Japan Mortality F

30
20
10
0

EC

GC

CRC

Fig. 1. Age-adjusted mortalities from gastrointestinal cancers in Japan and the United States.
CRC, colorectal cancer; EC, esophageal cancer; GC, gastric cancer. Mortality statistics from
the United States (20002003) and Japan (2003) have been used.

classication system proposed by Lauren [3] is still useful for facilitating

a general understanding of this disease. According to this system, gastric
cancer may be divided into diuse (undierentiated) and intestinal (dierentiated) types. These two types of gastric cancer show dierent genetic alterations and biologic behaviors, thereby inuencing the clinical decision
making, particularly the indications for endoscopic mucosal resection.
Box 1. Diversity of gastric cancer
Etiology
Infection
Helicobacter pylori
Epstein-Barr virus
Genetics
Hereditary gastric cancer (CHD1)
Lynch syndrome/HNPCC
Carcinogens
Nitric oxide
Location
Proximal (cardia)
Distal
Histology
Diffuse (undifferentiated)
Intestinal (differentiated)
Stage
Early
Advanced

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Infection
H pylori
EBV

Genetic Trait
HNPCC
Familial Gastric Cancer
Immune Response
Acid Secretion
Gender

Life Style
salt
nitrate
smoking
Vitamin/anti-oxidant

Fig. 2. Etiologic factors that increase the risk for gastric cancer. These factors interact with
each other resulting in gastric carcinogenesis.

Given the diversity of gastric cancer, it is important to clarify the features

of gastric cancer in Japan and to compare them with those in the United
States. The most common tumor locations between the two countries are
dissimilar [4]; most gastric cancer is located distally in Japan, whereas proximal cancer is dominant in the United States (Fig. 3A). The increase in
cardiac cancers and Barretts cancers has been pointed out in Western countries, and this has been shown to be negatively associated with Helicobacter
pylori infection [5]. Pathogenic mechanisms distinct from H pylori infection
seem to be operating for cancers arising at the esophagogastric junction.
A promising hypothesis to explain carcinogenesis in this area is chemical
injury attributable to nitrosating stress [6]. In Japan, most of the gastric cancers are related to H pylori infection regardless of the histologic types.
Genetic and epigenetic alterations leading to gastric carcinogenesis have
been elucidated during a long process of inammation associated with
H pylori infection (Fig. 4). Early cardiac cancers in Japan and those of
the United States are distinct in their association with reux esophagitis
[7]. Considering such dierences between the two countries, pathogenic
mechanisms of cardiac cancer should not be oversimplied.
Another dierence is the cancer stage at diagnosis. In Japan, T1 stage cancers compose more than half of the cases of gastric surgery, whereas less than
one third are T1 in the United States (Fig. 3B) [4]. Despite these dierences, the
overall surgical outcomes for stage-adjusted gastric cancers are similar
between the two countries, indicating that the biologic behaviors of gastric
cancer are similar [4]. One can therefore assume that gastric cancer can be curable if early detection coupled with a suitable interventional procedure is taken.
Screening program and endoscopic techniques for early detection
Because gastric cancer in its early stages is usually asymptomatic, screening among high-risk groups is necessary to increase the detection rate of

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Fig. 3. Comparison of gastric cancers in Japan and the United States. (A) Although distal
cancer predominates in Japan, the most frequent site of gastric cancer resected in the United
States is in the upper one third of the stomach. L, lower one third; M, middle one third; U,
upper one third; W, whole stomach. (B) In two Japanese institutions (KCC, Kanagawa Cancer
Center; YCU, Yokohama City University) about 50% of gastric cancers undergoing gastrectomy were stage I, whereas in the United States (MSKCC, Memorial Sloan-Kettering Cancer
Center), stage I cancers accounted for only 20%. (Adapted from Noguchi Y, Yoshikawa T,
Tsuburaya A, et al. Is gastric carcinoma dierent between Japan and the United States? A comparison of patient survival among three institutions. Cancer 2000;89:2239.)

early-stage cancer. A mass screening system was introduced in Japan more

than 30 years ago, contributing to the detection of more than 5000 cases of
gastric cancer, most of which were still in their early stages [8]. This program, however, is now criticized for its ineciency because the detection
rate is less than 0.2%, and it requires exposure to radiation. More ecient
methods for identifying high-risk groups using serum pepsinogen in combination with H pylori antibody titers has been investigated [9]. In the United
States, however, screening for gastric cancer is not judged to be cost eective
and will not be adopted as a national health preventive policy. Under such
circumstances, it is vitally important to improve the technical skills of endoscopists to detect subtle mucosal changes indicating early stages of gastric
cancer [10].
In Japan, the use of chromoendoscopy, magnication, and digital color
enhancement technology (Fig. 5) to assist in the dierential diagnosis of
suspicious lesions is increasing during routine examinations (see the article

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Fig. 4. Hypothetical pathways leading to gastric cancer. Most of the gastric cancers associated
with H pylori infection arise during a long-lasting inammatory process. Multiple genetic and
epigenetic changes involving many key regulatory factors occur in chronic gastritis, eventually
leading to cancer. The decrease in acid secretion seen in atrophic gastritis may augment this
process. Bacterial overgrowth with increased production of carcinogenic nitroso compounds,
decreased ascorbic acid secretion, and an elevation of gastrin are candidates for promoting
factors seen in hypochlorhydria.

by Yao and colleagues, elsewhere in this issue) [11]. Magnication endoscopy coupled with digital color enhancement, and similar techniques, can
be used only after endoscopists identify suspicious lesions. Intensive training
of endoscopists to conduct a careful examination on the entire stomach is
therefore essential before applying such sophisticated methods to diagnose
gastric cancer. The importance of careful examination is exemplied in
a case detected at an advanced, but still operable, stage by careful endoscopic examination in conjunction with color enhancement technology, as
shown in Fig. 6.
If the same technical expertise coupled with advanced endoscopic equipment is applied for routine endoscopic examinations, the number of patients
identied who have early stages of gastric cancer will denitely increase in
the United States, where most gastric cancers are found in advanced stages
with poor prognosis. Diagnostic training for the early detection of gastric
cancer (such as in the cardia) will help identify Barretts cancers also,
because the skills required for endoscopic observation, and an appreciation
of the subtle changes in mucosal color and microvascular pattern, are
basically the same in both cases.
The western dilemma: pathologic diagnosis of dysplasia
When endoscopists in Western countries detect suspicious lesions and
take biopsies, they may get a pathology report of mucosal dysplasia.

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Fig. 5. An endoscopically resected specimen of early gastric cancer (well-dierentiated tubular

adenocarcinoma). If the biopsy specimen is taken from the mucosal area marked A, the diagnosis of early cancer cannot be made because the sample is not suitable for evaluating invasion.
If a biopsy specimen is taken from area C, Western pathologists would diagnose the lesion as
dysplasia because the invasion criterion is not satised. If area B is submitted for evaluation,
however, a diagnosis of cancer can be made by the presence of obvious invasion into propria
mucosa (arrows).

Fig. 6. Endoscopic diagnosis of at type (0-IIb) of early gastric cancer. This type (0-IIb) of
early gastric cancer is most dicult to detect. (A) An area with subtle discoloration (whitish
change, so-called bleaching) may be noted by conventional endoscopy, but it can be easily
missed. (B) The color change becomes more evident with the digital color enhancement mode
(black arrow) (FICE, Fujinon intelligent color enhancement). (C) Once recognized, a switch
to the magnied view with digital color enhancement reveals abnormal tumor vasculatures
(tortuous, irregularly arranged vascular patterns) within the cancer. (D) Note the regular
arrangement of the vascular pattern outside the lesion (arrows indicate the tumor margin).

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Dysplasia, especially severe dysplasia, suggests early gastric cancer. It has

been reported that Japanese pathologists are better at the diagnosis of gastric cancer because they use cytologic and architectural abnormalities as
part of the diagnostic judgment, whereas Western pathologists use invasion
to submucosa as a requirement for a diagnosis of cancer [12]. The pathologic
diagnosis can be misleading, depending on the site of the biopsy, if one
depends on the invasion criteria for the diagnosis (Fig. 7). Realization of
this dierence in diagnostic criteria has prompted the development of
a new classication system for gastric epithelial neoplasia (the Vienna
classication) [13]. Unfortunately this system has not been widely adopted
yet. One might ask, which would be a better approach from a clinical standpoint? Because an undetermined but considerable portion of gastric dysplasia may evolve into invasive cancer in a relatively short time interval [14],
similar to the natural history of early gastric cancer in Japan (Fig. 8) [15],
it is rational that gastric dysplasia should not be followed but should be
treated more aggressively, like cancer.

Endoscopic treatment of early gastric cancer: indication and method

Retrospective studies of a large number of resected specimens has
revealed that most early gastric cancers (in which the tumor is limited to
the propria mucosa) do not metastasize to lymph nodes, indicating that
gastrectomies with extensive lymph node dissections may not be necessary
[16,17]. Less invasive treatment modalities, such as endoscopic resection,
have therefore been sought and advocated as a suitable therapeutic option.

Fig. 7. Importance of careful endoscopic observation. (A) A distant view of the corpus mucosa
appears to be normal except for slight nodularity of the gastric folds on the greater curvature.
(B) A closer look at the lower part of the corpus reveals fold convergence and disruption of the
nodular folds at the tips of the convergence. (C) A close-up view of the circled area in B. An
area of mucosal discoloration (bleaching) and small erosions are evident. Gastric folds show
caliber changes (tapering) in this area. These are typical features of an undierentiated gastric
cancer that will manifest itself as a scirrhous type of cancer. This type of cancer often evades
early detection even in Japan, and tends to be diagnosed at inoperable stages.

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High grade non-invasive neoplasia

(16)

F/U: 30 Mo.

Invasive adenocarcinoma
(11)
11/16 (69%)

Early gastric cancer

(56)

F/U: 39 M

Advanced gastric cancer

(36)
36/56=64 %

Fig. 8. The natural history of gastric high-grade noninvasive neoplasia (in Western criteria)
and early gastric cancer (in Japan). (Left) Gastric lesions diagnosed as high-grade noninvasive neoplasia were followed for 30 months. Eleven cases of invasive adenocarcinoma (69%)
developed from the high-grade noninvasive neoplasia initially diagnosed. (Right) The natural
history of early gastric cancer in Japan. Patients who refused to receive surgical operation
were followed for an average of 39 months. During the follow-up period, progression to
advanced-stage cancer was observed in two thirds of the cases. Figures were constructed
from the data presented in references [14] and [15].

Because endoscopic therapy can only treat and cure lesions limited to the
mucosa, strict criteria (the so-called guideline criteria) for selecting this
therapeutic option were formulated (Table 1).
Several methodologies are currently being used for endoscopic mucosal
resection (EMR). There is a technical limitation with EMR for en bloc
resection of lesions greater than 2 cm. A technical modality named endoscopic submucosal dissection (ESD) has been developed recently, virtually
eliminating this size restriction for resection. The technical details of ESD
are described by Dr. Gotoda elsewhere in this issue. Based on this technical
improvement, further extensions of the indications for endoscopic therapy
are being considered, and a large-scale nationwide outcome study is now
being conducted in Japan. This type of therapy requires a high level of technical skill, however, and is still accompanied by signicant complications,
such as bleeding and perforation. Only specialized institutions should be
qualied to perform such therapies, therefore. Furthermore, we need
long-term, large-scale outcome data before fully accepting this modality,
although a report from a single institution indicated an excellent longterm prognosis for guideline lesions treated with EMR [18]. Because the
background stomach harboring an early gastric cancer is a high-risk condition for developing metachronous cancer, periodic surveillance for early
detection of such lesions is mandatory [19].
Prevention of gastric cancer
Following the seminal discovery of H pylori, it is currently accepted that
most gastric cancer develops as a consequence of chronic gastritis caused by

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Table 1
Criteria for endoscopic therapy of early gastric cancer as recommended by the Japanese Gastric
Cancer Association
Guideline criteria

Extended criteria

Macroscopic appearance
Size
Histology

Intramucosal cancer
%2 cm
Dierentiated type

Ulcer/ulcer brosis

No

Intramucosal cancer
No limitation (elevated type)
Dierentiated type
Undierentiated type (R2 cm)
Yes (%3 cm)

Courtesy of the Japanese Gastric Cancer Association.

that bacteria. Because several eradication regimens are currently available

with reasonable cost and safety, therapeutic interventions have been attempted with promising results [20,21]. Eradication of H pylori should be considered an important primary preventive measure for gastric cancer in
countries, such as Japan, where the disease prevalence is still high and
cost consideration seems feasible.

Summary
Gastric cancer is a major health problem in Japan. It imposes a considerable health burden in the United States also, although the disease spectra
between the two countries are dierent. Nevertheless, gastric cancer in
any of its forms is a potentially curable disease when detected at an early
stage. It can be managed by minimally invasive methods, such as ESD, if
certain conditions are fullled. Although screening is eective for detecting
early gastric cancers, it must be complemented with proper training of the
endoscopists and use of complementary endoscopic techniques, such as
chromoendoscopy, magnication, and digital enhanced technology, to
detect early mucosal cancers. High-grade gastric dysplasia diagnosed by
Western pathologists should be regarded as an indication for ESD, not
only to ascertain its true depth of invasion but also to oer cure by complete
resection.

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