Editor: Joseph Sung
7. Gastric cancer
The worldwide annual incidence of new cases of gastric cancerboth sexesis estimated at nearly 900 000 in the IARCWHO database Globocan 2000; this accounts for almost 10% of new cancers in the world. Stomach cancer is frequent in Japan
and some other Asiatic countries, and in some countries of South America and Eastern and Northern Europe. The overall prognosis
of stomach cancer is poor because detection rarely occurs at the preclinical stage.
The stomach is lined with a single layer of columnar epithelium organized in invaginations, called pits and glands. At the
cardia there is a very short segment with mucous glands. In the glands of the fundic mucosa there are cells secreting acid
and pepsin. More distally, in the antral or pyloric mucosa, there are mucous glands. In adaptation to inflammation and reflux
at the junction of the esophagus and stomach, the epithelial squamocolumnar junction tends to migrate into the distal esophagus,
with development of a metaplastic columnar epithelium called Barrett's esophagus (BE). Columnar neoplasia occurs in the stomach
or in the esophagus with columnar metaplasia. At the esophagogastric (EG) junction and cardia, columnar neoplasia arises either
from the metaplastic lower esophagus or from the stomach.
In the upper digestive tract neoplasia occurs on a background of chronic inflammation. This results in striking differences
in the mechanisms of progression to premalignant and malignant lesions as compared to the colon. Inflammation and mucosal
atrophy are the consequence of exogenous and endogenous factors. Exogenous, aggressive factors include an infectious agent,
H. pylori, and dietary factors such as salt, nitrites, and deficiency in antioxidants and vitamins. Endogenous factors include
acid and biliary secretions. The diffuse epithelial alterations carry an increased risk of progression to neoplasia as compared
to normal, but this occurs only in a minority of cases; those lesions are classified as premalignant conditions. Circumscribed
and often non-protruding lesions of the epithelium with cell atypia and architectural disorganization are precursors of gastric
cancer and are classified as premalignant lesions. The signature of malignancy is the invasion of the lamina propria. The
risk of progression towards malignancy is high only when there is high-grade atypia. Moreover, small, malignant, neoplastic
lesions (called de novo carcinoma) may develop in the absence of identified precursors.
When there is malignancy with invasion of the submucosa, Eastern and Western experts use similar criteria for the diagnosis
of cancer. Divergences concern intramucosal neoplasia; the same lesion is called premalignant in the West (high-grade dysplasia)
and malignant (intramucosal cancer) in Japan. Recently a consensus classification was adopted after a workshop in Vienna.
Now the two types of lesions are included in the same group of the classification.
The detection of premalignant and early malignant lesions requires high-quality imaging, because most lesions are neither
protruding nor excavated. Gastroscopy is acknowledged as the 'gold standard' procedure and its role is further increased with the development of endoscopic mucosal resection (EMR).
The signature of malignancy in lesions of the gastric mucosa is invasion of the lamina propria. The Lauren classification
was based on the epidemiology of gastric cancer and is now confirmed by molecular biology: the tumor is classified as intestinal when there are recognizable glands, or diffuse if there is no cohesion between the malignant cells. The precursor adenomas exist only in the more frequent intestinal type; the diffuse type, in the absence of proven precursor, is called de novo carcinoma. The endoscopic appearance of the tumor is superficial when it is assumed that the muscularis propria is intact; other tumors are called advanced when it is assumed that there is deeper penetration.
The name early cancer suggests a superficial tumor with potential for complete cure after complete resection, i.e. a very low risk for lymph node
metastases; this applies to intramucosal and submucosal cancer in the stomach. The depth of invasion of superficial cancer
in the stomach wall is classified in the T item of the International TNM classification as intramucosal or submucosal (premalignant
lesions are not included in the TNM). In the group of intramucosal cancers high-grade dysplasia without invasion of the lamina
propria is classified as carcinoma in situ. In tumor registries the tumors are usually distributed in three groups according to their progression:
- Localized tumors, which are limited to the gastric wall and do not involve the serosa.
- Regional tumors, which show invasion of adjacent viscera (pancreas, spleen, peritoneum) or regional lymph nodes, or both.
- Distant tumors with metastases, either in lymph nodes or in distant viscera.
Premalignant gastric lesions
Most premalignant gastric lesions develop in a mucosa modified by chronic inflammation, which is a premalignant condition
. They form circumscribed, and often non-protruding, benign neoplastic lesions of the epithelium, with architectural disorganization
and cell atypia. The risk of progression towards malignancy is low in low-grade atypia and fairly high in high-grade atypia.
Premalignant lesions are clinically important. In Western countries benign neoplastic lesions of the columnar epithelium are
called 'adenoma' when they are protruding (polypoid) and 'dysplasia' when they are flat or depressed (non-polypoid). In Asian countries, both types of lesions are called 'adenoma' in the stomach, with a distinction between polypoid and flat or depressed adenomas . Neoplastic lesions of the digestive mucosa are called 'superficial' when the endoscopic appearance suggests that there is no invasion of the muscularis propria; this includes premalignant and
malignant intramucosal lesions.
Gastric polyps as premalignant lesions
Gastric polyps are frequent but do not play an important role as precursors of gastric cancer; indeed most of them are non-neoplastic
lesions ; the two most frequent types of non-neoplastic polyps are the fundic cystic  and the hyperplastic lesions [17,18]. However, when a gastric polyp occurs in a context of inflammation and atrophy of the gastric mucosa, it can be associated
with a synchronous premalignant or malignant lesion. This justifies a very systematic and complete exploration of the gastric
mucosa. A registry of gastric polyps has been established in Bayreuth and very large series have been published, as shown
in Fig. 1.
These account for approximately 10% of gastric polyps; they have a sessile morphology and some may reach a large size. Their
architecture is tubular or villous. A malignant focus is detected in less than 10% of cases but is more frequent when the
lesion is over 1 cm in diameter. The terminology flat or depressed adenoma  is used in Japan to describe non-protruding lesions with an adenomatous architecture; such lesions are less frequent than
polypoid adenomas, but have a higher risk of malignant transformation.
Cystic fundic polyps
These are small and shiny, and characterized by dilation of the neck of the gastric glands with shortened gastric pits; they
develop in a well-preserved fundic mucosa. They occur as sporadic or through a germline mutation in familial adenomatous colorectal
polyposis (FAP). In the FAP syndrome, fundic cystic lesions are organized as a polyposis syndrome ; the phenotypic molecular characters of neoplasia are present in this polyposis (cell atypia and second-hit mutation of the
APC gene) but the evolution towards malignancy is quite unusual. Sporadic cystic polyps are not neoplastic; they show a somatic
mutation of the a-catenin without progression to malignancy.
Hyperplastic or hyperplasiogenic polyps
These are detected as isolated or multiple lesions or as a polyposis syndrome. They are characterized by a proliferation of
foveolar cells with elongated gastric pits. They occur in a mucosa modified by inflammation and atrophy and may show areas
with intestinal metaplasia. Hyperplastic polyps often undergo regression after the eradication of H. pylori. They are non-neoplastic lesions, but malignancy may occur in large polyps in 24% of cases; in addition, synchronous neoplastic foci may develop at distance. The systematic removal of large hyperplastic
polyps is recommended because neoplastic foci are missed by simple forceps biopsies. Serrated adenomas (combining adenomatous
and hyperplastic features) are very rare in the stomach.
These are large non-neoplastic lesions with a congestive surface, even oozing blood; they are characterized by hypertrophy
of the lamina propria.
Hamartomas and juvenile polyps
Gastric hamartomas include gastric polyps in association with polyposis of the small intestine in the PeutzJeghers syndrome . This is an inherited cancer syndrome, with a germline mutation of the LKB1gene in 19p. The polyps show muscular fibers in continuity with the muscularis mucosae. The progression to malignancy tends
to occur in extraintestinal sites.
Juvenile polyps, isolated or organized in a polyposis syndrome, are also hamartomas ; their structure shows dilated cystic glands filled with mucus. They occur as sporadic lesions or through a germline mutation
of the (SMAD4/DCP4) gene in 18q in the juvenile polyposis syndrome, which may be associated with juvenile polyposis in the colon. The risk
of progression to malignancy occurs only when there is polyposis, but most cases occur in the colon.
Cowden syndrome or multiple hamartoma syndrome is caused by a germline mutation of the PTEN/MMAC1 gene in 10q and does not progress to malignancy.
In the rare CronkhiteCanada syndrome, an acquired disease with digestive polyposis, the gastric polyps are premalignant, with a high risk of malignant
Premalignant conditions in the gastric mucosa
Premalignant conditions of the gastric mucosa are the target of the primary prevention of cancer. In the stomach, neoplasia
occurs against a background of chronic inflammation with exposure to various pro-inflammatory factors, of which H. pylori infection is the principal. The diffuse alterations of the epithelium (atrophy, hyperplasy and/or intestinal metaplasia) are associated with an increased risk of cancer. Metaplasia, the transformation of an epithelium
to another type of epithelium with distinct morphology, occurs in the esophagus and stomach [23,24]. Intestinal metaplasia type I (or complete), is comprised of absorptive cells, goblet cells, and a few Paneth cells. Intestinal
metaplasia types II or III (or incomplete), show columnar 'intermediate' cells and goblet cells that secrete sialo-(type II) or sulfo-(type III) mucins.
In the proximal stomach, carditis, or inflammation of the epithelium at the cardia, is extremely frequent. Abnormalities include
elongated pits with hyperplasia and small areas of intestinal metaplasia. The source of intestinal metaplasia at the cardia
is the gastric stem cells . Carditis is not a premalignant condition and there is still debate about the causal factors of neoplasia at this site.
Chronic atrophic gastritis
In the distal (non-cardia) stomach, chronic atrophic gastritis is a premalignant condition. Inflammation of the lamina propria
develops in the oxyntic mucosa of the fundus in the autoimmune gastritis type A. However, H. pylori gastritis is the usual condition; it develops in patchy areas of the pyloric and oxyntic mucosa. Chronic gastritis results
in atrophy of the glands, and increased proliferation with loss of differentiation in surface and intestinal metaplasia.
Histopathological classification of gastric neoplasia
The depth of invasion of the tumor in the gastric wall is classified according to the T item of the TNM classification; this
applies to cancer and not to premalignant lesions. Superficial cancer is classified either as T m or T sm. Intraepithelial
cancer is also called 'in situ'. Advanced cancer is classified as T2 (muscularis propria involved), T3 (the tumor penetrates the serosa), T4 (tumor invades
adjacent structures). The invasion of the regional lymph nodes and distant metastases are classified in the N and M items.
Stage grouping combines the three items as shown in Fig. 2.
The tumor is also classified by the pathologist according to its tubular, acinary, papillary architecture, and to the grade
(well, moderately, poorly differentiated). The distinction in two types was established by Lauren in 1965, based upon epidemiology,
and is confirmed by molecular biology. Intestinal carcinomas form recognizable glands and occur in a background of intestinal metaplasia. Diffuse carcinomas consist of poorly cohesive malignant cells infiltrating the digestive wall.
Divergences in the classification on intramucosal benign or malignant neoplastic lesions occur between Eastern and Western
pathologists . The same lesion is classified as premalignant in the West (high-grade dysplasia) and malignant (intramucosal cancer) in
Japan. Recently a consensus classification was adopted and most differences disappear in the revised version of the Vienna
classification  as shown in Fig. 3.
The tendency is to abandon the terminology dysplasia and refer to intraepithelial neoplasia (IEN) or intramucosal neoplasia.
This applies not only to the stomach but also to the esophagus and the colon.
The lesions classified as high-grade dysplasia in the West or intramucosal carcinoma in the East are included in the same
large group 4, [Figs 410] which includes high-grade intramucosal neoplasia (lamina propria respected) and intramucosal cancer (lamina propria involved).
Geographical variations of risk
There is a trend to declining incidence of gastric cancer worldwide. However, the actual annual numbers of new cases are still
expected to increase in many countries, particularly in developing countries, in relation to the aging population, because
the magnitude of the risk increases sharply with age. Stomach cancer is still the second largest cause of death from cancer
in the world. Data on incidence and mortality from gastric cancer are available in cancer registries .
The risk in men is approximately twice that observed in women. In Japan, in spite of a declining incidence, the risk is particularly
high and stomach cancer is still the leading tumor site , accounting in 198589 for 31% of all-cancer incidence in males and 22% in females in eight population-based registries. The considerable geographical
variations in the risk are explained by environmental factors, as shown in studies examining the risk in Japanese migrants
to the USA .
Proximal and distal gastric cancer
A distinction should be made between cancer at the esophagogastric (EG) junction, which includes the proximal part of the
stomach (cardia), and cancer of the distal part of the stomach, called non-cardia stomach cancer . Tumors whose center is located at no more than 2 cm distally or proximally to the junction of the tubular esophagus to the stomach should be classified as in the EG region.
At the EG junction, tumors arise either in a very short segment of BE or in the gastric epithelium of the cardia. This duality
can be observed in surgical specimens and is confirmed by molecular biology [42,43].
Cancer in the proximal stomach (cancer at the cardia) is less frequent than in the distal stomach, and the proportion of stomach
cancers at the cardia varies from less than 5% to more than 35% in tumor registries using the classification of subsites in
Based on the analysis of the available data, it is estimated that cancer at the cardia represents, on average, 18% of all
cases of stomach cancer. The proportion of distal stomach cancer is higher in females than in males, and higher in the developing
world and Japan than in North America, Northern and Western Europe, and Australia/New Zealand.
Cancer at the EG junction
At the EG junction two distinct categories of tumors arise from a short segment of the Barrett's epithelium or from the gastric
cardia. In a study of tumors located within 2 cm distal or proximal of the EG junction, the proportion of males was higher in tumors classified as esophageal in origin
than in tumors classified as gastric in origin . There is still debate about the causal factors of neoplasia at the cardia: trauma from the alimentary passage, acid and
bile reflux, or H. pylori infection. Smoking plays a lesser role than in adenocarcinomas arising from BE and the proportion of smokers is lower in
gastric than in esophageal tumors .
Cancer in the distal or non-cardia stomach
For adenocarcinoma in the distal stomach, mucosal inflammation and atrophy is the premalignant condition. Autoimmune gastritis
type A is the causal factor in a small proportion of cases. In most cases; H. pylori infection is the central risk factor for gastritis and for the promotion of early stages of neoplastic transformation .
The niche of H. pylori is the stomach acidic milieu and the pathogen impact is modulated by the host response and the virulence of the strain. The
interference between bacterial antigens and blood-group substances explains a higher risk for stomach cancer in blood group
The prevalence of the infection in adults is high as shown in published data from population-based surveys of healthy adults,
prospective (cohort) studies, or case-control studies. In the age range 4564, the prevalence of infection is estimated at 58% in developed countries and 76% in developing countries.
A higher frequency occurs in African countries. In South Africa, the sero-prevalence is over 80%. In Gambia the high prevalence
of the infection results in a high frequency of chronic gastric inflammation, although the prevalence of gastric atrophy is
In China the prevalence of the infection is lower than in Africa.
Most infected persons never develop gastric cancer in the absence of other promoting environmental factors, such as a high
intake of irritants (salt and nitrates) and a low intake of antioxidants (fruit and vegetable) [63,64].
The relative risk for gastric cancer in H. pylori infection is estimated in prospective studies, using serological tests with a long interval between the initial blood sampling
and cancer detection. In the most recent meta-analysis from the Helicobacter and Cancer Collaborative Group, the Odds Ratio
for the association between the infection and distal gastric cancer is 5.9 when restricted to studies with an interval of
at least 10 years.
An estimation of the proportion of stomach cancer attributable to H. pylori infection requires the exclusion of cancer at the cardia, where H. pylori plays no role. An analysis based upon the average proportion of cancer at the cardia (18%) and the worldwide estimation of
the number of new cases of stomach cancer in 2000 in developed and in developing countries indicates that, for the year 2000,
there were around 725 000 new cases of non-cardia cancer.
Taking into account the estimated prevalence of the infection and the associated relative risk of 5.9, the proportion of cases
attributable to H. pylori infection is slightly higher in developing than developed countries, the figures being in the range of 7580%. In this way H. pylori infection is confirmed as a premalignant condition.
In conclusion, the etiology of stomach cancer is linked to environmental factors, including H. pylori-induced inflammation and atrophy of the gastric mucosa, and a diet rich in salt and nitrite and poor in fruit and vegetables.
The variable incidence in different countries of the world is linked to environmental factors.
Time trends in incidence and mortality from gastric cancer
A generalized decline of the disease
The generalized decline of incidence, particularly marked in the USA , suggests that regression occurs through changing lifestyle and that geographic differences result from variations in the
control of environmental factors. Time trends in the incidence of stomach cancer illustrate the role of environmental factors.
Studies on migrant populations coming from a country with a high risk for stomach cancer to a low-risk country have been conducted
in Japanese migrants in the USA (Hawaii, California, Washington state, New York City).
The incidence rate in Japanese migrants decreases in successive generations ; in 197386, the incidence rate for Japanese born in Asia was lower than in Japan but higher than that of US white natives (×4.3 for men and ×5.8 for women). For the second generation, US-born Japanese had a further decrease in incidence (×2.8 for men and ×2.9 for women). The high rate observed in the first generation of migrants suggests that environmental factors play a determinant
role in early infancy. The incomplete decrease of the risk in the second generation suggests the role of persisting ethnic
lifestyle characteristics in the USA.
Time trends in Japan
The decline in incidence and mortality from stomach cancer also occurs in Japan, with the concurrent intervention of a screening
policy. The temporal trends for the period 197595 in Japan and USA (a country with no screening policy ), show the respective influences of both factors.
At the beginning of the study period, the respective age-adjusted incidence rates in Japan and USA in 1975 were 76.0 and 9.52
per 100 000 for men, and 38.34 and 4.26 for women. From 1975 to 1995 the mortality-to-incidence ratio decreased in Japan from 0.8
in 1975 to 0.6 in 1995 for men and from 0.8 to 0.7 for women. In the USA the ratio remained stable. The decline of the ratio
in Japan is explained by the increasing percentage of cases detected at the localized stage in relation to screening.
With respect to mortality rates, a significant cohort effect is confirmed in Japan. When the relative risk for stomach cancer
in the 1910 cohort is assessed in reference (RR = 1) to the successive cohorts, the Odds Ratio for stomach cancer decreases in both sexes, and reaches the value 0.2 for the
cohorts born after 1950.
From inflammation to cancer
At the molecular and cellular levels, the development of premalignant lesions in the gastric epithelium, and the subsequent
evolution to malignancy, is the consequence of pro-inflammatory stress . Stress conditions may affect many signaling pathways within the epithelial cells and program them to develop into specific
differentiation pathways. Modifications of gene expression in response to stress factors may be reversible, and metaplasia,
a central event in gastric carcinogenesis, may result primarily from reversible events.
Irreversible changes are mutations that cause clonal expansion into a lesion with high potential for evolution towards neoplasia.
Among 'irreversible' events, the most common is mutation of the tumor suppressor gene TP53. Thus, there is a direct correlation between mutagenesis
and inflammation. Prevention strategies (such as eradication of H. pylori) aim at reversing the 'reversible' events, to restore normal epithelial function and differentiation patterns.
Gastric carcinogenesis follows the morphological pathway of H. pylori infection described by Correa [67,68] for the intestinal type of gastric canceratrophic chronic gastritisintestinal metaplasiadysplasia.
However, H. pylori infection may play a different role in the diffuse type of gastric cancer . The carcinogenic influence of H. pylori is suggested by the higher cell proliferation occurring in the H. pylori-infected stomach [70,71]. The balance between proliferation and apoptosis has been examined by immunofluorescent methods in biopsy samples from patients
with a normal gastric mucosa (negative for H. pylori infection) and from patients with chronic gastritis (positive for H. pylori infection). In chronic gastritis, the apoptosis index increases less than the proliferation index and there is an overall
decrease of the apoptosis/proliferation ratio. H. pylori infection induces an increased expression of COX 2 and is the source of an increased production of nitric oxide (NO) favoring
nitrosation and formation of carcinogens. However, the bacterium is not a direct carcinogen class I.
The APC mutation in gastric carcinogenesis
In colonic neoplasia, the primary event in the Fearon and Vogelstein sequence is the mutation of the APC gene (5q) and the
inactivation of the APC protein; then the accumulation of a-catenin triggers the mutation cascade. In gastric carcinogenesis, the APC mutation is not a primary event, and malignant
foci are present only in a small proportion of the polypoid adenomas . The early APC mutation present in benign precursors (polypoid or flat adenomas) is not the key of the progression towards
malignancy; moreover the APC mutation is often absent in carcinomas.
In a recent study of gastric neoplastic lesions , the APC mutation was present in 77% of polypoid adenomas (n = 35), 74% of non-protruding areas of dysplasia (n = 47), and only 3% of adenomas with focal cancer (n = 35) and 4% of 'intestinal'-type carcinomas (n = 54). Protruding or non-protruding premalignant lesions have the same phenotypic molecular characters and a similar rate of
proliferation (K-67 test); a high instability character (MSI-H) may explain the higher risk of malignancy of non-protruding
Mutagenesis in the Lauren classification
The Lauren classification of gastric tumors into two categories is now confirmed , with distinct pathways in intestinal or diffuse tumors.
In the intestinal type of differentiated carcinoma, precursor lesions (protruding or non-protruding adenomas) play a role. The sequence of
mutations includes altered oncogenes (K-ras, a-catenin), suppressor or regulatory genes (APC, TP53), and mismatch repair genes (hMLH1).
In the diffuse type of stomach cancer there are no precursors and the tumor is called a 'de novo'carcinoma. The somatic mutation in the regulatory gene (16q) for the transcription of the E-cadherin plays the major role.
Hereditary gastric cancer
Hereditary cancer plays a small role in the upper digestive tract. In hereditary syndromes, all of the mucosa is classified
as a premalignant lesion. This applies to hereditary stomach cancer, described in limited geographic areas in New Zealand
and Portugal. The diffuse type of gastric cancer relates to a germline mutation of the regulatory gene (16q) for E-cadherin [74,75]. The same somatic mutation occurs in sporadic diffuse cancer.
In other hereditary syndromes the increase in the risk for gastric cancer is less and the gastric mucosa is only classified
as a premalignant condition. This occurs in the HNPCC syndrome or non-polyposis hereditary colorectal cancer. Stomach or endometrial
carcinoma also occurs. In familial adenomatosis polyposis (FAP), gastric polyps of a fundic cystic polyposis show a second-hit
mutation of the APC gene  and may even be classified as neoplastic lesions which do not progress to malignancy. The risk of upper digestive cancer
in FAP is in the duodenum. Malignancy can also occur in the hamatomartous polyps of the PeutzJeghers syndrome (germline mutation of the LKB1 in 19p) or in juvenile polyposis syndromes (germline mutation on the SMAD4/DCP4 in 18q).
Symptoms of gastric cancer
Digestive symptoms of advanced gastric cancer are either a continuous or periodic pain, or digestive hemorrhage, or dysphagia
suggesting stricture at the cardia, or vomiting and stasis suggesting stenosis at the pylorus. Systemic symptoms are the loss
of weight and chronic anemia. Distant metastases, in the liver, can be the first clinical manifestation. Early cancer is asymptomatic
or associated with a pseudo-ulcerous post-prandial pain, or 'functional dyspepsia'.
Endoscopy in the diagnosis of gastric cancer
Upper gastrointestinal endoscopy is the gold standard procedure for the detection of gastric cancer. Advanced gastric cancer
with a tumor protruding or excavated in the stomach is easily detected. However, advanced diffuse and infiltrative tumors
involving all the thickness of the gastric wall (linitis) may have an inconspicuous signature at the surface of the mucosa;
a false negative conclusion is possible if the absence of expansion of the gastric wall and its rigidity are not detected.
Nowadays, the focus is on the detection of early neoplastic lesions with a superficial endoscopic pattern suggesting that
the lesion is limited to the mucosa or the submucosa. This superficial pattern corresponds either to a premalignant precursor
or to a carcinoma. In the stomach, most superficial neoplastic lesions are non-protruding and demand extreme care during endoscopy.
The first step is to detect a suspect zone of the mucosa that is slightly discolored, or elevated, or depressed, or with an
irregular microvascular network during the standard exploration.
The next step is the further examination of the abnormal zone after chromoscopy . In the stomach, the most commonly employed dye is indigo-carmine solution (0.51%), a contrast stain which enhances depressions where the dye accumulates.
At the EG junction
Neoplastic lesions arise from the esophagus in a short segment of BE, or from the gastric mucosa at the cardia. The detection
of superficial neoplastic lesions at the cardia is therefore indissociable from the exploration of the distal esophagus. The
careful exploration of the EG region with a retroflexion maneuver is a systematic step of upper GI endoscopy.
In the non-cardia stomach
The first step in the exploration of the mucosa is the detection of chronic gastritis. Then, the entire surface of the mucosa,
classified as a premalignant condition, is examined sector by sector, before and after indigo-carmine chromoscopy, in order
to detect any suspect area. Most authors adopt this method but some still use diffuse staining of the gastric mucosa with
methylene blue in order to detect intestinal metaplasia .
Technological advances in equipment
The most recent endoscopes based on digital technology have reached a high standard in resolution and color reproduction with
the surge of multiple technological advances . Two major directions are stressed: magnification with an optical zoom, and processing of the digital image captured by the
CCD. Digitization is easier for instruments with the RGB sequential system (series 200 of Olympus), than for the series with
a color chip (Exera of Olympus).
Magnification in endoscopy is now available, using either an optical zoom (×30 to ×80) or a combined optical and electronic zoom. Magnification is of considerable help for mapping the distinct types of epithelium
(oxyntic, cardial, and intestinal metaplasia) in the stomach and at the EG junction .
In a study conducted in Portugal  magnification in contrast, using methylene blue chromoscopy, was used in 136 patients with previously diagnosed gastric lesions
(gastritis, dysplasia, metaplasia). Comparison of endoscopic findings with the biopsies was controlled by five blind observers;
the reliability of the procedure for the detection of occult neoplastic areas was confirmed.
In neoplastic areas, magnification has two distinct applications: the analysis of the disorganized architecture of the epithelium
(pit pattern) in surface, and of the microvascular network disorganized by inflammation or neoplasia [82,83]. Magnification by the digital processing of the image is a promising technology ensuring a relatively reliable optical biopsy.
Digitization of the image
The structure enhancement processing system uses a digital filter to enhance the frequencies containing important information for the diagnosis and
reduce the non-useful frequencies; it is present in the RGB and color chip series of Olympus.
The color enhancement or index of hemoglobin (IHb) requires the sequential RGB system (model Celera 260 of Olympus); without altering the other colors, it will change
the color tone in the band of hemoglobin, shifting to the red the areas with more blood and hemoglobin and to the yellow the
areas poor in blood and hemoglobin. The IHb system enhances the color contrast of small neoplastic lesions.
Narrow band imaging (NBI) is linked to magnification. The incident light is restricted to narrow bands in the three fundamental colors (red,
green, blue) to obtain distinct superposed images in depth (red), intermediate (green), and extremely superficial (blue),
which result in increased relief of the magnified surface architecture, and enhanced view of the microvascular network.
Spectroscopic techniques offer a new perspective in research, and aim to open a new sector of molecular endoscopy; however,
they are probably not cost-effective and should not be used in routine diagnosis. UV fluorescence endoscopy, and trimodal
spectroscopy (absorption, fluorescence, and elastic dispersion) should contribute more to the study of neoplasia in Barrett's
esophagus, than in the stomach.
Spectroscopy in the near infra-red (NIRS) explores the deep layers of the mucosa or the submucosa, and is adapted to the analysis
of the microvascular network in neoplastic lesions after injection of indocyanine green as a fluorescent dye. The pooling
of fluorescence from indocyanine green is a signature of invasion of the submucosa.
Macroscopic appearance of digestive neoplastic lesions
The morphological appearance of advanced gastric cancer was classified by Borrmann in 1926 into four distinct types.
- Type 1polypoid carcinomas, usually attached on a wide base.
- Type 2ulcerated carcinomas with sharply demarcated and raised margins.
- Type 3ulcerated, infiltrating carcinomas without definite limits.
- Type 4non-ulcerated, diffusely infiltrating carcinomas, as shown in Fig. 11, and Fig. 12.
The Japanese gastric cancer association added a type 0 corresponding to neoplastic lesions with a superficial extension, limited
to the mucosa and the submucosa, and a type 5 for unclassifiable advanced tumors .
This morphological classification was adopted in Japan and further accepted for the esophagus and the colon. The type 0 lesions,
presumed to be superficial, were divided in type 0-I or protruding (polypoid), 0-II or-non-protruding, and 0-III or excavated,
as shown in Fig. 13 and Figs 14 and 15.
Type 0-I lesions are divided in type 0-Ip and type 0-Ispedunculated and sessile. In pedunculated polyps the base is narrow; in sessile polyps the base and the top of the lesion
have the same diameter. In non-protruding lesions the surface is either slightly elevated (type 0-IIa) or flat (type 0-IIb)
or slightly depressed (type 0-IIc); noteworthy elevated lesions are classified non-protruding when the protrusion from the
adjacent mucosa is not more than 2.5 mm; above this figure the lesions are classified protruding and sessile.
The Japanese classification of type 0 neoplastic lesions applies to premalignant lesions (low-grade or high-grade intraepithelial
neoplasia), carcinomas, and also to non-neoplastic lesions which may show a neoplastic component (juvenile or hyperplastic
polyps). In non-protruding lesions priority is given to the morphological subtypes; malignancy with invasion of the submucosa
is more frequent in depressed lesions (type 0-IIc).
Endoscopic classification of superficial neoplastic gastric lesions
At the EG junction
Premalignant and early malignant lesions at the EG junction and the cardia have the same morphology as in BE and the proportion
of depressed (0-IIc) lesions is less than in the non-cardia stomach.
In the non-cardia stomach
Most early neoplastic lesions (premalignant or malignant) are non-protruding, and most (7080%) are depressed (0-IIc) as shown in Fig. 16. The polypoid adenoma is a rare precursor compared to flat or slightly depressed areas. Focal cancer in the adenomatous polyp
is rare (8 cases out of a series of 118) and occurs when the size of the polyp is more than 1 cm ; on the other hand a complete exploration of the gastric mucosa is necessary because synchronous non-protruding neoplastic
areas may be present at distance from the polyp. In the very large histopathological series of gastric polyps from the Institute
of Pathology in Bayreuth [9,10,13], polypoid adenomatous lesions are not frequent while non-neoplastic polyps (fundic cystic polyps and hyperplastic polyp)
represent 80% of all lesions, as shown in Fig. 1.
Flat or depressed adenomas have a similar frequency of p53 mutations as protruding adenomas; on the other hand they carry
a higher risk of malignant transformation , as confirmed by the higher expression of CEA and Ca199.
In conclusion, most premalignant or early malignant lesions in the stomach are either completely flat or slightly elevated and often depressed.
This is confirmed by the data on the morphology of type 0 gastric cancer in the National Screening Campaign in Japan  (Fig. 16). In this series 70% of type 0 cancers have a non-protruding depressed morphology (type 0-IIc isolated or combined with other
type, and only 6.6% have a polypoid morphology.
Non-endoscopic procedures in the diagnosis of gastric cancer
Radiological imaging and ultrasound
Since the development of endoscopy, there are fewer indications for radiology as a diagnostic procedure of stomach cancer:
double-contrast radiological imaging proves less effective than endoscopy. However, in screening protocols the miniature photofluorography
is still accepted as a useful test. In the preoperative exploration of patients with advanced gastric cancer, other imaging
procedures such as the CT scan and transcutaneous ultrasound with high-resolution probes play a major role.
The assessment of histology samples classified as negative, indefinite, and low-grade intraepithelial neoplasia is poorly
predictive of the clinical future outcome. This applies particularly to Barrett's esophagus and a large number of biomarkers
of neoplasia have been proposed . The same biomarkers have also been tested in gastric columnar neoplasia. Biomarkers are tested in the tissue samples obtained
Ki67, or PCNA proliferating cell nuclear antigen have not been shown to be predictive of the future outcome.
P53 protein and TP53 mutations
Multiple non-prospective studies confirmed a high prevalence of the mutated p53 protein in high-grade intraepithelial neoplasia
and in confirmed cancer, but p53 immunochemical overexpression is not helpful in the prediction of the risk of cancer in premalignant
conditions such as chronic atrophic gastritis.
The DNA sequencing of p53 mutations is more reliable, but requires a sophisticated technology not compatible with routine
tests. In tumors of the EG region, the type of the p53 mutation differs according to the esophageal or gastric origin of the
tumor. The TP53 mutations in adenocarcinoma arising from BE shows a higher frequency of the G:C > A:T at CpG than in any other cancer type.
The ratio of cytokeratins (CK) has been proposed as marker for intestinal metaplasia in the esophagus and stomach . CK 7 is more abundant and CK 20 is less abundant in intestinal metaplasia arising from the esophagus. The cytokeratin ratio
also helps in the classification of cancer of the EG region.
In a study of 85 adenocarcinomas of the distal esophagus and 67 adenocarcinomas of the cardia, the CK 7+ and CK 20-pattern is characteristic of esophageal cancer. Ninety per cent of esophageal tumors are positive for CK 7 against
less than 45% for tumors at the cardia; 17% of esophageal tumors express CK 20 against 55% for tumors at the cardia.
Mucins have also been used as markers of intestinal metaplasia in Barrett's esophagus; there is a distinct pattern of mucins
with the MUC 5B, MUC 6 types.
In conclusion, biomarkers illustrate the successive steps in carcinogenesis, and may be positive in tissue samples collected in premalignant
conditions (Barrett's esophagus or chronic gastritis with H. pylori infection) or in premalignant lesions with low-grade atypia. However, their predictive value for the clinical outcome and
detection of those patients at high risk of developing a cancer is poor.
Staging of gastric cancer
In advanced cancer the major objective is the decision for a curative or palliative surgical resection, through the detection
of invasion in adjacent viscera or the presence of distant metastases.
In advanced cancer, tumor staging relies on non-endoscopic procedures such as transcutaneous US and CT. The PET scan using
fluorodeoxyglucose has proved to be more accurate than the CT scan in detecting lymph nodes. Endoscopic ultrasound (EUS) may
be of some help in assessing invasion of regional lymph nodes or of adjacent viscera.
In superficial type 0 tumors, staging of the depth of invasion in the submucosa helps in treatment decisions between curative
endoscopic mucosectomy or surgery. EUS with radial echoendoscopes or with miniprobes is widely used in Japan. In this indication
high-frequency (2030 MHz) thin probes introduced through the operative channel of the endoscope are superior to conventional echoendoscopes. This
proves particularly helpful for esophageal cancer. The efficacy of staging early gastric cancer (EGC) with a 30 MHz miniprobe
is hampered when there is an ulcer scar.
Clinical relevance of early diagnosis of gastric cancer
EG tumors are rarely detected at the preclinical stage, and the prognosis is poor. Common sense suggests that there should
be greater efforts to increase early preclinical detection. The secondary prevention of cancer is based on the early detection
(and treatment) of premalignant or malignant superficial lesions. Of course the prognosis of tumors detected in the preclinical
stage is improved when compared to that of symptomatic tumors detected at the advanced stage; however, an evaluation in terms
of costeffectiveness and costbenefit is legitimate.
Survival after treatment of a superficial cancer detected at the preclinical stage is much longer than for tumors detected
at the advanced stage. However, this optimistic figure involves lead-time bias.
Survival at the preclinical stage aggregates two periods: the time elapsed during the preclinical phase plus the time elapsed
from the first symptoms until the symptomatic detection.
The survival benefit is obvious if the final date of death is delayed, as compared to detection at the symptomatic period.
In addition the lead-time bias plays a role; tumors detected at the preclinical stage often progress very slowly and may even
not reach a symptomatic stage before death from another cause.
Treatment decisions for gastric cancer
The role of tumor staging
Treatment decisions are based on our knowledge of the tumor progression in successive stages. After staging the choice is
between treatment of the tumor with a curative intent, i.e. a complete destruction of the neoplastic tissue, and palliation
using surgery, endoscopic procedures, and chemotherapy.
When the tumor is localized there is a distinction between superficial cancer with a depth limited to the submucosa (T1 in
the TNM classification) with a low risk of lymphatic metastases, and advanced cancer where the tumor involves the muscularis
propria or the serosa (T2 and T3 in the TNM classification) with a high risk of lymphatic metastases. The risk of metastatic
lymph nodes is small, but never nil, for intramucosal neoplasia, and is significant when the depth of invasion in the submucosa
is over 500 µm.
Tumors with regional lymphatic metastases or tumors involving the adjacent viscera (T4 in the TNM classification) are classified
as regional, but may still prove resectable.
As a rule, in non-localized tumors with distant metastases a complete resection is impossible.
Treatment with curative intent
When the curative option is selected, the choice is between curative surgery with a R0 resection or curative endotherapy.
Surgery with a R0 resection and lymphadenectomy is the standard treatment of gastric cancer.
Endoscopic mucosal resection (EMR) for superficial cancer is an elective option for a significant proportion of the so-called
early gastric cancers (EGC), and the elective treatment of premalignant lesions [88,89]. EMR for gastric cancer is a common indication in Eastern Asia. Fewer indications are foreseen in Western countries with
the decreasing incidence of the disease and the low proportion of cases detected at the early stage. The guidelines for selecting
the EMR option are as follows:
- Early detection with the most recent models of video-endoscopes and the routine use of chromoscopy (indigo-carmine).
- Evaluation of the depth of invasion of the tumor according to its endoscopic morphology in the Japanese endoscopic classification
of superficial (type 0-II) neoplastic lesions with subtypes 0-I, 0-IIa, 0-IIb, 0-Iic, and III. Specific care is given to the
analysis of depressed lesions (0-IIc) which show an increased risk of deep invasion in the submucosa.
- EUS staging with a high frequency miniprobe.
- In operable patients a careful evaluation of the alternative management (i.e. surgery).
Other therapeutic options
When low-grade intramucosal lesions are detected in aged persons, expectant management is an acceptable option.
In advanced localized or regional cancer, chemotherapy and radiation protocols are options complementary to surgery.
In non-operable patients, endoscopic palliation aims at the restoration of the digestive lumen with expandable stents.
Endoscopic treatment with curative intent
According to the guidelines of the Japanese Gastric Cancer Society [84,85,89], there are increasing indications for endoscopic surgery in patients with premalignant lesions or early malignant gastric
For protruding lesions (polyps) the elective treatment is resection with a diathermic snare. Solitary polyps (adenomatous
or hyperplastic) are systematically resected if their size reaches 1 cm. Hamartomatous polyps of the PeutzJeghers syndrome are also resected.
In gastric polyposis, a few polyps are resected for a histopathological diagnosis. Non-protruding lesions can be destroyed
by thermal or non-thermal procedures. However, this yields no specimen for pathology. The most powerful instrument for thermal
destruction of tumors is the Nd:YAG laser. Other thermal procedures (electrocoagulation with a diathermic probe or the Argon
plasma coagulator) have been proposed for very superficial neoplastic lesions. Actually their efficacy is limited to the destruction
of small residual neoplastic areas after a more powerful intervention.
Photodynamic therapy, a non-thermal procedure, can be performed after administration of an exogenous fluorophore (photofrin)
or a metabolic precursor of protoporphrin IX (5-amino-laevulinic acid). The procedure is adapted to the curative treatment
of superficial and poorly delimited neoplastic areas . Presently, priority is given to endoscopic mucosal resection .
Technique of endoscopic mucosal resection (EMR)
The methodology of EMR for non-protruding neoplastic lesions in the stomach is now established, and is illustrated in Figs 1721. Most procedures require a single-channel rather than a double-channel endoscope. The technique using a transparent over-tube
with an accessory channel for the diathermic snare is useful for the resection of esophageal lesions; it is called the EEMR
(endoscopic esophageal mucosa resection) tube technique  and a single-channel endoscope is passed in the over-tube. There has been a considerable evolution of the devices offered
by various companies. Most of them are presented as EMR kits for single use.
The first step after the detection of the lesion is a careful morphological analysis with chromoscopy, using indigo-carmine
as a contrast agent. Treatment applies to lesions with a superficial endoscopic pattern, either premalignant or malignant.
If the size and morphology is compatible with an indication for EMR, the limits of the resection are marked on the adjacent
mucosa either with a diathermy device or with small clips. Lifting the lesion from the submucosa is of utmost importance;
it confirms the superficial character of the lesion and that there is a minimal risk of complications.
The standard procedure for lifting is submucosal injection with a special needle of up to 20 ml of saline with the addition of epinephrine (0.025 mg/ml). In order to prolong the lifting other solutions have been employed .
The delay before flattening of the mucosal bleb is short with saline (around 3 min) and can be prolonged (up to 20 min) when using a hyaluronic acid solution. However, the cost is increased. The resected specimen is prepared in the endoscopy
room, stretched on a cardboard, and fixed in neutral formalin. Parallel transverse histological sections will assess with
precision the depth of tumoral invasion in each sector. The best results are obtained with the en bloc resection of a single
specimen. After piecemeal resection a similar analysis requires a reconstitution of the position of the multiple fragments.
EMR with a cap : EMR-C (aspiration method)
A transparent cap is attached to the tip of a single-channel endoscope and a diathermic snare is prelooped in the rim of the
cap. The lesion is sucked into the cap and the snare is passed across the artificial polyp; resection is achieved with blended
diathermy current. In case of bleeding, hemostatic clips are used. En bloc resection for lesions up to 15 mm in diameter is possible with the standard cap, and up to 20 mm with a large cap model. Larger lesions can be treated by the piecemeal method.
EMR with a ligating cap : EMR-L (aspiration method)
In this procedure the transparent cap of an endoscopic ligator-kit operates the suction; the strangulation is ensured by a
ligating band. The protruded mucosal bleb is resected with a conventional snare. This procedure is well adapted to resection
of lesions in the upper third of the lesser curvature.
This procedure is performed either with a double- or a single-channel endoscope. After placing marks around the target lesion,
and lifting the lesion, a circular incision of the mucosa is performed with a needle-knife. The lesion raised by the circular
incision is resected with a standard snare. The specimen is removed with grasping forceps.
With this procedure, en bloc resection of large segments of the gastric mucosa is possible, but there is a higher risk of
hemorrhage. Hemo-clipping and suture clipping of the mucosal break is used. The safety of the incision method is improved
when using new models of endoscopic knives. The hook knife, curved at its tip, will not enter to an excessive depth.
The insulated tip needle-knife (IT knife) also prevents excessive depth, but the section is very slow and a preliminary small
incision of the mucosa is required for the insertion of the small sphere at the end of the needle. The triangular tip knife
(TT-knife) is the most recent device for mucosal incision. The introduction of the triangular tip at the interface of mucosa
and submucosa is easy, the progression of the tissue incision is fast, and the knife can be used for hemostasis.
EMR grasp-method [100,103]
Either an over-tube (EEMR) or a double-channel endoscope is required; after marking the limits and lifting, the lesion is
seized with grasping forceps which have been passed across the snare introduced through the other channel; resection is then
performed. The four points method is a variant of the grasp-method, where the limits of the lesion are marked with four short
clips with modified shortened arms. Then a jumbo grasping forceps lift the lesion with the clips for resection with the snare.
Indications for EMR
In the stomach most low-grade or high-grade intraepithelial (premalignant) neoplastic lesions have the same appearance as
early malignant lesions (intramucosal carcinoma or submucosal carcinoma). EMR is proposed for both types of flat or slightly
elevated lesions when their size is not over 2 cm.
If there is a depression on the lesion, the indication is legitimate when the size is not over 1 cm. However, wider indications have also been proposed  for well-differentiated cancer less than 30 mm without ulcer or ulcer scar, less than 20 mm if there is an ulcer scar, and less than 10 mm if there is a poorly differentiated cancer.
After pathological assessment, the safety of the endoscopic treatment is confirmed for intramucosal neoplastic lesions, and
for submucosal carcinoma when the invasion in the submucosa is less than 500 µm (micrometric method) below the limit of the muscularis mucosae. In other cases, EMR should be followed by surgery.
Results and complications of EMR
En bloc resection in a single fragment gives better results than piecemeal resection; the proportion of cases with complete
resection is higher and the rate of recurrence is lower. This is shown by the follow-up of large series . The proportion of complete resection is higher in en bloc (67%) than in piecemeal resection (11%), and the respective rates
of recurrence are 4% and 17%. In addition, the results depend on the topography of the lesion, en bloc resection being easier
in the lower third of the stomach.
In a series of EMR for early gastric cancer (EGC) treated at the National Cancer Center in Tokyo , intramucosal cancer was confirmed in 405 out of 479 cases, and complete resection was performed in 69%. In 104 of the 127
cases with incomplete resection no subsequent treatment was proposed and there was recurrence in only 17 cases during the
surveillance period. Major complications of EMR include severe bleeding and perforation; minor bleeding is frequent. The global
risk of complications in large Japanese meta-analyzes has been estimated at 0.5%; but higher figures (around 5%) are presented
in most individual series with a precise follow -up.
Surgery for gastric cancer
Many cases of early gastric cancer (EGC), according to the Japanese experience, are now treated with less aggressive modalities than gastrectomy, including
EMR or laparoscopic surgery; this will contribute to better quality of life of patients with ECG. Laparoscopic surgery provides
less pain, faster recovery, and a shorter hospital stay than conventional surgery. On the other hand, surgery remains the
treatment for advanced and localized gastric cancer (T2, T3). Various techniques have been proposed, such as ordinary open surgery, laparoscopic-assisted gastrectomy,
laparoscopic intragastric surgery, and pylorus-preserving gastrectomy .
Gastrectomy with curative intent is completed by lymphadenectomy. A complete resection of the tumor with safe margins is called
a R0 resection. Super-extended lymphadenectomy (D3/D4) involving resection of preaortic lymph nodes is seldom employed and the two current modalities are the lymphadenectomy
for perigastric lymph nodes only (D1), or the extensive lymphadenectomy concerning also lymph nodes around the vascular axis
(D2), which is the standard for advanced gastric cancer in Japan. Western surgeons still prefer D1 gastrectomy, because the
morbidity and mortality is less (in their hands). New trials in Western countries tend to recommend D2 gastrectomy, either
when the advanced cancer reaches the serosa or when perigastric metastatic lymph nodes occur in a superficial cancer.
Extent of the resection
A distal resection (four-fifths of the stomach) is recommended in distal gastric cancer, while total gastrectomy is recommended
in proximal gastric cancer and is often completed by splenectomy. When there is a local invasion of an adjacent viscus (liver
or pancreas), gastrectomy can be completed by a segmental resection of the region with invasion and omentectomy.
If liver or peritoneal metastases are present, a palliative gastrectomy is still relevant if there is severe obstruction or
chronic bleeding and anemia. Unresectable and obstructive tumors causing severe dysphagia or pyloric occlusion tend now to
be treated by endoscopic ablation (laser) or by stent placement, rather than by surgery.
Chemoradiation in advanced gastric cancer
Chemoradiation protocols (palliation)
Chemotherapy and radiation therapy have a marginal role. Only a slight benefit (and toxic effects) has been obtained in non-operable
gastric metastatic cancer with conventional agents, and 5 fluorouracil (5 FU) remains the principal agent used in association
with Methyl-CCNU or Mitomycin C or Epirubicin, and Cisplatinum. Better results are expected either from new modalities of
administration (infusional 5 FU) or from new agents such as Oxaliplatin and Irinotecan, and, in the future, growth factor
inhibitors and antiangiogenesis agents. Similarly, tumors are not affected by radiation protocols, which can prove toxic for
liver and intestine. On the other hand brachytherapy has proved helpful in the palliation of dysphagia from tumors at the
Adjuvant chemoradiation protocols
More positive results are obtained with combined chemoradiation protocols [113,114]. However, there is no room for current neo-adjuvant protocols in the treatment of gastric cancer. Adjuvant chemoradiation
protocols after surgery may prove beneficial as shown in the multicenter analysis conducted in North America by MacDonald
. The protocol INT 0116 combines radiation (45 Gy in 25 fractions) and two agents (5 fluorouracil and leucovorin). However,
the guideline recommending this protocol in North America has not reached consensus in other countries because the percentage
of D2 resection in the study was small (10%) and the D1 lymphadenectomy was often incomplete. There have been considerable
variations in the benefit afforded. Meanwhile, adjuvant chemoradiation protocol can be recommended for patients with a R0
resection and positive lymph nodes.
Endoscopic palliation with Nd:YAG laser
The Nd:YAG laser is a powerful tool adapted to the reduction of the tumor volume. The infrared photon beam of a Nd:YAG laser
source is transmitted across a flexible fiber passed through the operative channel of the endoscope, and aimed at the tumor
either at distance or in the tissue.
There are two distinct indications for Nd:YAG laser in palliation for non-operable patients: hemostasis and lumen ablation.
In patients with continuous blood oozing from the tumor and chronic anemia, repeated sessions of thermal coagulation of the
surface of the tumor at intervals of 4 weeks may reduce the blood loss and improve the status of the patient. The other indication
concerns severe dysphagia from obstructive fungating tumors at the EG junction. The procedure is concurrent with the placement
of an expandable stent, or brachytherapy. Nd:YAG laser ablation has also been combined with brachytherapy .
In conclusion, lumen recanalization at the EG junction through thermal destruction is possible. Dysphagia can be relieved by sessions at
4 week intervals, ensuring a correct nutrition; however, thermal destruction has poor results when the stricture is infiltrating
and non-exophytic; stent placement is usually required.
Endoscopic palliation with stents
Types of stents
Semi-rigid, plastic, non-expandable stents are used less now than metal expandable stents derived from intravascular stents,
constructed in stainless steel or with nitinol alloy (nickel, titanium). The stents are built either in a thin grid or knitted
mesh with the metal thread, or in a large grid in the Z model, or in a rigid coil. Depending on their structure the stents
may shorten when they expand. Models differ in rigidity and radial expansive force. With respect to prevention of reflux at
the EG junction, some stents are equipped with a distal antireflux cuff. Stents are usually delivered as a set mounted on
an introducer. Metal stents are either uncovered or covered. The drawback of uncovered stents is the obstruction by tumor
in-growth across the mesh. The drawback of covered stents is the risk of migration. Non-metallic expandable stents have recently
become available (Polyflex: stent from Rusch, Kernen, Germany). Prototypes of biodegradable stents made of a polymer of lactic
acid are preferred in the treatment of bronchial strictures.
Similar results in the relief of dysphagia are obtained with various types of expandable stents; however, the rate of complications
appears to be higher with the Z structure and with the coil structure. A randomized study comparing covered and uncovered
expandable stents placed at the EG junction  has shown similar relief of dysphagia and similar survival, but tumor in-growth requiring re-intervention was more frequent
with uncovered stents.
Placement of the stent and indications
The placement of a stent usually includes both endoscopic and fluoroscopic control. However, placement of self-expanding stents
without fluoroscopy has been reported, and placement without endoscopy, under fluoroscopy, is also possible.
The primary indication for stenting a stricture in gastric cancer is tumoral obstruction at the EG junction generating dysphagia
in non-operable patients [116,117].
More recently, stenting has been proposed as an alternative to palliative surgery for strictures at the gastric outlet . In non-operable patients the objective of re-establishment of the passage of food is the same when there is a prepyloric
cancer as when there is duodenal compression by a pancreatic cancer. Metal expandable stents are used. Radiological guidance
is often required, either alone, or in association to endoscopy. Endoscopic guidance alone is also possible using delivery
systems with an adapted length. Stents are pushed through an interventional endoscope with a large channel, or alongside the
endoscope. Special models of expandable stents are available. The Enteral Wallstent is 9 or 10 cm in length, with a diameter of 20 or 22 mm and is passed through the operative channel of an duodenoscope.
Results and complications of stenting
Results at the EG junction
For tumors at the EG junction the relief of dysphagia and improvement of nutrition is obtained in most cases in 24 h. The dysphagia score of from 4 (aphagia) to 0 (no dysphagia) is used to evaluate the efficacy in palliation as well as the
health status and the quality of life of the patient. The median survival after placement of a stent is estimated in the range
of 912 weeks . Other options in the palliation of a stricture at the EG junction include brachytherapy and lumen recanalization with a
thermal procedure (Nd:YAG laser), or photodynamic therapy.
A recent study  compared stenting to tumor ablation with the Nd:YAG laser. The median survival was longer in the thermal treatment group.
The health quality of life was impaired in both groups at the baseline, and remained stable in the thermal treatment group
while deterioration occurred in the stent group, with more pain. In conclusion, stenting is preferred when the tumor is infiltrative,
whereas Nd:YAG laser is preferred for obstructive tumors with a smooth fungating surface. In a second phase such tumors will
Results at the gastric outlet
Stenting for malignant strictures of the gastric outlet improves the passage of food, but biliary obstruction may develop
later. In patients with stenosis of the gastric outlet from pancreatic cancer, endoscopic palliation with stenting has given
results similar to those in operative gastro-jejunostomy
The toll of complications after placement of a stent is influenced by many factors, including the stent material, diameter,
and its radial force of expansion. Self-expanding stents have less complications than semi-rigid stents. Tumor ingrowth across
the mesh of uncovered stents or at the periphery of covered stents, food impaction in the stent, and migration may occur.
Tumor ingrowth requires recanalization with thermal procedures (argon plasma or microwaves). Migration requires extraction
and placement of another stent. Specific complications after placement at the EG junction are gastroesophageal reflux which
can result in further respiratory complications, and migration of the stent in the stomach. Specific complications after placement
of a stent in the gastric outlet are distal or proximal obstruction by the tumor growth, and migration of the stent in the
Guidelines in surveillance
Surveillance of the risk of gastric cancer after an index gastroscopy is also based on endoscopy; the general tendency is
to avoid repetition at short intervals. Surveillance occurs in two distinct situations:
When endoscopy has shown a premalignant condition (e.g. chronic atrophic gastritis with H. pylori infection and no neoplastic lesion), surveillance is not generally recommended in spite of a recent British study  showing a high yield of gastric cancer in patients with chronic gastritis who agreed to annual endoscopic surveillance. Specific
situations arise with surveillance after a partial gastrectomy for peptic ulcer, but this procedure has become rare. Endoscopic
surveillance after detection of pernicious anemia is recommended in the early period, but must not be unduly prolonged.
When index endoscopy has shown a premalignant lesion with IEN in the stomach, patients should enter a surveillance protocol
(when they have not been treated). The risk of progression from high-grade IEN to cancer is very high in the short term (around
80%), while the risk is low with low-grade IEN (less than 15% in 2 years) (in ). The progression from low-grade to high-grade IEN and to cancer is altogether inconstant and slow. Taking this into account,
lesions with high-grade IEN are generally treated immediately; surveillance applies to lesions with low-grade IEN. Endoscopic
exploration is repeated at intervals of 612 months and should not be limited to the targeted area, because metachronous lesions may develop. The same strategy also
applies to persons who have been treated by EMR for a premalignant or early malignant lesion in the stomach.
Prevention of gastric cancer
Primary prevention of gastric cancer is by the control of causal factors. There is a general belief that, in most countries,
primary prevention of stomach cancer has priority over secondary prevention. It aims to reduce the risk factors, which are
hypochlorhydria from chronic atrophic gastritis with H. pylori infection, and dietary factors, such as an excess of salt, nitrites, and nitrates, and a lack of antioxidants. H. pylori infection is just one of a number of factors in gastric carcinogenesis .
Prevention and H. pylori infection
A reduction in the prevalence of chronic atrophic gastritis has been proposed in countries with a high incidence of stomach
cancer. The large-scale eradication of H. pylori infection by vaccination has been proposed, or by serological screening, with antibiotic therapy for those testing H. pylori positive. The potential drawback of H. pylori eradication is the promotion of gastroesophageal reflux. At the individual level, eradication is recommended in persons who
have chronic atrophic gastritis at the index endoscopy and are positive for H. pylori. This can improve the status of the mucosa and is assumed to reduce the risk of cancer. In a recent study of 22 elderly men
positive for H. pylori the scores for atrophy and intestinal metaplasia were stable during the first part (7.5 years) of the follow-up without treatment
and regressed during the second part of the follow-up (2.5 years) after eradication.
Prevention through dietary intervention
A planned dietary intervention through addition of antioxidants (beta-carotene, retinol, alpha-tocopherol, vitamin C) has
been attempted in trials where the surrogate endpoint is the occurrence of premalignant gastric lesions. However, a major
confusing variable is the H. pylori status, which may differ between tested persons and their controls; therefore eradication of H. pylori in both groups is a requested preliminary. Prevention trials have been conducted in South America and Europe. In the cohort
study in Finland  daily supplementation for 58 years in 29 133 male smokers had no impact on the occurrence of neoplasia. The overall disappointing results of chemoprevention
trials contrast with the generalized decrease in the incidence through unplanned primary prevention.
Unplanned prevention occurs through changes in environmental factors which are supposed to play a major role during infancy,
as shown by the progressive decrease in the risk in successive generations for Japanese migrants to the USA .
The promoting environmental factors, linked to the lifestyle, include a diet rich in salt and poor in fruit and vegetables,
and H. pylori infection. This can be corrected by a diet characterized by a reduction of salty foods and an increased consumption of fruit
and antioxidant vitamins, and a reduction of the contamination in childhood for the H. pylori infection. The decline in the incidence of stomach cancer in Japan is often attributed to the generalization of a Western
style of life under the American influence, just after World War II, when the full impact of the declining trend occurred.
Actually the cause of the decline occurred much earlier, when Japan entered the industrial arena in the first decade of the
twentieth century, under the influence of Emperor Meiji, just after the Sino-Japanese and Russo-Japanese wars. Changing environmental
factors occurred in the infancy of cohorts born in 1910, and after 1910 as shown in an age-cohort study of the Osaka Cancer
Registry  during the period 197595.
Secondary prevention of gastric cancer
Secondary prevention of gastric cancer is based on the detection and treatment of premalignant and early malignant lesions
in asymptomatic persons (preclinical disease). However, flat precursors which are difficult to detect play the major role
in gastric cancerogenesis.
Gastroscopy and opportunistic screening
Gastroscopy, the gold standard procedure in the detection of non-protruding neoplastic lesions of the stomach, is proposed
for persons complaining from upper-digestive symptoms (gastroesophageal reflux or non-ulcer dyspepsia) or for asymptomatic
persons wishing to be reassured. However, in Western countries neoplastic lesions are rarely detected (12%) in such patients; this is why good-practice guidelines do not recommend prompt endoscopy in persons aged less than 45
years, and often delay the procedure until after a therapeutic trial.
However, studies on the appropriateness of endoscopy have shown that the rate of over-utilization (in non-appropriate indications)
is still less than the rate of under-utilization (in appropriate indications). Anyhow, when gastroscopy is performed in the
absence of alarming symptoms, the entire mucosal surface of the esophagus and stomach should be examined carefully with a
high-resolution instrument, in order to minimize false negative rates ; indeed the detection of non-protruding lesions, which are the major precursors of gastric cancer, deserves special attention.
A study of false negative results for gastric cancer has been conducted in Japan in the Fukui area [129,130]. In 3672 persons with a 'negative gastroscopy' in the regional hospital, selected to repeat the procedure after a delay of 13 years, a gastric cancer was found in 32 (less than 1%); this result confirms that the risk of missing a cancer after a negative
procedure is very small. When all gastroscopies in the regional hospital were compared to the population-based Tumor Registry
13 years after performance of the procedure, gastric cancer had been missed in 155 out of 814 cases (19%) found in the registry;
here the false negative rate is much higher. An appreciable proportion of gastric cancers are undiagnosed at the first procedure,
even in a country where endoscopy reaches a fairly high standard.
Mass screening detection of early cancer is appropriate when a simple screening test is available and when the prevalence
of the disease is high. Japan is the only country where mass screening for stomach cancer is a national policy, and has been
for four decades. The screen-detected cases (either early or silent disease) have had an impact on mortality rates , in spite of a declining cost-effectiveness .
Gastroscopy is performed in persons with a positive miniature radiophotofluorography. As an alternative, serologic biological
markers aimed at detecting atrophic gastritis have been proposed. A decreased ratio of pepsinogen I to III confirms atrophy
of the oxyntic mucosa, when an appropriate cut-off ratio is selected. The pepsinogen test tends now to be generalized as a
screening test . Positive serology for H. pylori or its cagA phenotype do not fulfill the criteria of a selection test. The mass screening campaign (combined to opportunistic
screening) proved beneficial as shown in Figs 2226. In Japan around 45% of cases are detected at an early and localized stage. The 5 year relative survival for stomach cancer
is over 40%.
A comparative study  of time trends on the incidence of gastric cancer in Japan (Osaka Cancer Registry) and in a country with no screening policy
(USA) has shown that the incidence rate of stomach cancer declined in Japan in the same way as it did for other countries
in the period 197595. However, the trend in Japan has two specific characters. The stage specific incidence declines only for regional stage
cancer, while the incidence of the localized stage cancer increases. Mortality rates decline more sharply than the incidence
rates. The policy of early detection of stomach cancer explains the increased incidence of localized cancer, and the dissociation
of the mortality rate.
In other countries
In the Western world, in the absence of a screening policy, most cases of stomach cancer are detected at the advanced stage,
with a correspondingly poor prognosis. Indeed a recent analysis of 57 407 cases in the National Cancer Data Base of the USA  shows that most cases are still detected at the advanced stage. In the USA and Europe the 5 year survival rate just reaches
Strategy of detection worldwide
Taking into account the generalized declining incidence, screening for gastric cancer does not deserve a public health policy
outside Japan, where the toll from stomach cancer is the highest. In other countries, detection depends on opportunistic screening
with gastroscopy in persons with non-alarming digestive symptoms (non-ulcer dyspepsia) after the age of 45.
High-grade IEN justifies treatment because most of these lesions will progress to advanced cancer . The secondary objective of the procedure is the detection of polyps. Benign adenomatous polyps may be associated with a
metachronous malignant non-protruding area. Gastric polyposis (fundic cystic or hyperplastic polyps) justifies an indication
for colonoscopy and a questionnaire for familial hereditary syndromes.
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