Cancer Therapy Vol 5, page 877
Cancer Therapy Vol 5, 877-894, 2007
Gastric adenocarcinoma: epidemiology, pathology
and pathogenesis
Review Article
Stacy Carl-McGrath1,*, Matthias Ebert2, Christoph Röcken1
1
Institut für Pathologie, Charité Universitätsmedizin Berlin, Germany
2
II. Medizinische Klinik des Klinikums rechts der Isar, Technische Universität München, Germany
__________________________________________________________________________________
*Correspondence: Stacy Carl-McGrath, Institut für Pathologie, Charité Universitätsmedizin, Charitéplatz 1, D-10117 Berlin, Germany;
Tel: +49 (0) 30 450 536248; Fax: +49 (0) 30 450536914; E-mail: stacy.carl-mcgrath@charite.de
Key words: Gastric cancer, Pathogenesis, Epidemiology, Helicobacter pylori infection, Diet, Epstein-Barr virus infection, Gastric
surgery, Chronic gastritis, Lifestyle, Intestinal metaplasia, Gene polymorphisms, Blood group A, Gastric ulcer, Autoimmune gastritis,
Precursor lesions, Pathology, Intraepithelial neoplasia, Histological classification, Adenomas, Polyps, Hereditary syndromes, Prognosis,
Polyposis syndromes, Hereditary nonpolyposis colorectal cancer,
Abbreviations: adenomatous polyposis coli, (APC); Epstein-Barr virus, (EBV); familial adenomatous polyposis, (FAP); Intestinal
metaplasia, (IM); N-methyl-N’-nitro-N-nitrosoguanidine, (MNNG); Peutz-Jeughers Syndrome, (PJS); serine/threonine kinase 11,
(STK11)
Received: 8 March 2007; Revised: 12 June 2008
Accepted: 24 June 2008; electronically published: October 2008
Summary
Gastric cancer is one of the most common cancers worldwide, ranking fourth in overall frequency, and accounting
for over 870,000 new cases and over 650,000 deaths annually. While the incidence of gastric cancer has decreased,
the absolute number of gastric cancer patients has increased due to an aging population. Mortality from gastric
cancer is second only to lung cancer, despite the dramatic improvement witnessed over recent decades in the
understanding of the epidemiology, pathology and pathogenesis of gastric cancer. Infection with H. pylori or
Epstein-Barr virus, dietary and lifestyle factors contribute to the risk of developing gastric cancer. Gene
polymorphisms have come to be recognized as crucial factors determining disease susceptibility in patients suffering
from chronic gastritis. However, prognosis is still poor, and the search continues for novel diagnostic markers that
may enable diagnosis of gastric cancer in its early stages, and novel patient-tailored therapeutic regimens.
I. Introduction via multiple sequential steps. Substance- or disease-related
Cancer annually accounts for 12 percent of total chronic inflammation or oxidative stress results in the
deaths worldwide, and in industrialised countries, 25 initiation of continual regenerative processes, where the
percent of people die of cancer each year. Although lung replacement of lost and injured cells through cell division
and breast cancers are the most common cancers in men offers an opportunity for the accumulation of genetic
and women, respectively, cancers of the gastrointestinal damage (Orlando, 2002). Characteristic for the
tract, including oesophageal, stomach, liver, colon, and progression to invasive cancer, the appearance of
pancreas cancers, are responsible for approximately 3 abnormal cells (dysplasia) is followed by the development
million new cases and over 2 million deaths each year of preneoplastic lesions, and then, finally, the emergence
(Hamilton and Aaltonen, 2000) making them the most of a carcinoma (Raza, 2000).
frequent cancers worldwide. However, incidence of these Cancers of the stomach are among the most frequent
cancers, compared with non-gastrointestinal cancers, gastrointestinal tract cancers, irrespective of gender- or
varies according to the geographical location, which is regional-specific variations. In this review, the last few
mainly due to regional variations in diet, lifestyle, and decades of research into the important factors influencing
bacterial or viral infections. the epidemiology, pathology and pathogenesis of gastric
Bacterial and viral infections leading to chronic cancer have been summarised. Unfortunately, although
inflammation play a major role in gastrointestinal surgery or combined surgery and radiochemotherapy may
carcinogenesis (Hamilton and Aaltonen, 2000). A range of be curative for a large proportion of tumours of the
gastrointestinal cancers arise from inflammation and are gastrointestinal tract, stomach cancers are the second
preceded by a lengthy precancerous process, developing leading cause of cancer-related deaths, exhibiting a
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persistently high mortality (10.4% of all cancer deaths per tumours (Mori et al, 1995; Carneiro and Sobrinho-Simoes,
year). The exceedingly poor prognosis of these cancers is 1996).
mostly due to presentation in an advanced stage, and the
limited range of treatment options. Decreasing gastric A. Histological classification
cancer mortality will require earlier diagnosis of these Various systems have been applied to the
cancers, as well as a wider range of therapeutic classification of gastric carcinomas, including the WHO
alternatives. (Hamilton and Aaltonen, 2000), Ming (Ming, 1977),
Laurén (Lauren, 1965b), and Goseki (Goseki et al, 1992)
II. Pathology classifications. The clinical significance of these
The primary epithelial tumour of the stomach is the classifications is limited, with only the Lauren and perhaps
adenocarcinoma, and develops from the stomach mucosa, the Goseki classifications providing prognostic
usually maintaining glandular differentiation. Other less assessments (Alekseenko et al, 2004). The TNM staging
common tumours of the stomach are the squamous cell of the gastric carcinoma, according to the guidelines set
carcinomas, and the adenosquamous carcinomas, out by the International Union Against Cancer (UICC)
combining characteristics of both the adenocarcinoma and (Wittekind and Sobin, 2002), is the most important
the squamous cell carcinoma to approximately equal prognostic factor in clinical practice (Alekseenko et al,
extent. Undifferentiated carcinoma lacks any differentiated 2004). However, the Lauren classification has been the
features and does not fit into any of the above categories. most successful system, as it defines two distinct
Gastric carcinomas can be classified according to histological entities, which clearly exhibit different clinical
their localization in the stomach. The antral-pyloric region and epidemiological characteristics, even in advanced
of the stomach is the most common site of stomach cancer, gastric cancers (Satoh et al, 2007).
and carcinomas of the body or corpus are located along the In the Laurén classification (Lauren, 1965a),
greater or lesser curvature. Cancers of the cardia are often intestinal-type carcinomas maintain the glandular
unable to be distinguished from cancers of the phenotype, with well- to moderately-differentiated
gastroesophageal junction, and are believed to be a tumours forming identifiable glands, often with poorly
separate entity, probably originating from the distal differentiated tumour cells at the invasive front. Typically
oesophagus. This review has been restricted to non-cardia arising on a background of intestinal metaplasia, these
adenocarcinomas, since the complex state-of-affairs tumours exhibit an intestinal, gastric and gastrointestinal
surrounding the cancers of the cardia and gastroesophageal mucinous phenotype. Diffuse-type carcinomas form no or
junction is outside the scope of this report. very few glandular structures, instead usually infiltrating
The diagnosis of gastric cancer is often delayed by the gastric wall, appearing diffusely distributed as small,
the lack of early symptoms, with early gastric cancer round single cells or poorly cohesive cell clusters. They
causing non-specific gastrointestinal complaints, such as may resemble signet-ring cells, and may contain small
dyspepsia, in only 50% of patients. Up to 90% of Western amounts of intestinal mucin. Additionally, mixed tumours
gastric cancer patients first present with advanced exhibit both intestinal and diffuse characteristics, and
carcinomas, which have more serious symptoms such as undifferentiated tumors are classified as indeterminate.
abdominal pain, bleeding, vomiting, or severe weight loss. The natural history of gastric carcinoma, in particular the
Endoscopic screening is considered to be the most association with environmental factors, incidence trends,
sensitive and specific diagnostic test for gastric cancer. and precursor lesions, is often evaluated with respect to
Dysplasia may present as a flat lesion or exhibit polypoid the Laurén classification.
growth, with depressed, reddish or discoloured mucosa.
Endoscopic detection of changes in colour, relief, and B. Precursor lesions
architecture of the mucosal surface enables the Although chronic atrophic gastritis and intestinal
classification of gastric cancers according to their metaplasia (section IV; F,G) may be considered to be
macroscopic growth pattern. Early gastric cancers may preneoplastic lesions, this setting may only facilitate the
feature protruded (Type I), elevated (Type IIa), flat (Type development of what is generally regarded as a true
IIb), depressed (Type IIc) or excavated (Type III) growth precancerous or precursor lesion, dysplasia. Dysplasia
(Hamilton and Aaltonen, 2000), whereas advanced gastric encompasses a large range of cellular and structural
carcinomas are classified into polypoid (Type I), fungating atypias, which are defined under the term intraepithelial
(Type II), ulcerated (Type III) or infiltrative (Type IV) neoplasia (Hamilton and Aaltonen, 2000), and lies
growth patterns (Borrmann, 1926; Hamilton and Aaltonen, between atrophic metaplasia and invasive cancer.
2000). Type II or III advanced gastric cancers are
commonly ulcerating, and the risk of penetration of the 1. Intraepithelial neoplasia
submucosa is highest in early gastric cancers with a Intraepithelial dysplasia may develop in the gastric or
depressed growth pattern (Type IIc), and in infiltrative intestinal metaplastic gastric epithelium, and can be
advanced gastric carcinomas (Type IV). The superficial categorized into four categories: indefinite for
spread of Type IV infiltrative (diffuse) tumours through intraepithelial neoplasia, low-grade and high-grade
the mucosa and submucosa result in flat, plaque-like intraepithelial neoplasia, and suspicious for invasive
lesions, which may exhibit shallow ulcerations. Serosal, cancer (Rugge et al, 2000; Schlemper et al, 2000).
lymphatic, and vascular invasion and lymph node Regenerative or reactive changes unable to be definitely
metastases are most frequent in the diffusely growing diagnosed are classified as indefinite for intraepithelial
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neoplasia. Intraepithelial neoplasia exhibits flat, elevated geographic distribution of gastric cancer varies from an
or polypoid, or slightly depressed growth patterns. annual incidence of more than 300,000 new cases in the
Histological classification of intraepithelial neoplasia as more developed regions of Europe, Japan, Australia, New
low- or high-grade depends on the severity of architectural Zealand and North America, to nearly 550,000 new cases
and cytological atypia. The mucosal structure is only per year in the developing or less developed regions of
slightly modified in low-grade intraepithelial neoplasia, Africa, Latin America and the Caribbean, Asia (excluding
maintaining tubular differentiation with the proliferative Japan), Micronesia, Polynesia and Melanesia. In high risk
zone limited to the outward portion, whereas high-grade areas, the intestinal-type adenocarcinoma is more frequent,
intraepithelial neoplasia exhibits increasing distortion of whereas the poorly differentiated diffuse-type carcinoma
the mucosal architecture, resulting in crowded possibly predominates in low risk areas.
irregular glands with obvious cellular atypia, and The incidence and mortality rates of gastric
proliferative activity distributed throughout the lesion. carcinoma are steadily declining. However, due to the
High-grade intraepithelial neoplasia is associated with a aging population, the absolute number of new cases per
higher risk of developing gastric carcinoma (Rugge et al, year is increasing (Munoz and Connelly, 1971; Hamilton
1994), particularly in association with Type III intestinal and Aaltonen, 2000). Below the age of 30, the incidence of
metaplasia. The progression from intraepithelial neoplasia gastric carcinoma is extremely rare, but thereafter rises
to carcinoma is diagnosed when the lamina propria or quickly and continuously, with the oldest age groups
muscularis mucosae are invaded by the tumour. having the highest rates. In males, the intestinal-type is
more common than the diffuse-type and the incidence
2. Adenomas rises faster with age, whereas the diffuse-type mainly
Circumscribed tubular and/or villous structures impacts younger individuals, frequently females. A
exhibiting intraepithelial neoplasia constitute the benign decline in incidence of the intestinal-type carcinomas is
lesions defined as adenomas. In contrast to Western largely responsible for the decline in overall incidence
countries, where adenoma only applies to macroscopic rates (Kaneko and Yoshimura, 2001; Henson et al, 2004),
protruding lesions, Japan includes flat, elevated and and has been correlated with the corresponding decrease in
depressed lesions in the adenoma classification. Gastric prevalence of H. pylori infection (The EUROGAST Study
adenomas, in the Western sense, are uncommon (Tamura, Group, 1993; Konturek et al, 2003). Both gastric cancer
1996), making up only 10% of all gastric polyps (Stolte et and H. pylori infection affect patients from low
al, 1994). Malignant transformation depends on the size socioeconomic backgrounds, associated with low social
and histological grade, occurring in 2% of lesions less than class, poor education, low hygiene standards, a diet
2 cm and in 40-50% of lesions larger than 2 cm, and more lacking fresh fruit and vegetables, but rich in starch and
frequently in flat adenomas. preserved meats, and atrophic gastritis. Indeed, the
distinctive epidemiological characteristics of gastric
3. Polyps cancer, in particular, the regional differences and
Hyperplastic gastric polyps typically arise in the chronological changes in incidence may be, in part, related
antrum in the presence of H. pylori gastritis, but only to H. pylori infection (Nagel et al, 2007). However, the
proceed to carcinoma in a minority of cases. Fundic gland incidence of the diffuse-type carcinoma may be increasing
polyps are most common in Western populations, without (Craanen et al, 1992b; Henson et al, 2004), which is
a background of H. pylori infection. Sporadically worrying given that these types of tumours have a worse
occurring fundic gland polyps have no malignant prognosis (Blok et al, 1997). An increase has also been
potential, often affecting patients receiving long-term observed for cancers localized to the gastro-oesophageal
proton pump inhibitor treatment. Fundic gland polyps may junction, some probably originating from the distal
also appear in the hundreds in familial adenomatous oesophagus caused by gastro-oesophageal reflux (Yamada
polyposis (FAP) patients (Watanabe et al, 1977), where and Kato, 1989). Cancers of the cardia and
dysplasia and subsequent carcinoma may develop in gastroesophageal junction are conspicuously increasing in
adenomatous polyps (Zwick et al, 1997; McGarrity et al, incidence and frequently exhibit a different pathogenesis
2000), an elevated polypoid dysplastic lesion occurring to non-cardia carcinomas.
seldom in the absence of FAP, with an absolute cancer risk
of up to 76% (Ming, 1998). IV. Pathogenesis
The pathogenesis of gastric cancer involves multiple
III. Epidemiology risk factors including dietary, infectious, occupational,
Gastric cancer is one of the most common cancers genetic and preneoplastic risk factors, most of which act
worldwide, ranking fourth in overall frequency, and on the gastric mucosal microenvironment over a prolonged
accounting for over 870,000 new cases and over 650,000 time period. The resultant sequential changes in the gastric
deaths annually (Stewart and Kleihues, 2003). Mortality mucosa that precede the development of invasive cancer
from gastric cancer is second only to lung cancer. Gastric are known as the ‘precancerous cascade’, first described in
cancer occurs more frequently in men than in women, with 1975 (Correa, 1992), where normal gastric mucosa is
the estimated number of new cases worldwide being transformed by chronic atrophic gastritis and develops
558,000 for males and 317,000 for females, respectively multifocal atrophy and intestinal metaplasia, followed by
accounting for 5.5% and 3.1% of all malignancies, the appearance of dysplasia and finally invasive carcinoma
excluding skin cancer (Hamilton and Aaltonen, 2000). The (Figure 1).
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Past research has concentrated on the identification and progression of gastric cancer (Stadtländer and
of the complex aetiology of environmental and genetic Waterbor, 1999; Chan et al, 2001; Correa, 2002; Kelley
risk factors, which may influence the initiation, promotion, and Duggan, 2003).
Figure 1. The multifactorial pathogenesis of gastric cancer. The development of gastric cancer progresses via multiple stages: the
complex interaction of external environmental factors with the host system acts on the gastric mucosal microenvironment over a
prolonged time period, usually resulting in chronic inflammation. The continual regenerative processes within the gastric mucosa
increase the risk of genetic mutations: the ‘precancerous cascade’ reflects the accumulation of various alterations that provide the cell
with the ability to proliferate and metastasize.
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A. Helicobacter pylori infection et al, 2000; Odenbreit et al, 2000; Stein et al, 2000;
H. pylori are Gram-negative, spiral-shaped bacteria Higashi et al, 2002). A greater degree of inflammation,
that can survive and proliferate in the acidic environment related to IL-8 production by epithelial cells, and a higher
of the stomach mucosa, living predominantly in the risk of developing gastric cancer is associated with CagA-
mucous layer overlying the normal gastric epithelium. H. positive, compared to CagA-negative H. pylori strains
pylori infection is usually acquired during childhood (Blaser et al, 1995; Queiroz et al, 1998). Another virulence
(Torres et al, 2000), and more frequently in families of factor, the vacuolating cytotoxin VacA, is found in almost
low socioeconomic status (Graham et al, 1991; Banatvala all H. pylori strains, and the expression of VacA varies
et al, 1993; Blaser et al, 1995; Webb and Forman, 1995; considerably between strains, which may be due to
Goodman and Correa, 2000). A range of epidemiological variations in the VacA gene structure. VacA is responsible
studies have provided evidence of the world-wide for epithelial cell damage, and is also associated with
association between H. pylori infection and the gastric carcinogenesis (de Figueiredo et al, 1998; Peek, Jr.
development of gastric cancer (Nomura et al, 1991; and Blaser, 2002).
Parsonnet et al, 1991; The EUROGAST Study Group, Chronic infection with H. pylori alters cell-cycle
1993; Asaka et al, 1994; Hansson et al, 1995; Huang et al, regulation and increases epithelial cell replication (Fiocca
1998), and are summarized elsewhere (Cover and Blaser, et al, 1994), despite initially enhancing apoptosis (Yanai et
1995; O'Connor et al, 1996). The identification of the al, 2003). Gastric vitamin C concentrations are decreased,
association between gastric carcinoma and H. pylori while the production of reactive oxygen species and
infection has been the most important development in reactive nitrogen intermediates is increased (Correa, 1992;
gastric cancer epidemiology, and H. pylori has been Blaser and Parsonnet, 1994; Cahill et al, 1994; Correa and
classified as a Group I carcinogen by the World Health Miller, 1998; Forman, 1998). The combination of
Organisation (WHO) (IARC, 1994). heightened proliferation with increased concentrations of
H. pylori infection results in chronic gastritis in the DNA mutagens promotes the likelihood of critical DNA
majority of infected persons (Kuipers et al, 1995; Valle et damage, and thereby the accumulation of mutations that
al, 1996), and is strongly associated with gastric atrophy drives the progression towards gastric cancer.
and intestinal metaplasia (Parsonnet et al, 1991; Kikuchi et
al, 1995; Wong et al, 1999). In humans (Craanen et al, B. Epstein-Barr virus infection
1992a; Rugge et al, 1996) and in experimental animal The human herpesvirus 4, or Epstein-Barr virus
models (Hirayama et al, 1996; Honda et al, 1998; (EBV), is an icosahedral herpesvirus containing double
Sugiyama et al, 1998; Watanabe et al, 1998), H. pylori stranded DNA that has been connected with gastric cancer.
induces the phenotypic changes of chronic gastritis, The EBV has been classified as a Group I carcinogen by
mucosal atrophy, intestinal metaplasia, and dysplasia, the WHO and IARC, and is ubiquitous in all human
which are characteristic for progression to intestinal-type populations. EBV is the cause of Burkitt’s lymphoma,
gastric cancer (Correa, 1992), and in Mongolian gerbils, sino-nasal angiocentric T-cell lympoma, Hodgkin’s
H. pylori infection causes gastric cancers (Watanabe et al, disease and nasopharyngeal carcinoma (IARC, 1997).
1998; Bergin et al, 2003). In humans, H. pylori plays a EBV-associated carcinomas are found in all geographic
role in approximately 60% of gastric cancer cases regions (Stadtländer and Waterbor, 1999), and are
(O'Connor et al, 1996), and is associated with a 2.7 to 12- approximately three-fold more frequently found in
fold risk of developing gastric cancer (Cover and Blaser, Japanese than in American populations (Watanabe et al,
1995). H. pylori infection is found in both intestinal- and 1997). EBV is associated with both intestinal- and diffuse-
diffuse-type gastric cancers (Forman et al, 1991; Nomura type gastric cancers (Shibata and Weiss, 1992), but may be
et al, 1991; Parsonnet et al, 1991; Talley et al, 1991), and more prevalent in the male than in the female (Tokunaga
the inflammatory response induced by the infection, as et al, 1993).
well as soluble products generated by H. pylori, influence The mechanism of EBV-mediated gastric
gastric carcinogenesis. Chemokines, such as interleukin-8, carcinogenesis is as yet unclear. Virus replication occurs
pro-inflammatory cytokines, such as IL-1, IL-6, and in pharynx and salivary gland epithelial cells. The
TNF!, and immunosuppressive peptides, such as IL-10, subsequent infection of lymphoid B-cells is mediated by
make up the complex network of inflammatory mediators the interaction of the gp350 viral envelope glycoprotein
involved in the host immune response to H. pylori and CD21, the C3d complement component CR2 (IARC,
infection. Polymorphisms in these genes shape the extent 1997). The viral glycoproteins gp85, gp25 and gp42 are
and magnitude of the host immune response. involved in host cell binding and viral envelope fusion,
Due to the genetic heterogeneity of the H. pylori with the virus persisting in a latent state until triggering of
genome, bacterial virulence factors also play a role in the host cell results in shedding of infectious virus
determining the outcome of a H. pylori infection. The Cag particles (IARC, 1997). Up-regulation of p53 is rarely
pathogenicity island is a large region of the H. pylori observed in EBV-positive carcinomas, but found in over
genome containing over 30 genes. Proteins encoded by 30% of EBV-negative carcinomas (Ojima et al, 1997;
this region form a Type IV secretion system, a cylinder- Chang et al, 2005) and p27 loss, p16 loss, cyclin D1
like structure that can directly transfer CagA protein into expression and NF-!B nuclear positivity are found more
gastric epithelial cells, where phosphorylation of a CagA frequently in EBV-positive gastric carcinomas (Chang et
tyrosine residue triggers signal transduction pathways and al, 2005). Despite the association of EBV infection with
induces morphological changes (Segal et al, 1999; Asahi the development of gastric carcinoma, there is no
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Carl-McGrath et al: Gastric Cancer Review
correlation with bcl-2 expression and p53 accumulation Although nitrosation is not carried out by H. pylori itself
(Gulley et al, 1996), leading to the conjecture that EBV (Vermeer et al, 2002), the interaction of N-nitroso
induces gastric carcinomas via different mechanisms than compounds with H. pylori infection may act
EBV-negative carcinomas (Ojima et al, 1997). synergistically with low vitamin C levels in causing
gastric carcinogenesis (Jakszyn et al, 2006). Indeed, the
C. Diet development of MNNG-induced adenocarcinomas in
Dietary factors play an important role in gastric animal models is enhanced by simultaneous infection with
carcinogenesis, since the presence or the introduction of H. pylori (Kodama et al, 2004).
carcinogens in food, as well as possible synthesis through A fruit and vegetable-rich diet is high in
the interaction of ingredients during preparation, may micronutrients, such as anti-oxidants and radical
contribute to the development of gastric cancer. A recent scavengers, which have a protective effect against gastric
wide-ranging prospective study into the nutritional factors cancer. The consumption of fresh fruits and vegetables is
involved in cancer (Gonzalez, 2006) has confirmed consistently associated with a reduction in risk for
previous findings that a high intake of smoked, salted and developing gastric cancer (Hu et al, 1988; Buiatti et al,
nitrated foods, high intake of carbohydrates and low intake 1989b; Kono and Hirohata, 1996; Hamilton and Aalton,
of fruit, vegetables and milk significantly increases the 2000; De et al, 2004; Jakszyn et al, 2006), particularly the
risk of developing stomach cancer (Howson et al, 1986; intestinal-type (Jakszyn et al, 2006), but may be limited by
Kramer and Johnson, 1995). In particular, regional cooking or processing (Hu et al, 1988; Buiatti et al,
variations in the consumption of dietary factors may 1989b). Folate deficiency and genetic alterations in folate-
influence the development of gastric cancer (Hu et al, metabolising enzymes increases the risk of developing
1988; Buiatti et al, 1989b; De et al, 2004;). Smoked foods gastric cancer (Larsson et al, 2006). A high intake of
may contain polycyclic aromatic hydrocarbons, which vitamin C (ascorbic acid) approximately halves the risk in
have been shown to cause gastric cancer in animal case-control studies (Neugut et al, 1996), but may require
experiments (Weisburger et al, 1986). High salt a longer duration of administration, since supplemental
consumption has been consistently associated with gastric vitamin C had no effect of the gastric cancer risk in a 5-
cancer risk (Buiatti et al, 1989a; Graham et al, 1990; year intervention trial (Blot et al, 1993). Vitamin C
Boeing et al, 1991; Hansson et al, 1993; Ramon et al, scavenges reactive radicals and may inhibit the formation
1993; Lee et al, 1995; Joossens et al, 1996; Kono and of nitroso compounds (Leach et al, 1991), thereby
Hirohata, 1996). Salt causes stomach irritation, damaging inhibiting radical-mediated DNA mutation (Drake et al,
the mucosa and leading to the development of atrophic 1996). Vitamin C, selenium, "-carotene and calcium
gastritis, as well as causing excessive cell replication and chloride have been shown to reduce the incidence of
increasing the mutagenicity of nitrosated foods (Tatematsu MNNG-induced gastric carcinomas (Kawasaki et al, 1982;
et al, 1975; Takahashi et al, 1984; Stadtländer and Kobayashi et al, 1986; Santamaria et al, 1987; Nishikawa
Waterbor, 1999). et al, 1992), and the effects of high salt intake may be
Foods high in nitrate may contribute, since the opposed by "-carotene (Stadtländer and Waterbor, 1999).
conversion of nitrate to nitrite, and the subsequent reaction Positive effects have also been reported for garlic, olive oil
with other nitrogen-containing substances, results in the and green and black tea (Buiatti et al, 1989b; De et al,
formation of N-nitroso compounds. N-nitroso compounds, 2004).
such as N-methyl-N’-nitro-N-nitrosoguanidine (MNNG),
have been demonstrated in animal experiments to be D. Lifestyle
mutagenic and carcinogenic (Druckrey, 1975; Magee et al, The relationship between alcohol consumption and
1976; Bulay et al, 1979). In the human stomach, N-nitroso smoking, and the risk of gastric cancer has been
compounds can be formed from dietary nitrate or nitrite, intensively studied. However, the results are inconclusive.
which suggests that a diet with a high intake of nitrate or In contrast to hepatocellular carcinomas, the association
nitrite may predispose to gastric cancer (Bartsch et al, between the development of gastric cancer and alcohol
1987; Kelley and Duggan, 2003; Jakszyn et al, 2006). consumption is particularly weak, and although a weak to
Patients with intestinal metaplasia, dysplasia and gastric moderate association has been found by most studies
cancer have exhibited increases in gastric nitrite (Stewart, (Nomura et al, 1990; Kabat et al, 1993; Hansson et al,
1967; Jones et al, 1978; Ruddell et al, 1978). A positive 1994; Vaughan et al, 1995), smokers may have a less than
correlation with gastric cancer has been observed for the two-fold increased relative risk, with few studies finding a
consumption of pickled foods containing nitrosated dose-response relationship (Hansson et al, 1994;
products (Sato et al, 1959; Haenszel et al, 1972), and the McLaughlin et al, 1995; Ji et al, 1996). Nevertheless,
utilization of fertilizers incorporating nitrate (Jones et al, cigarette smoke stimulates gastric cancer cell proliferation
1978; Fraser et al, 1980; Schlag et al, 1980). Additionally, (Shin et al, 2004b) and gastric adenocarcinomas have been
inadequately stored foods may facilitate the growth of induced experimentally in rats by catechol, a component
microorganisms that transform nitrate to nitrite, for of cigarette tar (Tanaka et al, 1995), which has been
subsequent endogenous nitrosation (Bartsch et al, 1992). shown to inhibit DNA synthesis (Li et al, 1997) and
The production of N-nitroso carcinogenic interfere with the elimination of transformed cells by
compounds from endogenous and exogenous sources by normal cells (Schaefer et al, 1995). Nicotine accelerates
bacteria found in the stomach (Leach et al, 1987) is tumor growth and promotes neovascularisation in an in
increased during gastritis-induced bacterial overgrowth. vivo model (Natori et al, 2003), and dose-dependently
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Cancer Therapy Vol 5, page 883
increases gastric cancer cell proliferation (Shin et al, whereas non-atrophic gastritis is more common in diffuse-
2004a), also affecting COX-2 expression, release of type carcinomas (Sipponen et al, 1994). Although atrophic
prostaglandin E2 and VEGF, and activating ERK gastritis is an early indicator of gastric cancer risk, there
phosphorylation (Shin and Cho, 2005). In the rat model of are no clear guidelines for clinical surveillance of high-
MNNG-induced carcinogenesis, long-term administration risk patient groups. Early identification of affected patients
of nicotine initiates the early development and increases may be accomplished by non-invasive screening for
the incidence rate of gastric tumours (Gurkalo and gastritis, which combines pepsinogen I, pepsinogen II and
Volfson, 1982). Additionally, production of tobacco- gastrin levels with H. pylori serology (de Vries et al,
specific nitrosamines from nicotine during burning of 2007).
tobacco or in vivo may promote cancer development (Shin
and Cho, 2005) G. Intestinal metaplasia
Exposure to workplace carcinogens may also play a Intestinal metaplasia (IM) often evolves as a
role in the development of gastric carcinoma. Exposure to response to chronic atrophic gastritis, and may be
N-nitroso compounds, as well as the nitrate and nitrogen classified into different subtypes, according to the widely-
oxide precursors, ionising radiation, crystalline silica, used Jass and Filipe system (Jass and Filipe, 1979).
organic and inorganic dusts, glycol ethers, hydraulic fluids Complete IM (small intestinal type, type I) consists of
and leaded gasoline have been suggested as occupational absorptive cells, Paneth cells and goblet cells, and can be
risk factors (Cocco et al, 1996; Parent et al, 1998), with distinguished by decreased expression of the gastric mucin
only generic dust exposure and possibly nitrosamines core proteins MUC1, MUC5AC, and MUC6, and
showing a consistent association. In general, the results are expression of the intestinal mucin MUC2 (Reis et al,
imprecise as the data is extremely limited, and no firm 1999). Incomplete IM (types II and III) coexpresses the
conclusions may be drawn. gastric mucins with MUC2, and is characterized by the
presence of columnar and goblet cells, with type II
E. Gastric surgery secreting neutral and acidic sialomucins and type III
A partial gastrectomy increases the risk of sulphomucins.
developing gastric cancer in the gastric remnant after 5-20 Intestinal metaplasia is connected with an up to 10-
years (Caygill et al, 1986; Viste et al, 1986; Lundegardh et fold increased risk of developing stomach cancer (Filipe et
al, 1988; Werner et al, 2001). In particular, the Bilroth II al, 1994), and is considered to be one of the most
operation, which increases bile reflux and leads to chronic important risk factors for the development of intestinal-
inflammation, exhibits increased incidence of dysplasia type gastric cancer (Leung and Sung, 2002). Type III IM,
(Grad, 1984). but not type I or II, is strongly associated with early and
advanced intestinal-type carcinomas, but not with diffuse-
F. Chronic gastritis type cancers or benign gastric lesions (Heilmann and
Nearly all cases of chronic gastritis result from H. Höpker, 1979; Jass and Filipe, 1979; Segura and Montero,
pylori infection (Kuipers et al, 1995; Valle et al, 1996), 1983; Rokkas et al, 1991; Craanen et al, 1992a; Craanen et
and chronic gastritis is a risk factor for the development of al, 1992b; Filipe et al, 1994). However, the association
gastric cancer, being present in the great majority of between the subtypes of intestinal metaplasia and the risk
gastric carcinoma cases (Sipponen et al, 1994). Gastric of developing gastric cancer has not been shown
acid secretion is altered by gastritis and atrophy, which conclusively (Ectors and Dixon, 1986; Ramesar et al,
results in elevated gastric pH and changed gastric flora, 1987; Petersson et al, 2002), and it has been suggested that
allowing anaerobic bacteria to colonize the stomach, intestinal metaplasia and gastric cancer may arise
increasing the production of N-nitroso compounds (Leach coincidentally (Hattori, 1986). Indeed, the extent of
et al, 1987). Additionally, gastritis is associated with atrophic gastritis is a better indicator of gastric cancer risk
increased production of oxidants and reactive nitrogen than the detection of intestinal metaplasia, and may be the
intermediates, which in combination with increased more appropriate analysis for clinical surveillance (de
expression of nitric oxide synthase (Mannick et al, 1996), Vries et al, 2007).
also increases the production of carcinogenic nitrosated
compounds. H. Gastric ulcer
The type of gastritis depends on the localization of Gastric ulcer is usually characterized by
the infection, and correlates with the clinical outcome accompanying gastritis, which may result from H. pylori
(Konturek et al, 2003). Antrum-predominant gastritis has infection. 6-20% of H. pylori infections result in peptic
high-acid secretion and an increased risk of duodenal ulceration, of which no more than one percent lead to
ulcer. The mixed antrum/corpus gastritis does not have a gastric cancer (Farthing, 1998). Although not a frequent
serious clinical outcome, as acid secretion is not affected. precursor of gastric carcinoma, the presence of gastric
Corpus-predominant gastritis is associated with gastric ulcer is moderately associated with the development of
atrophy, with the loss of acid-secreting parietal cells gastric cancers (Hole et al, 1987; Lee et al, 1990; Hansson
resulting in low acid levels, and has an increased risk of et al, 1996; Molloy and Sonnenberg, 1997).
gastric cancer. Increased severity of gastritis increases the
risk (Sipponen et al, 1994), in extreme cases up to 10-fold I. Autoimmune gastritis
(Sipponen et al, 1985). Atrophic gastritis is often One of the main causes of atrophic gastritis is
associated more with intestinal-type gastric cancers, autoimmune gastritis. The production of autoimmune
883
Carl-McGrath et al: Gastric Cancer Review
antibodies directed against parietal cells leads to the infection, being stronger in H. pylori-negative patients and
destruction of parietal cells and severe atrophy of the in diffuse-type carcinomas (Correa, 2002).
corpus mucosa. Antibodies directed against intrinsic The MUC-1 mucin is a glycoprotein involved in the
factor, and the lack of parietal cells that secrete gastric protection and lubrication of epithelial surfaces, detecting
intrinsic factor results in cobalbumin deficiency and potential external insults and interacting with signal
pernicious anemia. In patients with pernicious anemia, the transduction and cell adhesion proteins (Gendler, 2001).
risk of gastric cancer increases threefold (Hsing et al, MUC-1 contains a variable number of tandem repeats,
1993), and intestinal-type gastric cancer develops in with higher numbers of repeats encoding larger proteins
approximately 10% (Siurala et al, 1985). better able to respond to external stimuli. Gastric cancer
patients exhibit higher proportions of smaller MUC-1
J. Blood group A proteins, with smaller alleles linked to gastric atrophy and
An association between gastric carcinomas and the intestinal metaplasia (Carvalho et al, 1999; Correa, 2002).
blood group A has been reported (Aird et al, 1953;
Haenszel et al, 1976), which may be related to the VI. Hereditary syndromes
interaction between the Lewisb blood group antigen and H. Although most gastric carcinomas arise sporadically,
pylori (Carneiro et al, 1996). The association of the blood inherited familial genetic components are responsible for
group A with males, with diffuse-type gastric cancer is 8-10% of gastric cancer cases (Uemura et al, 2001). An up
stronger than with females, or intestinal-type gastric to threefold increase in risk of developing gastric cancer
cancer (Nomura, 1982; Kramer and Johnson, 1995). has been reported for relatives of gastric carcinoma
patients (Zanghieri et al, 1990; La Vecchia et al, 1992;
K. Gene polymorphisms Palli et al, 1994), which is associated with hereditary and
In recent years, genetic polymorphisms have come to environmental factors (Lichtenstein et al, 2000).
be recognized as crucial factors determining disease
susceptibility. Host gene polymorphisms frequently A. Hereditary diffuse gastric carcinoma
influence the magnitude of the host response, and this Familial diffuse gastric cancer is an autosomal
interindividual variation contributes to the clinical dominant inheritable disease, usually developing at an
outcome. The development of gastric cancer in a milieau early age (Huntsman et al, 2001). Germline mutations in
of chronic inflammation induced by H. pylori may be the E-cadherin (CDH1) gene generally result in truncated
significantly influenced by host gene polymorphisms. proteins, and lead to gastric cancer in 75% of patients
The proinflammatory cytokine interleukin-1 (IL-1) (Caldas et al, 1999), with an age of onset and diagnosis
gene cluster containing IL-1! and IL-1RN encodes IL-1" between 14 and 69 years. These tumors referred to as
and the IL-1" receptor antagonist, respectively, and the hereditary diffuse gastric carcinomas, and manifest as
risk of gastric cancer and its precursor lesions is increased diffuse, poorly differentiated adenocarcinomas with an
in the presence of H. pylori by polymorphisms in these infiltrative growth pattern, perhaps containing signet-ring
genes. An increased risk of developing H. pylori-mediated cells (Gayther et al, 1998; Guilford et al, 1998; Guilford et
hypochlorhydria and gastric atrophy is associated with the al, 1999). Additionally, methylation of the CDH1 gene
IL-1B-31*C or -511*T, and the IL-1RN*2/*2 genotypes promoter has also been reported to lead to hereditary
(El-Omar et al, 2000). These genotypes are also associated diffuse gastric carcinoma (Stone et al, 1999).
with a two- to three-fold increase in the risk of developing
gastric cancer, compared to individuals with less B. Hereditary nonpolyposis colorectal
proinflammatory genotypes (El-Omar et al, 2000,2003;
cancer
Figueiredo et al, 2002). Although a range of studies have
Hereditary nonpolyposis colorectal cancer (HNPCC)
reported lower risks, recent meta-analyses have supported
results from an underlying defect in DNA mismatch
the findings of the higher risk of the IL-1B-511*T, and the
repair, mainly involving the hMLH1, hMSH2, and the
IL-1RN*2 genotypes, particularly in association with
hMSH6 genes (Kinzler and Vogelstein, 1996; Peltomaki,
ethnic group and tumour type (Camargo et al, 2006;
2001). Although chiefly causing colorectal cancer, this
Kamangar et al, 2006; Wang et al, 2007).
inherited cancer susceptibility syndrome also results in
Although IL-1" is one of the most important
gastric cancers (Lee, 1971), usually of the intestinal-type,
proinflammatory cytokines mediating the effects of H.
with no accompanying H. pylori infection, and exhibiting
pylori infection (El-Omar et al, 2000), polymorphisms in
microsatellite instability (Lynch et al, 1993).
other proinflammatory cytokines, such as TNF# (308*A)
and IL-10 (ATA/ATA), have also been associated with
increased risk for gastric cancer (El-Omar et al, 2003). The C. Polyposis syndromes
more proinflammatory genotypes an individual has, the Rarely, gastric cancers also occur in gastrointestinal
higher the risk of developing gastric cancer (Figueiredo et polyposis syndromes, such as familial adenomatous
al, 2002). Gastric cancer and H. pylori infection has been polyposis (FAP) and Peutz-Jeughers Syndrome (PJS). A
linked with the human leukocyte antigen (Magnusson et higher risk of gastric cancer is associated with both FAP
al, 2001), with the *1601 allele significantly increasing the (Groden et al, 1991; Hofgartner et al, 1999) and PJS (Park
risk of gastric cancer (odds ratio 8.7; 95% CI 2.7-28). This et al, 1998). The involvement of the germline mutations of
association is seemingly independent of H. pylori the adenomatous polyposis coli (APC) or the
serine/threonine kinase 11 (STK11) genes, respectively,
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Cancer Therapy Vol 5, page 885
and the accompanying polyposis in the development of presence of distant metastases, with high serum levels
gastric adenocarcinoma is as yet uncertain. (>129pmol/l) correlating with a reduced survival rate
(Ebert et al, 2005). Furthermore, we provided evidence
VII. Prognosis that an insertion/deletion polymorphism in the angiotensin
The prognosis of gastric cancer depends on various I-converting enzyme gene influences tumor progression
pathological factors, such as the macroscopic type, the and metastatic behaviour in gastric cancer (Röcken et al,
depth of invasion, cancer-stromal relationship, histological 2005). The influence of further molecular genetic
growth pattern, lymph node involvement, lymphatic alterations on the prognosis of gastric cancer is currently
invasion, vascular invasion and tumour site (Yokota et al, the subject of numerous investigations (Becker et al, 2000;
2004), with the main prognostic factors being the TNM Oue et al, 2004; Yasui et al, 2005).
staging, along with the presence and extent of lymph node
metastases. Diagnostic improvements and advances in VIII. Molecular pathogenesis of
treatment options have improved the long-term survival of gastric cancers
early gastric cancer patients. Prognosis is correlated with A long-lasting chronic inflammation, often caused by
the tumour staging, worsening as the degree of infiltration viral or bacterial infection, initiates a cascade of reactive
increases (Lello et al, 2007). The 5-year survival rates in changes, which ultimately leads to the development of
stages Ia, Ib, II, IIIa, and IIIb/IV are 91%, 64%, 27%, cancer. It is generally believed that an ordered sequence of
18%, and 0%, respectively (Lello et al, 2007), with the genomic changes is reflected in the morphological and
survival rate of patients with early gastric cancers invading pathological transformation observed during the
but limited to the mucosa or submucosa being 90-100%, ‘precancerous cascade (Correa, 1992), whereby normal
compared to 60-80% for tumours reaching the muscularis gastric tissue progresses through precancerous lesions to
propria, and 41-50% for tumours limited to the subserosa well-differentiated carcinoma, which then further evolves
or serosa (Antonioli, 1994; Yoshikawa and Maruyama, to a less-differentiated form. Although the molecular
1985; Tanaka et al, 2004; Lello et al, 2007). However, the pathogenesis of gastric cancer during the ‘precancerous
prognosis of advanced gastric cancer remains poor, with cascade’ is not well known, the ‘adenoma-carcinoma
survival rates lower than 23% (Tanaka et al, 2004) and sequence’ is exemplified in the pathogenesis of colon
rarely exceeding 15% (Stewart and Kleihues, 2003). The carcinoma (Vogelstein et al, 1988), and can also be
depth of infiltration correlates with the presence of lymph observed, in a less well-defined way, in some intestinal-
node metastases, and the presence of regional lymph node type stomach cancers, and to a certain extent in diffuse-
metastases reduces the 5-year survival rate of early gastric type stomach cancer (Tahara, 2004). However, although
cancer patients from 90% to 70% in tumours invading the the progression to diffuse-type gastric cancer is
submucosa (Antonioli, 1994; Inoue et al, 1991). The morphologically similar and encompasses some of the
lymph node status and the ratio of metastasis- same molecular changes, evidence is lacking for an
positive/metastasis-negative lymph nodes are the strongest equivalent sequence of genetic events, despite the
markers of gastric cancer prognosis (Ichikura et al, 1999; common development on a background of increased
Yokota et al, 2004), and the N-ratio (metastatic/examined regenerative processes. The established sequence of
lymph nodes) has been validated as an independent molecular events that occur during the development of
prognostic factor in a large multi-centre series, even where intestinal- and diffuse-type gastric cancers is shown in
less than the recommended 15 lymph nodes have been Figure 2, and has been reviewed elsewhere (Tahara, 2004;
examined (Marchet et al, 2007). The 5-year survival rate Yasui et al, 2005).
for patients with metastases in 1-6 lymph nodes is 44%, The most common changes, whether genetic or
and drops to 30% for 7-15 lymph node metastases, ending epigenetic, that occur during the development from
with 11% for more than 15 lymph nodes metastases. The inflammation to carcinoma are clustered at genes involved
N-ratio classifications 0, 1, 2, and 3 exhibit 5-year survival in cellular regulatory pathways. The four main pathways
rates of 83.4%, 66.3%, 468%, and 19.0%, respectively. described below are interrelated and are not considered to
Unfortunately, most patients presenting with advanced be independent, as the components interact to provide a
gastric cancer already have lymph node metastases. coordinated control of cellular growth and proliferation.
Other prognostic factors include lymphatic and The p53 pathway regulates the cellular response to
vascular invasion, both being associated with lower abnormal oncogene expression and DNA damage,
survival rates (Hamilton and Aalton, 2000; Yokota et al, inducing either cell cycle arrest to permit DNA repair, or
2004), and the histological classification, whereby diffuse- apoptosis. Under physiologic conditions, p53 protein
type (Lauren classification) and mucous-rich (Goseki forms a complex with mdm2 protein, which promotes
classification) tumours may predict a worse prognosis rapid degradation of p53. Inhibition of this process leads
(Martin et al, 1994; Songun et al, 1999; Hamilton and to accumulation and functional activation of p53, inducing
Aalton, 2000). cell cycle arrest via the actions of p21. Genetic mutation of
In addition to the identification of reduced E- p53 occurs at a very high frequency in tumors of different
cadherin expression as an indicator of poor prognosis origin, including stomach (60%) (Tahara, 2004). Although
(Chan et al, 2001; Shimada et al, 2004), our own studies mutation of p53 is an early occurrence during gastric
have shown that the serum level of cathepsin B is carcinogenesis, p53 expression is rarely exhibited by early
increased in patients with gastric cancer compared to gastric lesions, but increases during the progression of
healthy controls, and correlates with T-category and the
885
Carl-McGrath et al: Gastric Cancer Review
gastric cancer (Feng et al, 2002). p21 genetic alterations phosphorylation of "-catenin, which is then degraded by
have not been found in gastric carcinomas (Tahara, 2004). the proteosome system. "-catenin also interacts with E-
The RB1 (retinoblastoma) pathway genes are cadherin, strengthening the structural integrity of epithelial
involved in the regulation of the G1 phase of the cell tissues. APC has a high frequency of mutation in intestinal
cycle. Following phosphorylation of Rb1 protein by cyclin type gastric (40-60%) cancers, which rarely occurs in
D/CDK4 complex, E2F transcription factors are released diffuse-type gastric carcinomas (Tahara, 2004). "-catenin
from Rb1, and DNA synthesis is initialized. p16 mutations occur quite frequently in intestinal-type (27%),
competitively inhibits the formation of the cyclin D/CDK4 but rarely in diffuse-type stomach cancer (Park et al,
complex, and, as a result, also the passage through the G1 1999). Mutations in E-cadherin have been detected in 50%
phase of the cell cycle. Gene amplification or over- of diffuse-type, but not at all in intestinal-type gastric
expression of cyclin D has not been detected in any gastric cancers (Tahara, 2004). Reduced expression of the E-
carcinomas (Yoshida et al, 1993), whereas reduced cadherin gene may also be due to hypermethylation of the
expression of p16 in about 47% of gastric cancers promoter (Tamura et al, 2000).
(Mattioli et al, 2007) is assumed to be due to As can be seen above, the actual pathway
hypermethylation of the promoter and related to components affected vary. Different combinations of
microsatellite instability (Shim et al, 2000). mutations are encountered in different patients, often in
The TGF" (transforming growth factor ") pathway tumors of the same type, and correspond to cancers that
contains genes involved in growth inhibition and react differently to treatment. Very few genes are changed
apoptosis, such as mannose-6-phosphate/insulin-like in the same way in a range of cancer types, and the pattern
growth factor 2 receptor (M6P/IGF2R), Smad2 and 4, and of genomic alterations leading to carcinogenesis shows
TGF-"R2. The TGF-"R2 gene is particularly susceptible great variability, with each cancer being characterized by
to microsatellite instability, and is mutated in 68% of its own array of genetic lesions. Despite the identification
gastric cancers with this feature (Pinto et al, 2003). of many oncogenes and tumor suppressor genes, there is
The APC (adenomatosis polyposis coli) "-catenin still a great need for the detection of further genes
pathway is responsible for cell-cell interaction, involved in fundamental cellular pathways, which may be
morphogenesis, and signal transduction. The APC protein commonly altered in the progression from inflammation to
in association with GSK-3" and axin induces gastric cancer.
Figure 2. The multi-step molecular pathogenesis of gastric cancer. The multistage process of gastric carcinogenesis is characterized by
the accumulation over time of various genetic and epigenetic alterations accompanying the cascade of pathological alterations. Well
differentiated or intestinal-type adenocarcinomas exhibit a different profile of alterations than poorly differentiated or diffuse-type
gastric cancer. Reproduced from Yasui et al, 2005 with kind permission from Gastric Cancer).
886
Cancer Therapy Vol 5, page 887
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