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Solid Tumour Section
Review
Gastric Tumors: an overview
Paul Lochhead, Emad El-Omar
Gastrointestinal Research Group, Division of Applied Medicine, School of Medicine and Dentistry,
Aberdeen University, Aberdeen AB25 2ZD, Scotland, UK (PL, EEO)
Published in Atlas Database: November 2008
Online updated version : http://AtlasGeneticsOncology.org/Tumors/GastricTumOverviewID5410.html
DOI: 10.4267/2042/44596
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2009 Atlas of Genetics and Cytogenetics in Oncology and Haematology
- Rare tumours
- e.g. Sarcomas, neuroendocrine carcinoma,
primary squamous cell carcinoma and
adenoacanthomas
Identity
Note
The vast majority of both benign and malignant
tumours of the stomach are of epithelial origin, with
mesenchymal and neuroendocrine tumours being much
less common. Gastric adenocarcinoma comprises in
excess of 95% of malignant neoplasms of the stomach,
and is thus the focus of this overview. Primary gastric
lymphoma is the second commonest malignancy
affecting the stomach with gastrointestinal stromal
tumours (GISTs) and rare tumours, such as carcinoids,
accounting for the remainder of cases.
Clinics and pathology
Disease
Benign Gastric Polyps
Note
Benign gastric polyps are found incidentally in 2-3% of
upper gastrointestinal endoscopies. Their incidence
increases with patient age. Small polyps are almost
always asymptomatic. Larger polyps may bleed due to
erosions or ulceration. Very large distal polyps may
produce obstructive symptoms.
Small hyperplastic and fundic gland polyps are
relatively common. They are generally regarded as
being of no significance although multiple fundic gland
polyps with evidence of dysplasia can occur in familial
adenomatous polyposis (FAP). Fundic gland polyps
and, to a lesser extent, hyperplastic polyps, occur with
increased frequency in patients on long-term proton
pump inhibitor therapy.
Inflammatory fibroid polyps (IFPs) are uncommon
solitary lesions that arise in the distal stomach. They
usually originate submucosally however the overlying
mucosa commonly develops erosions or ulceration.
IFPs are felt to be reactive in nature and are composed
of a mixture of proliferating fibroblasts, blood vessels
and inflammatory cells. Eosinophils are often present.
Helicobacter pylori has been implicated in the etiology
of IFPs as have chemical and mechanical irritants.
Adenomatous polyps in the stomach usually arise
against a background of chronic atrophic gastritis with
intestinal metaplasia although they too can occur in
FAP. Gastric adenomata are composed of dysplastic
Classification
Benign Tumours
Neoplastic
- Epithelial adenomas
- Fundic gland polyps
- GISTs
- Lipomas
- Leiomyomas
- Neural tumours (e.g. Schwannomas)
Non-Neoplastic
- Hyperplastic polyps
- Inflammatory fibroid polyps
- Hamartomatous polyps
- Juvenile
- Peutz-Jegher's Syndrome
- Cowden's Syndrome
Malignant Tumours
- Adenocarcinoma
- Primary gastric lymphoma
- GISTs
- Metastatic deposits
- Carcinoids
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Lochhead P, El-Omar E
gastric cancer. It is estimated that over 17% of gastric
cancers in Europe are directly attributable to cigarette
smoking.
epithelium with tubular and/or villous architecture.
Polyp size and the grade of dysplasia are felt to be
predictors of progression to carcinoma. Because gastric
adenomata, like those in the colon, represent a premalignant condition, excision (usually possible
endoscopically) is the treatment of choice.
Epidemiology
Gastric cancer is the second most common cause of
cancer-related death globally. Although the incidence
of gastric cancer has fallen significantly in most
countries over the past 70 years, the global incidence is
predicted to rise as a result of population growth. There
are marked geographical variations in the incidence of
gastric cancer. The highest incidence is found in
Eastern Asia, Eastern Europe and South America. In all
populations studied thus far, there is a male
preponderance in gastric cancer incidence with an
average male to female ratio of 2:1.
Disease
Gastric adenocarcinoma
Etiology
Helicobacter pylori
H. pylori is the single most important etiological agent
in the pathogenesis of gastric cancer. Numerous
epidemiological studies have demonstrated an
association between serological evidence of H. pylori
infection and gastric cancer risk. The conclusion of
several meta-analyses of these data is that chronic H.
pylori infection confers around a two-fold increase in
the risk of developing gastric cancer. H. pylori strains
expressing the cytotoxin-associated gene A antigen
(CagA) are associated with a further two-fold increase
in gastric cancer risk. The association with H. pylori
appears strongest for non-cardia gastric cancer, but
applies to both intestinal and diffuse histological
subtypes.
With respect to cancer of the gastric cardia, recent data
suggest that there are two distinct etiological subtypes:
one arising in the context of severe atrophic gastritis
and akin to non-cardia cancer, and a second arising in
non-atrophic mucosa, associated with gastrooesophageal reflux disease and resembling oesophageal
adenocarcinoma.
Host Genetics
Individual differences in the inflammatory response to
H. pylori infection, as determined by host genetic
polymorphisms, may predispose to the development of
a gastric cancer phenotype. Pro-inflammatory
polymorphisms have been described in the interleukin1 gene cluster, and tumour necrosis factor-alpha,
interleukin-10, interleukin-8, and interferon-gamma
genes. Having an increasing number of such proinflammatory genetic polymorphisms confers an
increased gastric cancer risk for an H. pylori-infected
individual.
Diet and Smoking
It has been postulated that diets rich in fruit and
vegetables are associated with a reduced risk of
gastric cancer. To date, data from large prospective
studies do not bear this out. Similarly, there are
conflicting data regarding the increased risk associated
with dietary salt and nitroso compound intake.There is
a dose-dependent relationship between smoking and
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(10)
Clinics
Early gastric cancer is most likely asymptomatic in
most patients, or may produce non-specific dyspeptic
symptoms. Alarm symptoms such as anorexia, weight
loss, dysphagia or gastrointestinal haemorrhage usually
betray advanced disease.
Pathology
Historically, gastric cancers were classified according
to the Laurén classification as being of either intestinal
or diffuse histological type. The pathogenesis of
intestinal type gastric cancer has been defined as
following a pathway from atrophic gastritis, through
intestinal metaplasia and dysplasia, to frank
malignancy. No such pathogenic sequence of
progression exists for diffuse type gastric cancer. More
recently, gastric cancers have been classified
anatomically as either cardia or non-cardia in origin.
Treatment
Resection with curative intent is the only treatment that
will result in long-term survival from gastric
adenocarcinoma.
Palliative
and
neo-adjuvant
chemotherapy improve survival in selected patients.
Prognosis
In Western countries, 90% of gastric cancers are
inoperable at presentation and thus 5-year survival rates
at are low. In Japan, where population-based screening
takes place, 5-year survival exceeds 50%.
Disease
Primary gastric lymphoma
Note
The vast majority of primary lymphomas arising in the
stomach are of non-Hodgkin's B-cell type.
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Gastric Tumors: an overview
Lochhead P, El-Omar E
Photomicrograph of a poorly differential intestinal type adenocarcinoma of the stomach. (Courtesy of Prof G Murray, Dept. of Pathology,
University of Aberdeen).
Recent series have demonstrated that low-grade
marginal zone lymphomas of mucosa-associated
lymphoid tissue (or MALT lymphomas) account for
over 50% of cases of primary gastric lymphoma.
Historically the predominant histological type was
diffuse large B-cell lymphoma (DLBCL).
H. pylori negative, or have nodal disease may be
treated in a similar manner to other lymphomas with
the use of systemic chemotherapy (e.g. CHOP),
immunotherapy (e.g. Rituximab) and/or radiotherapy
for localized disease. There is no evidence that surgery
is superior to medical therapy alone although surgical
intervention may be appropriate in specific scenarios
such as gastric outlet obstruction.
Etiology
The gastric mucosa is normally devoid of lymphoid
tissue. H. pylori is implicated as an etiological agent in
over 92% of cases of gastric MALT lymphoma.
Chronic H. pylori infection results in a lymphoid
follicular gastritis and so to the acquisition of gastric
MALT. MALT lymphomagenesis is thought to be
dependent on clonal expansion driven by H. pylori
antigenic stimulation. The mechanisms involved in the
transformation of low-grade gastric MALT lymphoma
to high grade DLBCL are not well understood.
Prognosis
The response of low grade MALT lymphoma to H.
pylori eradication is predicted by stage. Complete
response is achieved in all patients where disease is
limited to the gastric mucosa or submucosa. Complete
response rates fall where disease extends to the
muscularis or serosa, and no patients with nodal disease
achieve complete response with H. pylori eradication
alone.
The presence of the cytogenetic aberration
t(11;18)(q21;q21) predicts lack of response to H. pylori
eradication and is found frequently in H. pylori
negative MALT lymphomas. Strong nuclear expression
of BCL10, associated with t(1;14)(p22;q32), is also
associated with lack of response to antibiotic therapy.
Clinics
Patients with primary gastric lymphoma may present
with non-specific dyspeptic symptoms, early satiety, or
evidence of gastrointestinal haemorrhage due to
ulcerating disease. Systemic symptoms may be present
in advanced stage disease.
Disease
Pathology
Gastrointestinal Stromal Tumours
Note
Gastrintestinal stromal tumours (GISTs) are the
commonest mesenchymal tumours of the GI tract. They
are defined by the expression of CD117 (c-KIT), a
receptor tyrosine kinase. Gain-of-function mutations in
KIT or the platelet derived growth factor alpha gene
PDGFA) are critical to GIST tumourigenesis. Around
60% of GISTs arise in the stomach and approximately
25% of gastric GISTs display clinically malignant
behaviour. GISTs, however, account for only 1-3% of
malignant tumours of the stomach.
MALT lymphomas display cellular heterogeneity.
Lymphoid follicles may be present with tumour cells
located in the marginal zone. Lymphoepithelial lesions
are typical in gastric MALT lymphoma. Staging, using
a modified Ann Arbor system, can be achieved using
endoscopic ultrasonography.
Treatment
Eradication of H. pylori using standard antibiotic
regimens results in complete response in around 75%
of patients with limited stage MALT lymphoma.
Patients who fail to respond to antibiotic therapy, are
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Most GISTs are sporadic although a small percentage
occur in the context of neurofibromatosis type 1 and
the very rare Carney triad (in association with
functioning
extra-adrenal
paragangliomas
and
pulmonary chondromas).
Cytogenetics
Cytogenetics Morphological
Numerous abnormalities of chromosome structure and
number have been reported in gastric cancer series
although no specific aberration has yet been identified.
Those chromosomes most commonly involved in
simple numerical aberrations include X, Y, 1, 7, 8, 9,
17 and 20. Polysomy for chromosome 17 has been
reported to be associated with lymphovascular invasion
and nodal metastases.
Conventional cytogenetic analysis of 15 gastric cancers
using G-banding revealed structural aberrations most
commonly involving chromosomes 1, 11, 14, 7, 17, 6,
8 and 13. The aberration add(11)(p15) was found in
five of the cancers analysed.
Multicolour spectral karyotyping has been employed to
identify recurrent chromosomal rearrangements in
gastric cancer cell lines. Chromosome 8 was most
commonly involved in rearrangements. Recurrent
translocations, frequently involving known oncogene
and tumour-suppressor gene loci, were identified with
breakpoints most frequently occurring at bands 8q24
and 11q13.
Clinics
Small GISTs may be asymptomatic or found
incidentally at upper GI endoscopy. Acute or chronic
gastrointestinal haemorrhage, due to ulceration of the
gastric mucosa superficial to a GIST, is the commonest
clinical presentation. Large GISTs may produce
symptoms of gastric outlet obstruction or present with
pain/dyspepsia, early satiety and nausea.
Pathology
Gastric GISTs are highly cellular and tend to be of
either spindle cell or epithelioid subtypes. The
distinction between benign and malignant GISTs is not
clear-cut, rather they display a spectrum of biological
behaviour. Mitotic index, size and the use of
immunohistochemical proliferation markers may give
an indication of the malignant potential of a GIST.
Treatment
Surgical resection is the treatment of choice for GISTs.
There are favourable trial data supporting the use of the
tyrosine kinase inhibitor, Imatinib, in patients with
metastatic or unresectable GISTs.
Cytogenetics Molecular
Comparative genomic hybridization has been used to
screen for abnormalities of copy number in gastric
cancers. In a study of 62 gastric adenocarcinomas, and
6 cell lines, 84% of tumours and all of the cell lines
showed changes in DNA copy number. Specific
patterns of allelic gains and losses appeared to correlate
with different histopathological and disease-related
features, such as metastases.
Loss of heterozygosity (LOH) studies in gastric
adenocarcinomas have shown high LOH at
chromosome arms 1p, 3p, 4p, 5q, 7p, 8p, 9p, 12q, 13q,
17p, 18q and 22q. The intratumoural distribution of
LOH between early and advanced gastric cancer has
been compared, and suggests that multiple losses occur
as an early event in tumorigenesis with a few sporadic
losses occurring later in disease progression.
Disease
Gastric Carcinoid
Note
Gastric carcinoid tumours are rare, comprising only
0.5% of gastric tumours. They arise in the oxyntic
mucosa of the gastric corpus and fundus and are
comprised of non-functioning enterochromaffin-like
cells. Gastric carcinoid tumours may be sporadic or can
occur in the context of autoimmune atrophic gastritis,
Zollinger-Ellison syndrome and in the MEN-1
syndrome. Carcinoid tumours over 2cm in size are
associated with an increased risk of lymphovascular
invasion and metastasis, and resection is recommended.
Genes involved and proteins
Genetics
CDH1
Note
Around 10-15% of gastric cancers are familial.
Hereditary diffuse gastric cancer (HDGC) is a highly
penetrant autosomal dominant condition with an
average age at diagnosis of 38 years. Around one third
of families have inactivating mutations in the Ecadherin gene. Increased gastric cancer risk is observed
in a number of dominantly-inherited cancer
predisposition
syndromes
including
hereditary
nonpolyposis colon cancer (HNPCC), familial
adenomatous
polyposis
(FAP),
Peutz-Jegher's
syndrome and in BRCA2 mutation carriers.
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(10)
Location
16q22.1
Protein
CDH1 encodes E-cadherin, a member of the cadherin
superfamily of calcium-dependent cell adhesion
molecules. Downregulation of E-cadherin is observed
in a number of epithelial-derived human cancers and
promotes invasion through loss of epithelial cell-cell
adhesion.
Germinal mutations
Approximately 30-40% of HDGC kindred harbour
germ line mutations in CDH1.
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protein appears to interact with the MET protein
leading to activation.
Somatic mutations
Somatic mutations are found in more than 50% of
diffuse type gastric cancers but are not found in the
intestinal histological type. There is a significant rate of
LOH for CDH1 in sporadic gastric cancers (SGCs) of
both histological types. Downregulation via promotor
hypermethylation, along with mechanisms acting at
transcriptional and post-transcriptional level, may act
as the "second hit" in both inherited and sporadic
diffuse cancers.
APC
Location
5q21-q22
Protein
The APC tumour suppressor protein is a key
component of the WNT / Beta-catenin signalling
pathway.
Germinal mutations
Gastric fundic gland polyps are observed as an
extracolonic feature of FAP. Occasional malignant
transformation has been reported.
Somatic mutations
Whilst somatic APC mutations are common in gastric
cancers, their significance with regards to
tumorigenesis remains unclear. It has been postulated
that APC mutations play a role in adenoma formation
and dysplasia, rather than the promotion of malignant
progression.
C-MYC
Location
8q24.12-q24.13
Protein
The C-MYC proto-oncogene encodes a transcription
factor involved in activation of a number of genes
involved in cell proliferation.
Somatic mutations
C-MYC amplification/overexpression has been
described in around 16% of SGCs. Allelic gain through
chromosome 8 polysomy has been suggested as an
important mechanism of C-MYC amplification in
SGCs. C-MYC locus amplification is associated with
increased aggressiveness and metastasis in intestinaltype tumours.
TP53
Location
17p13.1
Protein
The transcription factor p53 plays a critical role in cell
cycle arrest, senescence, DNA repair and apoptosis.
Germinal mutations
Although not one of the classical Li-Fraumeniassociated neoplasms, early onset gastric cancers occur
uncommonly in Li-Fraumeni Syndrome (LFS) kindred.
Case reports exist of familial gastric cancer in Japanese
and Korean families with germ line p53 mutations. It
has been suggested that LFS may give rise familial
clustering of gastric cancer in regions with high gastric
cancer incidence.
Somatic mutations
Loss of functional p53 has been reported in virtually all
human cancers including gastric cancers. Data on the
significance of p53 mutations in SGC development,
progression, and prognosis are conflicting.
C-ERBB2
Location
17q21.1
Protein
C-ERBB2 (HER2) encodes p185, a tyrosine kinase cell
surface receptor structurally similar to human
epidermal growth factor receptor (EGFR). The protein
conformation of p185 permanently resembles the
ligand-bound state of EGFR. p185 is a potential target
for trastuzumab (Herceptin) therapy.
Somatic mutations
C-ERBB2 is amplified/overexpressed in 8-30% of
gastric cancers. C-ERBB2 expression is more common
in intestinal type tumours and is a marker of invasion
and metastasis. Somatic mutations within the kinase
domain have been reported in gastric cancers as well as
other solid tumours.
FGFR2
Location
10q26
Protein
K-SAM encodes the fibroblast growth factor receptor
2.
Somatic mutations
The oncogene K-SAM is amplified/overexpressed in
approximately 50% of diffuse type gastric cancers but
not in the intestinal histological type.
C-MET
Location
7q31
Protein
The MET proto-oncogene encodes a transmembrane
high affinity receptor for hepatocyte growth hormone.
Germinal mutations
A small number of case reports exist of germ line
mutations in MET predisposing to gastric cancer.
Somatic mutations
Overexpression of C-MET has been reported in both
histological subtypes of gastric cancer and is associated
with poor prognostic features. The H. pylori CagA
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(10)
COX2
Location
1q25.2-q25.3
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Lochhead P, El-Omar E
cases of HNPCC. HNPCC confers a 5% lifetime risk of
gastric cancer.
Somatic mutations
Micosatellite instability (MSI) is the hallmark of
defects in the MMR system. Around 15% of SGCs
show MSI, most frequently due to hypermethylation of
the MLH1 promoter. Recent data suggest that
mutations in known MMR genes in SGCs are
uncommon and likely arise as a result of the mutator
phenotype, rather than cause it.
Note
COX2 is upregulated in 49-83% of gastric cancers.
COX2 expression is particularly high in early gastric
cancers suggesting that it may play an important role in
early events in tumorigenesis. There is conflicting
evidence on the association between H. pylori and the
induction of COX2 in gastric cancer.
Protein
Cyclo-oxygenase 2 is an inducible enzyme responsible
for regulating prostaglandin biosynthesis. COX2
activity is normally undetectable in gastric mucosa.
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Location
1p36
Protein
The runt-related transcription factor 3 acts as a tumour
suppressor protein.
Somatic mutations
Silencing of RUNX3 has been reported in up to 60% of
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10q23.31
Protein
The "phosphate and tensin homolog" acts as a tumour
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DNA mismatch repair (MMR) enzymes.
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