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Gastric Cancer
Core Curriculum Lecture: Mamie Dong, Pradipta Ghosh
February 16, 2010
I. Introduction:
• 95% of gastric cancers are adenocarcinomas.
• The remaining 5% are lymphomas (second most common, includes MALT
lymphomas), sarcomas (including leiomyosarcomas and Kaposi’s sarcomas),
GISTs, carcinoids, and squamous cell carcinomas
• 2 distinct histologic subtypes of gastric adenocarcinomas: intestinal, diffuse
(discussed in more detail later)
Intestinal type – retained glandular structure, more localized
Diffuse type – no glandular structures, more spread out
Gastric Adenocarcinoma
II. Epidemiology
• Cancer status
Worldwide: 4th most common cancer, 2nd leading cause of cancer death
In the US: 14th most common cancer, 7th most common cancer death
Incidence of intestinal type has declined rapidly over the recent few
decades ? due to invention of refrigerators, with better food storage and
reduced need for salt-based preservation.
Incidence of diffuse type has declined more gradually
Incidence of distal gastric cancers has decreased, but proximal (cardia)
cancers have increased (some propose that these cancers are a separate
entity, more closely resembling Barrett’s associated esophageal
adenocarcinoma).
• Cancer Geography
Diffuse type has similar frequencies in all geographic locations
Intestinal type:
♦ Highest incidence in Eastern Asia, Andean regions of South
America, and Eastern Europe
♦ Lowest rates are in North America, Northern Europe, Africa,
Southeast Asia
♦ Higher geographic latitudes are associated with higher risk
♦ Migration studies of patients born in high risk countries and
moving to low risk countries shows that the risk is diminished but
still significantly higher than those who are ethnically from a high
risk country but born in a low risk country, indicating that early
environmental exposure, rather than genetic factors, have a greater
influence on risk.
• Race – In the US, Asian and Pacific Islanders have the highest incidence,
followed by black, Hispanic, white, and American Indian
• Gender
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Intestinal type is more common in males, 2:1 ratio worldwide
Diffuse type is equally distributed between males and females
• Age – Median age in the US at diagnosis is 70 for men and 74 for women
III. Brief Review of Gastric Anatomy
IV. Pathophysiology and Genetics
• Intestinal type – sequence of molecular events is incompletely understood, but
there seems to be s stepwise progression of neoplastic stages
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There may be temporary episodes of spontaneous regression to a less
advanced stage, though overall there is stepwise progression
Chronic Chronic Intestinal Dysplasia Carcinoma
Gastritis Atrophic Gastritis Metaplasia
Many Allows colonization of bacteria capable of converting
Loss of chief and dietary nitrates to mutagenic N-nitroso compounds
patients
parietal cell mass
remain at
this stage Increase in serum gastrin, which is a potent inducer of
Hypochlorhydria gastric epithelial cell proliferation
Decrease in luminal vitamin C, which is an
antioxidant
Non-atrophic gastritis predominates in the gastric antrum
♦ Presence of PMNs correlates closely with active colonization by
H.pylori
Chronic atrophic gastritis – loss of gastric glands
♦ This is the first histopathologic lesion of the preneoplastic cascade
Intestinal metaplasia
♦ Abnormal glands first appear at the junction of the antrum and
corpus, particularly in the incisura angularis
♦ Over time, foci of metaplasia becomes larger and more numerous
♦ Initially, glands resemble those in the small intestines (multiple
microvilli, mucus-producing goblet cells) – this is Type I or
complete
♦ At more advanced stages, glands resemble those in the colon – this
is Type II or incomplete, also called colonic metaplasia
Dysplasia
♦ Western definition - dysplastic cells which do not penetrate the
basement membrane
◊ Rate of progression from low grade dysplasia to carcinoma
is 0-23%
◊ Rate of progression from high grade dysplasia to carcinoma
is 60-85%
♦ Japanese definition – there is no specific lesion called “dysplasia”
◊ Western definition of low grade dysplasia would be termed
“adenoma” by the Japanese
◊ Western definition of high grade dysplasia would be termed
“carcinoma” by the Japanese
Invasive Carcinoma
♦ Western definition – atypical cells invading the stroma
♦ Japanese definition – atypical cells in any location
Genetics – complicated and not well defined
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♦ Oncogenes – K-ras, c-met
♦ Tumor suppressor genes – p53, APC, TFF
♦ Cell cycle regulatory molecules – cyclin E, p27
♦ Morphogenesis regulatory molecules – beta-catenin/Wnt signaling
♦ Cancer cells may actually be migrating bone marrow derived cells
rather than gastric epithelial cells
• Diffuse type – main carcinogenic event is loss of expression of E-cadherin, a key
cell surface protein for establishing intercellular connections
CDH1 gene mutations are found in 50% of diffuse type cancers
Hypermethylation of the E-cadherin tumor promoter may be present in
>80% of tumors that lack specific mutations in CDH1
Hereditary Diffuse Gastric Cancer
♦ Autosomal dominant, very high penetrance
♦ Lifetime cumulative risk is 40-67% in men, 60-83% in women
♦ Average age at diagnosis is 38
♦ Affected women are also at increased risk of lobular breast cancer
♦ Consensus criteria for diagnosis of Hereditary Diffuse Gastric
Cancer by the IGCLC (International Gastric Cancer Linkage
Consortium)
◊ >2 cases of diffuse type gastric cancer in 1st/2nd degree
relative with at least one relative 3 cases of diffuse type gastric cancer in 1st/2nd degree
relatives of any age
V. Risk Factors
• Environmental / Lifestyle Factors – more associated with intestinal type
Diet
♦ Risk: Salted, pickled, smoked foods, dietary nitrates
♦ Protective: Fruits and raw vegetables rich in vitamin C and beta-
carotene (reduces formation of N-nitroso compounds inside the
stomach)
Smoking
♦ Risk: dose-dependent
♦ Risk diminishes with smoking cessation > 10 years
Obesity – increases risk of gastric cardia cancers
Helicobacter pylori infection – The strongest risk factor. WHO classified
group 1 carcinogen
♦ Increases risk for both intestinal and sporadic diffuse type cancers
♦ Risk is estimated at approximately 3 cases per year for every
10,000 infected persons
♦ May be particular strains of H.pylori are associated with
malignancy
♦ H.pylori has an affinity for normal mucosa but not metaplastic,
dysplastic, or malignant tissue, so biopsy of lesions may miss
H.pylori
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♦ Infection in early life tends to lead to chronic inflammation
♦ Longer duration of infection increases risk
Ebstein-Barr virus – role in carcinogenesis is still unclear
♦ EBV is detected in 5-15% of gastric cancers worldwide
♦ Male predominance
♦ Preferential location in the gastric cardia or postsurgical gastric
stump
♦ Diffuse type, lymphocytic infiltration
Radiation exposure – in animal models can induce intestinal metaplasia
• Host Factors
Maybe particular genotype of interleukin may pose particular risk from
H.pylori infection
Blood group A patients are at 20% excess risk of cancer
Previous gastric surgery
♦ Partial gastrectomy promotes hypochlorhydria
♦ Bile reflux also stimulates intestinal metaplasia (so risk is higher
with Billroth II than Billroth I)
♦ Risk highest 15-20 years after surgery and increases with time
♦ But notably, chronic hypochlorhydria induced by H2 blockers or
PPIs does not lead to increased risk of cancer
Reproductive hormones are thought to have a protective role (risk is lower
in women)
High risk conditions or lesions
♦ Chronic atrophic gastritis, intestinal metaplasia, dysplasia
♦ Gastric polyps
◊ Fundic gland polyps associated with polyposis syndromes
(those that are sporadic or PPI-associated have virtually no
malignant potential)
◊ Hyperplastic polyps, particularly those >2cm have a small
malignant potential
◊ Adenomatous polyps have malignant potential
◊ ASGE guidelines: hyperplastic polyps >2cm and all
adenomatous polyps should be completely resected and
EGD repeated in 1 year
♦ Pernicious anemia – a result of autoimmune chronic atrophic
gastritis
◊ Associated with increased risk of intestinal type cancer
◊ Also associated with increased risk of gastric carcinoids
◊ ASGE guidelines: Single endoscopy should be performed
as screening, not enough data to support subsequent
surveillance endoscopies
♦ Gastric ulcers – risk of malignancy is increased in patients with
benign gastric ulcers, but unclear if there is malignant potential or
whether this reflects common risk factors (such as H.pylori)
◊ Gastric cancer risk is decreased among patients with benign
duodenal ulcers (? different H.pylori strains)
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◊ Do we need to repeat EGDs on all gastric ulcers to
document healing?
No consensus, old ASGE guidelines (now no longer
available on their website) says repeat EGD in 8-12
weeks with re-biopsy of any remaining ulcers. No
updated guidelines since then.
Some studies support second look EGD, others
conclude that there is no added benefit if adequate
numbers of biopsies were taken (ie, 7) on the first
EGD
♦ Various immunodeficiency syndromes
♦ Hypertrophic gastropathy (enlarged gastric folds), including
Menetrier disease (multiple sheet-like adenomas with associated
foveolar hyperplasia)
• Genetic Factors – more associated with diffuse type
Approximately 10% are familial (independent of H.pylori infection)
Diffuse type – strongly correlated with mutations in E-cadherin gene,
CDH1 (see above)
Intestinal type – genetic factors not so well established
Hereditary syndromes – HNPCC, FAP, Li-Fraumeni syndrome, Peutz-
Jeghers syndrome, Cowdens syndrome
VI. Classification
• Lauren system – by morphology
Intestinal (type 1)
♦ Retained glandular structure, morphologically similar to
adenocarcinomas arising in the intestinal tract, sharp margins
♦ Associated with most environmental risk factors
♦ No familial tendencies
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♦ Better prognosis
Diffuse (type 2)
♦ Scattered cell clusters without formation of glands due to lack of
intercellular adhesions.
♦ Deceptive margins (appear clear to the surgeon and pathologist,
but are often determined to be involved retrospectively) involving
large areas of the stomach
♦ Cancers tend to be multifocal and located beneath an intact
mucosal surface
♦ Linitus plastica – particularly aggressive form where the stomach
appears as a “leather-flask” shape on barium swallow due to poor
distensibility from extensive tumor infiltration
♦ Not recognizably influenced by most environmental factors
♦ No associated pre-malignant lesion
♦ More often in younger patients
♦ Associated strongly with genetic factors
• The Paris Classification – by endoscopic appearance, typically used for T1
lesions (see below), may be beneficial as a guide to endoscopic therapy
Type 0 – superficial polypoid, flat/depressed, or excavated tumors
Type 1 – polypoid, usually attached on a wide base
Type 2 – ulcerated with sharply demarcated margins and raised margins
Type 3 – ulcerated, infiltrative, without clear margins
Type 4 – nonulcerated, diffusely infiltrating
Type 5 – unclassifiable
• By Histology
Intestinal type
♦ Tubular
♦ Papillary
♦ Mucinous
Diffuse type = Signet-ring cell
Undifferentiated
• By Location
Proximal – fundus/cardia
♦ Incidence is rising
♦ More aggressive, worse prognosis, more likely diffuse type
Distal – antrum/body
♦ Most intestinal type cancers are in the incisura angularis
Currently, 30% of gastric cancers are in the antrum, 30% in the body, 40%
in the fundus/cardia
VII. Clinical Presentation
• History
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In the US, 25% present with localized disease, 31% with regional disease,
32% with metastatic disease
Early gastric cancer is usually asymptomatic
Advanced gastric cancer most frequently presents with weight loss (62% -
usually from insufficient caloric intake rather than catabolism) and
persistent abdominal pain (52%). Other symptoms may include nausea
(34%), dysphagia (26%), melena (20%), early satiety (18%), indigestion
(17%)
• Physical Exam – All physical signs are late events. None are pathognomonic.
Palpable enlarged stomach with succession splash
Hepatomegaly – liver metastases are usually multifocal or diffuse
Sister Mary Joseph node – periumbilical node
Virchow’s node – left supraclavicular lymph node
Irish node – left axillary node
Blumer shelf – shelf-like tumor of the anterior rectal wall
Krukenberg tumor – metastatic tumor to the ovary
• Paraneoplastic Syndromes – poor prognostic features
Sign of Leser-Trelat – sudden appearance of diffuse seborrheic keratoses
Dermatomyositis
Acanthosis nigricans
Circinate erythema
• Other Associated Abnormalities
Pseudoachalasia – from involvement of Auerbach’s plexus of tumors near
the GE junction
Trousseau’s syndrome – hypercoagulable state
Microangiopathic hemolytic anemia
Membranous nephropathy
• Pattern of Metastasis
Gastric cancer can spread by direct invasion, via lymphatics, or
hematogenously
Direct extension: most commonly omentum/peritoneum, pancreas,
diaphragm, transverse colon, duodenum, esophagus
Lymphatic drainage is through multiple pathways
Hematogenous spread commonly results in liver metastases
• Tumor markers – All have low sensitivity and specificity, and none are
recommended
♦ CEA, CA 125 – elevated in 45-50% of cases
♦ CA 19-9 – elevated in 20% of cases
• Imaging Studies
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EGD (white light, chromoendoscopy, magnification endoscopy, narrow
band imaging) – Diagnostic study of choice
♦ Single biopsy of an ulcerated lesion has a 70% sensitivity, while 7
biopsies increases the sensitivity to 98%
♦ Up to 5% of malignant ulcers appear benign grossly (benign ulcers
have folds which extend to the base of the ulcer)
Barium studies – Helpful when bulky proximal tumors prevent passage of
EGD scope
♦ Sensitivity may be as low as 14% in early gastric cancer
♦ ~75% diagnostic accuracy for advanced cancers
♦ May be helpful in diagnosis of linitis plastica, which is more
obvious on radiographic study than on endoscopy
Chest X-Ray – Can be used to assess for metastases, though CT is
preferred, especially for proximal cancers
CT or MRI of the abdomen/pelvis/+chest – Assess for metastases
♦ CT accurately assesses the T stage (see below) in only 50-70% of
cases
♦ Peritoneal metastases smaller than 5mm are frequently missed on
CT and 20-30% of patients with negative CTs will have
intraperitoneal disease on laparoscopy
PET scan – Usually not helpful
♦ Gastric cancer, particularly the diffuse type, can have low
metabolic activity
♦ Sensitivity for peritoneal carcinomatosis is 50%
♦ Medicare does not reimburse for PET for gastric cancer
Endoscopic ultrasound
♦ Allows for more precise T staging when CT or MRI does not show
metastatic disease (accuracy 77-93%). This is important when
considering endoscopic mucosal resection.
♦ Accuracy of N staging is only slightly higher than CT, but allows
FNA of suspicious nodes
♦ Not a requisite part of the staging workup as EUS findings rarely
affect the need for laparotomy. EUS is not recommended by the
NCCN (National Comprehensive Cancer Network) guidelines.
• Exploratory and Staging Laparotomy – Usually done to look for peritoneal
implants
NCCN guidelines say to “consider” laparotomy in patients who appear to
have locoregional disease (other than Tis, T1a, stage 4)
Peritoneal washings for cytology is recommended for patients without
visible implants as this predicts early relapse and some centers will give
neoadjuvant therapy
VIII. Staging and Prognosis
• TNM Staging System – used more extensively in the Western hemisphere, has
prognostic significance
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Primary Tumor – T stage is depth, not size
♦ Tx Primary tumor can not be assessed
♦ T0 No evidence of primary tumo
♦ Tis Carcinoma in situ: no invasion of lamina propia
♦ T1 Tumor invades lamina propria or submucosa
♦ T2 Tumor invades muscularis propria or subserosa
◊ T2a Tumor invades muscularis propria
◊ T2b Tumor invades subserosa
♦ T3 Tumor penetrates serosa (visceral peritoneum) without I
nvasion of adjacent structures
♦ T4 Tumor invades adjacent structures
Nodes – N stage is number of positive nodes, not location; Staging is not
reliable if fewer than 10 lymph nodes are examined.
♦ Nx Regional lymph nodes can not be assessed
♦ N0 No regional lymph node metastasis
♦ N1 1-6 positive regional lymph nodes
♦ N2 7-15 positive regional lymph nodes
♦ N3 >15 positive regional lymph nodes
Metastasis
♦ Mx Distant metastasis can not be assessed
♦ M0 No distant metastasis
♦ M1 Distant metastasis
Stage TNM 5 year survival
0 Tis, N0, M0 >90%
1A T1, N0, M0 60-80%
1B T1, N1, M0 50-60%
T2a/b, N0, M0
2 T1, N2, M0 30-40%
T2a/b, N1, M0
T3, N0, M0
3A T2a/b, N2, M0 20%
T3, N1, M0
T4, N0, M0
3B T3, N2, M0 10%
4 T4, N1-3, M0 90% after surgical resection, 65% without surgery)
• Median duration to progression without surgery is 37 months
• 50-70% are intestinal type
• Findings may be subtle on white light endoscopy, consider chromoendoscopy,
magnification endoscopy, or narrow band imaging
• Treatment
Standard is gastrectomy
Patients with elevated lesions 15 nodes removed, even in
academic and large volume hospitals
While Japanese literature reports 5 per 10 high-power fields
♦ Increasing size: 10cm
♦ Location: small bowel GIST more aggressive than gastric GIST
GISTs < 2cm tend to behave as “benign” masses, but all GISTs should be
considered to have malignant potential
• Treatment
Imatinib (Gleevac) – tyrosine kinase inhibitor
♦ FDA approved for adjuvant therapy of primary resected GIST and
for therapy of inoperable metastatic GIST
♦ Can also be used as neoadjuvant therapy to increase resectability
(should get biopsy first in this case)
Surgery – treatment of choice, the only chance for cure
♦ Wedge resection vs subtotal vs total gastrectomy and en bloc
resection of adjacent involved organs.
♦ Lymphadenectomy is not indicated as nodal involvement is rare
♦ Avoid rupturing the tumor during surgery as this will cause
peritoneal seeding
♦ Patients with recurrent disease with single lesion in peritoneum or
liver are candidates for resection
♦ Palliative resection for disseminated disease also increases survival
• Prognosis – 5 year survival ranges from 80-90% in patients with small tumors
and low mitotic index to 10-30% in patients with large tumors and high mitotic
activity
• Followup – periodic CTs and endoscopies, intervals not established
XIV. Intestinal Leiomyosarcoma
• Introduction, Pathogenesis, and Histology
Mesenchymal tumors of smooth muscle origin
20% of leiomyosarcomas are found in the GI tract, with 10% in the
stomach and 10% in the small intestines. Leiomyosarcomas of the
esophagus and colon are rare.
Histology shows spindle-shaped cells
• Epidemiology
Age: primarily middle-aged, 40’s-60’s
• Presentation
Tumor invades locally, with much of its growth being extraluminal
Usually asymptomatic, but if present, most commonly GI bleeding
GI obstruction is a late event
Metastasis is primarily hematologic to liver and peritoneum, and less
frequently to the lung.
Lymph node involvement is rare.
• Evaluation
EGD, EUS with guided biopsy, CT scan
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• Staging
Size and mitotic activity determine prognosis
• Treatment
Surgery is only hope for cure
Chemotherapy and radiation therapy of limited benefit, <40% response
• Prognosis – poor; overall 5-year survival 18-50%
• Followup – surveillance CT and endoscopies, interval unclear
References
1. Mañas MD, Domper A, Albillos A, et al. Endoscopic follow-up of gastric ulcer in a population at
intermediate risk for gastric cancer. Rev Esp Enferm Dig. 2009 May;101(5):317-24.
2. Amorena Muro E, Borda Celaya F, Martínez-Peñuela Virseda JM, et al. Analysis of the clinical
benefits and cost-effectiveness of performing a systematic second-look gastroscopy in benign
gastric ulcer. Gastroenterol Hepatol. 2009 Jan;32(1):2-8. Epub 2008 Dec 23.
3. National Comprehensive Cancer Network (NCCN) database and guidelines
4. UpToDate
a. “Clinical features, diagnosis, and staging of gastric cancer”
b. “Epidemiology of gastric cancer”
c. “Risk factors for gastric cancer”
d. “Pathology and molecular pathogenesis of gastric cancer”
e. “Screening and prevention of gastric cancer”
f. “Early gastric cancer”
g. “Surgery in the treatment of invasive gastric and gastroesophageal junction cancer and
prognosis”
h. “Local palliation for advanced gastric cancer”
i. “Association between Helicobacter pylori infection and gastrointestinal malignancy”
j. “Clinical manifestations, pathologic features, and diagnosis of extranodal (MALT) and
nodal marginal zone lymphomas”
5. eMedicine
a. “Gastric cancer”
b. “Mucosa-associated lymphoid tissue”
c. “Gastric gastrointestinal stromal tumors”
d. “Intestinal leiomyosarcoma”
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Questions
1. A 64-year-old patient with dyspepsia had an upper endoscopy that revealed a
gastric ulcer. After histologic assessment of endoscopic biopsies,
adenocarcinoma and H.pylori infection were diagnosed. Endoscopic ultrasound
indicated that the gastric adenocarcinoma was limited to the mucosa, but regional
lymph nodes were suspicious for malignancy. Abdominal CT scanning
confirmed suspicious lymph nodes adjacent to the stomach, but there was no
evidence of malignancy in other areas of the abdomen. Which of the following is
the most appropriate initial treatment?
a. Subtotal gastrectomy
b. Proton-pump inhibitor, amoxicillin, and clarithromycin for 10 days
c. PPI, metronidazole, clarithromycin, and tetracycline for 14 days
d. Radiation therapy
e. Chemotherapy
2. A 45-year-old female undergoes upper endoscopy for dysphagia. Gastric
erythema with mild gastric nodularity are observed, and endoscopic mucosal
biopsies reveal H.pylori and MALT lymphoma. Which of the following is the
most appropriate as the next management step?
a. No therapy
b. Subtotal gastrectomy
c. Staging laparoscopy
d. H.pylori eradication therapy with follow-up endoscopy in 6 weeks
e. Referral to an oncologist for chemotherapy
3. Which of the following is correct regarding the relationship between smoking and
gastric adenocarcinoma.
a. There is a dose-dependent relationship between smoking and gastric
cancer
b. There is a threshold effect of cumulative years of smoking and gastric
cancer
c. Smoking does not increase the risk of gastric cancer
d. Smoking is slightly protective against gastric cancer
4. Which of these syndromes is NOT associated with gastric adenocarcinoma
a. Li-Fraumeni syndrome
b. Hereditary non-polyposis colorectal cancer
c. Familial adenomatous polyposis
d. Cowdens syndrome
e. Petuz-Jeghers syndrome
f. Neurofibromatosis type 1