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Stomach Cancer

Fourth most common cancer


Second leading cause of cancer related death
Incidence in the world is decreasing, mainly intestinal-type. Diffuse-type is constant.
M:F = 2:1
Average age of presentation: 60-70 years
Change in the distribution:
o Incidence is shifting from the body and antrum, to the proximal stomach during the past
20 years
o Cancers involving the proximal stomach and esophagogastric junction (EGJ) have
increased steadily at a rate exceeding that of any other cancer, except melanoma and lung
cancer
o Proximal lesions are biologically more aggressive and have a worse prognosis, stage for
stage, than do distal gastric cancers
Current distribution:
o Distal 40%
o Middle 30%
o Proximal 30%
Risk Factors:
Environmental risk factors
1) Diet
High-salt diet particularly those with salted or smoked meats
Low fresh fruits and vegetables
High complex carbohydrates
Low animal fat and animal protein
o Mechanism:
Conversion of nitrates in the salted food to N-nitroso (containing NO group)
compounds by bacteria in the stomach
Presence of ascorbic acid (also Beta-carotene) in fresh fruits and vegetables,
which can remove the carcinogenic N-nitroso compounds and oxygen free
radicals
o Likely synergism between diet and H. pylori infection - Consumption of salted food
increases the possibility of persistent infection with H. pylori infection. H. Pylori
promotes growth of bacteria that generate the carcinogenic N-nitroso compounds. Also,
H. pylori can inhibit the secretion of ascorbic acid
o Refrigeration use has lowered the risk by reducing the amount of meat preserved by
salting alone and allowing the increased storage and consumption of fresh fruits and
vegetables
2) H. Pylori infection
Mechanism: Chronic inflammation
H. Pylori infection Chronic gastritis (Mainly in the body) Gastric atrophy Intestinal
metaplasia Dysplasia Intestinal-type adenocarcinoma

Presence of the cytoxan-associated gene A (cagA) is associated with increased virulence, and
increased carcinogenesis. (Japan has a much higher rate of cagA positive H. pylori infection
than in countries with lower rates of gastric cancer, such as the United States)
3) NSAIDs
Protective
4) Socio-economic status
Low socio-economic class: Increased risk of distal cancers
High socio-economic class: Increased risk of proximal cancers
5) Smoking
Increases the risk
6) Alcohol - Controversial
7) Previous gastric surgery
Billroth II > Billroth I (greater risk of regurgitation of alkaline bile and pancreatic juice after
Billroth II)
Host-related factors:
1) Blood group
Persons with blood group A are more susceptible
2) Family history
Mechanisms:
Clustering of H. pylori within families
Genetic predisposition for chronic atrophic gastritis, a precursor of gastric carcinoma
Association with cancer syndromes:
i. Hereditary nonpolyposis colorectal cancer (Lynch syndrome)
associated with microsatellite instability
2% to 3% of all colon and rectal cancers
increased risk of gastric and ovarian cancers
ii. Familial adenomatous polyposis
85% of patients have fundic gland polyps
Up to 40% of these having some type of dysplasia and over 50% contain a somatic
adenomatous polyposis coli mutation (APC)
Increased risk of potentially malignant duodenal polyps
Upper GI surveillance recommended
iii. Li-Fraumeni syndrome
mutation in the tumor suppressor p53 gene
iv. Hereditary diffuse gastric cancer
Inherited form of diffuse type gastric cancer
Autosomal dominant, high penetrance
Resulting from a gene mutation for the cell adhesion molecule, E-cadherin
Highly invasive tumor
Early onset, late presentation poor prognosis
Lifetime cumulative risk for advanced gastric cancer is 80%
Prophylactic total gastrectomy is recommended
v. Peutz Jeghers syndrome
3) Genetic factors
a. Activation of oncogenes
i. c-met (receptor for the hepatocyte growth factor)
ii. k-sam
iii. c-erbB2
b. Inactivation of tumor suppressor genes
i. p53
ii. p16
iii. APC (more frequent in intestinal-type)
c. Reduction of cellular adhesion
i. Loss of CDH1 gene, leading to loss in the cell adhesion molecule E-cadherin, can
be found in approximately 50% of diffuse-type gastric cancers
ii. [Gene coding for E-cadherin is CDH1]
d. Reactivation of telomerase
e. Presence of microsatellite instability
i. Microsatellites are lengths of DNA in which a short (one to five) nucleotide motif
is repeated several times. Microsatellite instability reflects a gain or loss of
repeat units in a germline microsatellite allele, indicating the clonal expansion
that is typical of a neoplasm
4) Gastric polyps
5 types: 2 are premalignant, 3 are not premalignant
a) Adenomatous polyps
Familial (APC gene mutation)
Risk of Ca increases with increasing size of the polyp
Endoscopic removal is indicated for pedunculated lesions and is sufficient, if the polyp is
completely removed, and there are no foci of invasive cancer on histologic examination
Operative excision indicated if polyp is:
1) Larger than 2 cm
2) Sessile
3) Has a proven focus of invasive carcinoma

b) Hyperplastic (Fundic) polyps


Benign lesions
Result from glandular hyperplasia and decreased luminal flow
Associated with proton pump inhibitor use
Negligible risk of carcinoma if isolated
Increased risk of Ca, if present with familial adenomatous polyposis (APC)
Do not require excision, regular surveillance, or cessation of therapy

c) Inflammatory polyps No risk of Ca

d) Hamartomatous polyps No risk of Ca

e) Heterotopic polyps No risk of Ca

5) Gastric ulcer
6) Achlorhydria
Pernicious anaemia
Antibodies directed against hydrogen-potassium ATPase in the gastric parietal cells
Leads to autoimmune chronic atrophic gastritis
Also associated with an increased risk of gastric carcinoid tumors (due to prolonged
achlorhydria resulting from parietal cell loss, compensatory hypergastrinemia, and
argyrophilic cell hyperplasia)
[When gastric carcinoma develops secondary to pernicious anaemia, the most common site is
Fundus]

Iatrogenic achlorhydria (PPIs)


PPIs are a risk factor only in presence of H. Pylori infection.
(Long term PPI use Achlorhydria Suitable environment for colonization of H. Pylori
Carcinogenesis)

7) Hypertrophic gastropathy (Menetriers disease)


Premalignant conditions:
[Premalignant condition is a histological change that occurs in a healthy mucosa that places the mucosa
at risk of malignancy]
Metaplasia-dysplasia sequence:
Chronic active non-atrophic gastritis Multifocal atrophic gastritis Intestinal metaplasia
(complete, then incomplete) Dysplasia Invasive carcinoma

Premalignant conditions for intestinal type:


1) Atrophic gastritis
Type A Autoimmune i.e. pernicious anaemia
Type B associated with H. Pylori
Both are associated with increased risk of Ca
2) Intestinal metaplasia
Intestinal metaplasia is defined by the replacement of the surface, foveolar, and glandular
epithelium in the oxyntic or antral mucosa by intestinal epithelium, which is easily
recognized by the presence of goblet cells
Intestinal metaplasia is further subdivided into three types:
i. Type I, in which the metaplastic shift is most obvious or complete, shows fully
formed small intestinal epithelium, including absorptive, goblet, and Paneth's cell
types
ii. Types II and III metaplasia, which are incomplete, consist of goblet cells interspersed
among gastric-type mucin cells
Type III metaplasia carries maximum risk
3) Dysplasia
Premalignant conditions for diffuse type: No definite pre-cancerous condition identified
Histological classification systems:
Laurens classigication and WHO classification are most widely used.
1) Laurens classification

2) WHO classification (microscopic)


a. Adenocarcinoma (most common 95%)
i. Papillary adenocarcinoma
ii. Tubular adenocarcinoma
iii. Mucinous adenocarcinoma
iv. Signet-ring cell carcinoma
b. Adenosquamous carcinoma
c. Squamous cell carcinoma
d. Small cell carcinoma
e. Undifferentiated carcinoma
f. Others
i. Carcinoma with lymphoid stroma (medullary carcinoma)
ii. Hepatoid carcinoma

3) Borrmann classification (gross)


I - Polypoid
II - Fungating, ulcerated with sharp raised margins
III - Ulcerated with poorly defined infiltrative margins
IV - Infiltrative, predominantly intramural lesion, poorly demarcated
V Linitis plastic

Linitis plastica

In about 5 percent of primary gastric cancers, a broad region of the gastric wall or even the
entire stomach is extensively infiltrated by malignancy, resulting in a rigid thickened stomach,
termed linitis plastic

Most commonly due to poorly differentiated (diffuse-type) infiltrating gastric cancers

Can, in rare circumstances, represent metastatic spread from lobular cancer of the breast

Extremely poor prognosis Metastatic disease at diagnosis, frequent nodal involvement, need
for extensive surgery for complete excision

4) Goseki classification (microscopic)


Type Tubules Intracytoplasmic Mucin
I Well differentiated Poor
II Well differentiated Rich
III Poorly differentiated Poor
IV Poorly differentiated Rich

5) Ming classification (microscopic)


Expanding
o Infiltrating cohesive cell aggregates
Infiltrative
o Diffuse permeative infiltration by single noncohesive cells or individual glands
Unclassified
6) Japanese classification for early carcinoma
[Early carcinoma is defined as limited to mucosa and/or submucosa (lymph nodes may or may not
be involved)]

I - Protruded
IIa - Elevated
IIb - Flat
IIc - Depressed
III - Excavated (full thickness of submucosa)
Signs and Symptoms
Symptoms due to tumour
Generally nonspecific - Epigastric pain, early satiety, and weight loss
Weight loss due to:
o Loss of appetite
o Early satiety
Frequently advanced stage at the time of diagnosis
The pain associated with gastric cancer tends to be constant, nonradiating, and is generally
not relieved by eating
More advanced lesions may present with either obstruction (distal tumours) or dysphagia
(tumours near the GE junction) depending on the location of the tumor
GI bleed
o Acute GI bleeding is somewhat unusual
o Chronic occult blood loss is common, and manifests as iron deficiency anemia and
heme-positive stool

Metastatic nodal disease


Supraclavicular (Virchows)
periumbilical (Sister Mary Josephs node)

Distant metastases
Hepatomegaly (Liver is the most common site for
Jaundice
Ascites
Drop metastases to the ovaries (Krukenbergs tumor) may be detectable on pelvic
examination
Peritoneal metastases can be felt as a hard nodularity (Blummers shelf in pouch of Douglas)
on rectal examination
Paraneoplastic syndromes
Trousseaus syndrome (migratory thrombophlebitis)
Acanthosis nigricans (hyperpigmentation of axilla and groin)
Peripheral neuropathy
Investigations

A major problem is the identification of patients at a time when they are potentially curable. In the
United States, two-thirds of patients present with stage III or IV disease, while only 10 percent have
stage I disease

To confirm diagnosis
History and physical examination, including evaluation of appropriate nodal areas (especially left
supraclavicular nodes) as well as the abdomen (Sister mary Josephs nodes) and rectal
examination (Blummers shelf)
Flexible Endoscopy and biopsy
Newer endoscopic techniques:
1. Magnifying endoscopy with narrow-band imaging (NBI): To observe the microvascular
architecture of the mucosa and microsurface pattern of the lesion
2. Endocytoscopy: Allows microscopic visualization of the mucosal surface
3. Virtual Endoscopy - Imaging examination of the GIT reconstructed by MD-CT

To stage the disease


Flexible Endoscopy and Endoscopic ultrasound (EUS)
o Locoregional staging: Provides more accurate staging evaluation of the tumor (T) and
nodal (N) stage than CT. Most accurate in distinguishing early gastric cancer (T1) from
advanced tumours.
o Can show enlarged (>5 mm) perigastric and celiac lymph nodes
o Metastatic staging: Less useful than CT
o Allows for preoperative biopsies
o Evaluation of a patient being considered for neoadjuvant therapy
o To identify tumors that may be amenable to endoscopic mucosal resection.
o Useful treatment modality in patients with obstruction or haemorrhage
[Flexible endoscopy: 7.5-to 12-MHz ultrasound transducer.
Stomach is filled with water to distend it.
Stomach wall is visualized as five alternating hypoechoic and hyperechoic layers
The mucosa and submucosa represent the first three layers (T1)
The fourth layer is the subserosa, invasion of which is a T2 tumor
The serosa is the fifth layer and tumor penetration of it is a T3 tumor]
Computed tomography (CT) - Abdomen and pelvis
CT - Chest for proximal lesions
o Locoregional staging: CT is less accurate than EUS for assessing the depth of tumor
invasion of the stomach wall (T) or regional nodal involvement (N)
o Metastatic staging: Useful to detect distant nodal or visceral metastases, ascites, or
carcinomatosis (M)
o Preoperative CT scans often underestimate the extent of disease (because of
radiographically undetectable metastases (occult metastasis) involving the liver and
peritoneum)
Positron Emission Tomograph
o Only 50% of gastric cancers are PET-avid, which limits its application
o PET may be an effective modality for monitoring response to neoadjuvant therapies,
sparing unresponsive patients further toxic treatment
Staging laparoscopy
o Ca stomach has high rate of occult metastatic disease
o Staging laparoscopy has been advocated as part of the workup for gastric cancer to
avoid unnecessary laparotomy in patients without a clear need for laparotomy
o Useful to detect occult metastasis
o Before neoadjuvant therapy: Peritoneal cytology - positive peritoneal cytology in the
absence of metastatic disease elsewhere identifies a group of patients who are at
particularly high risk for peritoneal failure
Table 49-5 TNM Classification of Carcinoma of the Stomach (AJCC 2010)
PRIMARY TUMOR (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ; intraepithelial tumor without invasion of the lamina
propria
T1 Tumor invades lamina propria, muscularis mucosae, or submucosa
T1a Tumor invades lamina propria or muscularis mucosae
T1b Tumor invades submucosa
T2 Tumor invades muscularis propria*
T3 Tumor penetrates subserosal connective tissue without invasion of visceral
peritoneum or adjacent structures ,
T4 Tumor invades serosa (visceral peritoneum) or adjacent structures ,
T4a Tumor invades serosa (visceral peritoneum)
T4b Tumor invades adjacent structures
REGIONAL LYMPH NODES (N)*
NX Regional lymph node(s) cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in 1-2 regional lymph nodes
N2 Metastasis in 3-6 regional lymph nodes
N3 Metastasis in 7 or more regional lymph nodes
N3a Metastasis in 7-15 regional lymph nodes
N3b Metastasis in 16 or more regional lymph nodes
DISTANT METASTASIS
(M)
M0 No distant metastasis
M1 Distant metastasis

ANATOMIC STAGE Prognostic Group


0 Tis N0 M0
IA T1 N0 M0
IB T2 N0 M0
T1 N1 M0
IIA T3 N0 M0
T2 N1 M0
T1 N2 M0
IIB T4a N0 M0
T3 N1 M0
T2 N2 M0
T1 N3 M0
IIIA T4a N1 M0
T3 N2 M0
T2 N3 M0
IIIB T4b N0 M0
T4b N1 M0
T4a N2 M0
T3 N3 M0
IIIC T4b N2 M0
T4b N3 M0
T4a N3 M0
IV Any T Any N M1
*A tumor may penetrate the muscularis propria with extension into the gastrocolic or gastrohepatic
ligaments, or into the greater or lesser omentum, without perforation of the visceral peritoneum
covering these structures. In this case, the tumor is classified T3. If there is perforation of the visceral
peritoneum covering the gastric ligaments or the omentum, the tumor should be classified T4.

The adjacent structures of the stomach include the spleen, transverse colon, liver, diaphragm,
pancreas, abdominal wall, adrenal gland, kidney, small intestine, and retroperitoneum.

Intramural extension to the duodenum or esophagus is classified by the depth of the greatest invasion
in any of these sites, including the stomach.

A designation of pN0 should be used if all examined lymph nodes are negative, regardless of the total
number removed and examined.

Tumors arising at the EGJ, or in the cardia of the stomach within 5 cm of the EGJ, that
extend into the EGJ or esophagus (Siewert III), are staged as esophageal rather than
stomach cancers.
However, tumors within 5 cm of the EGJ that do not extend into the esophagus are still
staged (and treated) as gastric cancers

A minimum of 15 nodes must be evaluated for accurate staging

Prognostic factors:

Most important prognostic factors are:

1. Depth of tumour invasion (T stage)


2. Lymph node status (N stage)
Treatment of Invasive Gastric Carcinoma

Complete surgical eradication of a gastric tumor with resection of adjacent lymph nodes represents the
best chance for long-term survival

Criteria for unresectability:


The only widely accepted criteria of unresectability for gastric cancer are:
1. Presence of distant metastases
2. Invasion of a major vascular structure, such as the aorta, or disease encasement or occlusion of
the hepatic artery, celiac axis or proximal splenic artery. Distal splenic artery involvement is not
an indicator of unresectability; the vessel can be resected en bloc with a left upper quadrant
exenteration: stomach, spleen and distal pancreas.
3. Medical contraindications to surgery

The lymphatics around the stomach are rich, and the presence of locoregional lymph node metastases
that are located geographically distant from the tumor (eg, celiac nodes with a primary tumor on the
greater curvature of the stomach) should not necessarily be considered an indicator of unresectability.

Since resection of the primary lesion also offers the most effective means of symptom palliation,
exploration may also be considered in patients with known metastatic disease, if the severity of
symptoms so dictates

Choice of surgery
The choice of operation for gastric cancer depends upon:
1. Location of the tumor within the stomach
2. Clinical stage
3. Histologic type

The major surgical considerations include:


1. Extent of gastrectomy
2. Extent of lymph node dissection
Extent of gastrectomy
1. Proximal (upper third) of the stomach that do not invade the esophagogastric junction (EGJ)
Total gastrectomy preferred over proximal subtotal gastrectomy, because:
a) Roux-en-Y reconstruction performed during total gastrectomy is associated with an
extremely low incidence of reflux esophagitis, compared to the high incidence of reflux
esophagitis after a proximal subtotal gastrectomy
b) Proximal subtotal gastrectomy may fail to fully remove the lymph nodes along the lesser
curvature. Thus, the most common site of nodal metastases may not be fully treated
surgically
2. Distal (lower two-thirds) of the stomach - Distal subtotal gastrectomy (with resection of adjacent
lymph nodes)
3. Large mid-gastric lesions or infiltrative disease (eg, linitis plastica) - total gastrectomy

Extent of lymph node dissection

Draining lymph node basins for the stomach have been divided into 16 stations by Japanese surgeons:
Stations 1 to 6 are perigastric
Stations 7-16 are located adjacent to major vessels, behind the pancreas, and along the aorta

D1 lymphadenectomy - Limited dissection: Removal of only the perigastric lymph nodes


D2 lymphadenectomy - Extended lymph node dissection: Removal of nodes along the hepatic,
left gastric, celiac and splenic arteries as well as those in the splenic hilum (Stations 1-11).
D3 lymphadenectomy - Superextended lymphadenectomy
o The term has been used by some to describe a D2 lymphadenectomy plus the removal
of nodes within the porta hepatis and periaortic regions (Stations 1-16), while others
use the term to denote a D2 lymphadenectomy plus periaortic nodal dissection (PAND)
alone
o Most Western surgeons (and the AJCC/UICC TNM staging classification) classify disease
in these regions as distant metastases and do not routinely remove nodes in these areas
during a potentially curative gastrectomy
Grouping of Regional Lymph Nodes (Groups 1-3) by Location of Primary Tumor*
Location of Primary Tumor in
Stomach
LYMPH NODE DESCRIPTION UPPER MIDDLE LOWER
STATION (NO.) THIRD THIRD THIRD
1 Right paracardial 1 1 2
2 Left paracardial 1 3 M
3 Lesser curvature 1 1 1
4sa Short gastric 1 3 M
4sb Left gastroepiploic 1 1 3
4d Right gastroepiploic 2 1 1
5 Suprapyloric 3 1 1
6 Infrapyloric 3 1 1
7 Left gastric artery 2 2 2
8a Anterior comm. hepatic 2 2 2
8p Posterior comm. hepatic 3 3 3
9 Celiac artery 2 2 2
10 Splenic hilum 2 3 M
11p Proximal splenic 2 2 2
11d Distal splenic 2 3 M
12a Left hepatoduodenal 3 2 2
12b, p Posterior hepatoduodenal 3 3 3
13 Retropancreatic M 3 3
14v Superior mesenteric vein M 3 2
14a Superior mesenteric artery M M M
15 Middle colic M M M
16a1 Aortic hiatus 3 M M
16a2, b1 Para-aortic, middle M 3 3
16b2 Para-aortic, caudal M M M

M, Lymph nodes regarded as distant metastasis.


*According to the Japanese Classification of gastric carcinoma (Japanese Gastric Cancer Association:
Japanese Classification of Gastric Carcinoma, 2nd English edition. Gastric Cancer 1:1024, 1998).
Arguments in favour of extended (D2/D3 VS D1) lymphadenectomy:

1. More accurately stages the disease


2. Failure to remove these nodes leaves behind the disease

Arguments against extended lymphadenectomy:

1. Higher associated morbidity and mortality (particularly if splenectomy is performed in order


to achieve extended lymphadenectomy)
2. Lack of a survival benefit for extended lymphadenectomy in most large randomized trials

National Comprehensive Cancer Network (NCCN) guidelines recommend that D2 lymph node
dissection is preferred over a D1 dissection
A pancreas and spleen-preserving D2 lymphadenectomy provides superior staging information
and may provide a survival benefit while avoiding its excess morbidity
Splenectomy during gastric resection for tumors not adjacent to or invading the spleen or the
tail of the pancreas increases morbidity and mortality without improving survival. Thus it is not
recommended unless there is direct tumor extension