CARCINOMA STOMACH

Pathophysiology & management

Dr Gireesh G N
 Anatomy
 Etiology
 Pathophysiology
 Classification
 Investigations
 Treatment
Anatomy
Divisions of stomach
 Cardia
 Fundus
 Body / Corpus
 Pyloric antrum
 Pyloric canal
 Arterial supply

 Most of the blood supply to the stomach is from the celiac

artery.

 Four main arteries:

 Left and right gastric along the lesser curvature

 Left and right gastroepiploic along the greater curvature.

 Blood supply to the proximal stomach also comes from the

inferior phrenic and short gastric arteries
 Venous drainage
 Left and right gastric veins drain into the portal vein

 Right gastroepiploic drains into the SMV

 Left gastroepiploic drains into the splenic vein

Lymphatic drainage is into four zones:
 Superior gastric

 Suprapyloric

 Pancreaticosplenic

 Inferior gastric/subpyloric

 All four drain into the celiac group of nodes and into
the thoracic duct.

 Gastric cancers drain into any of these groups

regardless of location of the tumor.
 Layers of stomach wall:
 Mucosa

 Epithelium, lamina propria, and muscularis mucosae

 Submucosa

 Smooth muscle layer

 Serosa
 ADENOCARCINOMA
EPIDEMIOLOGY & MAGNITUDE OF PROBLEM
 2nd most common cause of cancer death

 4th most common cancer in men : Lung > Prostate > Colorectal > Stomach

 5th most common cancer in women : Breast > Cervix > Colorectal > Lung
> Stomach

 Male : Female = 2:1

 Around 45-50% of gastric carcinoma present with an inoperable disease.

Risk factors
 Definite
Hp infection
Chronic atrophic gastritis
Intestinal metaplasia
Dysplasia
Adenomatous gastric polyps
History of gastric surgery (esp. Billroth II)
Genetic factors:
Family history of gastric cancer (first-degree relative)
Familial adenomatous polyposis (with fundic gland polyps)
Hereditary nonpolyposis colorectal cancer*
 Probable
High salt intake
Obesity (adenocarcinoma of the cardia only)
Pernicious anemia
H pylori
 a Gram-negative microaerophilic, spiral bacterium found in
the gastric mucosa in patients with severe gastritis
 In 1994, the International Agency for Research on Cancer
categorized H. pylori as a “class 1 human carcinogen” based
on a plethora of studies
 trigger a cascade of events that promote the sequential
progression of normal gastric epithelium through atrophic
gastritis, intestinal metaplasia, and dysplasia to carcinoma

Eslick GD. Helicobacter pylori infection causes gastric cancer A review of the epidemiological,
meta-analytic, and experimental evidence. World J Gastroenterol. 2006;12:2991–2999
H pylori..
 urease, protease, phospholipase, ammonia, and acetaldehyde
 disrupts gastric barrier function via urease-mediated myosin II
activation
 induces the production of reactive oxygen and nitrogen species
and suppresses the host antioxidant defense mechanisms,
leading to oxidative DNA damage
 Aberrant DNA methylation induced by H. pylori infection has
been found to be a significant risk factor

Yamaguchi S, Yamakido M, Taniyama K, Sasaki N, Schlemper RJ. Helicobacter

pylori infection and the development of gastric cancer. N Engl J Med.
H pylori…
 H. pylori strains containing the cag pathogenicity island
(cagPAI) are more virulent.
 The cagPAI is a 40-kb genome segment that encodes
approximately 30 genes including the cytotoxin-associated
gene A (cagA).
 The virulent cagA positive strains increase the risk of non-
cardia gastric cancer of both intestinal and diffuse types, but
not the risk of cardia cancer.

 multiple factors including host genetic factors, the strain of

bacteria, the duration of infection, and the presence or absence
of other environmental risk factors
H pylori..
 (1) simple gastritis
(2) duodenal ulcer phenotype
(3) gastric ulcer/gastric cancer phenotype
 An increased risk is associated with a low acid state.
 Hp-induced duodenal ulcer disease is associated with
a high gastric acid output as well as a reduced risk for
developing gastric cancer.
 Hp-infected patients develop chronic atrophic
gastritis at a rate of 1% to 3% per year of infection
 Dietary Factors
 High nitrate – N- nitroso compounds- mitogen &
carcinogen

 High salt – pickled food, dried and salted fish and meat

 Refrigerated food- low incidence of gastric cancer

 Cigarette smoking

 ?Alcohol

 Obesity
Salt intake
 enhances H. pylori colonization
 increases the risk of gastric cancer through direct damage to
the gastric mucosa resulting in gastritis.
 Salt is also known to induce hypergastrinemia and
endogenous mutations, promoting epithelial cell proliferation
which eventually leads to parietal cell loss and gastric cancer
progression

World J Gastroenterol. 2009;15:2204–2213.

Dietary nitrates
 Dietary nitrates are found either naturally in foods such as
cabbage, cauliflower, carrot, celery, radish
 Dietary nitrate is converted to carcinogenic N-nitroso
compounds (NNC) by gastric acid
 broiling of meats, roasting, grilling, baking, and deep frying in
open furnaces, sun drying, salting, pickling
 Benzopyrene in smoked foods

Mitacek EJ, Brunnemann KD, Suttajit M Nutr Cancer. 2008;60:196–203.

 Genetic factors
 MSI – MLH 1 & MLH2

 DNA Aneuploidy

 Deletion

 p53, FHIT, APC

 Decreased expression due to hypermethylation

 E- cadherin, p16, p27

 Amplification/ overexpression

 COX 2, HGF, VEGF, EGFR

 PREMALIGNANT CONDITIONS

 Intestinal metaplasia
 Type 1: complete- contain goblet cells & mature non
secretory absorptive cells

 Type 2 &3: incomplete- contain cells of varying stages of

differentiation

 Type 2 & 3 IM associated with 20 fold increased risk of

gastric cancer
 Chronic atrophic gastritis- loss of glandular tissue
1. EMAG- Environmental multifocal atrophic gastritis

 H. pylori associated

 Mostly associated with metaplasia

2. AMAG- Autoimmune metaplastic atrophic gastritis

 Anti parietal cell and intrinsic factor antibodies

 Atrophy is confined to body and fundus

 Associated with pernicious anemia

 Increased gastric cancer risk

 Gastric polyps
 Fundic gland polyp (50%) – benign

 Hyperplastic polyp (40%) - benign

 Adenomatous polyp (10%) – can undergo malignant

transformation
1. All gastric polyps should be at least biopsied;

2. All gastric adenomas, symptomatic polyps, and polyps with

dysplasia should be removed;

3. Hp, if present, should be eradicated in patients with hyperplastic

or adenomatous polyps.
 Previous Gastrectomy
 Hypochlorhydria

 Chronic gastroenteric reflux

 Atrophy of remaining fundic mucosa due to low antral

hormone secretion

 Gastric adenocarcinoma post Billroth2: Billroth 1= 4:1

 PUD – associated with non cardia cancer

 Ménétrier’s Disease
Types

 Proximal tumor- OG junction & cardia

 Distal tumor- fundus, body and antrum

 Ming classification
 Expanding (67%)

 Infiltrative (33%)
 Lauren classification
 Intestinal type
 Gland like tubular structures, similar to intestinal
glands
 associated with chronic atrophic gastritis, severe
intestinal metaplasia, and dysplasia
 Linked to environmental & dietary factors
 less aggressive than the diffuse type
 Diffuse type
 Lack glandular structure
 Consist of poorly cohesive cells that infiltrate the
wall of stomach
 younger patients and proximal tumors
 poorly differentiated
 Worse prognosis
 Early Gastric Cancer
 Mucosa and submucosa, regardless of lymph node status

 Types
 Type I- Exophytic lesion extending into the gastric lumen

 Type II -Superficial variant

 IIA: Elevated lesions with a height no more than the thickness of the
adjacent mucosa

 IIB: Flat lesions

 IIC: Depressed lesions with an eroded but not deeply ulcerated appearance

 Type III - Excavated lesions that may extend into the muscularis
propria without invasion of this layer by actual cancer cells
Japanese classification of early gastric cancer
 Paris classification
 Advanced gastric cancer
 Involves the muscularis

 Macroscopically classified by Bormann into four

types
 Polypoid

 Fungating

 Ulcerative

 Scirrhous
Borrmann classification of advanced gastric cancer
 Linitis Plastica
 Diffuse-type gastric cancer

 Tumor often infiltrates the submucosa and muscularis propria

 Superficial biopsies may be falsely negative

 Combination of strip and bite biopsy needed if suspicious for

linitis plastica
 Linitis Plastica, “leather bottle stomach”
 Spread of gastric cancer

Direct Spread Lymphatic spread

Tumor penetrates the Left supraclavicular node-

muscularis, serosa & Virchow’s node
Adjacent organs (Trosier’s sign)
(Pancreas,colon &liver)

Blood-borne Transperitoneal
metastasis spread
Usually with extensive Anywhere in peritoneal cavity
Disease where liver 1st (Ascitis)
Involved then lung & Krukenberg tumor (ovaries)
Bone Sister Joseph nodule
(umbilicus)
TNM staging
Clinical features
 80% - mimic PUD
 Weight loss – 60%
 Abdominal pain – 50%
 Vomiting – GOO
 Dysphagia
 Anorexia,early satiety
 Anemia,positive SOB
 Hypoproteinemia
Signs
 Pallor  Succussion splash
 pedal edema  VGP
 cachexia  Shoulder hand
 Epigastric mass syndrome – due to bone
 Hepatomegaly mets
 Ascites  Diplopia & blindness-
orbital mets
 Virchow’s nodes
 Virilization –
 Sister Mary Joseph’s
Krukenberg’s tumor
nodule
 Rectal shelf of Blumer
 Irish node
 Paraneoplastic syndromes
 Trousseau’s sign
 Neuropathies
 Nephrotic syndrome
 DIC
 Acanthosis nigricans
 Seborrheic keratosis (sign of Leser Trelat)
DIAGNOSIS
Endoscopy

 Gold standard

 Single biopsy from ulcer -> sensitivity ~ 70%

 Seven biopsies from ulcer -> sensitivity >98%

 Brush cytology increases sensitivity of single biopsies

Early gastric cancer
 AGA recommend OGD for

 Patients with age > 55 yrs with new onset

dyspepsia

 Patients with age <55 yrs with ‘alarm’ symptoms

 Wt loss

 Recurrent vomiting

 Dysphagia

 Evidence of bleeding

 anaemia
 EUS

 Endoscopic ultrasound (EUS) is helpful in determining

the proximal and distal extent of the tumour and provides
further assessment of the T and N stage
 It is less useful in antral tumours .
 EUS is more consistently accurate than CT for the
diagnosis of malignant lymph nodes
 Patterns associated with malignancy on EUS include
hypoechogenicity, round shape, smooth, distinct margin
and size >1 cm

Catalano MF, Sivak MV, Jr, Rice T et al. Endosonographic features

predictive of lymph node metastasis. Gastrointest Endosc 1994;
 T staging -
 The gastric wall is visualized as 5
concentric bands:

 T1-2 vs T3-4: 86%sensitivity 91%

specificity

 T1a lesion 83% sensitivity &

79%specificity

 EUS is slightly less accurate in the

assessment of nodal status as compared to
depth of tumor invasion
 CT
 MDCT- stomach wall can be seen as 3 layers
 Loss of fat plane b/w gastric mass & adjacent
organ- tumor invasion
 At present, the role of CT is mainly for the
detection of distant metastases and as a
complement to EUS for assessing regional lymph
node involvement.
 PET
 Not recommended as sole imaging for gastric
cancer:- because adeno ca have low FDG uptake
 Combined PET with CT increase mets detection
by 10%
 MRI
 When CT iodinated contrast is contraindicated
 For T staging, MR is comparable or minimally superior to
CT
Sohn KM et al. AJR Am J Roentgenol 2000;174:1551-7

 Inferior to CT in N staging

M staging - Improvement in detection of metastatic disease

compared with CT, when the contrast Ferumoxtran-10 is
used (sensitivity 100%)
Coburn NG. J Surg Oncol 2009;99(4):199–206
Motohara T, Semelka RC. Abdom Imaging 2002;27(4):376–83
 Laparoscopy with Peritoneal Lavage
 Detection of metastatic disease to the liver or
peritoneum

 Implications

 In resectable patients for staging

 In unresectable patients – determination of benefits of

combined chemo-radiation (radiation may not be
appropriate in metastatic disease)
 TREATMENT
Surgery
 Complete surgical eradication of a gastric
tumor with resection of adjacent lymph nodes
represents the best chance for long-term
survival.
 The extent of gastric resection depends on:
 tumor stage
 Location
 depth of invasion
 Nodal drainage
 Tumor histology/type
 Distal subtotal gastrectomy

For lesions in the distal (lower two-thirds) of the stomach.

 en bloc removal of the distal 75% of the stomach, 2 cm of

duodenum

 Greater and lesser omentum, associated lymphatic tissue

 Reconstruction - Billroth II gastrojejunostomy

 Spleen and pancreatic tail not removed in absence of

involvement
 For Proximal and esophagogastric junction tumors
Total gastrectomy is preferred than proximal subtotal
gastrectomy
 The Roux-en-Y reconstruction performed during total
gastrectomy is associated with an extremely low incidence
of reflux esophagitis

 Proximal subtotal gastrectomy may fail to fully remove the

lymph nodes along the lesser curvature.
 For stage IB–III gastric cancer, radical gastrectomy is
indicated.
 Subtotal gastrectomy may be carried out if a macroscopic
proximal margin of 5 cm can be achieved between the tumour
and the gastroesophageal junction.
 For diffuse cancers, a margin of 8 cm is advocated.
 Otherwise, a total gastrectomy is indicated

Gastric cancer: ESMO Clinical Practice GuidelinesAnnals of Oncology 27;2016

 Residual tumor (R) classification
 The absence or presence of demonstrable residual tumor after
conclusion of the treatment
 R0 resection -no demonstrable residual tumor

 R1 resection- microscopically demonstrable residual tumor (e.g.

diseased residual margin)

 R2 resection – macroscopically visible tumor

 Extent of lymphadenectomy
 D1 nodes are perigastric

 D2 nodes are along the hepatic and splenic arteries

 D3 nodes are the most distant

D1 versus D2 dissection

 MRC trial & Dutch trial observed that D2 dissection is

associated with high postoperative morbidity and mortality
without a statistically significant survival advantage.
Sasako M, Ponti A et al. Randomized clinical trial comparing survival after D1 or D2 g
gastrectomy for gastric cancer. Br J Surg 2014
 Long-term (15-year) follow-up from the Dutch trial demonstrated fewer
locoregional recurrences and gastric cancer-related deaths with D2
resection
 Consensus opinion is that, in Western countries, medically fit patients
should undergo D2 dissection that is carried out in specialised, high-
volume centres with appropriate surgical expertise and postoperative care

 The current UICC/AJCC TNM classification recommends excision of a

minimum of 15 lymph nodes to allow reliable staging

Gastric cancer: ESMO Clinical Practice GuidelinesAnnals of Oncology 27;2016

Endoscopic Mucosal Resection
EMR indicated in

1. Cancer is located in the mucosa and the lymph nodes are not
involved(on EUS)

2. Maximum size of the tumor is less than 2 cm when the lesion

is slightly elevated (type IIa) and less than 1 cm when the
tumor is flat or slightly depressed (type IIb or IIc) without an
ulcer scar

3. There is no evidence of multiple gastric cancers or

simultaneous abdominal cancers

4. Cancer is of the intestinal type.

EMR: injection-lift-cut technique Suction assisted EMR
Endoscopic submucosal dissection
 ESD indicated in

1. Mucosal intestinal-type cancer of any size without ulceration,

2. Mucosal intestinal-type cancer less than 3 cm with ulceration,

3. Submucosal intestinal-type cancer less than 3 cm and with

submucosal invasion less than 500 μm.

 Peri-operative Chemotherapy
MAGIC trial
 Randomised controlled study of 503 pts. With stage II or
higher gastric cancer that compared perioperative
chemotherapy with surgery alone.
 CEF (Cisplatin, Epirubicin, 5-FU)
 3 cycles as neo-adjuvant CT
 3 cycles as adjuvant CT
 5-yr survival, rate of local recurrence & distant metastasis
were improved in CT group
UK National Cancer Institute trial
 EOX (Epirubicin, Oxaliplatin, Capecitabine)
 longer overall survival than with CEF and decreased incidence
of thromboembolic phenomenon by substituting oxaliplatin for
cisplatin
 A study of the German AIO study group investigating a
perioperative FLOT regimen (fluorouracil, leucovorin,
oxaliplatin, docetaxel) versus ECF/X demonstrated higher
rates of pathological response for FLOT
 reasonable to use any fluoropyrimidine–platinum doublet or
triplet before surgery, although the strongest evidence is for
cisplatin/fluorouracil ± epirubicin
 . Recommended treatment duration is 2–3 months

Gastric cancer: ESMO Clinical Practice GuidelinesAnnals of Oncology 27;2016

 Intraperitoneal Chemotherapy (IPC)
 Recurrence following curative resection is likely due to
peritoneal carcinomatosis.

 Blood-peritoneal barrier prevents the chemotherapeutic agents

from achieving their cytotoxic effect.

 IPC : administering high doses of chemotherapy directly to the

peritoneum whilst reducing the systemic effects.

 Indicated in patients whose tumors are resected but high

likelihood of microscopic residual tumor. Treatment benefit is
more in stage 3 & 4 disease

 Increased risk of neutropaenia and intra-abdominal abscesses.

 Adjuvent chemoradiotherapy
 INT(0116) trial demonstrates improvement in survival with
post-operative chemoradiation than with surgery alone.

 postoperative CRT may be compensating for suboptimal

surgery

 In current postoperative CRT regimens, RT should preferably

be given as a concomitant regimen of fluoropyrimidine-based
CRT to a total dose of 45 Gy in 25 fractions
 UNRESECTABLE LESIONS: MANAGEMENT
Indications for unresectability
 Distant metastases

 Invasion of a major vascular structure such as the aorta

 Encasement or occlusion of the hepatic artery or celiac

axis/proximal splenic artery

 Nodes behind or inferior to the pancreas, aorto-caval region,

into the mediastinum, or in the porta hepatis

 Distal splenic artery involvement is not an indicator of

unresectability
 Chemotherapy
 cisplatin, docetaxel and trastuzumab

 EOX regimen (epirubicin, oxaliplatin, and capecitabine

[Xeloda])

 Monotherapy- docetaxel , irinotecan or taxanes such as

paclitaxel

 Surgical :- gastrojejunostomy
 Endoscopic management
Endoscopic stents, duodenal stenting across the obstructing tumor
Stent design:

Covered stent Uncovered stent

 Coated stent  Bare stent
 Can prevent tumor ingrowth  Tumor ingrowth possible-
 High migration rate causing stent occlusion
 More rigid & larger size-  Low migration rate
delivery is difficult  More flexible
 More chance of CBD  Less CBD obstruction
obstruction
 Stenting procedure: Fluoroscopic or Endoscopic

 Complications
 Perforation

 Fistula formation

 Stent migration/ haemorrhage

 Tumor overgrowth

 Stent collapse
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